Curcuma zedoaria (Christm.) Roscoe

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Malaysian Herbal Monograph

Temu kuning rhizome

Curcuma zedoaria (Christm.) Roscoe

Zingiberaceae

Figure 1 : Curcuma zedoaria. (a) Whole plant; (b) leaves; (c–d) rhizomes. (Photos courtesy of Institute for Medical Research, 2016)

DEFINITION

Temu kuning rhizomes consist of the powder of dried rhizomes of Curcuma zedoaria (Christm.) Roscoe (Zingiberaceae).

SYNONYM

Amomum latifolium Lam., Amomum zedoaria Christm., Costus luteus Blanco, Costus nigricans Blanco, Curcuma malabarica Velay., Amalraj & Mural., Curcuma pallida Lour., Curcuma raktakanta Mangaly & M. Sabu, Curcuma speciosa Link, Erndlia zerumbet Giseke, Roscoea lutea (Blanco) Hassk., Roscoea nigrociliata Hassk [ 1 , 2].

VERNACULAR NAMES

Setwall, Zedoary tumeric, White turmeric, Zedoary (English); Kunchur, Temu kuning, Temu putih (Malay); Er-shu [ 3 ], Yu jin (Chinese); Niruvisam, kichilikilhangu, poolan kilangu (Tamil) [ 4 ].

CHARACTER

Colour	Light yellow [ 6 ]
Odour	Aromatic [ 6 ]
Taste	Strong pungent [ 6 ]

IDENTIFICATION

Plant Morphology

C. zedoaria is perennial herb, grows up to 1.2 m in height, has both vertical aerial stem or pseudostems and horizontal underground tuberous rootstock or rhizomes. Rhizome conical branched robust, greyish brown to brown outside and pale yellowish inside. Leaves erect, glabrous, elliptic-oblong to oblong-lanceolate, up to 81 cm long, 18 cm wide, green with purple hue along the midrib; leaf sheaths 35–60 cm long. Inflorescence on a separate shoot, cylindrical, 10–20 cm long, 8–15 cm wide, arises from a leafless underground stem; bracts numerous, ovate to obovate, lower ones green, more or less tipped with pink, and upper ones purple, each containing several flowers. Flowers with yellowish-white corolla, 3.5–4.5 cm long; corolla tube 2 cm long; labellum bilobed, 2–2.5 cm long, 1.5–2 cm wide, yellowish white with dark yellow median band; staminode longitudinally folded, yellowish-white, anther with long spurs; ovary is villous. Capsules ovoid, triangular and dehiscing irregularly. Seeds oblong, and lanceolate, white in colour [ 4 , 7 , 8 ].

Microscopy

Powdered material consists of parenchyma cells; fragments of vessels with reticulate thickening; abundant of starch granules with varying size and shape, may be free or agglomerated; thin-walled fibers isolated [ 5 ,6 ].

Figure 2 : Microscopic characters of Curcuma zedoaria dried rhizome powder of 0.355 mm size. (a) Parenchyma cells (magnification 40x); (b) reticulate thickened vessels (magnification 40x); (c) starch granules (magnification 20x); (d) agglomerated starch granules (magnification 40x); (e) fibre (magnification 20x). [Scale bars: a, b, d = 50 µm; c, e = 100 µm]

Colour Tests

Observed colour of solution after treatment with various reagents:

Acetic anhydride and sulphuric acid (concentrated)

Red for triterpene

Thin Layer Chromatography (TLC)

Figure 3 : TLC chromatogram of demethoxycurcumin (S), ethanol extract of Curcuma zedoaria dried rhizome powder (L) observed under (a) visible light before derivatisation, (b) UV at 254 nm before derivatisation, (c) UV at 366 nm before derivatisation and (d) visible light after derivatisation

Test Solutions	Weigh about 5.0 g of C. zedoaria dried rhizome powder of 0.355 mm size in a conical flask and add 20 mL of ethanol. Sonicate the mixture for 30 min at room temperature. Filter the solution and use as test solution.
Standard solution	Dissolve demethoxycurcumin (CAS no: 22608-11-3) in ethanol to produce standard solution 20 µg/mL.
Stationary Phase	HPTLC Glass Silica Gel 60 F_254, 10 x 10 cm
Mobile phase	Chloroform : ethanol : acetic acid; (94 : 5 : 1) (v/v/v)
Application	Demethoxycurcumin (DMC) standard (S); 20 μL, 8 mm as a band. Ethanol extract of C. zedoaria dried rhizome powder (L); 20 μL, 8 mm as a band
Development distance	8 cm
Drying	Air drying
Detection	Visible light before derivatization; UV at 254 nm before derivatization; UV at 366 nm before derivatization; Visible light after derivatization with anisaldehyde-sulphuric solution. Preparation of anisaldehyde-sulphuric solution: 10 mL sulphuric acid is carefully added to 170 mL ethanol and 20 mL acetic acid. To this solution, 1 mL anisaldehyde is added. The plate was sprayed and heated at 100˚C for 5 min.

High Performance Liquid Chromatography (HPLC)

Test solution

Weigh about 5.0 g of C. zedoaria dried rhizome powder of 0.355 mm size in a vial and add 20 mL of ethanol. Sonicate the mixture for 30 min at room temperature. Evaporate to dryness. Reconstitute with 1 mL ethanol. Filter the solution and use as test solution.

Standard solution

Dissolve demethoxycurcumin (CAS no: 22608-11-3) in ethanol to produce 20 µg/mL standard solution.

Chromatographic system

Detector: UV 420 nm

Column: Symmetry, C18 column (5 µm, 100 Å, 3.9 x 150 mm)

Column oven temperature: 35°C

Flow rate: 0.8 mL/min

Injection volume: 5 µL

Mobile Phase (gradient mode)

Run Time (min)	A – 0.1 % Formic acid in water (%)	B – 0.1 % Formic acid in acetonitrile (%)
0.0	90	10
2.0	50	50
10.0	50	50
15.0	60	40
20.0	60	40
20.5	90	10
25.0	90	10

System suitability requirement

Perform at least five replicate injections of demethoxycurcumin (20 µg/mL). The requirements of the system suitability parameters as follow:

Symmetry factor (A_s) is not more than 1.5.
Percentage of relative standard deviation (RSD) of the retention time (t_r) for demethoxycurcumin standard is not more than 2.0%.

Acceptance criteria

Retention time (t_r) of demethoxycurcumin in the test solution is similar to the t_r of the standard solution.
The ultraviolet (UV) spectrum of demethoxycurcumin in the test solution is similar to the standard solution (optional supportive data).

(a)

(b)

Figure 4 : Whole HPLC chromatogram of (a) demethoxycurcumin standard solution (20 µg/mL) at t_r= 8.169 min and (b) ethanol extract of Curcuma zedoaria dried rhizome powder showing peak corresponding to demethoxycurcumin standard solution at t_r= 8.138 min

(a)

(b)

Figure 5 : HPLC chromatogram highlighting the elution region of demethoxycurcumin in (a) demethoxycurcumin standard solution (20 µg/mL) at t_r= 8.169 min and (b) ethanol extract of Curcuma zedoaria dried rhizome powder showing peak corresponding to demethoxycurcumin standard solution at t_r= 8.138 min.

Figure 6 : UV spectrum of demethoxycurcumin standard solution (20 µg/mL) and ethanol extract of Curcuma zedoaria dried rhizome powder.

PURITY TESTS

The purity tests are based on C. zedoaria dried rhizome powder of 0.355 mm particle size.

Foreign Matter

Not more than 2%

Ash Contents
Total ash	Not more than 9%
Acid-insoluble ash	Not more than 3%
Water-soluble ash	Not less than 1%

Loss on Drying

Not more than 12%

Extractive Values
*Water-soluble extracts*
Hot method	Not less than 21%
Cold method	Not less than 13%
*Ethanol-soluble extracts*
Hot method	Not less than 2%
Cold method	Not less than 1%

SAFETY TESTS

The safety tests are based on C. zedoaria dried rhizome powder of 0.355 mm particle size.

Heavy Metals
Arsenic	Not more than 5.0 mg/kg
Mercury	Not more than 0.5 mg/kg
Lead	Not more than 10.0 mg/kg
Cadmium	Not more than 0.3 mg/kg

*Microbial Limits*
Total bacterial count	Not more than 10⁵ cfu/g
Total yeast and mould count	Not more than 10⁴ cfu/g
Bile-tolerant gram negative	Not more than 10⁴ cfu/g

*Specific Pathogens*
Salmonella spp.	Absent in 25 g
Escherichia coli	Absent in 1 g
Staphylococcus aureus	Absent in 1 g
Pseudomonas aeruginosa	Absent in 1 g

CHEMICAL CONSTITUENTS

Aqueous extract of C. zedoaria rhizomes was found to contain polysaccharide with moieties (i.e. (1→6)-linked glucopyranosyl, (1→3,4)-linked galactopyranosyl, (1→2)-linked arabinopyranosyl and terminal rhamnopyranosyl) [ 9].

Ethanol (30%) extract of C. zedoaria rhizomes was found to contain sesquiterpene (i.e. curcumenone) [10].

Acetone (80%) extract of C. zedoaria dried rhizomes was found to contain sesquiterpenes (i.e. curcumenolactone A, B and C, curcumenone, 4S-Dihydrocurcumenone, curcarabrannol A and B, furanodiene, zederone, germacrone, 13-Hydroxygermacrone, glechomanolide, (+)-germacrone 4,5-epoxide, curdione, neocurdione, dehydrocurdione, curcumenol, isocurcumenol, isoprocurcumenol, alismoxide, 7α-11α-epoxy-5β-hydroxy-9-guaiaen-8-one, aerugidiol, zedoarondiol, isozedoarondiol, zedoalacone B, zedoarolide A and B, (+)-ar-Turmerone, bisacumol, bisacurone, β-eudesmol, β-dictyopterol, zedoarofuran, curzerenone and curcumadione) and curcuminoids [i.e. curcumin and bis(4-hydroxycinnamoyl)methane] [ 11 ].

Methanol extract of C. zedoaria rhizomes was found to contain essential oils (curcuzedoalide, curcuminol D and indole-3-aldehyde), sesquiterpenes (i.e. zedoarondiol, curcuzederone, ar-turmerone, β-turmerone, furanodiene, furanodienone, furanodienone isomer, zederone, curzerenone, curzeone, germacrone, 13-hydroxygermacrone, dehydrocurdione, curcumenone, zedoaronediol, 13-hydroxycurzerenone, 1-oxocurzerenone, curcolone, procurcumenol and ermanin), triterpenoids (i.e. β-sitosterol, stigmasterol, stigmast-4-en-3,6-dione, stigmasa-4,22-dien-3,6-dione, 6β—hydroxystigmast-4-en-3-one and 6β-hydroxystigmasta-4,22-dien-3-one), curcuminoid (i.e. curcumin) and flavonoid (i.e. naringenin) [ 12 , 13 , 14, 15 , 16 , 17 ].

Ethanol extract of C. zedoaria dried rhizomes was found to contain essential oils (1,8-cineol, camphor, isoborneol, borneol, β-elemene, (E)-β-caryophyllene, α-humulene, (E)-β-farnesene, germacrene D, β-selinene, germacrene B, caryophyllene oxide, curzerone, furanodienone, T-cadinol, α-cadinol, ar-turmerone, germacrone, curdione, curcumenol, α-(E)-atlantone), sesquiterpenes (i.e. curcolonol and guaidol), curcuminoid (i.e demethoxycurcumin) and a phenolic acid (i.e. 3,7-dimethylindan-5-carboxylic acid) [ 18 , 19 ].

Isopropanol extract of C. zedoaria dried rhizomes was found to contain essential oils (1,8-cineol, camphor, isoborneol, borneol, β-elemene, (E)- β-caryophyllene, α-humulene, (E)- β-farnesene, germacrene D, β- selinene, germacrene B, caryophyllene oxide, curzerenone, α- cadinol, furanodiene, germacrone, curdione, curcumenol, α-(E)- atlantone) [ 19 ].

Ethyl acetate extract of C. zedoaria dried rhizomes was found to contain essential oils (camphene, 1,8-cineol, camphor, isoborneol, borneol, α-terpineol, β-elemene, (E)-β-caryophyllene, α-humulene, (E)- β- farnesene, β-chamigrene, germacrene D, β-selinene, germacrene B, caryophyllene oxide, curzerenone, T-cadinol, furanodiene, germacrone, curdione, curcumenol, α-(E)-atlantone) [ 19 ].

Dichloromethane extract of C. zedoaria rhizomes was found to contain sesquiterpenes (i.e. curcumenone, zedoarol, 13-hydroxygermacrone, curzeone and curcumanolide A and B, and curmcumenol) [ 20 ,21 ,22].

Diethyl ether extract of C. zedoaria rhizomes was found to contain curcuminoids (i.e. diferuloylmethane, feruloyl-p-coumaroylmethane, and di-p-coymaroylmethane) [ 23 ].

Hexane extract of C. zedoaria dried rhizomes was found to contain sesquiterpenenes (i.e. germacrone, dehydrocurdione, curcumenol, zerumin A, isoprocurcumenol, curcumenone, procurcumenol, zerumbone epoxide, zederone and gweicurculactone) [ 24 ].

Pentane extract of C. zedoaria rhizomes was found to contain essential oil (i.e. camphor) and sesquiterpenenes (i.e. furandione and curzerene) [ 23 ].

Essential oil of C. zedoaria rhizomes is composed of α-pinene, camphene, sabinene, β-pinene, β-myrcene, D-limonene, eucalyptol (1,8-cineol, 1,8-cineole), γ-terpinene, linalool, camphor, isoborneol, borneol, 4-terpineol, α-terpineol, δ-elemene, caryophyllene, γ-elemene, valencene, α-caryophyllene, α-gurjunene, germacrene, β-selinene, curzerene, δ-cadinene, aristolene, β-eudesmol, β-eudesmene, β-elemenone, germacrone, curdione, neocurdione, β-elemene, ar-curcumene, zingiberene, α-farnesene, curzerene, β-sesquiphellandrene, germacrene B, β-turmerone and epi-curzerenone, β-farnesene, α-humulene, β-himachalene, β-bisabolene, α-curcumene, α-galacorene, calarene, elemol, curzerenone, spathulenol, α-cadinol, eudesmol, curcumol, isocurcumenol, farnesol, isospathulenol, 5-isopropylidene-3,8-dimethyl-1(5H)-azulenone, myrcene, p-cymene, trans-pinocarveol, p-cyymen-8-ol, β-terpineol, myrtenol, verbone, carvone, isobornyl acetate, β-bourbonene, cis-α-bergamotene, (E)-β-caryophyllene, α-santalene, trans-α-bergamotene, aromadendiene, β-chamigrene, germacrene D, α-agarofuran, caryophyllene oxide, furanodiene, T-cadinol, ar-tumerone, γ-(E)-atlantone, curcumenol, α-(E)-atlantone and fatty acids (i.e. 2-nonanol, 2-undecanol, 2-nonanone, 2-decanone, 2-undecanone and 1-oleoyl-2,3-distearoylglycerol) and 1,2,4-trimethoxy ethyl benzene) [ 17 , 19 , 25 , 26, 27 ].

MEDICINAL USES

Uses described in folk medicine, not supported by experimental or clinical data

Traditionally used for relieving malarial fevers, vomiting, hiccup, worm infestation, flatulence, intestinal infection, throat inflammations, discharges from genital organs and local skin infections. C. zedoaria also acts as a tonic and help to relief cough. Juice of the leaves can be drink for dropsy [ 28 ].

Biological and pharmacological activities supported by experimental data

Antipyretic activity

Ethanol (80%) extract of C. zedoaria rhizome (750 mg/kg) was administered orally as a single dose to Young Long-Evan rats (172 – 210 g) after 18 hr induction of pyrexia using Brewer’s yeast. The extract (750 mg/kg) showed significant (p < 0.001) antipyretic effect by measuring the rectal temperature at two hr (94.24 ± 0.44⁰F) and three hr (92.50 ± 0.39⁰F) similar as paracetamol (10 mg/kg) (2 hr: 96.38 ± 0.56⁰F; 3 hr: 91.98 ± 0.67⁰F) compared to untreated control group (distilled water) (2 hr: 96.38 ± 0.56⁰F; 3 hr: 95.70 ± 0.66⁰F) [ 29].

Analgesic effect

Curcumenol isolated from dichloromethane fraction of C. zedoaria rhizome (1-10 mg/kg) administered intraperitoneally to Swiss mice (25 – 35 g) 30 min before induction of abdominal constriction using acetic-acid showed analgesic effect with 50% inhibition of nociceptive response (ID₅₀) of 22 µmol/kg compared to diclofenac (ID₅₀ = 38 µmol/kg) [ 30 ].

Curcumenol isolated from dichloromethane fraction of C. zedoaria rhizome (3 – 15 mg/kg) administered intraperitoneally to Swiss mice (25 – 35 g) 60 min before induction of pain using formalin showed analgesic effect (42.2% pain inhibition) with ID₅₀= > 64 µmol/kg at zero to five min formalin-induced pain compared to diclofenac (ID₅₀ > 94 µmol/kg). The extract also showed analgesic effect at 15 – 30 min formalin-induced pain (ID₅₀= 29 µmol/kg) compared to diclofenac (ID₅₀ = 34.5 µmol/kg) [ 30 ].

Curcumenol isolated from dichloromethane fraction of C. zedoaria rhizome (1 – 10 mg/kg) administered intraperitoneally to Swiss mice (25 – 35 g) one hr before capsaicin induced-pain showed analgesic effect with ID₅₀= 12 µmol/kg compared to diclofenac (ID₅₀ = 47 µmol/kg) [ 30 ].

Anti-allergic activity

Aqueous acetone (80%) extract of C. zedoaria rhizome (400 mg/kg) was administered orally as a single dose to male ddY mice (25 – 30 g) after 47 hr induction of ear passive cutaneous anaphylaxis (PCA) using monoclonal anti-dinitrophenol (anti-DNP IgE) for duration of one hr. The extract significantly (p < 0.05) inhibited ear PCA reaction (34.0%) compared to anti-DNP IgE treated control with no inhibition [ 31 ].

Antioxidant activity

Methanol extract of C. zedoaria rhizome (50 µg/mL) showed antioxidant activity with hydroxyl free radical scavenging activity (46.03 ± 0.21%) compared to ascorbic acid (hydroxyl free radical scavenging activity: 52.33 ± 0.40%) [ 32 ].

Methanol extract of C. zedoaria rhizome (200 µg/mL) showed antioxidant activity with DPPH scavenging activity (62.31 ± 0.5%) compared to ascorbic acid (DPPH scavenging activity: 79.30 ± 0.1%) [ 32 ].

Hepatoprotective activity

Aqueous acetone extract of C. zedoaria rhizome (100 mg/kg) was administered orally to male ddY mice (25 – 27 g) one hr before liver injury induction using D-galactosamine/lipopolysaccharide. The blood samples were collected 10 hr after D-GaIN injection. The extract inhibited the increase of serum glutamic-oxaloacetate transaminase (s-GOT) and serum glutamic pyruvic transaminase (s-GPT). The extract showed significant (p < 0.01) reduction in serum (s-GOT: 2812.5 Karmen Unit) and (s-GPT: 2187.5 Karmen Unit) compared to untreated control (s-GOT: 8125 Karmen Unit; s-GPT: 6718.75 Karmen Unit) [ 32 ].

Antihyperlipidemic activity

Ethanol (50%) extract of C. zedoaria dried powder rhizome (200 and 400 mg/kg) was administered orally to adult male rats (150 – 220 g) for duration of 12 days before induction of hyperlipidemia using poloxamer. The extract significantly (p < 0.001) reduced total cholesterol level (200 mg/kg: 238.33 ± 5.98 mg/dL; 400 mg/kg: 231.0 ± 5.51 mg/dL) compared to poloxamer-treated control group (1 g/kg) (287.50 ± 12.61 mg/dL) [ 34 ].

Anti-angiogenesis activity

Essential oil of C. zedoaria rhizome (100 and 200 mg/kg) was administered orally to female C57BL/6 mice (six week old) for duration of 28 days after induction of melanoma using melanoma cell lines (B16BL6). The extract significantly (p < 0.05) reduces the weight of melanoma (2.48 ± 0.50 and 2.92 ± 0.66 g, respectively) and microvessel density (MVD: 20 and 30, respectively) compared to control (weight of melanoma: 4.34 ± 0.64 g; MVD: 48) [ 35 ].

Essential oil of C. zedoaria rhizome (100 and 200 mg/kg) showed anti-angiogenic activity with inhibition of vascular endothelial growth factor (VEGF) expression (225 and 175 ng/L, respectively) in mouse embryo fibroblast cell line (NIH3T3) compared to corn oil-treated control group (275 ng/L) using enzyme-linked immunosorbent assay [ 36 ].

Vascular-relaxation activity

Aqueous acetone (80%) extract of C. zedoaria rhizome (6.25 – 50.0 µg/mL) inhibited contraction of isolated rat thoracic aorta strips induced by high potassium (K⁺) dose-dependently (15.8 ± 3.4 – 98.8 ± 6.5%) with inhibition concentration at 50% (IC₅₀) of 18 µg/mL compared to nifedipine (28.4 ± 4.2 – 84.0 ± 3.7%; IC₅₀ = 6.4 nM) [ 37 ].

Anti-alcohol intoxication

Ethanol (30%) extract of C. zedoaria rhizome (1000 mg/kg) was administered orally twice daily to male ICR mice (five weeks old) for duration of seven days before induction of intoxication on day-eight using alcohol (40%). The extract significantly (p < 0.05) reduced drunkenness (41.3% intoxication) and blood alcohol concentration (1.31 mg/mL plasma) at 60 min compared to vehicle-treated control group (82.5% intoxication; 1.88 mg/mL plasma) [ 10 ].

Hexane fraction of C. zedoaria rhizome (300 mg/kg) was administered orally twice daily to male ICR mice (five weeks old) for duration of seven days before induction of intoxication on day-eight using alcohol (40%). The extract significantly (p < 0.05) reduce drunkenness (47.5% intoxication) and blood alcohol concentration (1.25 mg/mL plasma) at 30 min compared to vehicle-treated control group (75% intoxication; 1.85 mg/mL plasma) [ 10 ].

Curcumenone isolated from hexane fraction of C. zedoaria (10 mg/kg) was administered orally twice daily to male ICR mice (five weeks old) for duration of seven days before induction of intoxication on day-eight using alcohol (40%). The compound significantly (p < 0.05) reduce drunkenness (45% intoxication) and blood alcohol concentration (1.5 mg/mL plasma) while significantly (p < 0.05) increase liver alcohol dehydrogenase level (ADH: 1000 nmol/min/liver 1 g) at 60 min compared to vehicle-treated control group (slip-failing angle: 75% intoxication; blood alcohol concentration: 2.0 mg/mL plasma; ADH: 800 nmol/min/liver 1 g) [ 10 ].

Cytotoxic activity

Methanol extract of C. zedoaria rhizome showed cytotoxicity activity on nasopharyngeal carcinoma cell line (KB) (IC₅₀of 14.4 ± 0.7 µg/mL) and human cervical carcinoma (Ca Ski) cell line (IC₅₀= 14.2 ± 1.5 µg/mL) compared to doxorubicin (IC₅₀against KB: 0.27 ± 0.01 µg/mL; Ca Ski: 0.18 ± 0.06 µg/mL) using neutral red cytotoxicity assay [ 38 ].

Hexane fraction of C. zedoaria rhizome showed cytotoxicity activity on Ca Ski (IC₅₀= 16.4 ± 0.9 µg/mL) and breast cancer cell line (MCF-7) (IC₅₀ = 18.9 ± 0.7 µg/mL) compared to doxorubicin (Ca Ski: 0.18 ± 0.06 µg/mL; MCF-7: 0.0.5 ± 0.01 µg/mL) using neutral red cytotoxicity assay [ 38 ].

Curzerenone and alismol isolated from hexane fraction of C. zedoaria rhizome showed cytotoxicity activity on Ca Ski (IC₅₀= 8.9 ± 0.7 and 8.70 ± 1.1 µg/mL, respectively) compared to doxorubicin (IC₅₀ = 0.18 ± 0.06 µg/mL) using neutral red cytotoxicity assay. Compound alismol also showed cytotoxicity activity on MCF-7 (IC₅₀= 10.0 ± 0.7 µg/mL) compared to doxorubicin (IC₅₀= 0.05 ± 0.01 µg/mL) using neutral red cytotoxicity assay [ 38 ].

Curcumenol and curcumenone isolated from hexane extract of C. zedoaria rhizome showed cytotoxicity activity on MCF-7 (IC₅₀=9.3 ± 0.3 µg/mL and 8.3 ± 1.0 µg/mL, respectively) compared to doxorubicin (IC₅₀= 0.1 ± 0.0 µg/mL) using 3-[4, 5-dimethyl-thiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay [ 39 ].

Antiproliferative activity

Aqueous extract of C. zedoaria rhizome (5 and 10 µg/mL) significantly (p < 0.01) inhibit serum-induced human hepatic myofibroblast (hMF) cell proliferation (5 µg/mL: 32% and 10 µg/mL: 76%, respectively) over the time course (7-days incubation) compared to control group using MTT assay [ 39 ].

The extract (10 µg/mL) also inhibit serum-induced hMF cell proliferation with IC₅₀ of 8.5 µg/mL against pertussin toxin-treated cells compared to vehicle-treated cells using [3]-thymidine incorporation assay [ 39 ].

Aqueous extract of C. zedoaria rhizome (10 µg/mL) significantly (p < 0.05) inhibit platelet-derived growth factor (PDGF-BB)-induced hMF cell proliferation (6.5 ± 0.54 cells/well x 10⁴) after 24 hours incubation compared to control group (22.3 ± 4.65 cells/well x 10⁴) using MTT assay [ 41 ].

The extract (5-10 µg/mL) also significantly (p < 0.05) inhibit PDGF-BB-induced hMF cell proliferation (40.2 ± 6.8 – 47.2 ± 2.3% bromodeoxyuridine (BrdU) incorporation) after 24 hours incubation compared to control group using BrdU incorporation assay [ 41 ].

Anti-inflammatory activity

Furanodiene and furanodienone isolated from ethyl acetate (20%) fraction of C. zedoaria rhizome (1.0 µmol) were applied topically to mouse ear for 30 min before 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema. The compounds significantly (p < 0.05) inhibited edema with 75 and 53% inhibitory effect, respectively compared to indomethacin (1.4 µmol) (78% inhibitory effect) [ 14 ].

Antimetastatic activity

Aqueous extract of C. zedoaria rhizome (250 and 500 mg/kg) was administered intraperitoneally to male C57BL/6 mice (eight weeks old) two weeks before inoculation of B16 mouse melanoma cells line (1.3 x 10⁵cells/mouse) for duration of six weeks. The extract significantly (p < 0.05) reduce the weight of lung (0.177 g and 0.175 g, respectively) and number of surface nodules (150 and 154 of lung nodules, respectively) after 21 days compared to B16 cells-alone treated group (weight of lung: 0.215 g; number of surface nodules: 352 lung nodules) [ 42 ].

Antibacterial activity

Petroleum ether of C. zedoaria tuber (2.5 – 0.01 mg/mL) inhibited the growth of Bacillus subtilis with inhibition zone (IZ) of 15 mm and minimum inhibitory concentration (MIC) of 0.02 mg/mL, Microsoccus luteus (IZ: 13 mm, MIC: 0.01 mg/mL), Proteus mirabilis (9 mm, MIC: 0.04 mg/mL), Klebsiella pneumonia (8 mm, MIC: 0.02 mg/mL) compared to gentamycin (10 µg) (B. subtilis: 27 mm, M. luteus: 20 mm, P. mirabilis: 21 mm, K. pneumonia: 18 mm) and tetracycline (B. subtilis: 21 mm, M. luteus: 29 mm, P. mirabilis: 17 mm, K. pneumonia: 30 mm) using agar-well diffusion assay [ 43 ].

Essential oils (5 mL) in methanol (100 mL) of C. zedoaria rhizome inhibited the growth of Mycobacterium phlei (MIC: 1.2 mg/mL) with inhibition zone of 18 mm compared to oxacilin (MIC: 0.0001 mg/mL, inhibition zone: 20 mm). The extracts also inhibited the growth of S. aureus with inhibition zone of 12 mm compared to kanamycin (22 mm) using disc diffusion assay [ 44 ].

Antifungal activity

Ethanol extract of C. zedoaria rhizome inhibited C. albicans and C. dubliniensis with MIC of 2.6 ± 0.9 mg/mL, C. glabrata (MIC: 6.25 ± 0 mg/mL), C. krusei (MIC: 8.33 ± 3.6 mg/mL), C. tropicalis ATCC 750 and ATCC 13803 (MIC: 2.60 ± 0.9 mg/mL) and C. tropicalis ATCC 66029 (MIC: 1.56 ± 0 mg/mL). Meanwhile, the growth of fungal was inhibited with minimum fungicidal concentration (MFC) at > 25 mg/mL against C. albicans, C. glabrata, C. krusei, C. tropicalis ATCC 750 and ATCC 13803 while C. dubliniensis and C. tropicalis ATCC 66029 were inhibited at MFC of 25 ± 0 mg/mL compared to chlorhexidine using broth microdilution assay [ 45].

Petroleum ether of C. zedoaria tuber inhibited the growth of C. albicans with inhibition zone of 10 mm and MIC of 0.04 mg/mL, Aspergillus niger (8 mm, MIC: 0.15 mg/mL) while acetone extract inhibited C. albican (8 mm, MIC: 0.01 mg/mL), A. niger (8 mm, MIC: 0.01 mg/mL) compared to clotrimazole (8 mm) using agar-well diffusion assay [ 43 ].

Clinical studies

Information and data have not been established.

SAFETY INFORMATION

Preclinical studies (Toxicology studies)

Genotoxicity

Hydroalcoholic (50%) extract of C. zedoaria rhizome (39.06, 78.125 and 156.25 µg/mL) was treated on human lymphocytes for duration of four hours. The extract showed genotoxic activities with chromosomal aberrations (2.0, 2.5 and 6.5%, respectively) compared to Mitomycin C (0.3 µg/mL) (16.0% of chromosomal aberrations) using chromosomal aberration test [ 46 ].

Embryotoxicity

Essential oil of C. zedoaria rhizome (40 µg/mL) was treated on Sprague Dawley’s embryos (gestation day (GD) of 9.5) for duration of 48 hours. The extract showed significant (p < 0.01) developmental toxicity with reduction of yolk sac diameter (3.10 ± 0.47 mm), crown-rump length (2.53 ± 0.37 mm) and head length (1.33 ± 0.22 mm) while decrease the somite number (9.33 ± 1.51) and total morphological score (17.63 ± 2.07) compared to N,N-dimethylformamide-treated control (yolk sac diameter: 5.22 ± 0.49 mm, crown-rump length: 3.89 ± 0.49 mm, head length: 2.01 ± 0.16 mm, somite number: 22.25 ± 1.83, total morphological score: 34.88 ± 1.25) using ex-vivo whole-embryo culture assay [ 36 ].

Essential oil (200 mg/kg) of C. zedoaria rhizome administered orally to pregnant Sprague Dawley rats (age 10-12 weeks) from GD7 to GD17 significantly (p < 0.01) decrease number of live fetuses (7.6 ± 1.1), placental weight (0.305 ± 0.045 g), fetal weight (0.744 ± 0.072 g), crown-rump length (1.773 ± 0.063 cm) and head length (0.937 ± 0.059 cm) compared to corn oil-treated control group (number of live fetuses: 11.4 ± 1.5, placental weight: 0.379 ± 0.067 g, fetal weight: 0.955 ± 0.074 g, crown-rump length: 1.979 ± 0.086 cm, head length:1.048 ± 0.050 cm) [ 36 ].

Acute toxicity

Oral single dose acute toxicity study on female Sprague Dawley rats (aged between 8 and 12 weeks old) using aqueous extract of C. zedoaria rhizome showed no toxic effect on the parameters observed, including behavior, body weight, food and water intake. All rats were observed for 14 days prior to necropsy. No death was found throughout the study period. Necropsy revealed no significant abnormality. No-observed-adverse-effect level (NOAEL) is 2,000 mg/kg body weight [ 47 ].

Others (Adverse reaction, contraindication, side effect, warning, precaution)

Information and data have not been established.

DOSAGE

Information and data have not been established.

STORAGE

Store below 30^°C. Protect from light and moisture.

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