 Gen info
- Zanthoxylum is a genus of about 250 species of deciduous and evergreen trees, shrubs, and climbers in the family Rutaceae.
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The plant was first formally described by William Roxburgh in 1824, who gave it the name Fagara nitida, which was published in Flora indica. In 1824, de Candolle changed the name to Zanthoxylum nitidum in his book Prodromus Systematis Naturalis Regni Vegetabilis.
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Several of the species have yellow heartwood, which the generic name alludes to. It also refers to the yellow dye from the roots of some species.
- Etymology: The genus Zanthoxylum was first formally described in 1753 by Carl Linnaeus in the first volume of Species Plantarum. The name derives from Greek words xanthos (yellow) and xylon (wood).
Botany
• Zanthoxylum nitidum is a woody climber with curved prickles on the branchlets and thick, cone-shaped spines on the trunk and older branches. The leaves are pinnate, 100–340 mm (3.9–13.4 in) long with five to nine egg-shaped to elliptical leaflets. The leaflets are 45–100 mm (1.8–3.9 in) long and 20–50 mm (0.79–1.97 in) wide, the side leaflets sessile or on a petiolule up to 3 mm (0.12 in) long and the end leaflet on a petiolule 7–40 mm (0.28–1.57 in) long. The flowers are arranged in leaf axils or on the ends of branchlets in panicles or racemes up to 80 mm (3.1 in) long, each flower on a pedicel 1–1.5 mm (0.039–0.059 in) long. The four sepals are 0.5–0.8 mm (0.020–0.031 in) long and the four petals white or pale yellow, and 2–3 mm (0.079–0.118 in) long. The flowers are either functionally male or female, the male flowers with four stamens about 3.5 mm (0.14 in) long and four sterile, finger-like carpels. The female flowers lack stamens and have four carpels 1.5–2 mm (0.059–0.079 in) long. Flowering occurs from September to October and the fruit is a more or less spherical, red or brown follicle 5–7 mm (0.20–0.28 in) long. (3)
 • Stem: Vine stem diameters to 4 cm recorded. Stems armed with corky processes each ending in a spine, each of these structures resembles a rhinoceros horn. Leaves: Twigs and branches armed with numerous recurved spines, similar spines are also present on the underside of the compound leaf rachis and on the underside of the midrib of most leaflets. Leaflet blades about 5-9 x 2-4.5 cm, leaflet stalks about 0.5-3 mm long. Leaflet blade margins crenate with a large oil gland at the base of each tooth. Flowers: Inflorescence shortly branched. Pedicels about 1-3 mm long. Sepals broadly triangular, about 1 mm long, oil glands small and numerous. Petals ovate to elliptic, about 2-3 mm long, oil glands visible, small. Staminodes about 0.5 mm long. Carpels (ovaries) about 1.5-2 mm long, green, oil dots numerous. Stigma green, about 1.5 mm diam. Fruit: Ripe fruits red. Fruiting carpels 1-4 in each cluster, each carpel +/- globular, laterally compressed, about 5-7 mm diam., surface marked by large oil dots. Seeds shiny black, +/- globular, about 4-5 mm diam. Cotyledons about 4 mm long. Radicle about 0.5 mm long. (Australian Tropical Rainforest Plants)
Distribution
- Native to the Philippines.
- Also native to Assam, Bangladesh, Borneo, Cambodia, China South-Central, China Southeast, East Himalaya, Hainan, Laos, Malaya, Maluku, Myanmar, Nansei-shoto, Nepal, New Guinea, Philippines, Queensland, Sulawesi, Taiwan, Thailand, Vietnam. (1)
Constituents
- Study of stems and twigs isolated three new alkaloids, zanthocadinanine C (1), 7-methoxy-8-demethoxynitidine (2), and zanthonitiside I (3). (see study below) (7)
- Phytochemicals isolated include alkaloid, lignans, coumarins, terpenes, steroids.
-Study of essential oils of leaves, fruits, and stems by GC-MS-FID showed 35, 32, and 25 compounds accounting for 97.6, 91.7 and 96.2% of total EO contents, respectively. Leaf EO major compounds were  limonene (44.3%), ß-caryophyllene (12.5%), linalool (11.0%), germacrene D (5.3%) and α-pinene (4.9%); fruit EO major components were n-pentadecane (34.8%), sabinene (18.3%), and n-heptadecane (4.7%); and stem EO major components were 2-undecanone (72.3%), ß-caryophyllene (5.8%), and germacrene D (4.0%). (see study below) (10)
- Study of 95% EtOH extract isolated four new sesquiterpenoids (1-4), along with six previously described coumarins (5-10). (see study below) (13)
- Study of ethanol extract isolated 12 compounds: 9-demethoxynitidine (1), 8-dehydroxyl-buesgenine (2), 6β-hydroxymenthyldihydronitidine (3), zanthoxyline (4), rhoifoline B (5), nitidine (6), chelerythrine (7), bocconoline (8), dictamnine (9), γ-fagarine (10), skimmianine (11), and liriodenine (12). (see study above) (14)
- Study of chloroform and petroleum ether extracts of roots and leaves isolated 26 compounds: ( +)-9′-O-transferuloyl-5, 5′-dimethoxylaricriresinol (1), 8-(3′-oxobut-1′-en-1′-yl)-5, 7-dimethoxy-coumarin (2), 5, 7, 8-trimethoxy-coumarin (3), 5-(3′, 3′-dimethyl-2′-butenyloxy)-7, 8-dimethoxy-coumarin (4), 2-(5-methoxy-2-methyl-1H-indol-3-yl) methyl acetate (5), 2′-(5, 6-dihydrochleletrythrine-6-yl) ethyl acetate (6), 6-acetonyldi-hydrochelerythrine (7), 6β-hydroxymethyldihydronitidine (8), bocconoline (9), zanthoxyline (10), O-methylzanthoxyline (11), rhoifoline B (12), N-nornitidine (13), nitidine (14), chelerythrine (15), 4-hydroxyl-7,8-dimethoxy-furoquinoline (16), dictamnine (17), γ-fagarine (18), skimmianine (19), robustine (20), R-( +)-platydesmine (21), 4-methoxyl-1-methyl-2-quinoline (22), 4-methoxy-2-quinolone (23), liriodenine (24), aurantiamide acetate (25), 10-O-demethyl-12-O-methylarnottianamide (26). (see study below) (16)
 - Study of Z. nitidum isolated Skimmianine (1), a new discovered strong acetylcholinest3rase (AChE) inhibitor, along with nine weakly or non active compounds, toddalolactone (2), dictamnine (3), γ-fagarine (4), magnolone (5), (−)-(S)-edulinine (6), zanthodioline (7), edulitine (8), 5,6,7-trimethoxycoumarin (9), and haplopine (10). (see study below) (19)
- Study of stem bark isolated five novel alkaloids, zanthomuurolanine (1), epi-zanthomuurolanine (2), zanthocadinanines A (3) and B (4), and epi-zanthocadinanine B (5), composed of dihydrochelerythrine and a cadinane-type sesquiterpene linked by a methylene bridge. (20)
- Study of roots isolated five alkaloids, 5,6-dihydro-6-methoxynitidine (1), dictamnine (2), γ-fagarine (3), skimmianine (4), and 5-methoxydictamnine (5). (see study below) (25)
- Study of stems isolated a new alkylamide, (2E,6E,8E)-N-(2-methylpropyl)-10-oxo-2,6,8-decatrienamide (1), together with 22 known compounds (2–23). (26)
- Study of ZN roots isolated a new coumarin glycoside, Zanthoxylumoside A(1), seven known coumarins (2-8) and two known lignan glycosides (9, 10). (31)
Toxicity
- Parts: Roots, leaves, and fruits are poisonous.
- Toxic constituents: Nitidine, sanguinarine, and chelerythrine.
- Toxic dose: 40 g fresh leaves.
- Mechanisms of toxicity: Nitidine inhibits topoisomerase. It interferes with replication and transcription of DNA, leading to apoptosis of cells. Sanguinarine and chelerythrine have been shown to form DNA adducts in vitro and are suspected to be genotoxic.
- Poisoning features: Dizziness, vomiting, and diarrhea.
- Laboratory analysis: Nitidine, sanguinarine, and chelerythrine can be detected by HPLC-DAD and LC-MS/MS.
- Treatment: Supportive.
(12)
Properties
- The plant has been used as detoxifying, analgesic, and hemostatic herbal medicine for thousands of years. (5)
- Studies have suggested antibacterial, anti-biofilm, cytotoxci, anticancer, analgesic, anti-inflammatory, antinociceptive, locomotor-depressing, anti-leukemia, acetylcholinesterase inhibitory, STAT3 signaling pathway inhibitory, gastroprotective, antiviral, antifungal, neurotrophic and anti-neuroinflammatory properties.
Parts used
Leaves, bark, stems, seeds, fruit.
Uses
Edibility
- Caution / Toxicity: In Nepal, the fruits are used as condiment. Leaves sometimes eaten as vegetable. However, the roots, leaves, and fruits are poisonous, with as little as 40 g of leaves considered as a lethal dose. (3)
Folkloric
- Widely used in Chinese traditional medicine, i.e. for treating stomach ache, toothache, rheumatic arthralgia, traumatic injury, and venomous snake
bites. Also used for treatment of inflammations, various cancers, bacterial and viral infections, gastric and oral ulcers, and liver damage. (6)
- Used for gingivitis, diarrhea, paresis, boils, rheumatism, fever, colic, vomiting, cholera, etc.
- Root used to treat scald and aphtha, and as carminative, depurative, antiphlogistic, and febrifuge. Branches of stem bark and seeds used for diarrhea, fever, and cholera. In Assam, bark and stems are chewed as treatment of gingivitis and toothache. Fruit used for treatment of vomiting, colic, diarrhea; used as aromatic stimulant, anthelmintic, astringent, diaphoretic, and carminative. Decoction of leafy branches used for treatment of throat inflammation. (8)
Others
- Items of daily use: Used in preparation of daily items like toothpaste, mouthwash, soap, hand sanitizer, shampoo.
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Insecticidal and pesticidal.
Studies
• Antibacterial / Anti-MRSA Constituents / Anti-Biofilm / Roots: Study of roots isolated two new coumarins, 6-(3-oxo-butyl)-limettin (1) and toddalin (2), along with 24 known compounds, in which two isoquinoline alkaloids, 6-acetonyl-dihydrofagaridine (16) and 6-acetonyl-dihydrochelerythrine (17) showed anti-MRSA bioactivity in vivo and in vitro. Both exhibited synergistic action with ampicillin, which decreased the MIC significantly. Both compounds also showed significant ability to destroy bacterial biofilm combined with ampicillin. Combined administration showed strong scavenging effect on planktonic bacteria in vivo and cleared skin infection effectively in an in vivo model of wound infection. Compound 16 inhibited the influx of drug by combining with ampicillin or EtBr, resulting in decreased MIC. Results support the tradition use of Z. nitidum in treating bacterial infections and suggests potential for use against drug-resistant bacteria. (5)
• Cytotoxic Alkaloids against Human Cancer Cell Lines / Twigs and Stems: Study of stems and twigs isolated three new alkaloids, zanthocadinanine C (1), 7-methoxy-8-demethoxynitidine (2), and zanthonitiside I (3). The compounds were evaluated for cytotoxicity against 5 human cancer cell lines: KB, MCF-7, LNCaP, HebG-2, and LU-1. Compound 2 showed significant cytotoxic activity against all tested human cancer cell lines with IC50s ranging from 10.3 to 12.6 µM. (7)
• Analgesic / Anti-Inflammatory / Targeting ERK and NF-kB Signaling: Study evaluated the analgesic activity of Z. nitidum on mice with Complete Freund adjuvant (CFA)-induced chronic inflammatory pain. Extract dose of 100 mg/kg showed significant anti-inflammatory and analgesic effect in the mice model. Paw edema was significantly reduced and numbers of neutrophils were reduced. The mRNA levels of TNF-α, IL-1ß, IL-6, and NF-kB p65 were down-regulated after 7 days. Results suggest the extract attenuates CFA-induced inflammatory pain by suppressing the ERK1/2 and NF-kB signaling pathway at both peripheral and central level. (9)
• Antimicrobial / Anticancer / Essential Oils of Leaf, Fruit, Stems: Study of essential oils of leaves, fruits, and stems by GC-MS-FID showed 35, 32, and 25 compounds accounting for 97.6, 91.7 and 96.2% of total EO contents, respectively. The EOs of leaves, fruits, and stems exhibited antimicrobial activity against Bacillus subtilis, Escherichia coli, and Fusarium oxysporum with MIC values of 100 µg/mL. Leaf and branch EOs exhibited cytotoxic activity against all tested 5 human cancer cell lines. especially A-549 and HepG-2. Results suggest potential uses of Z. nitidum as natural microbial and antitumor agents. (see constituents above) (10)
• Nitidine Chloride / Potential as Anticancer Drug: Nitidine chloride (NC) is a benzophenanthridine alkaloid found in many plants, and mainly extracted from the roots or stems of Z. nitidum. Enzymatic and ultrasonic methods are recommended for extraction, resin adsorption and chromatography are usually used for separation and purification. NC possesses diversified therapeutical effects, such as anti-cancer, anti-inflammatory, anti-colitis, anti-malaria, anti-osteoporosis, anti-rheumatoid, etc. It has a few limitations including poor solubility, low bioavailability, and certain toxicity, which could be effectively resolved through formulations, such as nanoparticles, microsphere, and nano-micelle and studies of ADME/Tox properties. Nitidine chloride has great potential as a new drug, especially as anticancer. (11)
• Sesquiterpenoids / No Cytotoxicity against Cancer Cell Lines: Study of 95% EtOH extract isolated four new sesquiterpenoids (1-4), along with six previously described coumarins (5-10). Cytotoxicity of all isolates against five cancer cell lines (T24, HeLa, MGC-803, A549, and HepG2) was evaluated by MTT and found not to be cytotoxic. (13)
• Anticancer / Melanoma Cells WM9: Study of ethanol extract isolated 12 compounds: 9-demethoxynitidine (1), 8-dehydroxyl-buesgenine (2), 6β-hydroxymenthyldihydronitidine (3), zanthoxyline (4), rhoifoline B (5), nitidine (6), chelerythrine (7), bocconoline (8), dictamnine (9), γ-fagarine (10), skimmianine (11), and liriodenine (12). The proliferation inhibition activity of the 12 compounds against melanoma cells WM9 was evaluated by MTT method. Compound 3 and compound 6 showed potent anti-proliferation activity on WM9 cells with IC50s of 1.936 µM and 0.880 µM, respectively. Study suggests promising candidate molecules for discovery of new anticancer drugs. (14)
• Antinociceptive / Depressed Locomotor Activity / Stem Bark: Study evaluated aqueous and ethanol extracts of Z. nitidum stem bark for antinociceptive activity using acetic acid induced writhing and tail flick method in Swiss albino mice and locomotor activity using actophotometer. In the writhing test, the aqueous extract dose dependently and significantly inhibited writhes at doses of 75 and 150 mg/kbw (p<0.05 and p<0.01, respectively), while the ethanol extract produced significant protection at dose of 150 mg/kbw (p<0.05) In tail flick test, the ethanol extract showed significant increase in reaction time. In locomotor activity, the ethanol extract showed significant dose dependent depression of locomotor activity in mice. (15)
• Inhibitory Activity in HEL Leukemia Cell line / Roots and Leaves: Study of chloroform and petroleum ether extracts of roots and leaves isolated 26 compounds. Compounds 1, 2, 9, 10, 14, 15, and 24 showed good inhibitory activities in the leukemia cell line HEL, while compound 14 and 24 exhibited potent inhibitory activities with IC50s of 3.59 µM and 15.95 µM, respectively. Study for possible mechanisms suggest compound 14 caused S-phase arrest in HEL cells and induced apoptosis, whereas compound 24 only induced apoptosis. Results suggest compounds 14 and 24 have promising potential as anti-leukemia drug candidates. (see constituents above) (16)
• Gastroprotective / ASA and Stree-Induced Gastric Mucosal Damage / Stem Bark: Study evaluated an aqueous extract of stem bark of Z. nitidum for protective effects on gastric mucosal lesions in male Wistar albino rats against acetylsalicylic aid (ASA), ethanol and water immersion restraint stress induced gastric mucosal damage. Doses of 100 and 200 mg/kbw were given prior to chemical or stress challenge. Ranitidine was used as reference drug. Results showed the extract exhibited dose-dependent and significant amelioration of gastric mucosal lesions in both test models, thus confirming its antiulcer potential. (17)
• Attenuation of BMP-2-Induced Inflammation and Hyperpermeability: Bone morphogenetic protein-2 (BMP-2) is commonly applied in spinal surgery to augment spinal fusion. However, its pro-inflammatory potential have potential side effects, such as vascular hyperpermeability. Study evaluated the protective effect of Z. nitidum (ZN) on BMP-2-related hyperpermeability and inflammation on human umbilical vein endothelial cells (HUVECs). BMP-2 exhibited concentration dependent enhancement in production of pro-inflammatory cytokines, including interleukin (IL)-1α, IL-1ß, and TNF-α, which were suppressed by ZN. ZN inhibited BMPO-2-induced inflammatory response by suppressing the phosphorylation of NF-kBp65 and IkB, and the abnormal nuclear translocation of p65, The hyper-permeability of HUVECs induced by BMP-2 was also reversed by ZN. Results showed the ZN antagonized BMP-2 induced inflammation and hyperpermeability, and can be a therapeutic candidate for the treatment of BMP-2 induced side effects during spinal fusion. (18)
• Slimmianine / Potential Acetylcholinesterase Inhibitor: Study of Z. nitidum isolated Skimmianine (1), a new discovered strong acetylcholinest3rase (AChE) inhibitor, along with nine weakly or non active compounds. Skimmianine (1) inhibited 50% of AChE activity at concentrations of 8.6 µg/ml when IC50 of physostigmine as standard was 0.013 µg/ml. (see constituents above) (19)
• Angoline / IL-6/STAT3 Signaling Pathway Inhibitory / Roots: STAT3 signaling pathway is an important target for human cancer therapy. Study sought to identify novel inhibitory of STAT3 pathway from the roots of ZN. Bioassay-guided fractionation of MeOH extract using a STAT3-responsive gene reporter assay isolated angoline (1),, a potent and selective inhibitor of STAT3 signaling pathway (IC50 11.56 µM). Angoline inhibited STAT3 phosphorylation and its target gene expression and induced growth inhibition of human cancer cells. Study provides a novel lead for development of anticancer agents targeting the STAT3 signaling pathway. (21)
• Antibacterial / Stem Bark and Roots: Study evaluated the invitro antibacterial activity of aqueous and ethanol extracts from stem bark and roots of ZN against S. aureus, Streptococcus faecalis, B. cereus, Sarinia luta, B. subtilis, K. pneumonia and E. coli using disk diffusion method. Except for the aqueous extract of stem bark which was inactive against S. lutea and B. subtilis, all extracts at higher concentrations showed varying degrees of inhibitory activity against all bacteria. The ethanol extract of root was most active; the aqueous extract of stem bark, least active. Root extracts exhibited higher antibacterial effects than stem bark extracts. (22)
• Antibacterial Coumarins / Synergism with Antibiotics against MRSA: Study isolated and evaluated four natural coumarins, 5-geranyloxy-7-methoxycoumarin (Gm, 1), (5,7-dimethoxy-8-prenyloxycoumarin (artanin, Ar, 2)), isopimpinellin (Is, 3) and phellopterin (Ph, 4) for potential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Coumarins 1-4 showed promising inhibition against both MSSA and MRSA with MICs range of 8-64 µg/ml. Compounds 1-4 showed different degrees of synergism with 8 conventional antibacterial agents (chloramphenicol, gentamicin, fosfomycin, levofloxacin, minocycline, piperacillin/tazobactom, teicoplanin, and vancomycin against 10 clinical MRSA strains. Results showed the coumarins have high potentiating effect of the antibacterial agents against MRSA. Resistance reversal effects of antibacterial agents of chloramphenicol, levofloxacin. and minocycline warrant further study on combination therapy for MRSA infections (23)
• Rhoifoline A / Antinociceptive: Study of ethanol extract of ZN isolated Rhoifoline A (RA), a benzophenanthridine alkaloids. RA was evaluated for antinociceptive activity in mice using chemical and thermal models of nociception. Doses f 10, 20, 40, and 80 mg/kg exhibited significant inhibitions on chemical and thermal nociception. Results suggest the antinociceptive activity was unrelated to sedation or motor abnormality. The analgesic mechanism possible involved the NO-cGMP signaling pathway and L-type Ca2+ channels. (24)
• Antiviral / Antifungal / Root Alkaloids: Study of roots isolated five alkaloids, 5,6-dihydro-6-methoxynitidine (1), dictamnine (2), γ-fagarine (3), skimmianine (4), and 5-methoxydictamnine (5). Compounds 1,4, and 5 showed invitro antiviral effect against hepatitis B virus, and compounds 2, 3, and 5 exhibited marked antimitotic and antifungal activity. (25)
• Sanguinarine / Inhibition of H. pylori and Jack Bean Urease: Sanguinarine (SNG), a natural alkaloid isolated from ZN, possesses significant anti-Helicobacter pylori and gastric protection effects. Study evaluated the inhibition effect, kinetics, and mechanism of SNG against H. pylori urease (HPU) and jack bean urease (JNU). SNG showed remarkable suppression of HPU and JBU in concentration- and time-dependent manner with IC50 of 0.48 and 0.11 mM, respectively. The SNG could inhibit H. pylori urease targeting thiols and Ni2+, suggesting SNG as a new and promising urease suppressant. Results provide scientific evidence for the application of SNG and ZN for treating H. pylori-associated gastrointestinal diseases. (27)
• Phenylpropanoids / Neurotrophic and Anti-Neuroinflammatory: Study of ethanol extract of ZN var. tomentosum isolated three novel lignans (1, 5, and 6) and two novel quinic acids (16,17), along with 15 known phenylpropanoids. Compounds 2, 3, 7, and 16 showed excellent inhibition of LPS-induced NO (nitric oxide)-production. RT-PCR and Western blotting analysis indicated that the anti-neuroinflammatory mechanism of sesaminone (compound 2) was mainly through NLRP3/caspase 1 signaling pathways in LPS-induced BV2 microglial cells. (28)
• Potential MCF-7 Inhibitors of Alkaloid and Phenolic Compounds: Computational molecular simulation and assessment of drug-like properties evaluated the binding ability of 16 alkaloid and phenolic compounds isolated from ZN on tubulin protein. Compounds 8 and 10 were identified as potential candidates for inhibiting the function of tubulin at the active site regarding binding affinity, dock pose and ADMET property analysis. The findings shed light on the anticancer potential of compounds isolated from ZN. (29)
• Nitidumpeptins / Antiproliferative in Cancer Cells / Synergism with Gefitinib: Study isolated two novel cyclic hexapeptides, Nitidumpeptins A and B ( 1 and 2) from ZN var. tomentosum. Combination of Nitidumpeptin B (2) with gefitinib exhibted synergistic antiproliferative activity in acquired gefitinib-resistant non-small cell cancer cells (HCC827-gef). The underlying antiproliferative mechanism of compound 2 was attributed, in part, to suppression of YAP expression in HCC827-gef cells. (30)
• Toddalolactone / Inhibition of PAI-1 Activity / Promotion of Blood Circulation: ZN var. tomentosum is used as adjuvant to promote blood circulation and remove stasis. PAI-1 (plasminogen activator inhibitor-1) regulates the plasminogen activation system through inhibition of tissue-type and urokinase type plasminogen activators (tPA and PA). PAI-1 has been linked to fibrin deposition involved in organ fibrosis and atherosclerosis. Study showed the ethanol extract exhibited PAI-1 inhibitory activity, and identified toddalolactone as the main active component that inhibited the activity of recombinant human PAI-1 with IC50 of 37.31 µM. In vitro study showed toddalolactone inhibited the binding between PAI-1 and uPA, and thereby prevented the formation of the PAI-1/uPA complex. Intraperitoneal injection of toddalolactone to mice significantly prolonged tail bleeding and reduced arterial thrombus weight in a FeCl3-induced thrombosis model. The PAI-1 inhibition by toddalolactone may represent a novel molecular mechanism for NZ var. tomentosum for the treatment of thrombosis and fibrosis. (32)
Availability
Wild-crafted.
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