Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants
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Scutellaria baicalensis Georgi, or Chinese skullcap, has been widely used as a medicinal plant in China for thousands of years, where the preparation from its roots is called Huang-Qin. It has been applied in the treatment of diarrhea, dysentery, hypertension, hemorrhaging, insomnia, inflammation and respiratory infections. Flavones such as baicalin, wogonoside and their aglycones baicalein wogonin are the major bioactive compounds extracted from the root of S. baicalensis. These flavones have been reported to have various pharmacological functions, including anti-cancer, hepatoprotection, antibacterial and antiviral, antioxidant, anticonvulsant and neuroprotective effects. In this review, we focus on clinical applications and the pharmacological properties of the medicinal plant and the flavones extracted from it. We also describe biotechnological and metabolic methods that have been used to elucidate the biosynthetic pathways of the bioactive compounds in Scutellaria.
KeywordsScutellaria baicalensis Flavonoids Anti-cancer Metabolic biology Medicinal plants
黄芩是一种常用的药用植物, 中国人对它的使用了已有数千年历史。黄芩根的制备物, 为常用的中药材, 在中国传统医学中用来治疗腹泻、痢疾、高血压、出血、 失眠、炎症和呼吸道感染。黄芩根中主要的活性物质为黄酮物质黄芩苷, 汉黄芩苷及 苷元黄芩素, 汉黄芩素。药理学研究显示这些黄酮物质具有多种药物学活性, 包括抗 癌, 保肝、抗菌、抗病毒、抗氧化、抗惊厥和神经系统保护作用。在本综述里面, 我 们集中介绍了黄芩的临床应用及药物学活性。我们也介绍了用于研究黄芩中活性物质 代谢途径的生物技术及代谢生物学方法。
2 Clinical applications
Scutellaria baicalensis has been used as a medicine in several East Asian countries for more than 2000 years. Clinical data for this herb are accumulating and Huang-Qin alone has been reported to be useful for treating colds and bacterial pneumonia [7, 8].
In many Eastern countries, Huang-Qin is prescribed as a part of a multi-herb formulation. Huang-Qin is an important ingredient of Xiaochai Hutang (Chinese) or Sho-saiko-to (SST, Japanese) preparations, first described in Shanghan Lun (On Cold Damage), written by Zhang Zhongjing around 200 AD . This formulation was described as having ‘worked effectively in some instances where conventional Western therapies failed or proved to be insufficient to provide a palliative cure’ by Xue and Roy in 2003  and was subsequently taken up by the alternative medicine community in the USA . A study of the effects of SST on hepatitis was reported by a Japanese group in 1994 . Ninety-eight hepatitis patients were treated with SST and followed up for 5 years. Liver function was improved in 78 % of the hepatitis B patients and in 67 % patients with non-A non-B type hepatitis, with significantly reduced serum levels of aminotransferase AST, ALT, and rGTP . SST is also effective in hepatitis C patients. Eighty hepatitis C patients who were interferon-resistant were treated with SST combined with a common unspecified medicine or the common medicine alone. These patients were studied for 7 years during which time, 5 patients on the SST treatment achieved fully normalized enzyme functions. Liver enzyme normalization was observed in only one control patient. Conversely, 5 control patients (common medicine alone) progressed to liver cancer compared to just one on the SST combination therapy .
Lung Fufang, another traditional prescription using Huang-Qin, can prolong the survival rate of patients with primary bronchial pulmonary squamous cell carcinoma , and it has a similar effect on NSCLC (non-small-cell lung cancer) patients. Elderly people suffering from NSCLC and treated with Lung Fufang Prescription showed improved indices for the clinical syndrome and improved quality of life compared to the control group who were treated with normal chemotherapy plus a TCM (Traditional Chinese Medicine) placebo . Huang-Qin is also a major ingredient of Fuzheng anti-cancer prescription, which has been used in combination with chemotherapy and shown to have improved outcomes on NSCLC in middle and late stage patients, compared to conventional chemotherapy alone .
3 Pharmacology of Huang-Qin
3.1 Antitumor effects
Many studies have shown that S. baicalensis extract is cytotoxic to a broad range of cancer cells from humans, including brain tumor cells , prostate cancer cells  and HNSCC (head and neck squamous cell carcinoma) cell lines . Aqueous extracts of S. baicalensis roots induced apoptosis and therefore suppressed growth of lymphoma and myeloma cell lines, by changing the expression levels of Bcl genes, increasing cyclin-dependent kinase inhibitor p27 (KIP1) activity and decreasing expression of the c-myc oncogene . Similarly, S. baicalensis extracts were selectively toxic to several human lung cancer cell lines, but not to normal human lung fibroblasts. Increases in p53 and Bax protein activities may be responsible for these effects .
The flavones baicalin, wogonoside and their aglycones baicalein and wogonin are the major bioactives in Scutellaria roots and the major bioactive constituents responsible for anti-cancer effects of Huang-Qin [22, 23, 24]. Baicalin inhibits growth of lymphoma and myeloma cells . Wogonoside has anticancer effects on acute myeloid leukemia (AML) cell lines and on primary patient-derived AML cells. It increases significantly the transcription of phospholipid scramblase 1 (PLSCR1), a regulator of the cell cycle and differentiation-related genes . Baicalin, baicalein and wogonin have similar effects as S. baicalensis extracts against lung cancer cells . The anti-cancer activities of the Scutellaria-derived flavones have been mainly ascribed to their ROS scavenging ability, attenuation of NF-κB activity, cell cycle gene expression, COX-2 gene expression and prevention of viral infections [22, 26, 27].
In a high-throughput screen of over 4000 compounds to detect genotoxic compounds using a quantitative cell-based assay, Fox et al.  identified 22 antioxidants, including baicalein. Treatment of dividing cells with baicalein induced DNA damage and resulted in cell death. Despite this genotoxic effect, baicalein did not induce mutations, a major problem of conventional anticancer drugs, suggesting that baicalein and related flavones are strong candidates for improved chemotherapeutic agents .
Scutellaria baicalensis is the main component in the herbal remedy SST used for liver problems such as hepatitis, hepatic fibrosis and carcinoma [11, 29, 30]. Yang-Gan-Wan (YGW) is another prescription containing baicalin, which has long been known for its protective effects on the liver [31, 32]. This herbal prescription prevents and reverses activation of hepatic stellate cells, (HSC; the major pathogenic cell type in fibrogenesis) by epigenetic derepression of PPARγ (Peroxisomal proliferator-activated receptor γ), so preventing liver fibrosis. Baicalin is a major active phytocompound in Yang-Gan-Wan (YGW) and suppresses the expression and signaling by canonical Wnts, which are involved in epigenetic repression of PPARγ .
Several studies have suggested that S. baicalensis can effectively inhibit fibrosis and lipid peroxidation in rat liver [34, 35, 36]. Consumption of the roots and shoots of S. baicalensis inhibits mutagenisis caused by the aflatoxin-B1 mycotoxin in rat liver cells . The anti-fibrosis activity of S. baicalensis root extracts may be due to enhanced phosphorylation of the cAMP response element binding protein as proposed by Tan et al. , although extracts of Scutellaria baicalensis roots also arrest the cell cycle, activate the caspase system and activate ERK-p53 pathways resulting in apoptosis of HSC-T6 cells to prevent hepatic fibrosis .
3.3 Antibacterial and antiviral activities
Amongst 46 herb and spice extracts, S. baicalensis extracts have shown substantial antibacterial effects against Bacillus cereus, Escherichia coli, Listeria monocytogenes, Salmonella anatum and Staphylococcus aureus . Aqueous extracts of S. baicalensis roots have antimycotic properties against Aspergillus fumigatus, Candida albicans, Geotrichum candidum and Rhodotorula rubra . Baicalin, isolated from S. baicalensis, has been applied as a natural antibacterial agent against foodborne pathogens such as Salmonella and Staphylococcus spp. in homemade mayonnaise . Extracts of S. baicalensis can also enhance the antimicrobial activity of several antibiotics such as ciprofloxacin, ceftriaxone, gentamicin and penicillin G, against Staphylococcus aureus .
Xiaochai Hutang or Sho-saiko-to (SST) is effective against hepatitis, and a reduction of viral load has been observed in some patients treated with SST , indicating an antiviral function of Scutellaria extracts . Scutellaria root extracts can inhibit the replication of HCV-RNA significantly .
Baicalin has very good anti-HIV-1 activity as a non-nucleoside reverse transcriptase inhibitor . Moreover, baicalin can prevent the entry of HIV-1 into animal cells by perturbing the interaction between HIV-1 Env and HIV-1 co-receptors on the cell surface . Baicalin has been adopted as one of the popular lead natural products for preventing HIV infection . Differences in the inhibitory activities of baicalein and baicalin against HIV-1 reverse transcriptase have been evaluated by Zhao et al. . They found that baicalein has four times stronger inhibitory activity on HIV-1 reverse transcriptase than baicalin. However, baicalin can be deglycosylated to form baicalein in the human body .
Aqueous extracts of S. baicalensis elicit significant inhibition (91.1 %) of HIV-1 protease activity at concentrations of 200 µg/ml . Early in 1989, Ono et al.  reported baicalein could effectively inhibit reverse transcriptase activity of human immunodeficiency virus (HIV); 2 μg/mL baicalein inhibiting 90 % of the activity of HIV reverse transcriptases . Baicalein is also an inhibitor of HIV-1 integrase, an essential enzyme in the life cycle of the virus, by binding to the hydrophobic region of the HIV-1 integrase catalytic core domain to induce a conformational change . These effects of baicalein and baicalin on HIV have attracted considerable attention .
3.4 Other effects
In addition to the effects described above, preparations of S. baicalensis can also work as antioxidants, ROS scavengers [53, 54] and anticonvulsants . Recently, the neuroprotective effects of S. baicalensis and its component flavones, have been studied using both in vitro and in vivo models of neurodegenerative diseases. Results suggest that this medicinal plant may have promising applications in neuroprotection [56, 57].
4 Biotechnology to enhance S. baicalensis synthesis
Composition of multi-herb formulations containing S. baicalensis
Scutellaria baicalensis, Bupleurum falcatum, Pinellia ternate, Panax ginseng, Glycyrrhiza uralensis, Zingiber officinale, Ziziphus jujuba
Panax ginseng, Astragalus membranaceus, Lycium barbarum, Glossy privet fruit (Ligustrum lucidum), Sichuan fritillary bulb (Fritillaria cirrhosa), Radix Ophiopogonis (Ophiopogon japonicus), Platycodon grandiflorum, Scutellaria baicalensis, Lily bulb (Lilium brownii), Curcuma zedoary, pseudo-ginseng (Panax notoginseng), Oldenlandia diffusa
Fuzheng anti-cancer prescription
Astragalus membranaceus, American ginseng (Panax quinquefolius), Citrus reticulate, Pinellia ternate, Scutellaria baicalensis, Poria cocos, Atractylodes Lancea, Schisandra chinensis, Oldenlandia diffusa, Adenophora stricta, Salvia miltiorrhiza
Next-generation sequencing technologies have been employed to screen for candidate genes that may be responsible for biosynthesis of the flavones, and several structural genes including 6-hydroxylase, 8-O-methyltransferase, 7-O-glucuronosyltransferases have been suggested to be involved in their biosynthesis . Yuan et al. [70, 71] also screened RNA-sequencing databases and found that several MYB genes may be responsible for regulation of production of its flavonoids.
5 Flavonoid metabolism
The evolution of this specialised pathway for 4′ deoxyflavone biosynthesis occurred relatively recently, following the divergence of the Laminaceae  and may have been facilitated by the recruitment of a CoA ligase activity from a gene encoding an enzyme of fatty acid metabolism, that is specific for cinnamate. Effective competition for cinnamate in the face of high level expression of C4H may have paved the way for effective production of 4′- deoxyflavones in roots of S. baicalensis. Production of 4′- deoxyRSFs in roots is induced by methyl jasmonate treatment, suggesting that RSFs are made as part of a defence mechanism or for plant–microbe signalling [85, 86]. Understanding the regulation of this newly-evolved pathway may facilitate engineering of biosynthesis of these important bioactive metabolites. Their roles in defence in Scutellaria may also underpin some of their uses in traditional medicine, for example as anti-microbials.
The bioactive compounds baicalein, wogonin and their glysosides can be found in many species from the genus Scutellaria other than S. baicalensis . As in traditional Chinese medicine, the roots of S. amoena and S. likiangensis have been used commonly as alternatives to S. baicalensis. To date, 4′-deoxyflavones have been found only in Oroxylum indicum vent  and Plantago major L. outside the genus Scutellaria but in the order Lamiales . 4′-Deoxyflavones have also been reported in Anodendron affine and Cephalocereus senilis outside the order Lamiales [90, 91]. The evolution of metabolic pathways determining the taxa-specific distribution of these 4′-deoxyflavones is fascinating, and we suspect that convergent evolution has most likely influenced the development of metabolic pathways responsible for producing these specialised bioactive flavones in widely diverged plant species [92, 93].
This work was supported by CAS/JIC and Centre of Excellence for Plant and Microbial Sciences (CEPAMS) joint foundation. QZ and CM were supported by the Institute Strategic Program Understanding and Exploiting Plant and Microbial Secondary Metabolism (BB/J004596/1) from the BBSRC to JIC. QZ and XYC were also supported by the Special Fund for Shanghai Landscaping Administration Bureau Program (F132424, F112418 and G152421).
Conflict of interest
The authors declare that they have no conflict of interest.
- 4.Li S (1593 and republished in 2012). In: Compendium of materia medica (Bencao Gangmu). Huaxia Press, pp 543–546 (In Chinese)Google Scholar
- 5.Xu S (Around 200 AD and republished in 1978) Shuowen Jiezi (Explaining graphs and analyzing characters). Zhonghua Book Company, p 19 (In Chinese)Google Scholar
- 6.Ma JX (2013) Explanatory notes to Shennong Bencaojing People’s Medical Publising House, Beijing, 3:140Google Scholar
- 7.Huang ZH, Xu ZQ (1992) Single huang-qin for treatment of bacterial pneumonia. Shizhen Tradit Med Res 3:106–107 (In Chinese)Google Scholar
- 8.Chu WM (2010) Single Huang-qin was used for treatment of cold during pregnancy. Nei Mong J Tradit Chin Med 29:15Google Scholar
- 9.Zhang Z (Around 200 AD and republished in 1974). In: Shanghan Lun (On cold damage). People’s Medical Publishing House, Beijing, p 27Google Scholar
- 11.Wen J (2007) Sho-saiko-to, a clinically documented herbal preperation for treating chronic liver disease. HerbalGram 59:34–43Google Scholar
- 12.Yamamoto H, Miki S, Deguchi H (1994) Five year follow up study of Sho-saiko-to (Xiao-Chai-Hu-Tang) administration in patients with chronic hepatitis. J Nissei Hosp 23:144–149Google Scholar
- 13.Gibo Y, Nakamura Y, Takahashi N (1994) Clinical study of Sho saiko to therapy for Japanese patients with chronic hepatitis C. Prog Med 14:217–219Google Scholar
- 14.Pan MQ, Li YH, Liu JA, Tan YX (1990) Reports for 80 patients with bronchial lung squamous carcinoma (Mid or Late Stage) treated Lung FuFang and chemotherapy. J Tradit Chin Med Pharm 5:19–21Google Scholar
- 15.Pan MQ, Li YH, Jiang YL (2000) Clinical observation of old people NSCLC (mid or late stage) treated by Lung Fu Fang combined with chemotherapy. Shanxi Tradit Chin Med 31:389–390Google Scholar
- 16.Duan X, Jia CF, Duan M (2014) Treatmenf of non-small-cell lung cancer by FuZheng anti-cancer prescription combined with chemotherapy. Shanxi Tradit Chin Med 35:311–312Google Scholar
- 23.Wo D, Lamer-Zarawska E, Matkowski A (2004) Antimutagenic and antiradical properties of flavones from the roots of Scutellaria baicalensis Georgi. Food 48:9–12Google Scholar
- 34.Chen HJ, Liang TM, Lee IJ et al (2014) Effect of Scutellaria baicalensis on hepatic stellate cells. Planta Med 80:817Google Scholar
- 41.Bruzewicz S, Malicki A, Oszmianski J et al (2006) Baicalin, added as the only preservative, improves the microbiological quality of homemade mayonnaise. Pak J Nutr 15:30–33Google Scholar
- 44.Tang ZM, Peng M, Zhan CJ et al (2003) Screening 20 Chinese herbs often used for clearing heat and dissipating toxin with nude mice model of hepatitis C viral infection. Chin J Integr Tradit West Med 23:447–448Google Scholar
- 61.Joshee N, Parajuli P, Medina-Bolivar F et al (2010) Scutellaria biotechnology: achievements and future prospects. Bull Univ Agric Sci Vet 1:1843–5394Google Scholar
- 71.Yuan Y, Qi L, Yang J et al (2014) A Scutellaria baicalensis R2R3-MYB gene, SbMYB8, regulates flavonoid biosynthesis and improves drought stress tolerance in transgenic tobacco. Plant Cell Tissue Organ Cult 120:1–12Google Scholar
- 73.Yu Z, Hirotani M, Yoshikawa T et al (1998) Flavonoids and phenylethanoids from hairy root cultures of Scutellaria baicalensis. Solid State Nucl Magn Reson 13:488–492Google Scholar
- 85.Yang G, Guo LP, Guo XH et al (2012) Selectivity infection of arbuscular mycorrhizal fungi in medicinal plants. Chin J Inform Tradit Chin Med 19:53–55Google Scholar
- 86.Guo HJ, Wang W, He XL (2011) Effects of host plants on growth and development of arbuscular mycorrhizal fungi in Rhizospere of Scutellaria baicalensis. J Henan Agric Sci 40:98–2439Google Scholar
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