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Home , Alpinia, Alpinia galanga, Alpinia officinarum, Zingiberaceae

Chinese Herbal Medicines 11 (2019) 132–140

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Chinese Herbal Medicines

journal homepage: www.elsevier.com/locate/chmed

Review

Research and application of officinarum in medicinal field

∗ Ping Ding a, , Li Yang a, Chong Feng a, Jian-chun Xian b a School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510 0 06, b Guangdong Chinese Medicine Museum, Guangzhou University of Chinese Medicine, Guangzhou 510 0 06, China

a r t i c l e i n f o a b s t r a c t

Article history: Alpinia officinarum is a medicinal and food. Its dried has been widely used for the relief of Received 9 January 2018 symptoms such as stomach aches, colds, ulcer and diarrhea for hundreds of years. Recent pharmacological

Revised 28 May 2018 studies showed it has anti-inflammatory, anti-oxidative, antidiabetic, anti-ulcer, anti-diarrhea, antiemetic, Accepted 17 December 2018 analgesia, anticoagulation, antitumor and antivitiligo effects. In this study, we summarized the current Available online 6 April 2019 knowledge about its botanical resources, ethanopharmacological function, chemical constituents, phar- Keywords: macologies and pharmacokinetics, safety and toxicity, and clinical application. botanical resource ©2019 Tianjin Press of Chinese Herbal Medicines. Published by Elsevier B.V. All rights reserved. chemical constituents clinical application of Alpiniae Officinarum Rhizoma pharmacology

Contents

1. Introduction ...... 133 2. Botanical resource ...... 133 3. Ethnopharmacological function ...... 133 4. Chemical constituents ...... 134 4.1. Essential oils ...... 134 4.2. Flavonoids...... 134 4.3. Diarylheptanoids ...... 134 4.4. Other components ...... 135 5. Pharmacology and pharmacokinetics ...... 135 5.1. Antibacterial and antiviral activities ...... 135 5.2. Anticancer activities...... 135 5.3. Anti-inflammatory activities ...... 136 5.4. Other pharmacological activities...... 136 5.5. Mechanism of action for anti-gastrointestinal bleeding ...... 136 5.6. Pharmacokinetics ...... 136 6. Safety and toxicity evaluation ...... 136 7. Clinical application ...... 136 7.1. TCM application to therapeutics ...... 136 7.2. Cancer therapy ...... 137 8. Dietary usages ...... 137 8.1. used as medicated food ...... 137 8.2. Galangal health care ...... 138 8.3. Galangal tea ...... 138 9. Conclusion...... 138 Conflict of interest ...... 138

∗ Corresponding author. E-mail address: [email protected] (P. Ding). https://doi.org/10.1016/j.chmed.2019.04.003 1674-6384/© 2019 Tianjin Press of Chinese Herbal Medicines. Published by Elsevier B.V. All rights reserved. P. Ding, L. Yang and C. Feng et al. / Chinese Herbal Medicines 11 (2019) 132–140 133

Acknowledgments ...... 138 References ...... 138

1. Introduction ported to East Asia, Africa, , Middle East, and other countries. It was also widely used as a dietary supplement in food, Alpinia officinarum Hance (Gaoliangjiang in Chinese, lesser and . However, there are some adulterants in the market, galangal), is a spice widely used in Europe and China for over such as the of (Linn.) Willd., Alpinia chi- 10 0 0 years. It has also been used as a nensis (Retz.) Rosc., Alpinia japonica (Thunb.) Miq. and Alpinia cal- in China for curing stomach ache, relieving cold, invigorating carata Rosc. Those were relatives of A. officinarum and not the circulatory system, treating vomiting and reducing swelling used as galangal. It is necessary to distinguish them by means of ( Basri, Taha, & Ahmad, 2017 ). It was first recorded in Mingyi Bielu scientific methods ( Luo et al., 2011 ). edited by Hong-jing Tao (456–536 A.D.), and it is an item in

Chinese Pharmacopoeia 2015 (Pharmacopoeia Committee of P. R. 3. Ethnopharmacological function China, 2015 ). It is also an important dietary Chinese medicine with increasing worldwide concern. Modern studies have showed that Galangal has been widely used as an aromatic stomachic, anal- galangal has anti-inflammatory, anti-oxidant (Srividya, Dhanabal, gesic and antiemetic both in traditional Chinese and Ayurvedic

Misra, & Suja, 2010), anti-emetic (Shin, Kinoshita, Koyama, & Taka- medicines ( Tao, Wang, Zhu, Lu, & Wei, 2006 ). It is a that ef- hashi, 2002) and anticancer (Huo, Kang, Peng, Gao, & Yan, 2013; fectively acts mainly on the digestive system such as spleen and

Kim, Jeon, & Num, 2012; Wen et al., 2012; Xu and Zhao, 2013a) stomach. Its rhizome exerts therapeutic and health-maintaining activities. In this review, we introduced the botanical resource, actions mainly in the following aspects: relieving stomach ache, chemistry, ethnopharmacology and pharmacology, and clinical treating cold, invigorating the circulatory system and reducing application of galangal. However, there is still a lack of systematic swelling ( Pharmacopoeia Committee of P. R. China, 2015 ). There- collation and studies (Lai, Li, & Tan, 2016; Li et al., 2014). In this fore, it was often used to treat gastralgia, emesis, dysentery, acid paper, the herbal resources, chemical constituents, pharmacology, regurgitation and impaired renal function ( Jung et al., 2012 ). Galan- pharmacokinetics, safety, and toxicity evaluation of A. officinalis gal combined with other herbal medicines has been commonly in recent years are reviewed to develop the effective substance prescribed by homeopaths and herbalists. foundation of treating diseases in A. officinalis. In the traditional therapy, the decoction from the boiled galan- gal rhizome is used to stimulate digestion and treat stomach ache 2. Botanical resource and malaria in Vietnam ( Nguyen, Nguyen, & Adhikari, 2014 ). Being effective in flatulence, dyspepsia, vomiting and gastrosis, galangal Galangal ( Alpinia officinarum Hance) is a perennial rhizoma- also has been recommended as a remedy for the following con- tous herbal plant in the family of ( Fig. 1 ), distribut- ditions, for instance, sea sickness, vomiting and diarrhea caused ing in the tropical and subtropical regions of South Asia. It was by cholera, and nausea caused by barbiers. Additionally, its pow- originated in China and mainly cultivated in Xuwen, Guangdong der can be served as a quick cure for acute stomach pain for its Province. Now, the areas of its cultivation in Xuwen district were convenience. The herb is also used extensively throughout the East about 4500 hm 2 , accounting for over 90% of the cultivation area in as a snuff for nasal infections. A mixture of galangal and lime juice China. “Xuwen Liangjiang” with high yield and good quality, char- is used as a tonic for cough and cold. In , galangal is valued acterized by large area, has been regarded as the national origin of for its use in perfumes and deodorants. It is occasionally used as the protection of the area in 2006 in China. Historically, it was one an aromatic stimulant in atmospheric purifiers as well. In , of the royal tributes as perfumes, mosquito repellent and digestive the decoction of immature roots of galangal has the effects of elim- soup in Northern Song Dynasty in China. The products were ex- inating flatulence and dispelling evil wind. And 25% alcohol extract

Fig. 1. Morphological characteristics of A. officinarum . (A), which arranged in , terminal, erect or slightly curved, pubescent, corolla white, corolla lobes oblong; Crude drugs (B), which is cylindrical, curved, with branches, brown to dark brown, with fine vertical wrinkles and gray-brown wavy links. 134 P. Ding, L. Yang and C. Feng et al. / Chinese Herbal Medicines 11 (2019) 132–140 of the crushed fresh rhizome is used topically for ringworm skin icals and strengthening the mucous barrier through the role of NO infections ( Saralamp, 1996 ). ( Gao, Chen, Yang, & Jiang, 2016 ). It also can be used for prepara- tion of perfumes, pharmaceuticals, room sprays, lotion, and cos- 4. Chemical constituents metic products.

Galangal is mainly cultivated in Guangdong and 4.2. Flavonoids Provinces in China, where it is not only considered as an but also a healthcare food supplement. Its rhizome con- Flavonoids are one of the main chemical constituents of galan- tains a lot of nutrients including 5.25% proteins, 76.9% carbo- gal, including flavonoid aglycones and glycosides. Up until now, hydrates, 2.26% fat, 15% crude fiber and various trace elements 13 flavonoid aglycones and two flavonoid glycosides have been ( Indrayan et al., 2009 ). Galangal also has various bioactive ingredi- isolated from galangal rhizome. More specifically, 13 flavonoid ents including essential oils, flavonoids, diarylheptanoids, phenyl- aglycones include galangin ( Fig. 2 ), galangin-3-methylether, propanoids, glycosides and others. kaempferol, kaempferol-4-methylether, quercetin, quercetin-3- methylether, apigenin, isorhamnetin, rhamnocitrin, pinocembrin, 4.1. Essential oils 7–hydroxy-3,5-dimethoxyflavone, dihydrogalanginol and cate- chin ( Li et al., 2014 ). In addition, galangin-3- β- D -glucoside and  β d Galangal is a well-known pungent, aromatic plant and used as kaempferol-4 -methylether-3- - -glucoside were two flavonoid spice for flavouring food throughout Asian countries. The volatile glycosides found in galangal rhizome ( An, Yang, & Zou, 2006a ) . oils contribute to the aroma of galangal as one of the main Flavonoids showed a strong anti-oxidant activity, which mainly ingredients in the rhizome accounting for 1.5% of whole herb. A prevented against oxidative damage by reducing the production total of 75 compounds were identified by GC–MS in the oils, and of free radicals and scavenging free radicals ( Leyla et al., 2015 ). the major constituents were 1,8-cineole (28.3%), α-fenchyl acetate Especially, galangin has been reported to play multiple anticancer (15.2%), carotol (8.9%), α-terpineol (6.7%), α-eudesmol (4.5%), effects, such as prevention of tumourigenesis and antitumor ( E )-methylcinnamate (4.0%), camphor (3.4%), β-pinene (3.1%), proliferation ( Tolomeo et al., 2008 ) camphene (2.3%), borneol (1.7%), erpinen-4-ol (1.2%) and α-pinene (1.2%) ( Rana, Verdeguer, & Blazquez, 2010 ). 4.3. Diarylheptanoids The volatile oils in rhizome of A. officinarum can improve the NO level of serum and microcirculation of gastric mucosa. It Diarylheptanoids are one of the major characteristic con- showed anti-gastric ulcer activity by removing the oxygen free rad- stituents in galangal. Up to now, 48 diarylheptanoid compounds

Fig. 2. Chemical structures of major flavonoids and diarylheptanoids. P. Ding, L. Yang and C. Feng et al. / Chinese Herbal Medicines 11 (2019) 132–140 135 had been isolated from galangal rhizome, including 43 lin- liovirus, measles virus, and HSV-1 in vitro ( Konno et al., 2011 ).  ear diarylheptanoids, three-cyclic diarylheptanoids ( Fig. 2 ) and Sawamura et al. found two diarylheptanoids similarly to 7-(3 -  a diarylheptanoid bearing flavonol moiety ( Li et al., 2014 ). methoxyphenyl-4 –hydroxy)-5–hydroxy-3-one and 1,7-diphenyl-5– These chemical constituents showed various bioactivities; They hydroxy-3-one, showed the anti-influenza A/PR/8/34 (H1N1) virus inhibited the melanogenesis caused by B16 melanoma cells activities using the MTT method ( Sawamura et al., 2010a ). 7-   ( Matsuda, Nakashima, Oda, Nakamura, & Yoshikawa, 2009 ), in- (3 -methoxyphenyl-4 –hydroxy)-5-heptene-3-one ( Fig. 2 ) was a duced apoptosis, S-phase arrest, and differentiation of human neu- promising anti-influenza virus agent candidate for the treatment roblastoma cells ( Tabata et al., 2009 ), cytotoxic activities ( Sun et al., of influenza infection ( Sawamura et al., 2010b ). 2008 ), inhibited biosynthesis of prostaglandin and leukotrienes ( Kiuchi, Iwakami, Shibuya, Hanaoka, & Sankawa, 1992 ), and in- 5.2. Anticancer activities hibited proinflammatory mediators ( Yadav, Liu, & Rafi, 2003 ). Di- arylheptanoids also have antivirus bioactivities including influenza Galangin ( Fig. 2 A) is a 3,5,7-trihydroxyflavone that is a major virus ( Sawamura et al., 2010a; 2010b ), respiratory syncytial virus, compound in A. officinarum. Galangin with anticancer bioactivities, poliovirus, measles virus, herpes simplex virus, and type 1 po- such as liver cancer, lung cancer, esophageal cancer, stomach liovirus ( Konno et al., 2011, 2013 ). cancer, human head and neck squamous carcinoma cells in vitro ( Wang et al., 2017a; Wen, Wu, Luo, & Zhang, 2012; Xu et al., 4.4. Other components 2013a ). Cao et al. found that galangin may have beneficial effects by preventing renal cell carcinoma growth, inhibiting cell invasion Ly et al. isolated seven phenylalanine compounds and nine gly- via the epithelial-mesenchymal transition (EMT) and inducing cosides from the methanol extract of fresh rhizome of A. offici- cell apoptosis. Galangin exerted an antiproliferative property in narum ( Ly, Shimoyamada, Kato, & Yamauchi, 2003; Ly, Yamauchi, a dose-dependent manner. In addition, galangin induced cell Shimoyamada, & Kato, 2002 ). Some studies showed that there apoptosis by increasing the intracellular concentration of reactive were sesquiterpenes, monoterpenes, organic acids and lactones in oxygen species (ROS) at a large dose and inhibited cell invasion rhizome of A. officinarum ( An et al., 2006b ). Chen et al. found that by suppressing the EMT. Therefore, galangin combined with other abundant Zn, Mn, Fe, Mg, Ca and other essential trace elements drugs may increase the therapeutic potential ( Cao et al., 2016 ). were present in the rhizome of A. officinarum ( Chen, Yu, & He, Diarylheptanoids are another important components in galangal 2012 ). with extensive anticancer effects. Tabata et al. reported that two   diarylheptanoids including 7-(4 –hydroxy-3 -methoxyphenyl)-1-   5. Pharmacology and pharmacokinetics phenyl-4E-hepten-3-one and (5 R )-5–methoxy-7-(4 –hydroxy-3 - methoxyphenyl) -1-phenyl-3-heptanone) both showed significant Modern pharmacological studies have indicated that galangal cytotoxicity against neuroblastoma cell lines (IMR-32, SK-N-SH, have the following bioactivities, such as antibacterial, antiviral, and NB-39) by inducing nuclear shrinkage and fragmentation, anticancer, anti-oxidant, anti-inflammatory, anti-gastrointestinal and activating caspase-3 and caspase-9 ( Tabata et al., 2009 ). bleeding, anti-obesity, hypolipidemic activities, etc. Therefore, Liu et al. examined their cytotoxicity against human tumor cell we summarized it as follows to provide references for clinical lines HepG2, MCF-7, T98G and B16-F10 of two new diarylheptanoid application. dimmers including ( E )-7-(4-(2–hydroxy-3–methoxy-5-(( E )-5-oxo-7- phenylhept-3-en-1-yl)phenoxy)-3-methoxyphenyl)-1-phenylhept-      5.1. Antibacterial and antiviral activities 4-en-3-one and (4 E ,4 E )-7,7 -(2 ,6-dihydroxy-3 ,5-dimethoxy-[1,1 -  biphenyl ]-3,4 -diyl)bis(1-phenylhept-4-en-3-one) and four other Bacterial resistance to antibiotics is an important global prob- diarylheptanoids such as 7-(4-hydroxyphenyl)-1-phenyl-3- lem. How to solve this scientific problem is the concern of many heptanone, 5 S -ethoxyl-7-(4–hydroxy-3-methoxyphenyl)-1-phenyl- scientists. Eumkeb, Sakdarat, and Siriwong (2010) tested the activ- 3-hepta none, 5 R –hydroxy-7-(4–hydroxy-3-methoxyphenyl)-1- ity of galangin ( Fig. 2 ) alone and in combination with β-lactam an- phenyl-3-heptanone and (4 E ,6 E )-5–hydroxy-1-(4–hydroxy-3- tibiotics against β-lactam-resistant Staphylococcus aureus in vitro . methoxyphenyl)-7-phenylhepta-4,6–dien-3-one). The results Results showed that this combination exhibited synergistic effect showed that ( E )-7-(4-(2–hydroxy-3–methoxy-5-(( E )-5-oxo-7- by reducing the cfu/mL of this strain to 1 × 10 3 over 6 h. Galan- phenylhept-3-en-1-yl)phenoxy)-3-methoxyphenyl)-1-phenylhept- gin showed marked inhibitory activity against penicillinase and β- 4-en-3-one showed selective cytotoxicity against cell lines of lactamase. Other experiments have also showed that the combina- MCF-7 and T98G, while compound 6((4 E ,6 E )-5–hydroxy-1-(4- tion of ceftazidime and galangin caused damage to the ultrastruc- hydroxy-3-methoxyphenyl)-7-phenylhepta-4,6–dien-3-one) show- ture of the cells of this strain. The result showed that galangin, ed significant cytotoxicity against all tested tumor cell lines with baicalein and quercetin exhibited the activity to reverse bacterial IC50 in the range of 8.46 to 22.68 μmol/L (Liu, Liu, Guan, & Liang, resistance to β-lactam antibiotics against penicillin-resistant S. au- 2014 ). Sun et al. found that three diarylheptanoids including    reus. This might involve three major mechanisms: galangin influ- 7-(3 -methoxyphenyl-4 –hydroxy)-5–hydroxy-3-one(linear), 7-(3 -  enced the integrity of the cell wall and septum formation prior methoxyphenyl-4 –hydroxy)-5-heptene-3-one and 1-(4–hydroxy- to cell division, inhibited the activity of certain penicillinase en- 3-methoxyphenyl)-7-(3,4-dihydroxyphenyl)-4 E -en-3-hepta showed zyme by interaction with this enzyme, and caused cytoplasmic no bioactivities against the human neuroblastoma cell lines ( Sun membrane damage. Galangin may develop a valuable adjunct to β- et al., 2008; Tian et al., 2009 ). Alpinisin A ( Fig. 2 E) was a diaryl- lactam treatments against otherwise resistant strains of currently heptanoid analogue with sesquiterpene moiety isolated from the almost untreatable microorganisms ( Eumkeb et al., 2010 ). rhizome of A. officinarum . It was characterized with a diarylhep- Some diarylheptanoids isolated from A. officinarum were exam- tanoid linked to a chain-like sesquiterpenoid, which was different ined in the antiviral activities against respiratory syncytial virus from other diarylheptanoids. It showed significant inhibitory (RSV), poliovirus, measles virus, and herpes simplex virus type 1 effects against gastric carcinoma cell lines ( Wei et al., 2016 ).  (HSV-1). Results suggested that the main constituents, e.g. , 7-(3 - Other studies also showed that diarylheptanoids had significant  methoxyphenyl-4 –hydroxy)-5–hydroxy-3-one and 1,7-diphenyl-5– cytotoxicity against neuroblastoma cell lines and inhibited melano- hydroxy-3-one, exhibited antiviral activity against RSV. Most of genesis in theophylline-stimulated murine B16 melanoma 4A5 cells the tested diarylheptanoids showed bioactivities against RSV, po- ( An, 2006b; An et al., 2008; Matsuda et al., 2009 ). 136 P. Ding, L. Yang and C. Feng et al. / Chinese Herbal Medicines 11 (2019) 132–140

5.3. Anti-inflammatory activities 5.6. Pharmacokinetics

Previous studies indicated that galangin has multifaceted phar- Pharmacokinetic studies can help to greatly understand the macological activities, especially in anti-inflammatory roles, which in vivo process of Chinese material medica (CMM), investigate have been reported in several animal models, such as paw edema, the potential mechanisms of the compatibility of herbal for- asthma, and rheumatoid arthritis ( Honmore et al., 2016; Huh et al., mulas, and provide guidance for drug development and clin- 2013; Liu et al., 2015a ). Galangin also showed potential neuropro- ical application. However, most of CMM have not been in- tective effects and ameliorating apoptosis and mitochondrial dys- vestigated in that aspect because of unclear chemical compo- function ( Li et al., 2012a ). In addition, galangin inhibited β-amyloid sition including galangal. Only one article reported that the production and acetylcholinesterase activity, and had possibly ther- concentration-time course of galangin was best fit to a two- apeutic potential for Alzheimer disease as well as cerebral ischemia compartment open model after a single oral administration dose of

(Guo et al., 2010; Zeng et al., 2015). The mechanism may be related 100 mg/kg, and the main pharmacokinetic parameters T1/2 α, T1/2 β , κ γ −1 to the modulation of PI3K/Akt, NF- B, and PPAR- signaling path- Ka, AUC, C1/F and V1 /F were 19.415 min, 33.983 min, 0.059 min , ways ( Choi, Park, Park, Kim, & Kim, 2017; Zha et al., 2013 ). 101.722 mg ·min/L, 0.983 L/(min ·kg) and 5.073 L/kg for galangin of At the same time, Kim et al. clarify that galangal extracts signif- 90%; and 24.398 min, 31.719 min, 0.048 min −1 , 55.201 mg ·min/L, icantly suppressed degranulation of PMA/A23187, stimulated RBL- 1.812 L/(min ·kg) and 6.861 L/kg for galangin of 99%, respectively 2H3 cells and inhibited MAPK signaling pathway, especially p38 ( Li et al., 2012b ). activation. However, ERK and JNK were not affected ( Kim, Ahn, & Lee, 2015 ). 6. Safety and toxicity evaluation

There are few clinical reports on the toxicity or side effects for 5.4. Other pharmacological activities various organs directly related to the use of galangal. The skin ir- ritation test indicated that galangal oil induced only a slight irri- Pharmacological studies showed that galangal had a wide tation on the rabbit skin for 24 h. After one week of observation, range of uses in the treatment of gastrointestinal disorders, such no adverse effects were observed on the intact skin and scratched as anti-gastrointestinal bleeding, resisting gastric ulcer, and pro- skin of the rabbits. The weight, hair, skin, respiratory system and tecting gastric mucosa ( Kosar et al., 2009 ). Tian reported that limb activity of the rabbits were not shown to exhibit a signifi- five diarylheptanoids from galangal had the inhibitory activity cant abnormality ( Liu, Sun, & Li, 2015b ). In a randomized, placebo- of vomiting in chickens induced by oral administration of cop- controlled, and cross-over phase I clinical study in healthy volun- per sulfate. Among them, 1-(4–hydroxy-3-methoxyphenyl)-7-(3,4- teers, it is observed that topical ABS application for 120 min is not dihydroxyphenyl)-4 E -en-3-heptanone had the strongest effect, and different from the placebo, in terms of the both local skin findings the inhibition rate of vomiting was 71.0% at 20 mg/kg dose and systemic laboratory tests ( Balcik et al., 2012 ). Based on those ( Tian et al., 2009 ). The 80% alcohol extract of A. officinarum can reports, both routine oral administration and external use of galan- significantly relieve primary dysmenorrheal ( Huang et al., 2016 ). gal are considered to be safe. Galangin was able to improve vitiligo induced by hydroquinone in The LD of supercritical CO extracts and diarylheptanoids ex- mice, therefore, it might be a potential candidate for the treatment 50 2 tracts were 1.338 g/kg and 10.641 g/kg, respectively ( Cui, 2008 ). of vitiligo ( Huo et al., 2014 ). Galangin also had an inhibitory effect There were few side effects when people took galangal decoction on acetylcholinesterase (AChE) activity with the highest inhibition at the normal dose. Galangin, an active pharmacological ingredi- by over 55% and an IC of 120 μmol/L and an enzyme-flavonoid 50 ent of its rhizome, showed no significant toxicity to animals by inhibition constant of 74 μmol/L. AChE inhibitors are widely used  calculating the albumin, alanine aminotransferase, and glutamic- for the treatment of Alzheimer s disease (AD). The results sug- oxalacetic transaminase ( Ren et al., 2016 ). gested that flavonoids could be potential candidates for further de- velopment of new drugs against AD ( Guo et al., 2010 ). 7. Clinical application

5.5. Mechanism of action for anti-gastrointestinal bleeding 7.1. TCM application to therapeutics

The basic mechanism of action for Ankaferd Blood Stopper ® Galangal, a well-known CMM, has been used as an aromatic (ABS, Ankaferd blood stopper), a standardized mixture of herbal stomachic, analgesic and antiemetic in Asia. It is innocuous, edi- extracts from five including A. officinarum appears to be ble, and completely non-toxic, tastes pungent and has warm char- the formation of an encapsulated protein network that provides acter. It can improve appetite, help to settle stomach upsets, and focal points for erythrocyte aggregation. Rather than affecting an stimulate blood flow, health and vitality, in addition to its frequent individual clotting factor, this protein mesh affects the entire phys- use as a sexual stimulant entering into stomach and spleen merid- iological hemostatic process that controls bleeding. Blood cells, ian ( Pharmacopoeia Committee of P. R. China, 2015 ). It was of- particularly erythrocytes and activated leukocytes, were found to ten used for stomachache caused by cold, usually combined with aggregate rapidly in the presence of ABS, thereby participating Cyperi Rhizoma , or in conjunction with Presl, in the network formation. ABS-induced formation of the protein Foeniculi Fructus , and Corydalis Rhizoma to enhance analgesic ac- network with vital erythrocyte aggregation covers the entire tion. It should not be used alone due to its irritating. Clinical use of physiological hemostatic process. Vital erythrocyte aggregation galangal mixed with Artemisiae Argyi Folium and Glycyrrhizae Radix takes place with the spectrin and ankyrin receptors on the surface has a hemostatic effect on the gastrointestinal tract. Its mecha- of red blood cells. Those protein and the required ATP bioenergy, nism may be exercised by affecting endothelial tissue, blood cell are included in the ABS protein library. ABS also up-regulates the proliferation and hemodynamics ( Kosar et al., 2009 ) . Beyazit et al. GATA/FOG transcription system affecting erythrocytes functions. assessed the methodological quality of the included studies about Urotensin-II is also an essential component of ABS and represents galangal for hemostatic effect, considering that this agent not only the link between injured vascular endothelium, adhesive proteins, had hemostatic effect, but also had other therapeutic advantages, and active red cells ( Beyazit, Kekilli, Haznedaroglu, Kayacetin, & such as antitumor, anti-inflammatory, wound repairing and so on, Basaranoglu, 2011 ). compared to traditional methods ( Beyazit et al., 2011 ). P. Ding, L. Yang and C. Feng et al. / Chinese Herbal Medicines 11 (2019) 132–140 137

Pharmacological studies and clinical practice showed that bility, such as, with Cyperi Rhizoma , prepared , Magnoliae Of- galangal had the effect of inhibiting Helicobacter pylori, Staphylococ- ficinalis Cortex , at the general usage of 3 −6 g. Galangal is taken by cus aureus, Bacillus cereus, Pseudomonas aeruginosa and Escherichia decoction after slicing or pilling, powdering. It is prohibited to use coli and anti-oxidation ( Srividya et al., 2010; Zhang, Dai, Liao, & when patients have yin deficiency and heated syndrome. Ding, 2010 ). It was effective in treating gastrelcosis by inhibiting Galangal is used in the following forms in clinical medication: acidity, improving anti-oxidant capacity, and increasing protective (1) Liangfu Capsule: made by extracts of galangal and Cyperi Rhi- factors ( Wang et al., 2011 ). A study revealed that water extract of zoma slices. It is easily absorbed and can be used for treating galangal had good resistance effect on gastric ulcer probably by re- stomachache or cancer pain. (2) Liangfu microemulsion: it is re- ducing the plasma GAS, IL-1, and the concentration of TNF- α, and ported that this microemulsion has better anti-inflammation and raising levels of serum COX-2 and PGE 2 ( Wei et al., 2015 ). On analgesic effect than Liangfu Capsule via oral administration due the other hand, galangal had analgesic effect that its main com- to its improved absorbtion and bioavailability ( Du, Niu, Xu, Du, & pounds, galangin and apigenin each half, were observed by body- Feng, 2008 ). It reveals that microemulsion drug delivery system of torsion and hot-plate methods ( Yang, Sha, Chen, & Chen, 2008 ). compound TCM is a promising research field. Although its mecha- The ancient prescription Liangfu Pill consisted of A. officinarum and nism of enhanced absorption should be studied further, the result Cyperus rotundus L. are now widely used for treatment of stom- can provide reference for the clinical development of new drugs. ach pain, dysmenorrhea caused by cold and qi stagnation. Modern (3) Modified Liangfu granule: It was made by Liangfu preparations pharmacological studies illustrated the mechanism of galangal and mixed with the rhizome of Dioscorea nipponica . Clinical and experi- laid foundations for new drug discovery. mental studies indicated that it could be used alone or jointly with chemotherapy or 5-Fu for treating advanced gastric cancer ( Wang, 7.2. Cancer therapy Guo, Hou, Chen, & Tian, 2017b; Xu et al., 2013b ). The fundamen- tal research of this formula showed that it could also inhibit liver Galangal has been widely used as a traditional herbal medicine cancer, esophageal cancer, and breast cancer. The principle was for analgesics and antiphlogistic drugs in Asian countries. Recent that this formula could decrease the expression of VEGF, MVD and studies have demonstrated that it contains volatile oil, flavonoids then impede the formation of tumor micro vasculature ( Luo, Ma, and diarylheptanoids. Flavonoids are major components in galan- & Chen, 2008 ). (4) Galangal transdermal absorption in vitro : recent gal rhizome, accounting for 3.4% ( Lin, 2001 ). Galangin is one of studies indicated that galangin can penetrate the complete skin of the most important flavonoids in the rhizome of galangal, with mice and rats, however, the penetration quantity is far lower than a 3-hydroxyflavone skeleton. Nearly a dozen years of research on exfoliating skin and dermis skin. The result provides the basis for the anticancer effect of galangal has been widely concentrated developing preparations using galangin as APIs in the treatment of on galangin. Related studies have been demonstrated that it has vitiligo. widely antineoplastic activities including colon cancer ( Ha et al.,

2013), mammary cancer (Murray, Yang, & Sherr, 2006), liver 8. Dietary usages cancer ( Wang et al., 2017a ), melanocarcinoma ( Huo, Kang, Peng,

Gao, & Yan, 2013), promyelocytic leukemia (Bestwick et al., 2006), Rhizoma of A. officinarum , Zingiberaceae, a ginger family herb prostate cancer (Szliszka et al., 2011) and so on. Its action mech- exhibiting stimulant and carminative bioactivities, is widely used anisms include prevention of tumor cell proliferation not only by in European and Asian countries as spicy and medici- intervening cyclin and cyclin dependent kinase expression and nal uses. Closely resembling ginger in appearance, it is often used inducing apoptosis through the mitochondria and endoplasmic in medicated food, flavourings and tea in China. It can improve reticulum apoptotic pathways, but also with the function of the appetite and stimulate the blood stream throughout the body inhibiting tumor cell invasion and metastasis by inducing focal and the brain. It is especially useful in flatulence, dyspepsia, vom- adhesion kinase and epithelial-mesenchymal transition. More- iting, and sickness in stomach. It is also used as a sexual stimu- over, galangin can downregulate the expression of anti-apoptotic lant. In the folk, farmers often use it as repellent for protecting protein to increase the chemosensitivity of drug-resistant tumor. stored grains from insect infestation ( Lu et al., 2015 ). Some prod-

The above pharmacological and biological studies of galangin are ucts could be conveniently made at home for different purposes, as helpful for finding anticancer precursor compounds and screening follows. multi-targets anti-tumor agents, which lays the foundation for discovering new antitumor drugs combined with the theory of traditional Chinese medicine (TCM). 8.1. Galangal used as medicated food Galangal is not only an important herb in CMM, but also one of the food healthcare products. According to TCM theory, it is Generally speaking, galangal is often used to treat stomach dis- pungent in flavour and hot in nature, beneficial to the spleen and eases. For instance, galangal chicken nuggets are used to make stomach channel and has the effect of stomachache-relieving and with rooster, Citri Reticulatae Pericarpium , and pepper. A detailed relieving pain. Pungent taste has a dispersing and activating effect method is to stew the above things together about 2 h for treating in the qi and blood, essentially in treating various patterns of qi stomachache or gastrohelcoma. Erjiang Pill was made of Zingiberis or blood stagnation. in hot nature can variously warm yang , Rhizoma and galangal, mixed evenly after being powdered, then dispel cold, and warm the channels. Therefore, in clinical prac- made-pill with pasty as bean size. This pill should be eaten on an tice, galangal is mainly used for treating stomachache, vomiting empty stomach twice a day when you have stomachache disease caused by cold and belching and acid swallowing, chest paining by by cold. The compatibility with Pinelliae Rhizoma Preparatum , gin- warming middle energizer to promote qi , and arthritis by warm- ger could be used to treat diarrhea and vomiting caused by inward ing yang . Decades of researches showed that galangal can mainly invasion of pathogenic cold. Galangal with roots of Fangji ( Stepha- play a role in the following aspects: anti-inflammatory functions, nia tetrandra S. Moore) Decoction could be used to treat lumbar warming stomach, dispelling wind and relieving pain, antitumor and pedal pain by external washing therapy. Its total flavonoid ex- and invigorating the circulatory system, dispersing stagnated liver tracts also can decrease blood lipid ( Fang, Xia, Wang, & Ji, 2015 ). qi for promoting bile flow, anti-obesity and hypolipidemic effect It is recommended as a remedy for sea-sickness and its powder is ( Liu, Fu, & Ding, 2012 ). Galangal could usually be used in compati- used as a snuff for catarrh. 138 P. Ding, L. Yang and C. Feng et al. / Chinese Herbal Medicines 11 (2019) 132–140

8.2. Galangal health care spice its use as antiemetic. Galangal is mainly produced in Zhanjiang and Guangdong Provinces, called one of the tenth Guang Hebal Galangal rhizomes were widely used in ancient and medieval Medicines. It has been used in health care and daily life of peo- Europe, where they were reputed to smell of roses and taste of ples. Modern studies of pharmacology and chemistry showed that sweet spice. Its use in Europe has dramatically declined, however, its main components are volatile oils, flavonoids, and diarylhep- and is now mainly used in Eastern Europe. It is used in Russia for tanoids, showing rich medicinal diversities. Especially, pharmaco- flavoring vinegar and the liqueur Nastoika. It is still used as a spice logical activities of its flavonoids and diarylheptanoids were ex- and medicine in Lithuania and Estonia. In Asia, the rhizomes are tensively studied including anti-inflammatory, anticancer and anti ground into powder for use in curries, drinks, and jellies. In India, multi-drug resistant strains. Furthermore, galangin, a natural active an extract of galangal is used in perfumes, and Tatars prepare a tea compound, is a type of bioflavonoid isolated from galangal that has with it. In many countries, galangal has not come into use among extensive resistance to different types of cancers, showing the ef- physicians, but is sold extensively in ethnic markets and by street- fects of inhibiting tumor cell proliferation, promoting tumor cell corner venders under such names as “colic root”, “the wonderful apoptosis, and inhibiting tumor cell invasion and metastasis, indi- East India root”, etc., and is said to be a certain cure for toothache, cating that galangin has potential to be an anticancer drug. headache, upset stomach, etc. ( Basri et al., 2017 ). The herbs and In view of medicinal use, we should focus on the food, spice spices are recommended for prevention and cure of various dis- and other side applications of galangal to promote its comprehen- eases including cancer. The roots contain volatile oils, flavonoids, sive utilization and realize its industrialization. galangol, kaempferid, galangin, alpinin, starch, etc. The active prin- ciples of these spices are volatile oils. Lin et al. reported that galan- Conflict of interest gal acetate is responsible for its active spicy and pungent ( Lin et al.,

2016). The authors declare no conflict of interest. In folk, galangal are widely used as flavourings in food, such as meat product, Far East sweet wine, bitter beer, and cooking food

(, Malay food). It is the main constituent of five spice powder Acknowledgments and baked chicken powder. This work was supported by the National Key R&D Pro-

8.3. Galangal tea gram of China (No. 2017YFC1701104) and Guangdong Province Applied Science and Technology R&D Special Fund Project (No.

Tea is widely consumed as a health-promoting beverage in 2015B020234002). China with a very long history. Natural has been at- tracted more attention since it was categorized by the Chinese References regulatory authority as one new food resource in 2013. Based in An, N. , Yang, S. L. , & Zou, Z. M. (2006a). Flavonoids of Alpinia officinarum . Chinese its traditional use, a series of studies about natural herbal tea Traditional and Herbal Drugs, 37 (5), 663–664 . have been conducted on their chemistry, pharmacology, nutritional An, N. (2006b). Studies on the chemical constituents of alpinia officinarum hance, profile and toxicology, such as Lingzhi tea, ginseng tea, gingko studies on the lipophilic chemical constitutes of euphorbia soongarica Boiss . Un- published Doctoral dissertation, Beijing: Peking Union Medical College, Chinese tea and vine tea (Miranda-Henriques, Diniz Mde, & Araújo, 2014; Academy of Medical Science . Wan, Jiang, Sun, Xu, & Xiao, 2017 ). Galangal tea has certain cu- An, N. , Zou, Z. M. , Tian, Z. , Luo, X. Z. , Yang, S. L. , & Xu, L. Z. (2008). Diarylheptanoids rative effect with hyperlipidemia, hyperglycemia, antio-xidant and from the rhizomes of Alpinia officinarum and their anticancer activity. Fitoper- anti-inflammatory activities. Galangal and Cyperi Rhizoma tea each apia, 79(1), 27–31. Balcik, O. S. , Koroglu, M. , Cipil, H. , Kaftan, O. , Maral, S. , Gurel, A. , et al. (2012). 10 g are boiled 1 h followed by adding brown sugar and mixing in A placebo-controlled, randomized, double-blinded, cross-over phase-I clinical boiled water for oral taking, which are helpful for the patients of study indicating the safety of topical ankaferd hemostat in healthy volunteers. chronic gastritis caused by qi stagnation. Galangal 2 g combined Journal of Hematology & Oncology, 22(4), 267–274. Basri, A. M. , Taha, H. , & Ahmad, N. (2017). A review on the pharmacological activi- with Cinnamomi Cortex 3 g, Angelicae Sinensis Radix 1 g, Magnoliae ties and phytochemicals of Alpinia officinarum (Galangal) extracts derived from Officinalis Cortex 2 g and Ginseng Radix 1 g are boiled together, then bioassay-guided fractionation and isolaion. Pharmacognosy Reviews , 11 (21), making tea with decoction, having the effect of warming the mid- 43–56. Bestwickv, C. S. , & Milne, L. (2006). Influence of galangin on HL-60 cell proliferation dle energizer to dispel cold. The tea composed of Bombyx Batryt- and survival. Cancer Letters, 243 (1), 80–89 . icatus and galangal tea each 10 g can expel wind and clear away Beyazit, Y. , Kekilli, M. , Haznedaroglu, I. C. , Kayacetin, E. , & Basaranoglu, M. (2011). cold, disperse phlegm and relieve pain. It has a significant thera- Ankaferd hemostat in the management of gastrointestinal hemorrhages. World Journal of Gastroenterology, 17 (35), 2219–2840 . peutic effect on cold headache. In folk, drinking galangal tea could Cao, J. Y. , Wang, H. N. , Chen, F. F. , Fang, J. Z. , Xu, A. M. , & Xi, W. (2016). Galangin alleviate drunk. Galangal tea is made in the following steps: wash inhibits cell invasion by suppressing the epithelial-mesenchymal transition and galangal, dry it and then grind into powder; load powder every inducing apoptosis in renal cell carcinoma. Molecular Medicine Reports, 13 (5), 4238–4244 .

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