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Etlingera pavieana (Pierre ex Gagnep) R.M.Sm. (Zingiberaceae family) is commonly found in Southeast Asia. The rhizome of the plant is used as a spice and folk medicine in southeastern Thailand and Cambodia. The extracts, essential oil, and compounds from E. pavieana were found to possess a variety of pharmacological activities like anti-inflammatory, antioxidant, antiatherogenic, and antimicrobial effects. Furthermore, phytochemical studies have reported the presence of various chemical constituents, the main being phenylpropanoids such as trans-4-methoxycinnamaldehyde (MCD) and 4-methoxycinnamyl p-coumarate (MCC). Therefore, E. pavieana seems to be a potential source of natural products for treatment of various diseases and promotion of good health.
chapter and author info
Faculty of Science, Department of Biochemistry and Research Unit of Natural Bioactive Compounds for Healthcare Products Development, Burapha University, Thailand
Faculty of Science, Center of Excellence for Innovation in Chemistry, Burapha University, Thailand
Faculty of Science, Center of Excellence for Innovation in Chemistry, Burapha University, Thailand
Faculty of Science, Department of Chemistry and Research Unit of Natural Bioactive Compounds for Healthcare Products Development, Burapha University, Thailand
*Address all correspondence to: firstname.lastname@example.org
Plant-based nutraceuticals or functional foods have gained attention due to their health promotion and safety in comparison to synthetic food ingredients [1, 2]. Presently, worldwide researchers have focus on scientific evaluation of medicinal plants to detect their pharmacological activities. Zingiberaceae family is distributed worldwide and comprises approximately 52 genera and 1587 species . It is about 300 species belonging to 26 genera found in Thailand . The plants in this family are the natural sources for traditional medicine, foods, spice, and other ethnobotanical uses . Etlingera pavieana(Pierre ex Gagnep) R.M.Sm. is a member of the Zingiberaceae family and a medicinal plant of southeastern Thailand . Several in vitroand in vivopharmacological experiments and phytochemistry studies of E. pavieanahave been reported. This chapter has presented comprehensive information about morphological characteristics, traditional uses, pharmacology activities, and phytochemical constituents of E. pavieana, which provide the data to plan future studies.
2. Botanical description and uses of Etlingera pavieana(Pierre ex Gagnep) R.M.Sm.
E. pavieanais endemic to Southeast Asia including Thailand, Cambodia, Laos, and Vietnam. This plant is locally known in Thai as rew-hom/raew hawm . It is a perennial rhizomatous herb. The leafy shoots can grow to a height of 1–2.5 m (Figure 1A). The leaves are narrowly obovate, green, and glabrous (Figure 1B). The rhizomes are long-creeping, slender (0.7–1.5 cm in diameter), and fragrant (Figure 1C). Inflorescence arises from the rhizomes and is partially embedded in the ground (Figure 1D). To date E. pavieanais found in the natural habitats and cultivated in fruit gardens in southeastern Thailand for commercial purposes as food and herbs . The young shoots are eaten as a culinary vegetable, and the rhizomes are used as a spice, an ingredient in noodle soup “Moo Lieng,” and as medicines. The reported medicinal uses of the rhizomes are relieving fever and flatulence and helping the digestive system and diuresis [5, 6]. In Cambodia, the E. pavieanarhizome is boiled in water with Amomum verumBlackw. and sugar to make a drink as a tonic and as a medicine for relieving stomach disorder and pharyngitis .
3. Phytochemical constituents of E. pavieana
It has been recently reported that the investigation of rhizomes of Etlingera pavieanafrom Thailand resulted in isolation of an uncommon compound which is (E)-((E)-3-(4-methoxyphenyl)ally) 3-(4-hydroxyphenyl) acrylate or 4-methoxycinnamyl p-coumarate (MCC) (1) and a series of phenylpropanoids such as (E)-3-(4-methoxyphenyl)prop-en-1-amine (2), 3-(4-methoxyphenyl) prop-2-enal, or trans-4-methoxycinnamaldehyde (MCD) (3), (E)-4-methoxycinnamic acid (4), and (E)-1-methoxy-4-(3-methoxyprop-1-enyl) benzene (5) as shown in Figure 2 . Moreover, Srisook et al. have reported the isolation of the bioactive compound 1and its two precursors, (2E)-3-(4-methoxyphenyl)prop-2-en-1-ol or 4-methoxycinnamyl alcohol (MCA) (6) and (E)-3-(4-hydroxyphenyl)prop-2-enoic acid or p-coumaric acid (CM) (7), from the rhizome of E. pavieanaby activity-guided isolation . The other three common phenylpropanoids, (E)-4-methoxycinnamaldehyde (3), trans-anethole (8), and trans-methyl isoeugenol (9), were also extracted from the plant by Srisook and colleagues (unpublished data).
The essential oil investigation of rhizome of E. pavieanaresulted in trans-anethole (8) (48.5%) and elemicin (10, 13.8%) as major compounds , while Srisook et al. have investigated that the hydrodistillation of leaves of E. pavieanayielded methyl chavicol (11) as the most predominant product (93%) (unpublished data).
4. Pharmacological activities of E. pavieana
It is reported that E. pavieanapossess various pharmacological activities such as antioxidant [10, 11]; antimicrobial [7, 12]; anticancer against breast, cervix, liver, colon, and small cell lung cancer [7, 13]; and anti-inflammatory effects[8, 14, 15, 16]. The detailed information is shown below.
4.1 Anti-inflammatory effect
Inflammation is a complex biological response to pathogenic agents and chemical as well as physical stimuli to get rid of the stimulants . Macrophages are inflammatory cells that are considered as the first line of defense against various stimuli . Upon contact with injurious stimuli, macrophages are activated and produce a large amount of inflammatory mediators and cytokines such as reactive oxygen species (ROS), nitric oxide (NO), prostaglandins (PGs), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, and IL-12 [19, 20, 21, 22, 23, 24]. It is well-known that excess and prolonged secretion of these mediators and cytokines has participated in the pathogenesis of a variety of inflammatory diseases such as inflammatory bowel diseases , osteoarthritis , cancer , multiple sclerosis , neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease [28, 29, 30], atherosclerosis, and cardiovascular diseases [24, 31, 32, 33]. Therefore, substances inhibiting the secretions of these mediators and cytokines may be used to treat or prevent a variety of inflammation-related diseases. Since some Zingiberaceae species including Curcuma comosa, Amomum tsao-ko, Kaempferia parviflora , Zingiber officinale, Alpinia officinarum, Alpinia priceiHayata , and Alpinia katsumadaiHayata  exhibit anti-inflammatory effects in vitroand in vivo, Srisook and colleagues, therefore, designed the experiment to determine anti-inflammatory activity of E. pavieanausing lipopolysaccharide (LPS)- induced inflammation in RAW 264.7 murine macrophage cell model. A 95% ethanol extract of E. pavieanarhizomes was successively fractionated with hexane and ethyl acetate which was evaluated for anti-inflammatory effect on macrophage cells by inhibiting the production of inducible nitric oxide synthase (iNOS)-catalyzed NO. The hexane, ethyl acetate, and water fractions of rhizomal ethanol extracts of E. pavieanadisplayed anti-inflammatory effect on macrophage cells. Among them, ethyl acetate fraction was the most potent fraction. Furthermore, activity-guided isolation of this fraction showed that the bioactive compounds were phenolic compounds including 4-methoxycinnamyl alcohol (MCA), trans-4-methoxycinnamaldehyde (MCD), 4-methoxycinnamyl p-coumarate (MCC), and p-coumaric acid (CM) .
Mankhong et al. reported that 4-methoxycinnamyl p-coumarate, as the most potent compound extracted from E. pavieanarhizomes, exhibited an inhibitory effect on the production of cyclooxygenase-2 (COX-2)-catalyzed PGE2, NO, IL-1β, and TNF-α on LPS-stimulated RAW 264.7 murine macrophages with IC50 values of 14.1 ± 2.3, 32.7 ± 4.7, 3.0 ± 0.5, and 26.8 ± 5.7 μM, respectively. MCC compound inhibited gene expression of iNOS, COX-2, IL-1β, and TNF-α in a concentration-dependent manner through downregulating NF-κB, PI3K/Akt, and AP-1 signaling pathways [14, 16]. Furthermore, MCC attenuated LPS-reduced COX-1 expression in LPS-stimulated RAW 264.7 macrophages. It suggests that MCC possesses anti-inflammatory activity with selective inhibitory effect on COX expression .
Recently, trans-4-methoxycinnamaldehyde, another compound isolated from E. pavieanarhizomes, suppressed the formation of NO and PGE2 as well as the expression of their synthesizing enzymes, iNOS and COX-2, on LPS- and Pam3CSK4-induced RAW 264.7 cells. The IC50 values of NO and PGE2 inhibition were 49.9 ± 4.7 and 87.6 ± 5.6 μM, respectively. The mechanism underlying anti-inflammatory activity of MCD could be inactivation of NF-κB and JNK/c-Jun signaling pathways . Moreover, MCD showed a significant anti-inflammatory activity in rat models of acute inflammation. It was evident from this study that MCD (3 mg/ear) reduced ethyl phenylpropiolate (EPP)-induced ear edema by 51.5% inhibition. The second animal model used in this study was carrageenan-induced paw edema. Rats were orally administrated with MCD at doses of 75, 150, and 300 mg/kg for 1 h before injection with carrageenan. MCD can significantly decrease paw edema in a dose-dependent manner at 1, 3, and 5 h after carrageenan stimulation. Since edema formation induced by EPP and carrageenan is attributed to a release of several inflammatory mediators [41, 42], it is implied that the mode of MCD anti-inflammatory action in vivomodel is mediated in part by suppression of inflammatory mediators.
We also investigated anti-inflammatory effect of essential oil of E. pavieanaleaves on LPS-induced RAW 264.7 macrophages. The essential oil of E. pavieanaleaves at 25–100 μg/mL exhibited a concentration-dependent inhibition effect on NO production without significant cytotoxicity (Figure 3A). Incubation of cells with essential oil caused reduction of iNOS protein and mRNA expression (Figure 3B,C). The compound responsible for anti-inflammatory effect of essential oil of E. pavieanaleaves might be methyl chavicol, a main phytoconstituent of this essential oil (unpublished data).
4.2 Antiatherogenic effect
Atherosclerosis is a chronic inflammatory disorder which leads to cardiovascular diseases (CVDs) [43, 44]; it is a major cause of death in the world [24, 45]. Endothelial dysfunction is an early step in the development of atherosclerosis. It involves with reduced NO bioavailability, low-grade inflammation, and oxidative stress [44, 46, 47, 48]. The initiation of atherosclerotic lesion is influenced by the expression of cell adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on the vascular surface of the endothelial cells resulting in recruitment of leukocytes into the vascular tissue . Inhibiting the expression of ICAM-1 and VCAM-1 leads to reduction of leukocyte emigration and retardation of the development of atherosclerosis. Thus, the substance that inhibits the expression of these cell adhesion molecules may be considered as anti-atherosclerosis agent that prevents vascular inflammatory disorders.
The rhizomal ethanol extract of E. pavieanawas assessed for its anti-vascular inflammatory effect in human umbilical vein endothelial cells (EA.hy926 cells). Endothelial activation is upregulated by various pro-inflammatory cytokines, including TNF-α secreted under inflammatory conditions. The E. pavieanaextract inhibited TNF-α-induced expression of ICAM-1 and VCAM-1 protein and mRNA in a concentration-dependent manner. The inhibitory effect of the rhizome extract in endothelial cells is caused from interfering with the activation of NF-κB and JNK/c-Jun signaling pathways. Moreover, Akt activation by E. pavieanarhizome is associated with negative regulation of inflammation. This anti-vascular inflammatory activity was attributed in part due to the presence of the two most active phenolic compounds of which were 4-methoxycinnamyl p-coumarate and trans-4-methoxycinnamaldehyde .
It is believed that decrease in endothelium-derived NO, produced by endothelial NO synthase (eNOS), results in reduced NO bioavailability [44, 49]. Another study was carried out to demonstrate antiatherogenic effect of E. pavieanarhizome. EA.hy926 endothelial cells incubated with the ethanol extract of E. pavieanarhizome (12.5–200 μg/mL) caused increased NO level in a concentration-dependent manner. This induction might be partly mediated by the activation of eNOS enzyme via phosphorylation at Ser1177 .
4.3 Antioxidant effect
Accumulating evidences suggest that not only inactivation of eNOS enzyme but also increased superoxide level leads to the reduction in NO bioavailability [24, 49]. Superoxide anion is produced by the mitochondrial electron transport chain and several enzymes in the endothelial cells. Superoxide anion is then oxidized to hydrogen peroxide and other physiological reactive species such as hydroxyl radical and hypochlorous acid . Moreover, it reacts with NO to form highly reactive peroxynitrite leading to eNOS dysfunction [24, 47]. Chronic inflammation is also closely associated with oxidative stress which generated excess ROS .
The hexane, ethyl acetate, and water fractions of ethanol extract of E. pavieanarhizomes have shown in vitroantioxidant effects, which are evaluated by various antioxidant activity assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, reducing power and ferrous ion chelating activity . E. pavieanarhizomal extract has also been assayed, its ROS scavenging activity in EA.hy926 endothelial cells, using 2,7-dichlorodihydrofluorescein diacetate (H2DCF-DA) probe. TNF-α markedly induced ROS formation, while the extract (25–100 μg/mL) concentration dependently inhibited ROS level . Thus, the data indicate antioxidant effect of E. pavieanamediated in part by counteract with ROS.
4.4 Anticancer activity
A number of plant-derived compounds can prevent progression of cancer [51, 52] and possess anticancer activity . The ethanol extract from E. pavieanarhizomes exhibits cytotoxic effect against several cancer cell lines such as breast adenocarcinoma MDA-MB-231, hepatoma HepG2, cervical carcinoma HeLa, and C33A. The IC50 values were ranging from 160 to 192 μg/mL, respectively. Trans-4-methoxycinnamaldehyde, an active compound isolated by cytotoxicity-guided isolation from E. pavieanarhizomes, has shown cytotoxic effects against C33A, colorectal carcinoma HCT116, MDA-MB-231, and HepG2 with the IC50 values of 34.3, 38.7, 39.3, and 40.7 μM, respectively . Tachai and Nuntawong  reported that 4-methoxycinnamyl p-coumarate exhibited inhibitory activity on cell growth of human breast cancer (MCF7), human oral cavity cancer (KB), and human small cell lung cancer (NCI-H187) with IC50 values of 25.1, 20.2, and 34.8 μM, respectively . Essential oil from the rhizomes was found to have cytotoxic effect against NCI-H187 (IC50: 31.7 μg/mL) .
4.5 Antimicrobial activity
Various solvent extracts of E. pavieana(ethanol, acetone, dichloromethane, ethyl acetate, petroleum ether, and hexane) were found to be active against Gram-positive bacteria (Bacillus cereus, B. subtilis, Staphylococcus aureus, Listeria monocytogenes) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Vibrio parahaemolyticus, and Salmonella typhimurium). Antimicrobial activity of leaves was higher than that of stem and rhizome . Tachai and Nuntawong demonstrated that hexane, dichloromethane, and methanol extracts of E. pavieanarhizomes were inactive against Mycobacterium tuberculosis, while MCC exhibited its antimicrobial activity against M. tuberculosiswith minimum inhibitory concentration at 50 μg/mL .
In this chapter, we have provided the information on botanical aspects, dietary and traditional uses, phytochemicals, and pharmacological activities of Etlingera pavieanawhich is distributed in Southeast Asia. The major active compounds are phenylpropanoids such as trans-4-methoxycinnamaldehyde, and 4-methoxycinnamyl p-coumarate. Its rhizomes exhibit anti-inflammatory, antioxidant, antiatherogenic, antimicrobial, and anticancer activities. The pharmacological activities reported here confirm therapeutic efficacy of E. pavieanarhizomes which might be developed into medicines or nutraceuticals for the treatment and prevention of various diseases, especially inflammation-related diseases. However, in vivo toxicology studies of E. pavieanarhizomes should be performed along with the clinical trials.
This work was financially supported by the Research Grant of Burapha University through the National Research Council of Thailand (Grant no. 10/2555, 43/2558, 44/2558, 75/2559, 76/2559, 151/2560) and by the Research Unit of Natural Bioactive Compounds for Healthcare Products Development. The authors are highly grateful to the Center of Excellence for Innovation in Chemistry (PERCH-CIC) and the Commission on Higher Education, Ministry of Education, Thailand.
Conflict of interest
The authors have no conflict of interest to declare.
Klaokwan Srisook and Ekaruth Srisook (September 23rd 2019). Pharmacological Activities and Phytochemicals of <em>Etlingera pavieana</em> (Pierre ex Gagnep) R.M.Sm, Medicinal Plants - Use in Prevention and Treatment of Diseases, Bassam Abdul Rasool Hassan, IntechOpen, DOI: 10.5772/intechopen.89277. Available from:
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