Dong Quai

Angelica gigas (of the family Umbelliferae) is a herb from Korean medicine traditionally used for the treatment of blood flow (cognitive and cardiovascular),^[1] inflammatory disorders,^[2] and gynecological conditions as well as anemia. It is known as Dang gui, although specifically 'Korean Dang Gui' (or Cham-dang-gui^[3]) as angelica sinensis also has the title of Dang Gui (specifically, Chinese Dang Gui).^[4] Along these lines, a third herb in the same family (Angelica acutiloba) is known as 'Japanese Dang Gui'.^[4]

Angelica gigas is one of the three herbs bearing the title of Dang Gui, and is specifically known as Korean Dang Gui of Cham Dang Gui. It has traditionally been used for female health and blood flow

The composition of angelica gigas roots (the medicinally used part of the plant) includes:

• The coumarin derivative Decursin^[5] at 2412-2608μM or 3.3-5.9% of the root dry weight^[6][7] at up to 15.80+/-1.23% in an 80% ethanolic extract (INM-176)^[1] or 53.10+/-0.85% in a 10:1 concentration 50% ethanolic extract^[8]
• Decursinol^[5] at 286.4-323.5μM or 2.4-2.9% of the root dry weight^[6][9] at up to 0.16+/-0.02% of an 80% ethanolic extract^[1] and decursinol angelate^[10]
• Marmesin at 196.4 -268.5μM and its glycosides Nodakenin (191.1-196.7μM^[9]) and nodakenetin^[11]
• Aegelinol (racemic mixture of (+)agasyllin and (-)agasyllin)^[11]
• Xanthotoxin and Xanthyletin^[12]
• Isoimperatorin^[12] and prenyletin^[11]
• Peucedanone and peucedanol^[12] as well as two peucedanol molecules bound together (via a dimethyleneoxy bridge), known as Gigasol^[11]
• 7-hydroxy-6-(2R-hydroxy-3-methylbut-3-ethyl)coumarin^[12][9]
• Choline at 791.5-1029μM^[9]
• Ferulic acid^[1]
• Chlorogenic acid^[1]
• Minor polyacetylenes^[13]

Angelan; a 10kDa polysaccharide made of arabinose, galactose, and galacturonic acid in a 4.4:5.0:9.4 molar ratio (87.1% carbohydrate, 8% protein, 4.9% minerals)^[14][15][16] is also a component of the roots, whereas a slightly different polysaccharide (AG-C) exists in the seeds.^[16]

There is an essential oil content of the leaves which is approximately 4.34% by weight, somewhat comparable to other plants in the angelica family.^[17]

The coumarin derivatives appear to be the main bioactives in this plant, mostly decursin and decursinol. While decursinol is better absorbed, there is significantly more decursin in the plant

Decursin and decursinol angelate appear to be lipophilic as they are extracted to a higher degree in 50-100% ethanol (3,142-3,341ppm and 2,547-2,778ppm, respectively) than a water extract (182 and 153, respectively).^[18]

KMKKT (ka-mi-kae-kyuk-tang) is a formulation which contains angelica gigas (6.9%) alongside benincasa hispida (17.2%), phaseolus angularis (17.2%), bletilla striata (8.6%), tulipa edulis (8.6%), panax ginseng (8.6%), patrinia villosa (8.6%), asini gelatinum (8.6%), astragalus membranaceus (8.6%), and zanthoxylum piperitum (6.9%).^[19]

EstroG-100 (also known as Estromon) appears to be a 32.5:32.5:35 mixture of Cynanchum wilfordii, Phlomis umbrosa, and angelica gigas which ultimately has 0.57% nodakenin and 0.08% shanzhiside methylester (from phlomis ubrosa).^[20]

HemoHIM is a formulation of cnidium officinale (not cnidium monnieri), paeonia japonica, and angelica gigas that is obtained via a 4 hour decoction of equal parts of all three herbs followed by an 80% ethanolic extract; HemoHIM appears to confer anti-allergic properties^[21][22] and was made with the intention of promoting the immune system and protection from radiation damage.^[23] It appears to have a nodakenin (0.58+/-0.04%), chlorogenic acid (0.33+/-0.05%), and paeoniflorin (1.32+/-0.15%) content.^[22]

Decursinol appears to have relatively high absorption in Caco-2 cells and efflux appears to be mediated by transporters,^[24] and at least in the dosage range of 1-20mg/kg in rats it appeared to exhibit good absorption,^[24] nearly complete at low concentrations (2mg/kg).^[25]

At low doses, the absorption of the major coumarins appears to be nearly complete; superloading not tested

240mg/kg decursin (plus decursinol angelate) oral ingestion has been detected in the plasma of mice at 0.25 hours (0.54+/-0.36µg/mL), 1 hour (0.44+/-0.39µg/mL), and 3 hours (0.51+/-0.43µg/mL) with a T_max of 30 minutes.^[26]

240mg/kg of decursinol has been detected in plasma at 0.25 hours (14.9+/-9.6µg/mL), 1 hour (11.2+/-3.2µg/mL), and 3 hours (8.8+/-4.7µg/mL)^[27] with a T_max of 0.7 hours.^[26] Lower oral doses in rats (5-20mg/kg) have noted a T_max of 0.4 hours at 5-10mg/kg and 0.9 hours with 20mg/kg, and the C_max of these lower doses seems to be 1.43µg/mL with 5mg/kg and 3.86-4.56µg/mL with 10-20mg/kg (no dose dependence).^[24]

Three weeks of supplementation of angelica gigas extract to mice (250-500mg/kg) results in a blood decursinol level of 0.72-1.05µg/mL (measured three hours after last dose) whereas 100mg/kg isolated decursin resulted in a serum level of 6.79+/-3.79µg/mL.^[27]

When looking at tumor bearing mice, oral ingestion of 500mg/kg angelica gigas extract appears to increase tumor concentrations of decursinol (0.59+/-0.21µg/g) similar to 100mg/kg decursinol itself (3.69+/-1.53µg/g) but the extract failed to increase tumor concentrations of decursin or decursinol angelate.^[27]

The active coumarins are absorbed following oral ingestion of angelica gigas in mice, and decursinol appears to be better absorbed than does decursin or decorsinol angelate

9–18% of decursinol is not bound to serum albumin in the plasma of humans.^[24]

Infusions of decursin seem to have a very rapid half-life (0.08+/-0.02 hours) due to rapid first pass metabolism into decursinol which appears to be complete, as decursin could not be detected in plasma within an hour.^[28]

In rats at least, decursin appears to be rapidly and completely metabolized into decursinol

Decursinol angelate has been noted to inhibit the activities of the CYP1A2, CYP2D15, and CYP3A12 enzymes in vitro.^[29]

Theophylline is a drug that is metabolized mostly (90%) by CYP1A2 and CYP2E1^[30] and ingestion of decursinol angelate (5-25mg/kg) for three days prior to theophylline (10mg/kg) in rats noted that the higher dose of decursinol angelate increased systemic exposure to theophylline as assessed by C_max (18.67% increase), half-life (20.87% increase), and AUC_24h (17.94% increase) while the lower dose of 5mg/kg was not significantly effective.^[31]

Decursinol angelate, at high oral doses, may be a biologically relevant CYP1A2 inhibitor

300-600mg/kg of IMN-176 (around 15% decursin) oral ingestion to rats appears to be able to reduce astrocyte activation induced by Aβ(1-42)^[1] and 300-600mg/kg of IMN-176 for three days after LPS induced neuroinflammation significantly improved cognition, thought to be due to reducing microglia activation (noted in vitro).^[32]

It appears that decursin is able to activate ERK at 10μM, which causes nuclear translocation of Nrf2 and induction of heme-oxygenase 1 (HO-1) ultimately protecting neuronal cells from Aβ(1-42) mediated toxicity.^[33] An increase in HO-1 appears to be vital for protection against Aβ(1-42), as inhibiting it preserves toxicity,^[33] and while it wasn't traced back to ERK decursinol angelate has also been found to induce Nrf2 to protect against Aβ(1-42).^[34]

Components of angelica gigas appear to be neuroprotective secondary to reducing the activation of glial cells (which occurs in response to inflammatory stressors)

Cognitive dysfunction induced by scopolamine or Aβ(1-42) (two cholinergic toxins) appears to be suppressed with an 80% ethanol extract at 300-600mg/kg oral ingestion in rats, with the higher dose having a potency comparable to 5mg/kg donepezil.^[1] Cognitive protection has also been noted against LPS.^[32]

Due to the decursinol content, angelica gigas can inhibit acetylcholinesterase in vitro with an IC₅₀ of 178.80μg/mL^[1] or isolated decursinol at 28μM;^[12] this is significantly weaker than donezepil (0.11μg/mL).^[1] Marmesin, xanthotoxin, and isoimperatorin also inhibited acetylcholinesterase albeit at a weaker potency.^[12]

Appears to be able to inhibit acetylcholinesterase, although it is unsure how relevant this is to oral supplementation (a moderate potency paired with low oral bioavailability and uncertain transport into the brain)

The inhalation of angelica gigas essential oils appears to prevent the release of dopamine from nicotine ingestion in the nuclear accumbens and significantly reduced the bevahioral sensitization to nicotine.^[4]

Decursinol appears to have analgesic effects at 5-200mg/kg oral intake in mice subject to tail-flick and hot-plate tests with most efficacy coming from 100-200mg/kg and 30 minutes after oral ingestion^[35] and elsewhere the analgesic effects against acetic acid writhing were noted with 50mg/kg decursinol (but not 10-25mg/kg) oral intake with a potency similar to 200mg/kg aspirin and the same dose of acetominophen.^[36]

Decursinol failed to be synergistic with either aspirin or acetominophen.^[36]

In mice, oral intakes of decursinol at fairly respectable levels (assuming an ethanolic extract) seem to be effective for pain relief with a potency comparable to reference drugs

A combination supplement containing angelica gigas, Cynanchum wilfordii, and Phlomis umbrosa (257.05mg of the mixture twice daily) for 12 weeks in menopausal women appeared to reduce menopausal symptoms to 38% of baseline (placebo down to 81%) as assessed by the Kupperman menopause index.^[20] The benefits appeared to influence all measured symptoms including vaginal dryness.^[20]

Although this herb is commonly used for female health, there is not much evidence on the herb against menopausal symptoms and none that isn't confounded with the inclusion of other herbs

The polysaccharide known as Angelan injected at 30mg/kg into NOD mice (a model of autoimmune diabetes^[37]) every other day from weeks 8-24 of life prevented diabetes from occurring and when it was intervened later (15-20 weeks) it prevented a furthering of diabetes development although it failed to show a rehabilitative effect and failed to protect against streptozotocin.^[15]

Decursin appears to concentration-dependently inhibit the ability of insulin to induce adipocyte proliferation (3 T3-L1 cells) with 20μg/mL almost inhibiting half of the increase.^[38]

Decursin given to mice fed a high fat diet at 200mg/kg of the diet over seven weeks was able to significantly inhibit fat gain associated with normalizing the alterations of leptin, resistin, IL-6, and MCP-1 (all of which were increased in high fat diet relative to control yet normalized with decursin).^[38]

May have minor anti-obese effects

Supplementation of angelica gigas (crushed into an ultrafine powder) at 500mg/kg for 8 weeks in a rat model of menopause is associated with increases in improved serum alkaline phosphatase and less bone loss in the trabecular and cortical bone areas.^[39] This was thought to be related to the increase in circulating estrogen.^[39]

Angelan does not appear to have a mitogenic potential on macrophages^[40] and injections of angelan (30mg/kg) to diabetic mice has failed to modify macrophage derived cytokines (IL-6 and IL-12).^[15] While angelan itself does not appear to be cytotoxic to macrophages, an ethanolic extract of angelica gigas appears to be cytotoxic with an IC₅₀ of 46.38µg/mL in vitro.^[8]

Angelan does not appear to significantly proliferate macrophages

Elsewhere, in vitro macrophages seen to be activated as assessed by inductions of iNOS, TNF-α, and IL-1β in response to angelan activating NF-kB.^[41][42] When compared to lipopolysaccharide (LPS), 10µg/mL of angelan is less effective than 20ng/mL LPS while 100µg/mL angelan is equivalent to 200ng/mL LPS.^[41] While LPS signals through the CD14 receptor, angelan appears to partially signal via both the CD14 and CD3 receptors^[41][43] which signals through MAPK (p38 and ERK1/2) towards NF-kB.^[44][43] Angelan does not appear to potently induce AP-1 like LPS does.^[43]

Angelan appears to activate macrophages, and does so via the CD3 (beta-glucan) and CD14 (LPS) receptors. The overall effect is somewhat similar (due to activating NF-kB) although the way the macrophage is activated differs from the reference molecule LPS

The activation of COX enzymes and PGE2 release in macrophages from croton oil (20µg/mL) appears to be fully prevented with 1-10µg/mL of an ethanolic extract of angelica gigas; the increase in IL-6 seen with croton oil is also prevented, and this extract had a high concentration of decursin (53.10+/-0.85%) and decursinol angelate (17.94+/-0.19%).^[8] Against LPS, 10µg/mL of a methanolic extract has outright failed to prevent COX-2 induction.^[45]

Elsewhere, decursin has been found to directly inhibit NF-kB activation at 20-40µM with complete inhibition at 80µM.^[46] It was noted that IκB phosphorylation was blocked which caused the inhibition of NF-kB, but ERK was not blocked by decursin.^[46]

Other components in angelica gigas (probably the main decursin molecules) appears to be antiinflammatory on macrophages rather than stimulatory, and this occurs at a remarkably low concentration and is likely relevant following oral supplementation

Due to the potent NF-kB inhibition of decursin, the practical relevance of angelan on macrophages is uncertain and it is possible that this stimulatory effect doesn't really matter when it comes to oral supplementation since decursin circumvents the efficacy of angelan. That being said, if ERK activation without NF-kB activation is desired then the combination may prove useful

Angelan appears to possess a mitogenic effect on B-cells (despite no such influence on macrophages nor T cells) and increased antibody production in the 3-100µg/mL range with maximal efficacy at 30µg/mL.^[40] This appeared to be relevant in vivo, where 30mg/kg of angelan as an injection to mice over 19 days where tumor growth (B16F10 melanoma tumors, which are responsive to B-cells) was suppressed and survival enhanced.^[40]

Angelan^[40] as well as other polysaccharides from angelica gigas^[16] do not appear to possess a mitogenic effect on T-cells in vitro.

In vitro, angelan can stimulate IL-4 mRNA within four hours at a concentration of 1-100µg/mL although it appears to lose this efficacy with longer incubation.^[40]

Injections of angelan (30mg/kg) to diabetic mice have failed to modify circulating cytokines of the Th1 (IFN-γ) or Th2 (IL-4 and IL-10) class.^[15]

Injections of angelan (30mg/kg) have failed to modify effector molecules of NK cells.^[15]

50-500mg/kg of an ethanolic extract of angelica gigas root extract to mice for five days prior to croton oil application appears to significantly reduce erythema and edema (no dose dependence noted) and vascular leakage (dose dependent benefits).^[8]

2,4-dinitroflurobenzene (DNFB) is a topical allergin known to work via cytotoxic CD8+ T-cells, which causes skin hypersensitivity^[47] and causes a shift from Th1 lymphocytes towards Th2 lymphocytes^[48][49] as well as a macrophage response.^[50] Oral intake of 160-500mg/kg of an ethanolic extract of angelica gigas (likely around 50% decursin by weight as it used the same extraction method as this study^[8]) was able to suppress white blood cell and neutrophil recruitment to the area and reduced inflammation in a dose-depednent manner.^[3]

Oral intake of angelica gigas extracts with a high decursin content appear to be able to suppress inflammatory skin conditions in mice

Angelica gigas extract appears to have antiandrogenic properties in prostate cells (via suppressing PSA secretion) with an IC₅₀ value around 1μg/mL, this is thought to be due to decursin which has an IC₅₀ value of around 400ng/mL (1.3μM) which is a potency exceeding bicalutamide.^[19]

Based on this potency, synthetic derivatives have been made and tested in vivo with efficacy.^[51]

Decursin appears to be a very potent androgen inhibitor when tested in vitro, exceeding the potency of bicalutamide; in vivo studies are warranted

Supplemention of 500mg/kg of an ultrafine powder of angelica gigas over eight weeks in a rat model of menopause appears to be able to increase circulating estradiol concentrations by 19.2% (relative to regular powder) and 54.1% (relative to control).^[39]

Angelica gigas appears to be estrogenic, which may be due to the coumarins since enhancing their absorption enhances the effects of the herb

Angelan (the polysaccharide from angelica gigas) has been noted to be synergistic with doxorubicin (0.3g/kg) in mice bearing melanoma tumors when assessing tumor migration and overall survival^[52] and the bioactive decursin appears to be synergistic with doxorubicin as well (albeit in myeloma cells) associated with suppressing activation of STAT3 and mTOR (two prosurvival proteins) in vitro with 40-80μM decursin.^[53]

Multiple components of angelica gigas appear to be synergistic with doxorubicin

A study assessing the B-cell mitogenic potential of the polysaccharide form angelica gigas (Angelan) noted that injections of 30mg/kg angelan daily for 19 days was able to suppress the growth and enhance survival (18.1 days up to 40 days) of mice implanted with B16F10 melanoma tumors^[40] which was credited towards enhanced B-cell mediated cytotoxicity. An increase in B-cell proliferation in tumor bearing mice has been replicated elsewhere.^[52]

This has been noted elsewhere where angelan (30mg/kg for 60 days) was able to perform equally to 0.3mg/kg doxorubicin yet the combination of the two was synergistic and prevented any deaths within 60 days (all of control died within 24 days).^[52] The incidence of metastasis was reduced 54% with angelan, and this was again synergistic with doxorubicin, thought to be due to how 30-100μg/mL prevented 90-99% of tumor adhesion in a Matrigold assay and reduced invasion.^[52]

Angelan is not directly toxic to tumor cells despite being anti-metastatic.^[40][52]

Angelan appears to be useful against melanoma tumor cells in mice, and while it does not appear to actively kill the tumor cells (cytotoxicity) it enhances B-cell concentrations which may be cytotoxic and is suppressive of metastasis. It appears to be synergistic with doxorubicin

Decursin has shown cytotoxic abilities in a few prostate cancer cell lines (LNCaP, DU145, and PC-3).^[54][19]

Decursin itself can cause cell cycle accumulation in the G₁ phase at 10-20μM although with slightly less efficacy than 5-20μg/mL anglica gigas extract.^[19]

Mechanistically, this may be due to its antiandrogenic potential^[19] or possible due to PKC activation; decursin has been noted to activate PKC^[7] and other PKC actiators have been noted to cause apoptosis in prostate cancer cells.^[55][56] Finally, the inhibition of VEGF seen with 2-20μM decursin in prostate cells (2μM abolishing the effects of VEGF, 5-20μM causing less proliferation than control) possess antiproliferative effects.^[10]

This has been noted in vivo with 30mg/kg given to mice intraperitoneally.^[6]

There appear to be multiple mechanisms by which decursin can inhibit prostate cancer growth, and they all appear to happen at low enough concentrations that they could be relevant following supplementation

In a study testing the anti-angiogenic potential of decursin, injections of 4mg/mL decursin daily for 21 days in mice injected with lung cancer cells abolished expression of VEGF as well as phosphorylation of both JNK and ERK (but not Akt); tumor growth was 65-70% less than control mice when measured at day 16.^[10]

The anti-angiogenic effects appear to hold some promise in lung tumors, and this awaits further testing

Astragalus membranaceus in a 3:1 ratio with angelica gigas is known as KSG-002 (a 1:1 ratio being known as KSG-001) and KSG-002 appears to be able to be able to inhibit macrophage-induced tumor proliferation due to inhibiting NF-kB activation in macrophages, causing less TNFα secretion and less infiltration.^[57] In mice implanted with breast cancer cells, KSG-002 appears to be able to reduce tumor size at 500mg/kg (although KSG-001 appeared to increase it) after 34 days or oral supplementation.^[57]

A 3:1 ratio of astragalus membranaceus:angelica gigas appears to reduce breast tumor size in mice, although an additive and/or synergistic relationship has not yet been demonstrated

The combination of angelica gigas and ligusticum wallichii is known as Fo Shou San in Traditional Chinese Medicine for the purpose of atherosclerosis and hypertension.^[58] When tested in vitro, each herb's water extract by itself were able to induce relaxation in a concentration dependent manner between 0.3-3mg/mL although a 1:1 ratio of the two extracts was most potent with an EC₅₀ of 1.08mg/mL (outperformed a 3:1 and 1:3 combination).^[58] When fed to rats, 100mg/kg of the combination at 1:1 was able to reduce mean arterial pressure by 7.2+/-1.6mmHg which was greater than either herb in isolation at the same dose;^[58] This study is duplicated on Medline.^[59]

The combination of these two herbs' water extracts in a 1:1 ratio appears to be synergistic in regards to reducing blood pressure and improving blood vessel relaxation

The aroma of angelica gigas essential oil appears to be able to prevent a dopamine release into the nuclear accumbens from nicotine and prevents sensitization to nicotine as assessed by locomotion.^[4]

The usage of angelica gigas as aromatherapy may reduce the sensitization to nicotine by preventing dopamine release

A single oral dose of isolated decursin or decursinol angelate have been noted to be lethal in a few tested ICR mice (100mg; 2,500-4,000mg/kg for mice and estimated dose of 200-320mg/kg in humans); a full LD₅₀ test was not performed.^[60]