
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12177-9
10.1016/j.heliyon.2024.e36146
e36146
Review Article
Recent advances in Scutellariae radix: A comprehensive review on ethnobotanical uses, processing, phytochemistry, pharmacological effects, quality control and influence factors of biosynthesis
Ma Wentao ab
Liu Tianyu ab
Ogaji Omachi Daniel ab
Li Jin a
Du Kunze dkztcm@tjutcm.edu.cn
abc⁎
Chang Yanxu tcmcyx@tjutcm.edu.cn
abc⁎⁎
a State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
b Tianjin Key Laboratory of Phytochemistry and Pharmaceutical Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
c Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
⁎ Corresponding author. State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China. dkztcm@tjutcm.edu.cn
⁎⁎ Corresponding author. State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China. tcmcyx@tjutcm.edu.cn
20 8 2024
30 8 2024
20 8 2024
10 16 e3614617 2 2024
22 7 2024
9 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Background

Scutellariae radix (SR) is the dried root of Scutellaria baicalensis Georgi. It has a long history of ethnic medicinal use, traditionally recognized for its efficacy in clearing heat， drying dampness, eliminating fire， removing toxins, stopping bleeding and tranquilizing fetus to prevent miscarriage. Clinically, it is used to treat cold, fever, migraine, hand-foot-and-mouth diseases, liver cancer and inflammatory diseases.

Purpose

The review aims to provide a comprehensive reference on the ethnobotanical uses, processing, phytochemistry, pharmacological effect, quality control and influence factors of biosynthesis for a deeper understanding of SR.

Results and conclusion

A total of 210 isolated components have been reported in the literature, including flavonoids and their glycosides, phenylpropanoids, phenylethanoid glycosides, phenolic acids, volatile components, polysaccharides and others. The extract of SR and its main flavonoids such as baicalin, baicalein, wogonin, wogonoside, and scutellarin showed antioxidant, anti-inflammatory, anti-tumor, antiviral, hepatoprotective, and neuroprotective effects. However, further studies are required to elucidate its mechanisms of action and clinical applications. The pharmacodynamic evaluation based on traditional efficacy should be conducted. Although various analytical methods have been established for the quality control of SR, there are gaps in the research regarding efficacy-related quality markers and the development of quality control standards for its processed products. The regulatory mechanisms of flavonoids biosynthesis remain to be explored while the influence of environmental and transcription factors on the biosynthesis have been studied. In conclusion, SR is a promising herbal medicine with significant potential for future development.

Graphical abstract

Image 1

Highlights

• SR is an attractive herb with multiple traditional efficacy and excellent prospects.

• The main components of SR are flavonoids which have various pharmacological effects.

• The historical applications, processing, and biosynthesis of SR are summarized.

• The quality markers related to the biological activity of SR are yet to be explord.

Keywords

Biosynthesis
Flavonoids
Quality control
Scutellariae radix
Abbreviations

ALT alanine transferase

AST aspartate transaminase

BNDF brain-derived neurotrophic factor

CNKI China National Knowledge Infrastructure

CUMS chronic unpredictable mild stress

CREB cAMP response element binding

CHOP C/EBP-homologous protein

DCs dendritic cells

ERK extracellular signal-regulated kinase

ERS endoplasmic reticulum stress

FAS first apoptosis signal receptor

G-CSF granulocyte colony-stimulating factor

GM-CSF granulocyte macrophage colony-stimulating factor

GSH glutathione

HK-MRSA heat-killed methicillin-resistant Staphylococcus aureus

IL interleukin

IP interferon-inducible protein

Iκ-Bα inhibitor kappa B alpha

IC50 50 % inhibiting concentration

IRF7 IFN regulatory factor 7

JNK c-Jun N-terminal kinase

Jak2 janus kinase signal transducers 2

LIX lipopolysaccharide-induced CXC chemokine

MCP monocyte chemotactic protein

MPTP N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MAE microwave-assisted extraction using water

NF-κB Nuclear factor-B

NOX4 NADPH oxidase-4

PARP-1 poly ADP-ribose polymerase-1

STAT signal transducer and activated transcription

Stat3 signal transducer and activator of transcription 3

TLR4 Toll-like receptor 4

TNF tumor necrosis factor

TG triglyceride

TrkB tropomyosin-related kinase B

UC ulcerative colitis

VEGF vascular endothelial growth factor
==== Body
pmc1 Introduction

Scutellariae radix (SR) is the dried root of Scutellaria baicalensis Georgi, belonging to the family of Labiatae, and is typically harvested in autumn [1]. It was first recorded in Shennong Bencao Jing and had a long history of usage in many classical Chinese medical works, such as Shanghan Zabing Lun, Wupu Bencao, Bencao Gangmu [2]. In China, SR mainly originates from Inner Mongolia, Sichuan, Shanxi, Shandong, Hebei, Henan, and other provinces [3]. As a commonly medicinal herb, SR is also cultivated in other countries and regions around the world, particularly in Korea, Japan, and Southeast Asia [4].

According to the theory of traditional Chinese medicines (TCMs), SR acts on the lungs, gall bladder, spleen, stomach, large intestine and small intestine. It is traditionally believed to clear heat and dry dampness, eliminate fire and remove toxins, stop bleeding and tranquilize fetus to prevent miscarriage [5]. In modern clinical practice, SR has been extensively studied. It is used to treat cold, fever, migraine, primary hepatocellular carcinoma, hand-foot-and-mouth diseases (HFMD), gingivitis and other diseases [[6], [7], [8], [9], [10]]. At present, a total of 210 components has been reported in the literatures, including flavonoids and their glycosides, phenylpropanoids, phenylethanoid glycosides, phenolic acids, polysaccharides, volatile components and others. It was reported that the extract of SR, baicalin, baicalein, wogonin, wogonoside, and scutellarin had antioxidant, anti-inflammatory, anti-tumor, antiviral, hepatoprotective, and neuroprotective effects.

Although the botany, chemical components, pharmacological activities, pharmacokinetics and toxicology of SR studies have been reviewed [[11], [12], [13]], there is a gap in summarizing and evaluating its traditional historical applications, processing methods, quality control, and factors influencing biosynthesis. The retrospect of SR historical uses can better analyze its medicinal properties to provide a theoretical basis for modern pharmacological research based on TCM theories. Quality control is the basis for ensuring the effectiveness and safety of SR. The biosynthetic research of SR promotes the development of synthetic biology and metabolic engineering of root-specific flavonoids. Hence, this paper provides an updated review of the ethnobotanical uses, processing, phytochemistry, pharmacological effects, quality control, and influence factors of biosynthesis of SR for scientific study.

2 Methods

The reviewed information was obtained from published literature in various scientific databases. The search was conducted by using the keywords “Scutellaria baicalensis”, “Scutellaria baicalensis Georgi”, or “Scutellariae radix” in PubMed, Springer, Web of Science, ScienceDirect, Wiley Online Library, CNKI, and WanFang Database. The search covered literatures were published from 2010 to 2024. Additionally, information from Chinese medical books and Ch. P were also included to provide a comprehensive overview of SR. The botanical information of SR was described using the Flora of China (http://www.iplant.cn/foc).

3 Botany

SR is a perennial herb that blooms from July to August and bears fruit from August to September (Fig. 1). The SR plants has branched, fleshy rhizomes, and up to 2 cm in diameter. The stems are ascending and have subglabrous or antrorsely to spreading puberulent. The papery leaves are lanceolate to linear-lanceolate in shape with puberulent petioles. The front of the blade is darker in color compared to the back. Racemes grow at the tip of stems and branches, which basal bracts are similar to the leaves while the upper bracts are subglabrous and ovate-lanceolate to lanceolate. Pedicels of 3 mm in length are puberulent. The corollas are about 2.3–3 cm long. Their outer part is densely glandular pubescent and the inner saccate part is pubescent. Nutlets are ovoid and have a fruiting umbilicus on the ventral side near the base (http://www.iplant.cn/foc). Details of the various parts of the SR plant are collated in Table 1.Fig. 1 Photograph of Scutellariae radix: inflorescences (A), stems and leaves (B), and medicinal materials (C).

Fig. 1

Table 1 Detailed information on the main parts of the Scutellariae radix plant.

Table 1Parts	Size	Shape	Color	
Rhizome	2 cm in diameter	Elongated and branched	–	
Stem	30 cm–120 cm	Obtuse quadrangular	Green	
Blade	1.5–4.5 cm long, 0.5–1.2 cm wide	Lanceolate to linear-lanceolate	Black-green	
Raceme	7–15 cm long	Conical	–	
Bract	4–11 mm	Lanceolate to linear-lanceolate (basal bract); Oval-lanceolate to lanceolate (upper bract)	–	
Calyx	4 mm (flowering stage); 5 mm (fruiting stage)	–	–	
Scutellum	1.5 mm (flowering stage); 4 mm (fruiting stage)	–	–	
Corolla	2.3–3 cm long	–	Purple, fuchsia, or blue	
Nutlet	1.5 × 1 mm	Ovoid	Black-brown	

4 Ethnobotanical uses

4.1 Traditional historical applications

SR is a common Chinese herbal medicine, with the traditional efficacy of clearing heat and drying dampness, eliminating fire and removing toxicity, stopping bleeding and tranquilizing fetus to prevent miscarriage [14]. It was widely used in many ancient Chinese prescriptions, formulated for its diverse effects.

As early as the Eastern Han Dynasty, there were many prescriptions involving SR recorded in Shanghan Zabing Lun, such as Gegenqinlian decoction, Huangqin decoction, Huanglian Ejiao decoction, and Banxia Xiexin decoction [15]. Among these, Gegen Qinlian decoction was a formula for relieving both superficial and internal disorders [16]. Huangqin decoction had the efficacy in clearing heat and relieving dysentery, harmonizing the middle Jiao and alleviating pain [17]. In the formulation compositions of Gegen Qinlian decoction and Huangqin decoction, SR developed an effective use in clearing heat and drying dampness. This efficacy of SR had persisted through other dynasties, such as Longdan Xiegan decoction and Baixianpi powder in the Song Dynasty and Huangqin Huashi decoction in the Qing Dynasty. In Huanglian Ejiao decoction and Banxia Xiexin decoction, SR showed its ability to clear heat and lower fire. Huanglian Ejiao decoction, consisting of SR, Coptidis rhizoma, and Asini Corii Colla, had the effects of nourishing Yin and clearing heat. Banxia Xiexin decoction was used to mildly regulate cold and heat, relieve oppression and resolve hard mass. During the Tang Dynasty, Huanglian Jiedu decoction, which contained SR for its eliminating fire and detoxifying toxins, had been recorded in the Waitai Miyao. In the prescription, SR played a crucial role in clearing the fire of the Upper Jiao. In the Yuan and Ming Dynasties, SR was added in several gynecological prescriptions for nourishing Yin, tonifying blood, and tranquilizing fetus to prevent miscarriage. For instance, the Antai pill recorded in Danxi Xinfa was formulated with the SR, which had the efficacy of tonifying the kidneys and calming the fetus. Yixue Rumen recorded a formula called Gujing pill, which was used to treat Yin deficiency and blood heat, pre-menstruation and abnormal color of menstruation in women. The main uses of SR in the traditional prescriptions of various dynasties are detailed in Table 2.Table 2 Traditional uses of Scutellariae radix.

Table 2Dynasty	Work	Prescriptions	Form	Effect	
Eastern Han Dynasty (202–220 BCE)	Shanghan Zabing Lun	Gegen Huangqin Huanglian Decoction	Puerariae Lobatae Radix, Scutellariae Radix, Coptidis Rhizoma, Glycyrrhizae Radix Et Rhizoma, Praeparata Cum Melle	Relieving superficies and clearing interior	
Huangqin Decoction	Scutellariae Radix, Paeoniae Radix Alba, Glycyrrhizae Radix Et Rhizoma, Jujubae Fructus	Clearing heat and stopping dysentery, harmonizing the spleen and stomach, and relieving pain	
Ganjiang Huangqin Huanglian Renshen Decoction	Zingiberis Rhizoma, Scutellariae Radix, Coptidis Rhizoma, Ginseng Radix Et Rhizoma	Warming spleen and stomach for dispelling cold, reveling heat, bloated stomach, and astriction	
Huanglian Ejiao Decoction	Scutellariae Radix, Coptidis Rhizoma, Asini Corii Colla, Paeoniae Radix Alba	Nourishing yin for lowering fire and clearing heat	
Banxia Xiexin Decoction	Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix Et Rhizoma, etc	Mildly regulating cold and heat, relieving oppression and resolving hard mass	
Huangqin Jia Banxia Shengjiang Decoction	Scutellariae Radix, Paeoniae Radix Alba, Jujubae Fructus, Zingiberis Rhizoma	Clearing heat and stopping vomiting, nourishing lung qi	
Tang Dynasty (618 CE–907)	Waitai Miyao	Huanglian Jiedu Decoction	Scutellariae Radix, Coptidis Rhizoma, Phellodendri Chinensis Cortex, Gardeniae Fructus	Purging fire and removing toxicity	
Song Dnasty (960 CE–1279)	Xiaoer Yaozheng Zhijue	Longdan Xiegan Decoction	Conyzae Herba, Scutellariae Radix, Alismatis Rhizoma, Gardeniae Fructus, etc.	Clearing excessive fire of liver and gallbladder and eliminating dampness-heat in xiajiao	
Song Dnasty (960 CE–1279)	Taiping Shenghui Fang	Baixianpi Powder	Dictamni Cortex, Scutellariae Radix, Gentianae Macrophyllae Radix, Glycyrrhizae Radix Et Rhizoma, etc	Clearing heat and removing dampness	
Yuan Dynasty (1271 CE–1368)	Danxi Xinfa	Antai Pill	Scutellariae Radix, Atractylodis Macrocephalae Rhizoma	Nourishing blood and tranquilizing fetus to prevent miscarriage	
Ming Dynasty (1368 CE–1644)	Yuji Weiyi	Huangqin Shaoyao Decoction	Scutellariae Radix, Glycyrrhizae Radix Et Rhizoma, Glycyrrhizae Radix Et Rhizoma	Clearing heat and stopping bleeding	
Ming Dynasty (1368 CE–1644)	Waike Zhengzong	Huangqin Qingfei Drink	Scutellariae Radix, Chuanxiong Rhizoma, Angelicae Sinensis Radix, Paeoniae Radix Rubra, etc	Cooling blood and harmonizing nutrient	
Ming Dynasty (1368 CE–1644)	Yixue Rumen	Gujing Pill	Scutellariae Radix, Paeoniae Radix Alba, Testudinis Carapax Et Plastrum, Phellodendri Chinensis Cortex, etc	Nourishing yin and clearing heat, consolidating channel for hemostasis	
Qing dynasty (1616 CE–1912)	Wenbing Tiaobian	Huanglian Huangqin Decoction	Scutellariae Radix, Coptidis Rhizoma	Clearing heat and removing turbidity	
Huangqin Huashi Decoction	Scutellariae Radix, Amomi Fructus Rotundus, Tetrapanacis Medulla, Poriae Cutis, etc	clearing heat and promoting diuresis	

4.2 Modern uses

SR has a variety of effects for treating numerous clinical diseases. For instance, SR could be used to treat colds during pregnancy without adverse effects on the fetus after birth [6]. The pain of migraine could be alleviated by treatment with SR [10]. A retrospective clinical analysis indicated that SR reduced the symptoms of fever, blisters, rash, and oral lesions in hand-foot-and-mouth diseases because of its inhibitory effect on enterovirus 71, the causative agent of HFMD [8]. A double-blinded randomized clinical test suggested that SR enhanced the efficacy of metformin in type 2 diabetes patients. SR in combination with metformin increased the glucose tolerance and inhibited the expression of inflammatory markers [18]. The extract of SR performed well in inhibiting the plaque development and alleviating gingivitis [7]. SR could modulate cell proliferation and apoptosis, as well as influence the infiltration of T cells and macrophages in the tumor microenvironment [17]. A clinical study showed that baicalin capsules could improve the immune ability and the liver function of cancer patients, reducing the side effects caused by chemotherapy [9].

Furthermore, with the help of modern pharmaceutical processes, SR is combined with several Chinese herbs to create more widely accepted Chinese patent medicines. For instance, Niuhuang Qinggan capsule, Fufang Qinlan oral liquid, and Pudilan Xiaoyan capsule have the main effects of clearing heat and eliminating toxins. Gong Liu Qing capsule and Gongning grain are effective in nourishing blood and removing blood stasis, thus treating gynecological diseases. Some commonly used Chinese patent medicines that contain SR are shown in Table 3.Table 3 Chinese patent medicines containing Scutellariae radix.

Table 3Type	Preparation Name	Main Compositions	Dosage of SR	Function	References	
Tablet	Shiduqing Pian	Rehmanniae Radix, Angelicae Sinensis Radix, Salviae Miltiorrhizae Radix Et Rhizoma, Scutellariae Radix, etc	125 g	Nourishing blood and moisturizing skin, dispelling pathogenic wind for relieving itching	[1]	
Tablet	Chaihuang Pian	Bupleuri Radix, Scutellariae Radix	1000 g	Clearing heat and resolving superficies syndrome	[1]	
Tablet	Tongxuan Lifei Pian	Perillae Folium, Peucedani Radix, Platycodonis Radix, Scutellariae Radix, etc	120 g	Resolving superficies syndrome for dispelling cold and unblocking stuffy orifice	[1]	
Tablet	Hexue Mingmu Pian	Typhae Pollen, Rehmanniae Radix, Ecliptae Herba, Scutellariae Radix, etc	45 g	Cooling blood for hemostasis, nourishing yin and improving eyesight	[1]	
Tablet	Biyankang Pian	Pogostemon cablin Benth, Centipedae Herba, Dendranthema indicum, Scutellariae Radix,etc	109 g	Clearing heat and removing toxicity	[1]	
Tablet	Niuhuang Jiangya Pian	Saigae Tataricae Cornu, Margarita, Bovis Calculus Artifactus, Scutellariae Radix, etc	–	Clearing heart and dissipating phlegm, suppressing hyperactive liver for tranquilizing the mind	[1]	
Pill	Qingfei Yihuo Wan	Gardeniae Fructus, Anemarrhe Naerhizoma, Fritillariae Thunbergii Bulbus, Scutellariae Radix, etc	140 g	Clearing lung to stopping cough, expectorant and facitating feces excretion	[1]	
Pill	Antai Wan	Angelicae Sinensis Radix, Chuanxiong Rhizoma, Atractylodis Macrocephalae Rhizoma, Scutellariae Radix, etc	200 g	Nourishing blood and tranquilizing fetus to prevent miscarriage	[1]	
Pill	Qingre Liangxue Wan	Scutellariae Radix, Rehmanniae Radix	500 g	Cooling blood, clearing heat, and nourshing yin	[1]	
Pill	Gegen Qinlian Wan	Puerariae Lobatae Radix, Coptidis Rhizoma, Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle, Scutellariae Radix	375 g	Clearing heat and removing toxicity, promoting diuresis and relieving diarrhea	[1]	
Pill	Yinhuang Wan	Lonicerae Japonicae Flos Extract, Scutellariae Radix Extract	160 g	Clearing heat and dispelling wind pathogen, relieving sore throat and removing toxicity	[1]	
Pill	Tongqiao Erlong Wan	Bupleuri Radix, Gentianae Radix Et Rhizoma, Aloe, Scutellariae Radix, etc	120 g	Clearing liver-fire, unblocking stuffy orifice, and moistening dryness for relaxing bowels	[1]	
Capsule	Niuhuang Qinggan Jiaonang	Lonicerae Japonicae Flos, Forsythiae Fructus, Margaritifera Concha, Scutellariae Radix, etc	166.7 g	Clearing heat and removing toxicity, resolving superficies syndrome	[1]	
Capsule	Pudilan Xiaoyan Jiaonang	Taraxaci Herba, Corydalis Bungeanae Herba, Isatidis Radix, Scutellariae Radix, etc	271 g	Clearing heat and removing toxicity, reduce swelling and relieving sore throat	[1]	
Capsule	Jiuwei Gantai Jiaonang	Notoginseng Radix Et Rhizoma, Curcumae Radix, Tribuli Fructus, Scutellariae Radix, etc	160 g	Invigorating the spleen and dispersing the stagnated liver-energy, resolving blockages, and unblocking veins	[1]	
Capsule	Gongliuqing Jiaonang	Murrayae Folium Et Cacumen, Zanthoxyli Radix, Aucklandiae Radix, Scutellariae Radix, etc	769 g	Promoting blood circulation for removing blood stasis	[1]	
Capsule	Fufang Niuhuang Xiaoyan Jiaonang	Bovis Calculus Artifactus, Gardeniae Fructus, Cinnabaris, Scutellariae Radix, etc	190.6 g	Clearing heat and removing toxicity, sedative and tranquilizer	[1]	
Grain	Sanjiu Weitai Keli	Murrayae Folium Et Cacumen, Zanthoxyli Radix, Poria, Scutellariae Radix, etc	153.85 g	Clearing heat and drying dampness, activating blood and relieving pain	[1]	
Grain	Qinghou Liyan Keli	Chebulae Fructus Immaturus, Bambusae Caulis In Taenias, Platycodonis Radix, Scutellariae Radix, etc	36 g	Clearing heat, relieving sore throat, and moistening throat	[1]	
Grain	Huanglian Shangqing Keli	Coptidis Rhizoma, Gardeniae Fructus, Forsythiae Fructus, Scutellariae Radix, etc	192 g	Clearing heat and dispelling wind pathogen, clearing heat and reveling pain	[1]	
Grain	Gongning Keli	Rubiae Radix Et Rhizoma,
Typhae Pollen, Sanguisorbae Radix, Scutellariae Radix, etc	117 g	Removing blood stasis and clearing heat, consolidating channel for hemostasis	[1]	
Grain	Xiao'er tuire keli	Isatidis Folium, Isatidis Radix, Moutan Cortex, Scutellariae Radix, etc	180 g	Dispelling wind pathogen and resolving superficies syndrome, removing toxicity and relieving sore throat	[1]	
Mixture	Fufang Yuxingcao Heji	Houttuyniae Herba, Isatidis Radix, Forsythiae Fructus, Scutellariae Radix, etc	25 g	Clearing heat and removing toxicity	[1]	
Mixture	Fufang Qinlan Koufuye	Lonicerae Japonicae Flos, Forsythiae Fructus, Isatidis Radix, Scutellariae Radix, etc	500 g	Dispelling the evil in the superficies with drugs of pungent taste and cool nature, Clearing heat and removing toxicity	[1]	
Mixture	Bidouyan Koufuye	Magnoliae Flos, Schizonepetae Herba, Menthae Haplocalycis Herba, Scutellariae Radix, etc	112 g	Clearing heat and promoting diuresis, unblocking stuffy orifice	[1]	

5 Processing

5.1 Evolution of processing methods of SR

Processing is a conventional pharmaceutical procedure that transforms crude drugs into decoction pieces. Some auxiliary materials, such as wine, vinegar, and honey, are often added during processing process to enhance the efficacy and reduce the toxicity of Chinese herbs [19]. Although SR was applied early, its processing was not officially recorded until the Tang Dynasty. The fine cutting of SR was first recorded in the Qianjin Yaofang [20]. During the Song Dynasty, stir-frying processing, wine soaking, and vinegar processing emerged. Stir-frying involved gently heating SR to enhance its medicinal properties and directing its effects upward in the body. Vinegar processing promoted the efficacy of SR in the blood, commonly used in treating menstrual disorders [21,22]. In the Yuan and Ming dynasties, wine-processed SR and charred SR were widely used [20]. Charred SR had the effects of stopping bleeding and clearing heat, which was mostly used in the treatment of vomiting and epistaxis. Wine processing included wine stir-frying, wine washing, wine steaming, wine boiling, and other forms. With the ascending power of wine led to the medical effects of clearing the heat of the upper jiao [23]. In brief, the various processing methods of SR in the past dynasties were diversified. However, there were only six processing methods still in use today, including SR piece, wine-processed SR, charred SR, stir-fried SR, honey-processed SR, and ginger-processed SR [24]. SR piece and wine-processed SR are listed in the Chinese Pharmacopoeia (version 2020), but the difference in their quality is not distinguished. The evolution history of SR processing is shown in Table 4.Table 4 Evolution of Scutellariae radix processing methods.

Table 4Dynasty	Processing methods	Classic sources	References	
Tang dynasty (618 CE–907)	Fine cutting	Qianjin Yaofang	[20]	
Song dynasty (960 CE–1279)	Stir-frying processing, Wine soaking, Vinegar processing	Taiping Huimin Heji Ju Fang, Renzhai Zhi Zhi Fang, Weisheng Jianyifang	[21,22]	
Yuan dynasty (1271 CE–1368)	Wine washing, ginger processing	Danxi xinfa	[20]	
Ming dynasty (1368 CE–1644)	Wine stir-frying, Wine steaming, Making charcoal, Vinegar processing, Salt processing,	Yinhai Jingwei, Yizong Bidu, Paozhi Dafa, Shoushi Baoyuan, Renshu bianlan	[20,22]	
Modern	Stir-frying, wine processing, making charcoal, cutting, honey processing, ginger processing	–	[24]	

5.2 Modern research on processing SR

Modern analytical techniques showed the chemical components and their in vivo absorption were altered after different processing. Using ultrahigh performance liquid chromatography (UHPLC), the flavonoid content in charred SR, wine-processed SR, and crude SR could be determined [25]. The results revealed that the processing led to the decomposition of flavonoid glycosides and a decrease in their content. The charring of SR reduced the content of volatile components of SR [26]. An ultrahigh performance liquid chromatography coupled with electrospray ion source-mass spectrometry (UHPLC-ESI-MS/MS) method was employed to determine the absorption of ten flavonoids of crude and wine-processed SR in mice, such as baicalin, baicalein, scutellarin, scutellarein, and others. It indicated that the pharmacokinetic parameters of most flavonoids in wine-processed SR were significantly different from those of the crude SR, which portrayed that wine processing could improve the bioavailability of main flavonoids [27]. In addition, compared to crude SR, wine-processed SR was more effective in reducing the inflammatory factors in a lipopolysaccharide-induced murine model of acute lung injury. Non-targeted metabolomics implied that crude SR and wine-processing SR act on different metabolic pathways [28].

In recent years, the differentiation and identification of SR and its processed products had also begun to attract the attention of researchers. Utilizing fingerprinting combined with back propagation-artificial neural network modeling, baicalein, baicalin, wogonin, and wogonoside were selected as quality control markers for crude SR, wine-pressed SR, and charred SR, and their content was determined. Based on quantitative data, principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were employed to discriminate between them [29]. Following sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) experiment, SR was found to possess β-glucuronidase, which catalyzed the conversion from flavonoid glycosides to aglycones. However, this enzyme was inactivated in wine-processed SR and steamed SR. Thus, the conversion rate between flavonoid glycosides and aglycones could be determined to distinguish crude SR from processed samples [30]. Interestingly, electronic tongue technology detected that the bitterness of SR decreased while the saltiness increased after wine-processing. Subsequently, PCA analysis of various taste monitoring values showed that the differences between these two tastes could distinguish different SR before and after wine-processing. Based on the different taste response values of the electronic tongue, a fisher discriminant model was established to realize the rapid classification of SR and its processed products [31].

In summary, there are obvious differences between crude SR and processed SR in terms of component contents, metabolic absorption, and pharmacological activity. Furthermore, the similarity in appearance between crude SR and its processed products (mainly wine-processed SR and steamed SR) can easily lead to clinical misuse and affect therapeutic efficacy. Therefore, the comprehensive analytical methods should be developed and the corresponding quality control standards for processed SR should be established to ensure their rational application.

6 Phytochemistry

Hitherto, 210 components have been isolated from SR, including flavonoids and their glycosides, phenylpropanoids, phenylethanoid glycosides, phenolic acids, polysaccharides, volatile components, and others. The main characteristic components are flavonoids and their glycosides, which are also the most abundant secondary metabolites in SR. The various types of chemical components and their representative compounds in SR are illustrated in Fig. 2. The detailed information about 210 components from SR is seen in Table 5.Fig. 2 Types of chemical components and their representative components in Scutellariae radix.

Fig. 2

Table 5 Phytochemical components of Scutellariae radix.

Table 5Number	Name	Chemical formula	Identification methods	References	
Flavonoids and flavonoid glycosides	
1	baicalein	C15H10O5	1H NMR,13C NMR	[32]	
2	wogonin	C16H12O5	1H NMR,13C NMR	[32]	
3	skullcapflavone II	C19H18O8	TLC, 1H NMR,13C NMR	[33]	
4	tenaxin I	C18H16O7	TLC, 1H NMR,13C NMR	[33]	
5	apigenin	C15H10O5	1H NMR,13C NMR	[34]	
6	oroxylinA	C16H12O5	1H NMR,13C NMR	[32]	
7	luteolin	C15H10O6	1H NMR,13C NMR	[35]	
8	chrysin	C15H10O4	1H NMR,13C NMR	[36]	
9	5,7,2′,5′-tetrahydroxy-8,6′-dimethoxyflavone	C17H14O8	1H NMR,13C NMR	[37]	
10	5,7,2′,6′-tetrahydroxyflavone	C15H10O6	1H NMR,13C NMR	[32]	
11	chrysin-6-C-α-L-arabinopyranosyl-8-C-β-D-glueopyranosid	C26H28O13	1H NMR,13C NMR	[32]	
12	5,7-dihydroxy-6,8-dimethoxyflavone	C17H14O6	1H NMR,13C NMR, APCI-MS	[11]	
13	5,7,2′-trihydroxy-6,8-dimethoxyflavone	C17H14O7	1H NMR,13C NMR, EI-MS	[38]	
14	5,8-dihydroxy-6,7-dimethoxyflavone	C17H14O7	1H NMR,13C NMR, MS	[39]	
Number	Name	Chemical formula	Identification methods	References	
15	5,8,2′-trihydroxy-6,7-dimethoxyflavone	C17H14O7	UV, IR, TLC, 1H NMR,13C NMR,	[40]	
16	norwogonin	C15H10O5	1H NMR,13C NMR, APCI-MS	[11]	
17	5,2′,5′-trihydroxy-6,7,8-trimethoxyflavone	C18H16O8	UV, IR, TLC, 1H NMR,13C NMR	[41]	
18	4′-hydroxywogonin	C16H12O6	1H NMR,13C NMR, EI-MS	[38]	
19	5,2′-dihydroxy-6,7,8,3′-tetramethoxyflavone	C19H18O8	1H NMR,13C NMR, FAB-MS	[42]	
20	2′-hydroxychrysin	C15H10O5	UV, IR, TLC, 1H NMR,13C NMR	[41]	
21	5,7,2′,3′-tetrahydroxyflavone	C15H10O6	IR, 1H NMR,13C NMR	[43]	
22	6-hydroxyluteolin	C15H10O7	HPLC-MS/MS	[44]	
23	salvigenin	C18H16O6	1H NMR,13C NMR, APCI-MS	[11]	
24	5,7,2′,5′-tetrahydroxyflavone	C15H10O6	1H NMR,13C NMR,FAB-MS	[45]	
25	5,7,6′-trihydroxy-2′-methoxyflavone	C16H12O6	UV, IR, TLC, 1H NMR,13C NMR	[41]	
26	5,7-dihydroxy-6,8,2′,3′-tertramethoxyflavone	C19H18O7	1H NMR,13C NMR, APCI-MS	[11]	
Number	Name	Chemical formula	Identification methods	References	
27	3,5,4′-trihydroxy-6,7,8-trimethoxyflavone	C18H16O8	HPLC-MS/MS	[44]	
28	5,7,6′-trihydroxy-8,2′-dimethoxyflavone	C17H14O7	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
29	viscidulin Ⅲ	C17H14O8	1H NMR,13C NMR	[32]	
30	5,7,2′-trihydroxy-6′-methoxyflavone	C16H12O6	1H NMR,13C NMR, APCI-MS	[11]	
31	5,7-dihydroxy-8,2′,3′,6′-tetramethoxyflavone	C19H18O8	1H NMR,13C NMR, ESI-MS	[47]	
32	5,8-dihydroxy-7-methoxyflavone	C16H12O5	TLC, 1H NMR,13C NMR	[48]	
33	7-O-methylwogonin	C17H14O5	IR, 1H NMR, 13C NMR	[49]	
34	5,8,2′-trihydroxy-7-methoxyflavone	C16H12O6	UV, IR, TLC, 1H NMR,13C NMR,	[40]	
35	5,7,4′-trihydroxy-8-methoxyflavone	C16H12O6	1H NMR,13C NMR, EI-MS	[38]	
36	skullcapflavone I	C17H14O6	UV, IR, TLC, 1H NMR,13C NMR	[41]	
37	viscidulin II	C17H14O7	UV, IR, TLC, 1H NMR,13C NMR	[41]	
38	rivularin	C18H16O7	1H NMR,13C NMR,FAB-MS	[45]	
39	6′-hydroxy-5,6,7,8,2′-pentamethoxyflavone	C20H20O8	1H NMR,13C NMR, EI-MS	[38]	
Number	Name	Chemical formula	Identification methods	References	
40	6,6′-dihydroxy-5,7,8,2′-tetramethoxyflavone	C19H18O8	1H NMR,13C NMR, EI-MS	[38]	
41	5,7-dihydroxy-6,4′-dimethoxyflavone	C17H14O6	TLC, 1H NMR,13C NMR,	[50]	
42	2′-hydroxy-6,7,8-trimethoxyflavone	C18H16O6	1H NMR,13C NMR	[51]	
43	5,7,2′-trihydroxy-6,8-dimethoxyflavone	C17H14O7	1H NMR,13C NMR	[51]	
44	norwogonin-7-O-β-D-methylglucuronide	C22H20O11	1H NMR,13C NMR	[51]	
45	wogonin-7-O-β-D-ethylglucuronide	C24H24O11	1H NMR,13C NMR, ESI-MS	[52]	
46	baicalein-7-O-β-D-ethylglucuronide	C23H22O11	1H NMR,13C NMR, ESI-MS	[52]	
47	viscidulin Ⅲ-2′-O-β-D-glucopyranoid	C23H24O13	1H NMR,13C NMR, EI-MS	[38]	
48	6,2′-dihydroxy-5,7,8,6′-tetramethoxyflavone	C19H18O8	1H NMR,13C NMR, EI-MS	[38]	
49	2′-hydroxy-5,6,7,8,6′-pentamethoxyflavone	C20H20O8	1H NMR,13C NMR, EI-MS	[38]	
50	5,2′,6′-trihydroxy-6,7-dimethoxyflavone 2′-O-β-D-glucoside	C23H24O12	1H NMR,13C NMR, SI-MS	[53]	
51	5,2′,6′-trihydroxy-6,7,8-trimethoxyflavone 2′-O-β-D-glucoside	C24H26O13	1H NMR,13C NMR, SI-MS	[53]	
52	5,6′-dihydroxy-6,7,8,2′tetramethoxyflavone	C19H18O8	UPLC-Q-orbitrap MS	[54]	
53	velutin	C17H14O6	1H NMR,13C NMR	[55]	
Number	Name	Chemical formula	Identification methods	References	
54	tenaxin II	C16H12O6	1H NMR,13C NMR	[55]	
55	5,6,7-trihydroxy-8-methoxyflavone	C16H12O6	1H NMR,13C NMR	[55]	
56	8,8″-bibaicalein	C30H18O10	1H NMR,13C NMR, EI-MS	[38]	
57	baicalin	C21H18O11	1H NMR,13C NMR	[55]	
58	baicalein-7-O-β-D-glucoside	C21H20O10	1H NMR,13C NMR	[55]	
59	baicalein-7-O-β-D- methylglucuronide	C22H20O11	1H NMR,13C NMR	[55]	
60	scutellarin	C21H18O12	TLC, HPLC, 1H NMR,13C NMR	[56]	
61	wogonin-7-O-β-D-methylglucuronide	C23H22O11	TLC, 1H NMR, 13C NMR	[57]	
62	baicalein-6-O-β-D-glucuronide	C21H18O11	HPLC-MS/MS	[44]	
63	6-hydroxyluteolin-7-O-β-D-glucoronide	C21H18O13	HPLC-MS/MS	[44]	
64	luteolin-7-O-β-D-glucuronide	C21H18O12	HPLC-MS/MS	[44]	
65	8-methoxyflavone-5-O-β-D-glucoside	C22H20O10	HPLC-MS/MS	[44]	
66	apigenin-7-O-β-D-glucoside	C21H20O10	1H NMR,13C NMR, APCI-MS	[11]	
67	oroxylin A-7-O-β-D-glucoside	C22H22O10	HPLC-MS/MS	[44]	
Number	Name	Chemical formula	Identification methods	References	
68	5,6′-dihydroxy-7,8-dimethoxyflavone2′-O-β-D-glucoside	C23H24O12	UV, IR, TLC, 1H NMR,13C NMR	[41]	
69	5,6′-dihydroxy-6,7,8-trimethoxyflavone 2′-O-β-D-glucoside	C24H26O13	1H NMR,13C NMR, SI-MS	[53]	
70	5,6′-dihydroxy-6,7-dimethoxyflavone 2′-O-β-D-glucoside	C23H24O12	1H NMR,13C NMR, APCI-MS	[11]	
71	5,7,6′-trihydroxyflavone-2′-O-β-D-glucoside	C21H20O11	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
72	viscidulin III-6′-O-β-D-glucoside	C23H24O13	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
73	wogonin-5-O-β-D-glucoside	C22H22O10	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
74	chrysin-7-O-β-D-glucuronide	C21H18O10	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
75	5,2′-dihydroxy-6-methoxyflavone-7-O-β-D-glucuronide	C22H20O12	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
76	wogonoside	C22H20O11	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
77	oroxyloside	C22H20O11	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
78	norwogonin-7-O-β-D-glucuronide	C21H18O11	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
Number	Name	Chemical formula	Identification methods	References	
79	5-hydroxy-7,8,6′-trimethoxyflavone2′-O-β-D-glucuronide	C24H24O13	UV, IR, 1H NMR, 13C NMR	[58]	
80	chrysin-8-C-β-D-glucoside	C21H20O9	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
81	viscidulin III-2′-O-β-D-glucopyranoside	C23H22O14	1H NMR,13C NMR, APCI-MS	[11]	
82	quercetin-3-O-β-D-glucuronide	C21H18O13	HPLC-MS/MS	[44]	
83	5,6,8-trimethoxy-3′,4′-methylenedioxyflavone-7-O-β-D-glucoside	C26H28O12	1H NMR,13C NMR, HPLC-ESI-MS	[59]	
84	3,5,8-trimethoxy-3′,4′-methylenedioxyflavone7-O-β-D-glucoside	C26H28O12	1H NMR,13C NMR, HPLC-ESI-MS	[59]	
85	chrysin-6-C-β-D-glucoside-8-C-α-L-arabinopyranoside	C26H28O13	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
86	chrysin-6-C-α-L-arabinopyranoside-8-C-β-D-glucoside	C26H28O13	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
87	chrysin-6-C-β-L-arabinopyranoside-8-C-β-D-glucoside	C26H28O13	HPLC-MS/MS	[44]	
88	chrysin-6-C-β-D-glucoside-8-C-β-L-arabinopyranoside	C26H28O13	HPLC-MS/MS	[44]	
89	chrysin-6-C-β-arabinofuranoside-8-C-β-D-glucoside	C26H28O13	HPLC-MS/MS	[44]	
90	chrysin-6-C-β-D-glucoside-8-C-β-arabinofuranoside	C26H28O13	HPLC-MS/MS	[44]	
Number	Name	Chemical formula	Identification methods	References	
91	chrysin-3-C-α-arabinopyranoside-8-C-β-D-glucoside	C26H28O13	1H NMR,13C NMR, HPLC-ESI-MS	[59]	
92	scutevulin	C16H12O6	UV, IR, TLC, 1H NMR,13C NMR	[41]	
93	chrysin-6-C-β-D-glucoside	C21H20O9	1H NMR,13C NMR,FAB-MS	[45]	
94	dihydrooroxylin A	C16H14O5	TLC, 1H NMR,13C NMR	[33]	
95	alpinetin	C16H14O4	TLC, 1H NMR,13C NMR	[33]	
96	naringenin	C15H12O5	HPLC-MS/MS	[44]	
97	pinocembrin	C15H12O4	HPLC-MS/MS	[44]	
98	isocarthamidin	C15H12O6	HPLC-MS/MS	[44]	
99	carthamidin	C15H12O6	HPLC-MS/MS	[44]	
100	(2S)-5,7,4′-trihydroxy-6-methoxyflavanone	C16H14O6	1H NMR,13C NMR, APCI-MS	[11]	
101	(+)-eriodictyol(2S)-5,7,3′,4′-tetrahydroxyflavanone	C15H12O6	1H NMR,13C NMR, APCI-MS	[11]	
102	(2S)-5,7,2′,5′-tetrahydroxyflavanone	C15H12O6	1H NMR,13C NMR, APCI-MS	[11]	
103	(2S)-5,7,2′,6′-tetrahydroxyflavanone	C15H12O6	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
Number	Name	Chemical formula	Identification methods	References	
104	(2S)-7,2′,6′-trihydroxy-5-methoxyflavanone	C16H14O6	1H NMR,13C NMR, APCI-MS	[11]	
105	5,6,7-trihydroxy-4′-methoxyflavonone	C16H14O6	TLC, 1H NMR,13C NMR,	[50]	
106	5,7,2′-trihydroxy-6-methoxyflavonone	C16H14O6	TLC, 1H NMR,13C NMR,	[50]	
107	5,7,2′-trihydroxyflavone	C15H12O5	1H NMR,13C NMR	[51]	
108	(2S)-5,7,6′-trihydroxyflavanone 2′-O-β-D-glucopyranoside	C21H22O11	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
109	naringenin-7-O-glucoronide	C21H20O11	HPLC-MS/MS	[44]	
110	pinocembrin-7-O-glucoronide	C21H20O10	HPLC-MS/MS	[44]	
111	(2S)-5,7,2′,5′-tetrahydroxyflavanone-7-O-β-D-glucoside	C21H22O10	1H NMR,13C NMR, APCI-MS	[11]	
112	(2S)-5,7-dihydroxy-6-methoxyflavanone-7-O-β-D-glucoside	C22H24O9	1H NMR,13C NMR, APCI-MS	[11]	
113	(2S)-5-hydroxy-6-methoxyflavanone-7-O-β-D-glucoside	C22H24O10	1H NMR,13C NMR, APCI-MS	[11]	
114	(2S)-5,7,6′-trihydroxyflavanone-2′-O-β-D-glucoside	C20H20O11	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
115	dihydrobaicalin	C21H20O11	1H NMR,13C NMR, APCI-MS	[11]	
Number	Name	Chemical formula	Identification methods	References	
116	(2S)-5-hydroxy-6-methoxyflavanone-7-O-β-D-glucuronide	C22H22O11	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
117	(2S)-5,6,3′,4′-tetrahydroxyflavanone-7-O-β-D-glucuronide	C21H20O13	1H NMR,13C NMR, APCI-MS	[11]	
118	isocarthamidin-7-O-β-D-glucuronide	C21H20O12	HPLC-MS/MS	[44]	
119	3,5,7,6′-tetrahydroxyflavone-2′-O-β-D-glucoside	C21H20O12	1H NMR,13C NMR, APCI-MS	[11]	
120	patuletin-7-O-β-D-glucuronide	C22H20O14	1H NMR,13C NMR, HPLC-ESI-MS	[59]	
121	5,7,6′-trihydroxy-2′-methoxyflavonol	C16H12O7	1H NMR,13C NMR, ESI-MS	[50]	
122	5,7,2′,6′-tetrahydroxyflavonol	C15H10O7	1H NMR,13C NMR, EI-MS	[38]	
123	(2R,3R)-3,5,7,2′,6′-pentahydroxyflavanone	C15H12O7	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
124	4′,5,7-trihydroxy-6-methoxyflavanone	C16H16O5	UV, IR, TLC, 1H NMR,13C NMR,	[40]	
125	2′,6′,5,7-tetrahydroxyflavanone	C15H14O5	UV, 1H NMR,13C NMR	[60]	
126	delphinidin-3-O-(6-O-malonyl)-β-D-glucoside-5-O-β-D-glucoside	C30H33O20	1H NMR,13C NMR, ESI-MS	[61]	
127	2,6,2′,4′-tetrahydroxy-6′-methoxychalcone	C16H14O6	UV, IR, TLC, 1H NMR,13C NMR	[41]	
Number	Name	Chemical formula	Identification methods	References	
128	2,4′-dihydroxydihydrochalcone-3′-C-β-glucoside-6′-O-β-D-glucoside	C27H34O15	1H NMR,13C NMR, ESI-MS	[62]	
Phenylpropanoids	
129	4'-(β-D-glucopyranosyloxy)-3,3′,5,5′-tetramethoxy-9,9′-epoxylignane-4,7′-diol	C28H38O13	1H NMR,13C NMR, ESI-MS	[63]	
130	4'-(β-D-glucopyranosyloxy)-3,3′,5′-trimethoxy-9,9′-epoxylignane-4,7′-diol	C27H36O12	1H NMR,13C NMR, ESI-MS	[63]	
131	4'-(β-D-glucopyranosyloxy)-3,3-dimethoxy-9,9′-epoxylignane-4,7′-diol	C26H34O11	1H NMR,13C NMR, ESI-MS	[63]	
132	(+)-syringaresinol-4-O-β-D-glucoside	C28H36O13	1H NMR,13C NMR	[64]	
133	veraguensin	C22H28O5	1H NMR,13C NMR	[55]	
134	galgravin	C22H28O5	1H NMR,13C NMR	[55]	
135	denudanolide B	C20H22O6	1H NMR,13C NMR	[55]	
136	denudatin B	C21H24O5	1H NMR,13C NMR	[55]	
137	(2R,3R,3aS)-5-allyl-2-(3,4-dimethoxy-phenyl)-3a-methoxy-3-methyl-3,3a-dihydrobenzofuran-6(2H)-one	C21H24O5	1H NMR,13C NMR	[55]	
138	eupomatenoid-7	C20H20O4	1H NMR,13C NMR	[55]	
139	trans-caffeic acid methyl ester	C10H10O4	1H NMR,13C NMR	[51]	
140	trans-caffeic acid	C9H8O4	1H NMR,13C NMR	[51]	
141	4-O-β-D-glucosyl-trans-p-coumaricacid	C15H18O8	1H NMR,13C NMR	[65]	
142	4-O-β-D-glucosyl-cis-p-coumaricacid	C15H18O8	1H NMR,13C NMR	[65]	
143	ferulic acid methyl ester	C11H12O4	1H NMR,13C NMR, ESI-MS	[66]	
Phenylethanol glycosides	
144	salidroside	C14H20O7	UV, IR, 1H NMR, 13C NMR	[58]	
145	darendoside A	C19H28O11	1H NMR,13C NMR	[64]	
146	darendoside B	C21H32O12	1H NMR,13C NMR	[64]	
147	martynoside	C31H40O15	UV, IR, 1H NMR, 13C NMR	[58]	
148	acteoside	C29H36O15	UV, IR, 1H NMR, 13C NMR	[58]	
149	isomartynoside	C31H40O15	1H NMR,13C NMR	[64]	
150	leucosceptoside A	C30H38O15	UV, IR, 1H NMR, 13C NMR	[58]	
151	cistanoside D	C31H40O15	IR, UV, 1H NMR,13C NMR, ESI-MS	[46]	
Phenolic acids	
152	benzoic acid	C7H6O2	TLC, 1H NMR,13C NMR	[33]	
153	phenylacetic acid	C8H8O2	1H NMR,13C NMR	[65]	
Number	Name	Chemical formula	Identification methods	References	
154	syringaldehyde	C9H10O4	1H NMR,13C NMR, ESI-MS	[66]	
155	vanillin	C8H8O3	1H NMR,13C NMR, ESI-MS	[66]	
156	p-hydroxybenzoic acid	C7H6O3	1H NMR,13C NMR	[51]	
157	protocatechuic acid	C7H6O4	1H NMR,13C NMR	[51]	
Others	
158	N1,N5,N10-Tri-p-(E,E,E)-coumaroylspermidine	C33H33O6N3	HPLC-MS/MS	[44]	
159	pellitorine	C14H25NO	1H NMR,13C NMR, ESI-MS	[66]	
160	(E)-4-[(2-methylpropyl)amino]-4-oxo-2-butenoicacid	C8H13NO3	1H NMR,13C NMR, ESI-MS	[66]	
161	4,5-dihydropiperlonguminine	C16H21NO3	1H NMR,13C NMR, ESI-MS	[66]	
162	futoamide	C18H23NO3	1H NMR,13C NMR, ESI-MS	[66]	
163	piperlonguminine	C16H19NO3	1H NMR,13C NMR, ESI-MS	[66]	
164	sinapoylhexoside	C16H20O10	HPLC-MS/MS	[44]	
165	7-O-Acetylloganic acid	C18H26O11	HPLC-MS/MS	[44]	
166	lutein	C40H56O2	1H NMR, 13C NMR	[67]	
167	β-carotene	C40H56	1H NMR, 13C NMR	[67]	
168	stigmasterol	C29H48O	1H NMR,13C NMR, EI-MS	[38]	
Number	Name	Chemical formula	Identification methods	References	
169	β-sitosterol	C29H50O	1H NMR,13C NMR, EI-MS	[38]	
170	daucosterin	C35H60O6	1H NMR,13C NMR, EI-MS	[38]	
171	(+)-crotepoxide	C18H18O8	1H NMR,13C NMR, ESI-MS	[66]	
Volatile components	
172	benzylalcohol	C7H8O	GC-MS	[67]	
173	isopropylcyclohexane	C9H18	GC-MS	[68]	
174	octane	C8H18	GC-MS	[68]	
175	hexanoicacid	C6H12O2	GC-MS	[68]	
176	3,5-Difluoro-N,N-dimethylaniline	C8H9F2N	GC-MS	[68]	
177	benzaldehyde	C7H6O	GC-MS	[68]	
178	3, 7-dimethyl nonane	C11H24	GC-MS	[68]	
179	benzeneacetaldehyde	C8H8O	GC-MS	[68]	
180	acetyl valeryl	C7H12O2	GC-MS	[68]	
181	3, 7-dimethyl decane	C12H26	GC-MS	[68]	
182	undecane	C11H24	GC-MS	[68]	
Number	Name	Chemical formula	Identification methods	References	
183	camphor	C10H16O	GC-MS	[68]	
184	2, 5, 9-trimethyl decane	C13H28	GC-MS	[68]	
185	octanoic acid	C8H16O2	GC-MS	[68]	
186	3, 8-dimethyl undecane	C13H28	GC-MS	[68]	
187	dodecane	C12H26	GC-MS	[68]	
188	benzylideneacetone	C10H10O	GC-MS	[68]	
189	3-ethyl-3-methyl decane	C13H28	GC-MS	[68]	
190	nonanoic acid	C9H18O2	GC-MS	[68]	
191	4, 6-dimethyl dodecane	C14H30	GC-MS	[68]	
192	tridecane	C13H28	GC-MS	[68]	
193	1, 2-dihydro-1, 1, 6-trimethyl-naphthalene	C13H16	GC-MS	[68]	
194	succinicacid, diisobutylester	C12H22O4	GC-MS	[68]	
195	β-caryophyllene	C15H24	GC-MS	[68]	
196	butanedioicacid,methyl-,bis(1-methylpropyl)ester	C13H24O4	GC-MS	[68]	
197	pentadecane	C15H32	GC-MS	[68]	
Number	Name	Chemical formula	Identification methods	References	
198	GermacreneD	C15H24	GC-MS	[68]	
199	9-Cedranone	C15H24O4	GC-MS	[68]	
200	diphenyl amine	C12H11N	GC-MS	[68]	
201	benzophenone	C13H10O	GC-MS	[68]	
202	hexanedioic acid,bis(2-methylpropyl)ester	C14H26O4	GC-MS	[68]	
203	13-tetradecenylacetate	C16H30O2	GC-MS	[68]	
204	diisobutyl phthalate	C16H22O4	GC-MS	[68]	
205	eicosane	C20H42	GC-MS	[68]	
206	heneicosane	C21H44	GC-MS	[68]	
207	1,2-benzenedicarboxylic acid, butyl8-methylnonylester	C22H34O4	GC-MS	[68]	
208	2, 2′-methylenebis[6- (1, 1-dimethylethyl)-4-methyl- phenol	C23H32O2	GC-MS	[68]	
209	hexatriacontane	C36H74	GC-MS	[68]	
210	tetratetracontane	C44H90	GC-MS	[68]	

6.1 Flavonoids and their glycosides

At present, there were 93 flavones and their glycosides (1-93) [11,[32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59]], 29 flavanones and their glycosides (94–118, 124–126) [11,33,36,44,46,50,51], [40,60,61], 5 flavonols (119–123) [11,38,46,50,59], and 2 chalcones (127, 128) [41,62] were isolated from SR (Fig. 3). Flavonoids are rich in pharmacological activities. Baicalin has wide clinical applications with multifarious pharmacological effects, such as antitumor, antimicrobial, antiviral, and antioxidant effects [69]. Baicalein is the aglycone of baicalin. It has promising antineoplastic activity and potent neuroprotective activity [70,71]. Wogonin had the anti-inflammation and anti-oxidation effects [72]. Scutellarein has been verified with anti-cancer properties [73]. Oroxylin A is regarded as a potential antitumor agent, which possesses a great potential in the treatment of multiple cancers such as brain, liver, lung, breast, cervical, gall bladder, and others [74].Fig. 3 The structures of flavonoids and their glycosides (1–128).

Fig. 3

6.2 Phenylpropanoids

Currently, the phenylpropanoids isolated from SR include four lignan glycosides, six lignans, and five simple phenylpropanoids [51,55,[63], [64], [65], [66]]. Among these, veraguensin (133), galgravin (134), denudanolide B (135), denudatin B (136), (2R,3R,3S)-5-allyl-2-(3,4-dimethoxy-phenyl)-3a-methoxy-3-methyl-3,3a-dihydrobenzofuran-6(2H)-one (137), and eupomatenoid-7 (138) were obtained by SR aqueous extracts. Notably, 4’-(β-D-glucopyranosyloxy)-3,3′,5,5′-tetramethoxy-9,9′-epoxylignane-4,7′-diol (129), 4’-(β-D-glucopyranosyloxy)-3,3′,5′-trimethoxy-9,9′-epoxylignane-4,7′-diol (130), and 4’-(β-D-glucopyranosyloxy)-3,3-dimethoxy-9,9′-epoxylignane-4,7′-diol (131), three lignan glycosides isolated from SR for the first time, were shown to have good anti-osteoporotic properties in an in vitro experiment [63]. The structures of phenylpropanoids are displayed in Fig. 4.Fig. 4 The structures of phenylpropanoids (129–143) and phenylethanoid glycosides (144–151).

Fig. 4

6.3 Phenylethanoid glycosides

Phenylethanoid glycosides possess multiple pharmacological effects such as anti-inflammatory, antioxidant, antibacterial, antitumor, and antiviral effects, as evidenced by both in vivo and in vitro studies [75]. In the literature reported, a total number of 8 phenylethanoid glycosides of SR are documented including salidroside (144), darendoside A (145) darendoside B (146), martynoside (147), acteoside (148), isomartynoside (149), leucosceptoside A (150), and cistanoside D (151) [46,58,64]. Their structures are shown in Fig. 4.

6.4 Phenolic acids

Phenolic acids are commonly found in fruits and vegetables, and are known for their biological activities such as antioxidant and antitumor [76,77]. A total of 6 common phenolic acids were isolated and identified from SR, such as benzoic acid (152) [33], phenylacetic acid (153) [65], syringaldehyde (154), vanillin (155) [66], p-hydroxybenzoic acid (156), and protocatechuic acid (157) [51]. The structures of phenolic acids are shown in Fig. 5.Fig. 5 The structures of phenolic acids (152–157) and others (158–171).

Fig. 5

6.5 Volatile components

Volatile oils in plants generally have an aromatic odor and are not miscible with water. Using GC-MS, various parts from SR plants were found to contain different kinds of volatile components with different contents. Specifically, 39 volatile components (172–210) were detected from the roots of SR [68].

6.6 Polysaccharides

Polysaccharides play an essential part in medicine because of their extremely rich pharmacological activities, such as antioxidant, antiviral, antitumor, and immunomodulation. They are also used in the development of functional food [78]. Presently, two pure polysaccharides, SP1-1 and SP2-1, were isolated from SR. These polysaccharides exhibited anti-inflammatory activity, reduced the levels of pro-inflammatory cytokines and enhanced the intestinal barrier, thereby improving the symptoms of colitis in mice [,[79], [80]].

6.7 Others components

Other components such as alkaloids, terpenoids, and sterols are also found in SR. Five alkaloids: pellitorine (159), (E)-4-[(2-methylpropyl)amino]-4-oxo-2-butenoicacid (160), 4,5-dihydropiperlonguminine (161), futoamide (162), and piperlonguminine (163), and an epoxycyclohexene (171) were isolated from SR [66]. Terpene components such as sinapoylhexoside (164), 7-O-acetylloganic acid (165), lutein (166), and β-carotene (167) were detected by HPLC and HPLC-MS [44,67]. Detailed structures of these compounds are displayed in Fig. 5.

7 Pharmacological effects

Numerous studies showed that SR possesses lots of pharmacological activities such as antioxidant, anti-inflammatory, antitumor, antiviral, hepatoprotective, and neuroprotective effects. Some of the pharmacological activities of SR and its representative components are found in Table 6. The related action mechanisms are shown in Fig. 6.Table 6 Pharmacological exprimental studies of Scutellariae radix.

Table 6Extract/Compound	In vivo/in vitro expriment	Dosage	Administration approach	Result	Mechanism	Reference	
Antioxidant effects	
ethanol extract of SR (60 %)	In vivo, TNBS-induced UC murine model	100 mg/kg and 200 mg/kg	Oral administration	Increasing the activity of GSH-PX, CAT, and SOD	Upregulation of TGF-β expression	[81]	
baicalin	In vitro, LPS-induced bEnd.3 cells model	8 μg/mL	–	Scavenging ROS and MDA, increasing SOD	Activating of the Nrf-2 signaling pathway	[82]	
wogonin	In vivo, TAC- induced cardiac hypertrophy murine model; In vitro, angiotensin II-induced H9C2 cells and neonatal rat cardiomyocytes model	10 mg/kg	Intragastric administration	Improving cardiac hypertrophy and inhibiting oxidative stress	Regulating of Nrf-2 signaling pathway	[83]	
wogonin	In vivo, murine testicular dysfunction caused by cadmium model	10 mg/kg	Oral administration	Inhibiting the production of MDA and elevating the levels of SOD, CAT and GPx	Upregulating mRNA levels of Nrf-2	[84]	
norwogonin	In vitro, hypoxia-induced PC12 cells model	100 μmol/L	–	Enhancing the activity of SOD, CAT, and GSH-Px and inhibiting the production of intracellular ROS and MDA and the expression of HIF-1α and VEGF proteins	Regulating of mitochondrial-dependent apoptosis pathway	[85]	
Anti-inflammatory	
water extract of SR	In vitro, LPS-induced macrophages model	0.1 μg/mL, 1 μg/mL and 10 μg/mL	–	Inhibiting the pro-inflammatory cytokines	Downregulating of the NF-κB signaling pathway	[86]	
baicalin	In vitro, Mϕs and DCs cell inflammation model caused by Pam3CSK4 and PGN and the Mϕs cell inflammation model caused by HK-MSRA	50–200 μM	–	Dose-dependently inhibited the inflammatory reactions and the production of IL-6, TNF-α, and IL-1β	Inhibiting the activation of ERK, JNK MAPK, and NF-κB pathways	[87]	
baicalein	In vitro, poly I:C-induced RAW 264.7 cells	100 μM	–	Inhibiting calcium release, excessive production of NO, and inflammatory factors	Inhibiting the endoplasmic reticulum stress-CHOP/STAT pathways	[88]	
skullcapflavone II	In vitro, TNF-α/IFN-γ-induced atopic dermatitis cells model	25 μg/mL	–	Down-regulate the expression levels of TARC, CTSS, and MDC	Restraining the NF-κB, STAT1, and p38 MAPK signaling pathways	[89]	
scutellarin	In vitro, IL-1β induced ATDC5 cells model	50 μM	–	Down-regulating the expression levels of MMPs family	Blocking the activiation of NF-κB/MAPK signalings induced by IL-1β	[90]	
Antitumor	
80 % ethanolic extract of SR	In vitro, EGFR TKI-Resistant PC9 Cell Lines	25 μg/mL, 50 μg/mL, 100 μg/mL	–	Inhibiting cell viability and colony formation in the four cell lines	Inhibiting STAT3 activity triggering apoptosis	[91]	
The extract of SR	In vitro, Ovarian cancer cell lines	100 mg/mL	–	Down-regulating HIF-1α expression	Inhibiting MAPK/ERK and PI3K/AKT signaling pathways	[92]	
baicalin	In vitro, colon cancer cells	IC50 = 165.5 μM	–	Inhibiting the growth of HT-29 colon cancer cells and preventing its apoptosis in a dose-dependent manner	Down-regulating the expression of oncomiSR	[93]	
wogonoside	In vitro, PANC-1 andSW1990 cells; In vivo, inoculated PANC-1 cells murine model	100 μM; 80 mg/kg	Gastric lavage	Inhibiting the stem cell-like transition and mesenchymal transition and suppressing tumour enlargement	Inhibiting the activation of the TRAF6/NF-κB/p65 signal pathways	[94]	
wogonin	In vitro, DU145 and 22Rv1 prostate cancer cell lines; In vivo, subcutaneous DU145 and 22Rv1 xenograft murine model	100 μM;100 mg/kg	Intravenous injection	Inhibiting the tumor growth, modulating the metabolism of fatty acid, and inducing apoptosis in human prostate cancer cells.	Activating the AKT-SREBP1-FASN signaling network	[95]	
Antiviral	
SR extract	In vivo, CVB3-induced myocarditis murine model; In vitro, CVB3-infected Hela cells and primary myocardial cells	400 mg/kg; 400 μg/mL	Intra-gastric administration	Reducing the high mortality rate caused by CVB3 and preventing the replication of CVB3	Inhibiting the expression of p38 and AKT	[96]	
baicalin	In vitro, Marek's disease virus-infected chicken embryonic fibroblasts	20 μg/mL	–	Reducing viral infectivity, inhibiting the viral expression, and down-regulating IRF7 expression	–	[97]	
baicalin	In vivo, RSV-infected murine model; In vitro, RSV-infected lung adenocarcinoma HEp-2 cell line	200 mg/kg; IC50 = 0.0894 mg/mL	Oral administration	Respiratory syncytial virus were inhibited	Activating IFN, inhibiting the transcription of NS1 and NS2 mRNAs, down-regulating the expression of viral protein M, and promoting the release of ribosomal protein L13a	[98]	
baicalein	In vitro, DENV-2-infected VERO cells	IC50 = 5.39 μg/mL	–	Dengue virus type 2 were supressed	Presenting a good virucidal activity, inhibiingt virus replication, and resisting virus adsorption	[99]	
wogonin	In vitro, human lung epithelial cells (A549) and MadinDarby canine kidney cells	10 μg/mL	–	Preventing the replication of the influenza A virus and the formation of influenza B virus plaques	Inhibiting the AMPK signaling pathway	[100]	
Hepatoprotective Effects	
methanolic extract of SR	In vivo, acute alcohol-induced liver injury murine model and TM-induced liver injury murine model	160 mg/kg	Intragastric administration	Increasing concentration of GSH and decreasing the concentration of MDA and hepatocyte injury markers (ALT, AST, and TG) in a dose-dependent manner	Inhibiting ERS and down-regulating GRP78 protein expression	[101]	
baicalin	In vivo, ethanolic -induced liver injury murine model	50 mg/kg	Intragastric administration	Up-regulating microRNA-205 expression and promoting its binding to importinα5	Suppress NF-κB signaling transduction	[102]	
baicalein	In vivo, CCL4-induced liver injury murine model	33 mg/mL	Intragastric administration	Ameliorating liver injury induced by CCl4 in rats	Activating cellular autophagy and inhibiting endoplasmic ERS	[103]	
baicalin	In vivo, 17α-ethinylestradiol-induced cholestatic liver injury murine model	200 mg/kg	Oral administration	Decreasing the expression levels of inflammatory factors and hepatic uptake transporters, but increasing the hepatic efflux transporters	Activating the Sirt1/HNF-1a/FXR signal pathway	[104]	
scutellarin	In vivo, CCL4-induced liver injury murine model	0.12 mmol/kg	Oral administration	Reducing biochemical markers of liver injury and inflammatory factors, improving centrilobular necrosis and hepatocyte apoptosis in liver tissue	Inhibiting CYP2E1 and IκBα/NF-κB signaling pathways, and modulating the endogenous metabolites involved in lipid metabolism and bile acid homeostasis	[105]	
Neuroprotective effects	
baicalin	In vivo, APP/PS1 mice	103 mg/kg	Intragastric administration	Improving the dyskinesia, promoting the inactivation of microglia, reducing the number of pro-inflammatory cytokines, and inhibiting neuronal apoptosis induced by neuroinflammation	Inactivating the NLRP3 inflammasome and blocking the TLR4/NF-κB signal pathway	[106]	
baicalin	In vivo, chronic unpredictable mild stress-induced depression murine model	50 mg/kg	Intragastric administration	Improve cognitive dysfunction, elevating the protein ratios of p-ERK/ERK and p-CREB/CREB and up-regulating the expression levels of ERK mRNA and CREB mRNA	Modulating the BDNF/ERK/CREB signalling pathway	[107]	
baicalein	In vivo, MPTP-induced PD-like murine model	560 mg/kg	Intragastric administration	Reducing the loss of dopamine neurons and inhibitting glial cell activation and proliferation	Preventing NLRP3/caspase-1/GSDMD signal pathway	[108]	
baicalein	In vivo, rotenone-induced depression-like murine model	300 mg/kg	Oral administration	Improving depression-like behaviour, reducing levels of pro-inflammatory cytokines, decreasing α-synuclein accumulation, and maintaining neurotransmitter homeostasis	Activating BDNF/TrkB/CREB signaling pathways	[109]	
wogonin	In vivo, the middle cerebral artery occlusion murine model	10 μmol/L	Oral administration	Reducing nerve injury and improving nerve function	Regulating TGF-β1 signal pathway	[110]	

Fig. 6 Changes in biomarkers and signaling pathways of Scutellariae radix on pharmacological effects.

Fig. 6

7.1 Antioxidant effects

When excessive free radicals accumulate in the body, oxidative stress may lead to many serious diseases [111]. It was reported that SR had prominent antioxidant activity and its flavonoids were also recognized as natural antioxidants. These components inhibit the overproduction of free radicals, reduce the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), thereby alleviating oxidative stress and increase the activity of antioxidant markers in vivo. The activation of the Nrf2 signaling pathway is the key mechanism by which they exert an antioxidant effect.

The ethanolic extract of SR (60 %) effectively inhibited the excessive production of ROS and enhanced the activities of glutathione peroxidase (GSH-PX), catalase (CAT), and superoxide dismutase (SOD) in LPS-induced RAW264.7 cells and 2,4,6-trinitro-benzene sulfonic acid-induced murine model of ulcerative colitis (UC). Moreover, the 60 % ethanolic extract of SR at a concentration of 200 mg/kg significantly suppressed myeloperoxidase (MPO) activity and transforming growth factor β1 protein expression compared with mesalazine (active control, 100 mg/kg) [81].

Baicalin, wogonin, norwogonin, and scutellarin, compounds extracted from SR, also had antioxidant activities. In a methotrexate-induced mitochondrial damage model, the activities of antioxidant enzymes (CAT, SOD, and GSH-PX) were restored by baicalin [112]. In addition, baicalin (8 μg/mL) could decrease ROS and MDA and augment the activity level of SOD in bEnd.3 cells, through the activation of the Nrf-2 signaling pathway [82]. Wogonin (10 mg/kg) similarly reduced the production of ROS and MDA and activated SOD, CAT, and GSH-PX, which were achieved by the same pathway [83,84]. Norwogonin (100 μmol/L) inhibited the release of lactate dehydrogenase, improved cell morphology, and alleviated hypoxia-induced cell damage. It was good at enhancing the activity of SOD, CAT, and GSH-PX, inhibiting the production of intracellular ROS and MDA, and repressing the expression of HIF-1α and VEGF proteins in hypoxia-induced PC12 cells [85]. Scutellarin (100 mg/kg), in the rats of transient middle cerebral artery occlusion injury, decreased the oxidative-related damage factors, including 3-nitrotyrosine, 4-hydroxynonenal, 8-hydroxydeoxy-guanosine, neurotrophin-3, PARP1 and ROS [113]. In addition, a method of HPLC-PDA-ESI-MS combined with free radical reaction was developed to detect the antioxidant activities of baicalin, baicalein, scutellarin, scutellarein, wogonoside, and chrysin-7-glucuronide. Among these, baicalein showed the highest scavenging capacity against superoxide radicals and lipid radicals; wogonoside showed the highest scavenging ability against hydroxyl radicals; scutellarein displayed the highest reactivity during lipid peroxidation [114].

Antioxidants play an important role in human health. There is no doubt that the excellent antioxidant properties of SR can reduce the effects of ROS on cellular functions, heralding its potential for the treatment of cardiovascular diseases, Alzheimer's disease, cancer, and other disorders related to oxidative stress. Consequently, researchers should focus on this phenomenon and conduct appropriate clinical studies to explore its therapeutic applications in the future.

7.2 Anti-inflammatory effects

The aerial parts extract and water extract of SR have been shown to inhibit the expression of VEGFR1, TNF-α, IL-1β, and IL-6, and block the NF-κB signaling transduction in LPS-induced cell inflammatory models [115,86]. In the Mϕs and DCs cell inflammation models induced by Pam3CSK4, PGN, and HK-MSRA, the administration of varying concentrations of baicalin (50–200 μM) dose-dependently inhibited the inflammatory reactions and the production of IL-6, TNF-α, and IL-1β. Further study suggested that it was related to the inactivation of ERK, JNK, MAPK, and NF-κB signaling pathways [87]. In complete Freund's adjuvant-induced inflammatory pain rats, 60 % ethanolic extract of SR (3–6 g/kg) relieved inflammatory pain, suppressed the expression of NF-κB, COX-2 and P2X3, and inhibited the release of inflammatory factors [116].

Other studies also showed that baicalin inhibited the production of inflammatory factors by negatively modulating the RhoA/ROCK signaling pathways [[117], [118], [119]]. At a concentration of 100 μM, baicalein inhibited calcium release, excessive production of NO, and inflammatory factors, including IL-1α, IL-6, MCP-1, IP-10, LIX, VEGF, G-CSF, GM-CSF, in cells induced by polyinosinic-polycytidylic acid. It also suppressed the mRNA expression of STAT1, STAT3, and Fas, which were mediated through the ERS-CHOP/STAT pathway [88]. Wogonin was able to suppress the production of proinflammatory cytokines, reduce the phosphorylation of p65, and increase the expression of Iκ-Bα protein in inflammatory tissues. It was concerned with the inhibition of NF-κB-P65 signaling pathway [120,121]. Skullcapflavone II (25 μg/mL) was found to downregulate the expression levels of atopic dermatitis-associated cytokines, including thymus- and activation-regulated chemokine, cathepsin S, and macrophage-derived chemokine, by restraining the NF–κB, STAT1, and p38 MAPK signaling pathways [89]. At a concentration of 50 μM, scutellarin downregulated the expression levels of MMPs family and blocked the activation of NF-κB/MAPK signaling induced by IL-1β in an osteoarthritis model [90]. Besides, the dextran sulfate sodium salt-induced mice were administered 200 mg/kg SP1-1 by gavage for 10 days, a polysaccharide isolated from SR, which markedly inhibited the production of IL-1β, IL-18, and TNF-α. The reduction of infiltration in colon macrophages and the inactivation of caspase-1 in peritoneal macrophages could be detected in mice treated with SP1-1. The anti-inflammatory effects of SP1-1 were attributed to the activation of the NF-κB signal pathway and the inhibition of NLRP3 inflammasome [79].

The levels of several proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-18, MCP-1, and IP-10, were inhibited by the extract of SR, baicalin, baicalein, wogonin, skullcapflavone II, and the polysaccharide of SR. Furthermore, the NF-κB signaling pathway is critical for them in down-regulating the expression of inflammatory factors, up-regulating the expression of anti-inflammatory cytokines, and improving the inflammatory response. These provide strong evidence that SR treats inflammatory diseases.

7.3 Antitumor effects

The ethanolic extract of SR (80 %), at the concentration of 25–100 μg/mL, had excellent antitumor activity against the EGFR TKI-resistant human lung cancer cells: H1299, H1975, PC9/ER, and PC9/GR, by inhibiting STAT3 activity triggering apoptosis [91]. Hypoxia inducible factor-1α (HIF-1α) was often considered to be one of the key factors in controlling tumor growth and metastasis [122]. The extract of SR (100 mg/mL) was able to down-regulate HIF-1α expression, block the synthesis of HIF-1α, and accelerate the catabolism in ovarian cancer cell lines after three days of treatment. Its action mechanism was attributed to inhibiting MAPK/ERK and PI3K/AKT signaling pathways [92]. The extract of SR (250 μg/mL) could target and inhibit the viability of human hepatocellular carcinoma cells SK-Hep-1, promote its apoptosis, and prevent its migration, thus preventing the development of hepatocellular carcinoma [123]. The total flavonoid aglycones extract of SR showed eminent inhibitory effects on pancreatic cancer cell lines, especially BxPC3 tumor (IC50 = 6.5 μg/mL). It could regulate apoptosis and autophagy to prevent tumor cell survival by activating the caspase signaling pathway and inhibiting the PI3K/Akt/mTOR signaling pathway respectively [124].

Growing studies indicated that compounds from SR exhibited inhibitory activities against the development of a variety of cancer cells, including colon, pancreatic, bladder, gastric, and prostate cancer. Baicalin was found to inhibit the growth of HT-29 colon cancer cells (IC50 = 165.5 μM), prevent dose-dependently its apoptosis, and suppress the expression of oncogenic transcription factor c-Myc. It down-regulated the expression of oncogenic miRNAs [93]. In addition, baicalin induced ferroptotic cell death and showed inhibitory activities against 5637 (at the concentration of 20 μg/ml) and KU-19-19 (at the concentration of 40 μg/ml), two types of bladder cancer tumor cells [125]. Wogonoside (100 μM) inhibited the stem cell-like transition and mesenchymal transition in PANC-1 and SW1990 cells. Moreover, tumor mass enlargement was suppressed by wogonoside (80 mg/kg) in the inoculated PANC-1 cells murine model. Inactivation of the TRAF6/NF-κB/p65 signaling pathways was the main action mechanism [94]. Wogonin equally inhibited tumor growth, which modulated the metabolism of fatty acid, and induced apoptosis in human prostate cancer cells. It was achieved by activating the AKT-SREBP1-FASN signaling network [95]. 7-O-methylwogonin (IC50 = 30 μM) selectively inhibited Polo-like kinase 1 (Plk1) activity, induced mitotic delay, and increased mitotic aggregation in Hep3B cells, similar to the mechanism of BI 2536, a specific Plk1 inhibitor [126]. Oroxylin A modulated the polarization of M1-like macrophages, reduced the number of M2-like macrophages, and promoted the infiltration of T cells, thereby inhibiting the development of hepatocellular carcinoma [127]. A recent study showed that oroxylin A, as a natural inhibitor of Recepteur d'origine Nantais, inhibited osteoclasts and reduced the number of osteoclasts induced by breast cancer [128].

SR and its isolated compounds had broad-spectrum antitumor activity. They do well in inhibiting cell proliferation, promoting apoptosis, and inducing cellular autophagy, thus inhibiting the further development of tumors. However, most of the studies on the antitumor activities related to SR were carried out in vitro intracellularly and lacked corresponding in vivo experimental validation. Various animal cancer models should be utilized to advance in vivo studies of the effects of these compounds, and subsequent clinical validation is necessary. This will greatly facilitate the development of lead compounds for antitumor drugs and the screening of potential antitumor drugs.

7.4 Antiviral effects

SR, along with its compounds baicalin, baicalein, and wogonin, have outstanding preventive and curative effects on a variety of viruses. In a vitro experiment, 400 μg/mL SR extract prevented the replication of Coxsackievirus B3 (CVB3) in primary cardiomyocytes and attenuated the toxicity of CVB3 in HeLa cells. In a vivo experiment, SR extract (400 mg/kg) reduced the high mortality rate caused by CVB3, and inhibited the expression of p38 and protein kinase B to inhibit the replication of CVB3 [96]. The flavonoid extract of SR effectively hindered the process of adsorption and replication of the tick-borne encephalitis virus at a concentration of 9 μg/mL. The virus was directly inactivating at concentrations of the extract greater than or equal to 5 μg/mL [129]. Additionally, the flavonoid extract of SR showed potential against the influenza A virus [130].

Baicalin (20 μg/mL) significantly reduced viral infectivity, inhibited the viral expression, and down-regulated IRF7 expression in chicken embryonic fibroblasts infected with Marek's disease virus [97]. When respiratory syncytial virus (RSV)-infected rats were orally administered 200 mg/kg baicalin for five days, type I interferon was activated, the expression of viral protein M was suppressed, and the release of ribosomal protein L13a was increased. These mechanisms determined the superior inhibitory effect of baicalin against RSV [98]. Notably, the combination of baicalin and resveratrol could enhance its anti-RSV effect [131]. Before and after dengue virus type 2 (DENV-2) infection, VERO cells were treated with baicalein. The results showed that baicalein had a good activity of anti-DENV-2 (IC50 = 1.55 μg/mL) and inhibited virus replication (IC50 = 6.46 μg/mL). Added to that, pretreatment of cells with baicalein prevented virus adsorption (IC50 = 7.14 μg/mL) [99]. In human lung epithelial cells and Madin-Darby canine kidney cells infected by influenza virus, wogonin prevented the replication of the influenza A virus and the formation of influenza B virus plaques, by inhibiting the AMPK signaling pathway [100].

7.5 Hepatoprotective effects

SR and its root-specific flavonoids had multiple protective effects against alcoholic liver diseases and liver injury. These hepatoprotective effects involve the inhibition of oxidative markers and inflammatory factors, which are closely related to the antioxidant and anti-inflammatory properties.

After treatment with the methanolic extract of SR (160 mg/kg), the concentration of GSH in mice with alcoholic liver injury increased while the concentration of MDA and hepatocyte injury markers (alanine transaminase, aspartate transaminase, and triglyceride) decreased in a dose-dependent manner. Immunohistochemical examination and ELISA assay showed the expression level of the glucose regulated protein 78 kDa (a typical marker of ERS) decreased [101]. Additionally, the aqueous extract of SR (100 mg/mL) showed hepatoprotective effect in mice with a high-fat diet and long-term alcohol consumption. It was able to reduce the activities of liver enzymes such as alanine transaminase, aspartate transaminase and lactate dehydrogenase, inhibit endogenous cholesterol synthesis and act as a 3-hydroxy-3-methylglutaryl-coenzymeA reductase inhibitor in mice [132].

Baicalin (50 mg/kg) was also effective in the treatment of alcoholic liver disease. However, its mechanisms were up-regulating microRNA-205 expression and promoting its binding to importinα5 to suppress NF-κB signaling transduction [102]. Baicalein, at a concentration of 33 mg/mL, ameliorated liver injury induced by CCl4 in rats, through activating cellular autophagy and inhibiting endoplasmic ERS [103]. Interestingly, baicalein and baicalin inhibited elevated IL-6, TNF-α, and IL-1β, reduced serum alanine transferase levels, and suppressed hepatic myeloperoxidase activity in the acetaminophen-induced liver injury. Therefore, these compounds could ameliorate autophagy, which involved JAK2/STAT3, MAPK, and ERK signaling pathways respectively [133,134]. In 17α-ethinylestradiol-induced liver injury of rats, baicalin (200 mg/kg) decreased the expression levels of inflammatory factors and hepatic uptake transporters but increased the hepatic efflux transporters. Its potential mechanism was associated with modulating the sirtuin 1/hepatic nuclear receptor-1a/farnesoid X receptor signal pathway [104]. Besides, baicalin attenuated cirrhosis induced by TAA via NOX4/NF-κB/NLRP3 inflammatory vesicles [135]. Scutellarin also had a hepatoprotective effect, which reduced biochemical markers of liver injury and inflammatory factors, and improved centrilobular necrosis and hepatocyte apoptosis in liver tissue [105].

7.6 Neuroprotective effects

An ethanolic extract of SR was administered orally to rats with spinal cord injury at a dose of 100 mg/kg. It inhibited the expression of pro-inflammatory factors as well as the carbonylation and nitration of proteins, significantly restrained the apoptosis of neurons and oligodendrocytes, and improved the functional recovery after spinal cord injury [136]. The ethanolic extract of SR (50–100 μg/mL) was able to exhibit neuroprotective effects against excitotoxic neuronal cell death by blocking N-methyl-D-aspartate receptors [137]. The water extract of SR had potential antidepressant effects, and it improved depressive-like behavior in chronic unpredictable mild stress mice. Daily administration of 0.75 g/kg or 1.5 g/kg of SR water extract up-regulated the levels of transforming growth factor-β3, p-SMAD2/3, and NEDD9 proteins and increased the number of doublecortin-, microtubule-associated protein 2-, and neuronal nucleus-positive cells in the hippocampus of the model mice [138].

Baicalin, baicalein, and scutellarin can alleviate neuroinflammation as well as inhibit neuroapoptosis and glial cell activation, thus exerting neuroprotective effects. It implies their potential to treat neurological diseases, such as Alzheimer's disease, Parkinson's disease, and depression. Baicalin has shown promise in improving symptoms in mouse models of Alzheimer's disease and depression. In the development of Alzheimer's disease, neuroinflammation is closely related to neuronal apoptosis [139]. In APP/PS1 mice, baicalin (103 mg/kg) effectively improved dyskinesia, promoted the inactivation of microglia, reduced the number of proinflammatory cytokines, and inhibited neuronal apoptosis induced by neuroinflammation. It acted as a neuroprotective agent by inactivating the NLRP3 inflammasome and blocking the TLR4/NF-κB signaling pathway [106]. Besides, compared with the positive drug fluoxetine treatment, baicalin (50 mg/kg) also improved cognitive dysfunction in CUMS-induced depression mice. Moreover, baicalin elevated the protein ratios of p-ERK/ERK and p-CREB/CREB and up-regulated the expression levels of ERK mRNA and CREB mRNA, by modulating the BDNF/ERK/CREB signaling pathways [107].

Baicalein was able to improve MPTP-induced motor dysfunction and depression caused by Parkinson's. Intragastric administration of 560 mg/kg baicalein for 9 days reduced the loss of dopamine neurons and inhibited glial cell activation and proliferation in MPTP-induced mice. Baicalein developed a neuroprotective effect by preventing the NLRP3/caspase-1/Gasdermin D signal pathway [108]. Correspondingly, it had been demonstrated that treatment of SH-SY5Y cells with 50 μM baicalin could alleviate the neurotoxicity caused by the neurotoxic agent MPP+ (the active metabolite of MPTP) [140]. In a rotenone-induced depression murine model, the treatment of 300 mg/kg baicalin improved depression-like behavior, reduced the levels of proinflammatory cytokines, decreased the accumulation of α-synuclein, maintained neurotransmitter homeostasis and activated BDNF/TrkB/CREB signaling pathways [109].

Scutellarin (100 mg/kg) promoted the conversion of microglia phenotype from M1 to M2, thereby exerting anti-inflammatory and neuroprotective effects to moderate neuroinflammation. It acted by blocking the p38 and JNK signaling pathways and activating the ERK1/2 signaling pathway [141]. Studies also manifested that wogonin attenuated cortical damage in γ irradiation-induced rats and neurological damage in cerebral ischemia rats to improve neurological function [110,142]. However, the precise mechanisms underlying these effects remain unclear and warrant further investigation.

It can be seen that the extract and active components of SR exhibit excellent neuroprotective effects. Moreover, it is necessary to use a variety of classical animal models of neurological diseases to comprehensively evaluate their mechanism of action, which can provide new insights for the development of drugs and clinical treatments for neurological disorders.

8 Quality control

Quality control is the key basis for guaranteeing the quality and clinical efficacy of traditional Chinese medicines (TCMs) [143]. It is of great significance to employ analytical techniques to optimize extraction methods, establish the fingerprints, determine content, characterize components, and screen the quality markers for the effectiveness and safety of SR.

8.1 Green extraction methods

At present, several green extraction technologies have been developed for SR, including ultrasound-assisted deep eutectic solvent extraction, deep eutectic solvent combined with ultrahigh pressure extraction, enzyme-assisted extraction, ultrasound-assisted enzyme extraction, microwave-assisted ionic liquid extraction, and ultrasound-assisted ionic liquid extraction. The optimal extraction conditions and extracted components are summarized in Table 7.Table 7 Green extraction methods of Scutellariae radix.

Table 7Methods	Optimal extraction conditions	Extracted components	Reference	
Ultrasound-assisted deep eutectic solvents	Betaine: acetic molar ratio 1:4, water content 40 %, extraction temperature 52 °C, extraction time 23 min, and liquid-solid ratio 1:100 g/mL	Total flavonoids from SR	[144]	
Microwave-assisted deep eutectic solvents	L-proline: urea molar ratio 2:1, water content 40 %, extraction temperature 110 °C, extraction time 20 min, and liquid-solid ratio 40 mL/g	Baicalin, baicalein and wogonin	[145]	
Deep eutectic solvent-based ultrahigh pressure extraction	Choline chloride: lactic acid molar ratio 1:1, water content 40 %, pressure 400 MPa, extraction time 4 min, and liquid-solid ratio 110 mL/g	Baicalin	[146]	
Ultrasound-assisted enzymatic extractin	Cellulase concentration 1.1 %, pH 5.5, extraction temperature 56.5 °C, extraction time 39.4 min, and ultrasonic power 200 W	Baicalein and wogonin	[147]	
Ultrasound-assisted enzymatic extraction	Cellulase concentration 165.6 U/mL, extraction temperature 57.3 °C, extraction time 50 min, ultrasonic power 225 W, and liquid-solid ratio 44.8 mL/g	The polysaccharides of SR	[148]	
Enzyme-assisted extraction	Cellulase concentration 20 U/mL, cellulase digestion time 24 h, pH 7.0, and extraction time 3 h	Baicalin	[149]	
Ionic liquid-based microwave-assisted extraction	[C8mim]Br concentration 1.0 M, irradiation time 90 s, irradiation power 400 W, and liquid-solid ratio 1:6 (g/mL)	Flavonoids	[150]	
Ultrasound-assisted ionic liquid-based liquid-liquid extraction	Volume ratio 3:3, extraction time 60 min, ultrasound-assisted extraction time 5 min, temperature 70 °C, and liquid-solid ratio 1:40	Baicalin and baicalein	[151]	

Deep eutectic solvents (DES) are widely used because of their low toxicity, chemical stability, and high biodegradability properties [144]. Using ultrasound-assisted extraction with betaine: acetic (molar ratio 1:4), under optimal extraction conditions, the extraction of total flavonoids of SR was achieved with high efficiency and the activity of the extract was not affected [145]. Similarly, efficient extraction of baicalin, baicalein and wogonin could be achieved using a natural DES (L-proline and urea, molar ratio 2:1) combined with microwave-assisted extraction. The results of in vitro bioactivity assay showed that the extracts possessed desirable antioxidant activity [146]. The use of choline chloride: lactic acid (molar ratio 1:1) assisted by ultrahigh pressure extraction could exceptionally disrupt the root tissue, facilitating the efficient extraction of baicalin [152]. It was remarkable that a green and cyclically switchable supramolecular DES was developed and prepared for the extraction of flavonoids from SR. It combined excellent extraction efficiency with reduced processing time and could be recycled up to 5 times while maintaining an extraction efficiency of more than 90 % [153].

An ultrasound-assisted enzyme pretreatment extraction method was developed. It could effectively break the glycosidic bonds of baicalin and wogonoside in SR, thus enhancing their extractive rate [147]. In addition, the extraction of polysaccharides in SR could also be achieved by using ultrasound-assisted cellulase extraction [148]. It was worth noting that the cellulase from the endophytic bacteria of SR roots could be enriched by the enzymatic production process, and was subsequently used to assist in the extraction of baicalin, which created a new reference pathway for the extraction of active components in Chinese medicine [149].

The use of ionic liquids is an excellent method for extracting the active components of SR, with the advantages of low volatility, easy miscibility with water, and easy recycling [154]. An ionic liquid microwave-assisted extraction method was employed to disrupt the internal structure of SR, which achieved a high yield of total flavonoid extracts within 90s [150]. The extraction and separation of baicalin and baicalein could be achieved by an ionic liquid ultrasound-assisted extraction method based on a liquid-liquid dispersion system. In this system, the strongly polar baicalin was dispersed in the aqueous phase, while the weakly polar baicalein was dispersed in the ionic liquid phase [151].

The continuous development and innovation of extraction methods can help us to extract more components of SR faster, and even achieve a rapid targeted extraction of active components only by optimizing the extraction conditions. It also provides a powerful reference for research on extracting components from natural products containing flavonoids.

8.2 Fingerprints

Chinese herb fingerprint technology is a comprehensive and quantifiable quality control tool for herbs, characterized by wholeness, ambiguity, and specificity [155,156]. Fingerprints established by capillary electrophoresis, high performance liquid chromatography (HPLC), ultra-fast liquid chromatography with a diode array detector (UFLC-DAD), and ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) are used to rapidly evaluate the quality of SR from different batches, regions, and growth patterns. Moreover, the integration of fingerprints with chemometrics as well as activity-integrated fingerprints can elucidate the relationship between the components and their efficacy, aiding in the screening of effective substances.

Capillary electrophoresis was used to establish fingerprints of SR to distinguished samples from different origins by combining quantitative analysis of identified components such as baicalin, baicalein, and wogonin [157]. HPLC-guided fingerprints of 58 batches of wild and cultivated SR were established, and the quantification of baicalin, baicalein, and wogonin were completed, revealing that the flavonoid glycoside content of cultivated SR was higher than that of wild SR [158]. A UFLC-DAD method was developed to establish fingerprints of SR from different regions to achieve a rapid quality evaluation. Compared with the conventional HPLC method, it had a shorter run time, better compound separation, and a higher resolution [159]. Additionally, UHPLC-MS was developed to establish SR fingerprints. 23 compounds were identified which enhanced the characterization of common peaks in the fingerprints and improved the analytical efficiency [160]. The correlation analysis between HPLC fingerprints and the results of screening antibacterial components of SR were performed by multivariate statistical analysis in chemometrics. Baicalin, baicalein, wogonin, wogonoside, and oroxylin A-7-O-β-D-glucuronide were screened as key antibacterial components [161]. A multi-dimensional-multi-information integrated Xanthine oxidase and superoxide anion fingerprint has been established. It offered an activity-integrated fingerprint that evaluated the quality of SR from different batches and origins in terms of both chemical components and efficacy [162].

8.3 Analytical methods

Content determination and characterization of the components are also part of quality evaluation of SR. Several methods are employed to analyze the chemical components of SR, such as isocratic high performance liquid chromatography with diode array detection (isocratic HPLC-DAD), ultra-high performance liquid chromatography with photo diode array (UHPLC-PDA), ultra high performance liquid chromatography coupled with a Q-Exactive hybrid quadrupole-orbitrap mass spectrometry, ultra- high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), and high performance liquid chromatography-diode array detection coupled with quadrupole time-of-flight mass spectrometry (HPLC-DAD-Q-TOF-MS).

For the quantification of the main chemical components of SR, an isocratic HPLC-DAD method was developed to determine the content of baicalin, baicalein, wogonoside, and wogonin in 70 % ethanolic extracts of SR [163]. Subsequently, using a UHPLC-PDA method, the quantification of ten flavonoids of SR, including baicalin, baicalein, wogonoside, wogonin, chrysin, apigenin, and others, were accurately and rapidly completed [164].

In the qualitative analysis of SR, the method of UHPLC coupled with a Q-Exactive hybrid quadrupole-orbitrap mass spectrometry with a combination of a four-step analytical strategy successfully identified 132 chemical components [165]. Similarly, five major groups of 118 chemical components in SR were identified by UHPLC-Q-TOF-MS with a combination of diagnostic ions and neutral loss [166]. These methods facilitate the rapid identification of chemical components by avoiding the analysis of extensive non-targeted mass spectrometry data. In addition, the HPLC-DAD-Q-TOF-MS method allowed qualitative and quantitative determination of active components in SR roots and leaves after ultraviolet-B radiation [167].

8.4 Quality markers

Quality markers are chemical substances that reflect the intrinsic quality of TCMs and are closely related to their functional properties [168]. The key to the quality control of TCMs is their material basis [169]. Therefore, screening of quality markers is an important element to improve quality of SR.

An epidermal growth factor receptor (EGFR)/carboxymethylcellulose (CMC) column-online-HPLC-MS method was successfully established to achieve the screening of the tumor-targeting active components in SR. The results showed that baicalein was the potential quality marker acting on the epidermal growth factor [170]. An ultrafiltration HPLC-MS method was developed to screen of α-glucosidase, lipoxidase, and superoxide dismutase inhibitors of SR [171,172]. Based on the technical approach, 13 potential markers inhibiting α-glucosidase such as wogonin, chrysin, oroxylin A, skullcapflavone II, viscidulin III, tenaxin I and others, as well as 5 potential markers inhibiting lipoxidase and superoxide dismutase such as baicalin, wogonoside, chrysin-6-C-arabinosyl-8-C-glucoside, and oroxylin A-7-O-glucuronide, were screened. HPLC-PAD-QTOF-MS combined with a multivariate statistical strategy achieved the characterization of raw and processing SR and screening for chemical markers. The quantification of the selected markers, mainly including baicalin, baicalein, wogonin, wogonoside, and skullcapflavone II were also accomplished. It could be used for the quality evaluation of SR and its processing products [29,173]. Additionally, the establishment of LC-MS integrated with a bioassay for cellular NO generation inhibitory activity and an assay for DPPH/ABTS free radical scavenging activity allowed the online screening of quality markers related to anti-inflammatory and antioxidant in SR [174].

It is clear that baicalin, baicalein, wogonin, wogonoside, skullcapflavone II, oroxylin A, and chrysin are considered the potential quality markers of SR. However, there are many gaps in the study of the efficacy-related quality markers. Therefore, it is necessary to conduct biological-level validation to establish the evaluation methods that truly reflect the intrinsic quality of SR.

9 Influence factors of biosynthesis

Flavonoids, as the dominant secondary metabolites and medicinal active components in SR, have pharmacological effects such as anti-inflammatory [175], antioxidant [176], anti-cancer [177], antiviral, immunomodulation effects [178], and neuroprotective effects [179]. It manifests that they can serve as a source for the development of new drugs. However, these secondary metabolites are accumulated in specific parts of SR plants, and their total content is low, resulting in a few medicinal parts and a high cost of medicinal use. Notably, the application of synthetic biology and metabolic engineering based on biosynthesis can solve this problem [180]. Therefore, the analysis of the influence factors and regulatory mechanism of flavonoids biosynthesis in SR have attracted wide attention.

9.1 Biosynthetic pathway of flavonoids in SR

Biosynthesis is a chemical synthesis process that takes place in living organisms, which is controlled by enzymes to produce various secondary metabolites [181]. The biosynthetic pathway of SR flavonoids, mainly divided into above-ground and below-ground parts, has been well studied (Fig. 7). For the above-ground part of SR, naringenin, a product of phenylalanine via phenylpropanoid metabolism, is generally considered a precursor for the synthesis of scutellarein and scutellarin. Its biosynthetic pathway is as follows. Firstly, phenylalanine is catalyzed by phenylalanine ammonia-lyase (PAL) to form cinnamic acid, which is used as a substrate for cinnamoyl 4 hydroxylase (C4H) to produce 4-coumarate. Then, it sequentially undergoes 4 Coumarate:coenzyme A ligase (4CL) activation, chalcone synthase (CHS) catalyzed condensation, and chalcone isomerase (CHI) catalyzed isomerization to form naringenin. Next, the C-ring of naringenin is oxidized to produce apigenin under the action of flavonoid synthase II-1 (FNSII-1). Finally, apigenin undergoes cyclic hydroxylation under the modification of flavonoid 6-hydroxylase (F6H) to produce scutellarein, which is glycosylated to form scutellarin [182].Fig. 7 The biosynthetic pathway of flavonoids in Scutellariae radix and the influence of environmental factors and transcription factors on related enzymes. LR: light quality; MC: Moisture content; T: temperature.

Fig. 7

Nevertheless, biosynthesis of root-specific flavonoids in SR are more complex than the aerial parts. First of all, cinnamic acid is sequentially decorated by cinnamate-CoA ligase-like 7 (CCL-7), chalcone synthase (CHS), and chalcone isomerase (CHI) to produce pinocembrin [183]. Subsequently, under the conversion of flavonoid synthase II-2 (FNSII-2), pinocembrin is used as a substrate to generate chrysin. It is catalyzed by flavonoid 8-hydroxylase (F8H) to produce norwogonin or by flavonoid 6-hydroxylase (F6H) to produce baicalein [184]. In the end, norwogonin is converted to wogonin in the effect of phenylpropanoid and flavonoid O-methyltransferases (PFMOT). Baicalein is converted to baicalin with the participation of glucuronosyltransferases (sbUGATs) or oroxin A (baicalein-7-O-β-D-glucoside) with the participation of glucuronosyltransferases (sbUGTs) [[185], [186], [187]].

9.2 Influence of environmental factors on flavonoids biosynthesis

9.2.1 Light quality

Ultraviolet-A (UV-A) accounts for 98 % of UV radiation and affect the secondary metabolites of plants [188,189]. Biosynthesis in the both above-ground parts and roots of SR can be affected by UV-A. It increased the content of total flavonoids and signaling molecules (NO and H2O2) of SR and augmented the key enzymes activity (PAL, C4H, and 4CL) in the biosynthesis of aerial parts [190]. The content of baicalin, baicalein, wogonin, and wogonoside increased and new compounds (including pectolinarigenin, puerarin, isokaempferide, and jaceosidin) appeared in the roots of SR after 5 days of post-harvest UV-A irradiation [191].

Ultraviolet-B (UV–B) is one of the known abiotic stresses and is capable of causing the accumulation of secondary metabolites in plants [192,193]. UV-B effectively led to intracellular NO production, which was seen as a signaling molecule regulating the synthetic pathway of baicalin. Therefore, in SR cell cultures stimulated by UV-B, the content of baicalin was 3.1 times higher than that in unstimulated SR cell cultures [194]. UV-B also contributed to the increased content of glycoside ligands (baicalein, wogonin, and scutellarein), which led to the decrease in the content of glucuronides (baicalin and wogonoside) [195]. In addition, white light emitting diodes treatment for two weeks resulted in the accumulation of flavonoid secondary metabolites in the SR roots, mainly baicalin, baicalein, and wogonin [196].

The findings provide a reference for how to select appropriate light quality conditions to increase the content of active components during the SR cultivation process.

9.2.2 Moisture content

Water deficit is a stress factor for the product quality and affect the secondary metabolites of medicinal plants [197]. The total flavonoid content of 3-month-old SR increased markedly after 50 and 70 days of cultivation in 12 % soil water content. Further research found that the expression of PAL, CHS, and sbUGAT were elevated in the absence of water. Meanwhile, lack of water reduced the content of endogenous gibberellin protein but increased the content of indoleacetic acid-related protein in the roots and leaves of SR. The application of these inhibitors could return the flavonoid content to a normal level. Therefore, the lack of water affected flavonoid synthesis by modulating hormone metabolism in SR [198]. The effects of different degrees of drought on baicalin biosynthesis in SR had been studied. Under mild drought, PAL, 4CL, C4H, and CHS activities were elevated and their corresponding gene expression levels increased, promoting baicalin biosynthesis. However, in the case of severe drought, the opposite is true [199].

Collectively, harvesting under a prolonged water deficit should be avoided in the cultivation of SR. Appropriate reduction of water in the soil can increase the content of flavonoids in SR, especially baicalin.

9.2.3 Temperature

The low temperature (10 °C) led to the decrease in the content of baicalin and total flavonoids of SR, while the high temperature (40 °C) promoted the conversion of baicalein to baicalin. It was caused by the decrease of β-glucuronidase expression and the increase of sbUGAT expression at high temperatures [200]. At 25 °C, SR plants showed good growth of callus and increased content as well as accumulation of baicalin. The correlation analysis implied that baicalin content was positively associated with the expression of PAL, C4H, and CHS [201]. Interestingly, the content of baicalin, baicalein, and wogonin in SR seedlings, cultivated in a 4 °C growth chamber, was higher than those cultivated at room temperature. It indicated that appropriate lower temperature also promoted the accumulation of major flavonoids [202].

The regulation of secondary metabolite synthesis in SR is a balance in response to changes in abiotic stress factors. Environmental factors act on enzymes in the flavonoid biosynthetic pathway. Therefore, using the effects of environmental factors on the biosynthesis rationally, it is possible to cultivate high-quality SR. However, how to make a good balance between yield and the effects of abiotic stress factors needs to be further explored.

9.3 Influence of transcription factors on flavonoids biosynthesis

Transcription factors are important regulators at the level of gene transcription that activate or repress the expression of specific genes to affect biological processes including metabolism and biosynthesis [203].

SbMYB3, SbMYB12, SbMYB45, and SbMYB86.1 are key transcription factors in the biosynthesis of flavonoids in SR and are all R2R3-MYBs, which are considered to be the largest MYB subfamily in plants. Among them, SbMYB3 and SbMYB12 promoted the accumulation of root-specific flavonoids. SbMYB3 bound to SbFNSII-2 promoters and strengthened its transcription. Thus, the overexpression of SbMYB3 increased the content of baicalin, baicalein, wogonoside, and wogonin in the subsequent biosynthesis of hairy roots [204]. SbMYB12, a novel S20 R2R3-MYB transcription factor, was found to bind to SbCHI-2, SbCCL7-4, and SbF6H-1 promoters. It could promote the production of baicalin and wogonoside in the root of SR [205]. Nevertheless, SbMYB45 and SbMYB86.1 identified from SR played a key role in the flavonoid biosynthesis in SR leaves. The expression of SbCHI promoter was activated and the accumulation of flavonoids, especially baicalin, was augmented by them [206]. In addition, SbMYB18/32/46/60/70/74 genes were identified from the nucleus of SR. Among them, SbMYB18/32/60/70 had transcriptional activation properties, which might play a role in the regulatory mechanisms of biological processes [207]. Whether they affect the biosynthesis of flavonoids in SR and the related regulatory mechanisms deserves further study. Another study portrayed that the transcription factor Lc activated the expression of SbPAL1, SbC4H, Sb4CL and SbUGAT as well as the transcription factor PAP1 activated the expression of SbPAL1, SbPAL2, SbPAL3, SbC4H, Sb4CL, SbCHI, and SbUGAT to increase the content of flavonoids in the root of SR [208].

In summary, the relationship between transcription factors and genes involved in biosynthesis of SR was revealed (Fig. 7). The understanding of the mechanisms of formation and regulation of active components in SR was strengthened. Overexpression of transcription factors increases the flavonoid content and accumulation in aerial parts and root of SR, which sheds new light on the metabolic engineering.

10 Conclusion and future perspectives

SR is an intriguing traditional herbal medicine that has been widely valued since ancient times. This paper provided an updated review of its ethnobotanical uses, processing, phytochemistry, pharmacological effects, quality control, as well as regulatory factors of biosynthesis. In the field of traditional historical applications, different efficacies of SR had been developed, such as harmonizing the liver and spleen, clearing heat and removing toxicity, tonifying blood and calming the fetus, combining it with other traditional Chinese medicines to provide good therapeutic effects in different types of diseases. Phytochemical studies had demonstrated a total of 210 components were isolated and identified from SR, including flavonoids, phenylpropanoids, phenylethanoid glycosides, phenolic acids, volatile components, polysaccharides and others. On this basis, the pharmacological activities of SR extract and its bioactive components were further investigated. The results showed the extract of SR, baicalin, baicalein, wogonin, wogonoside, and scutellarin had abundant pharmacological effects. In addition, skullcapflavone II showed an anti-inflammatory effect, and total flavonoids extract of SR, 7-O-methylwogonin, and oroxylin A showed antitumor effects.

Nevertheless, while reviewing the detailed contents of SR, some key problems were exposed and deserved further exploration. Firstly, the processed SR are increasingly used in clinical practice, but its quality control indicators are not perfect. Processing plays an important role in altering the efficacy of SR, and further studies are needed to understand its influence mechanism. Secondly, numerous components have been isolated from SR and the proportion of flavonoids is the highest, so most of the studies on the pharmacological activity have been focused on these components, ignoring the biological activity of other components. Thirdly, SR had conspicuous medicinal value, but the in vivo mechanisms of action related to antitumor had not been fully elucidated and the relationship between hepatoprotective effects and anti-inflammatory effects is unclear. Fourthly, though “nature and flavor”, “channel tropism”, “ascending and descending, floating and sinking” and “traditional efficacy” of SR are clear, there are few modern pharmacological studies that are based on the traditional efficacy. Fifthly, in the quality control of SR, analytical methods and fingerprints had been widely studied. However, most of the results in quality markers stay at the level of chemical analysis and lack corresponding biological experiments. Sixthly, there is insufficient research that exists on the regulatory mechanisms of environmental factors, especially on the development of new transcription factors in flavonoid biosynthesis.

In response to the above problems, the following viewpoints are proposed: (1) Analytical tools such as near-infrared spectroscopy, liquid chromatography, mass spectrometry combined with auxiliary tools including chemometrics and electronic tongue technology can be used to establish quality control indicators for processed SR. In addition, experiments on differences in animal tissue distribution of the chemical components and comparative pharmacokinetic experiments should be applied to visualize the reasons why the processing alters the effects of SR. (2) In future pharmacological studies, advanced techniques and methods should be utilized to complement the pharmacological effects of other components in SR, so as to expand the therapeutic material basis more comprehensively. (3) With the aid of network pharmacology, in vivo pharmacological experiments, metabolomics, proteomics, and transcriptomics, the action mechanisms of SR in terms of antitumor and hepatoprotective effects can be unraveled to support its clinical applications. (4) Under the guidance of the TCM theory of treatment based on syndrome differentiation, animal models of TCM syndrome related to the efficacy of SR are supposed to establish. Combined with modern pharmacological methods to clarify the action mechanisms and targets of SR's efficacy. It is of great significance for the clinical use and secondary development of SR. (5) To obtain more bioactive markers related to the efficacy, corresponding activity screening, pharmacokinetic and pharmacological assays of potential quality markers should be conducted. It is helpful to exhaustively elucidate the pharmacodynamic material basis of SR. (6) Studies oriented towards action mechanisms of regulatory factors linked to flavonoid biosynthesis should be carried out. It would provide theoretical references for the cultivation of SR with excellent quality and large-scale production of root-specific flavonoids.

Conclusively, SR has numerous bioactive components and is rich in the pharmacological effects, which has outstanding medicinal values. It is reviewed in terms of the ethnobotanical uses, processing, phytochemistry, pharmacological effects, quality control and influence factors of biosynthesis. The purpose is to provide a foundation for secondary exploitation and subsequent studies on clinical applications of SR.

Data availability

Data will be made available on request.

CRediT authorship contribution statement

Wentao Ma: Writing – original draft, Methodology, Data curation. Tianyu Liu: Writing – original draft, Data curation. Omachi Daniel Ogaji: Writing – review & editing. Jin Li: Supervision. Kunze Du: Writing – review & editing, Supervision. Yanxu Chang: Writing – review & editing, Supervision, Project administration, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following is the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Acknowledgments

This work was supported by the 10.13039/501100010041 Tianjin Committee of Science and Technology in China (23ZYJDSS00010 ).

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36146.
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