Eucommia Bark

More commonly referred to as the Gutta-Percha or Rubber Bark tree or the traditional chinese medicine known as Du Zhong, Eucommia ulmoides (of the Eucommiaceae family) is a medicinal plant where both the leaves and the bark have been used for the purposes of hastening relief of back pain, to increase stamina and recover from fatigue, and to make bones and muscles stronger^[1] while promoting longevity and fertility.^[2] When used in Kampo medicine, it goes by the name of Tochu^[3] and the leaves are sometimes used to brew Tochu tea.

This plant also has some usage as a tree that can produce rubber^[4] due to the trans-polyisoprene compounds it can produce,^[5][6] which is why the tree also has the common name of 'Rubber Bark Tree'.

Eucommia ulmoides is a medicinal plant recommended to support vitality and strength, and also has commercial benefits as the tree can be used to manufacture rubber

The bark (ethanolic extract unless otherwise stated) has been noted to include:

• Geniposidic acid (0.925% of bark) and its aglycone geniposide (0.488%) and genipin (0.214%)^[7]
• Trans-polyisoprene compounds, used mostly in rubber making^[6]
• Lignans (+)-pinoresinol-4,4′-di-O-β-D-glucopyranoside (pinoresinol diglucoside^[8]), (+)-pinoresinol-4-O-β-D-glucopyranosyl(1→6)-β-D-glucopyranoside, (+)-medioresinol-4,4′-di-O-β-D-glucopyranoside, (+)-syringaresinol-4,4′-di-O- β-D-glucopyranoside, (−)-olivil-4′-O-β-D-glucopyranoside, (−)-olivil-4-O-β-D- glucopyranoside, and (+)-pinoresinol-4-O-β-D-glucopyranoside^[9] with both syringaresinol diglycoside (0.214%) and (+)-pinoresinol-di-β-d-glucopyranoside (0.991%) being quantified^[7]
• Licoagroside F (28.78+/-0.81μg/g)^[10]
• The flavonoids Baicalein (0.28+/-0.010μg/g), wogonin (0.20+/-0.0027μg/g), and oroxylin A (0.09+/-0.0040μg/g)^[10]
• Caprylic acid (involved in androgen signalling^[1] and also found in coconut oil)
• Triterpenoids^[1]
• Chlorogenic acid (0.302%)^[7]

Whereas the leaves of Eucommia ulmoides include:

• The irioid glycosides Geniposidic acid (10.1-17.4mg/g),^[11][12] Aucubin (6.5-19.7mg/g; geniposidic acid without the carboxylic acid group),^[12][13] and Asperuloside (13.7-27.8mg/g)^[14][15]
• Quercetin (0.27-0.62mg/g) as isoquercetin, rutin (7.6-14.3mg/g), and 3-O-sambubioside^[11][12] as well as 3-O-alpha-L-arabinopyranosyl-(1->2)-beta-D-glucopyranoside^[16]
• Kaempferol and astragalin (kaempferol 3-O-beta-D-glucopyranoside)^[16]
• Licoagroside F at 8.97+/-0.41μg/g^[10]
• Baicalein (0.23+/-0.002μg/g), Wogonin (0.19+/-0.0030μg/g), and Oroxylin A (0.04+/-0.0004μg/g)^[10]
• Lignans Syringaresinol di-O-Glc (275.53+/-0.99μg/g) and Pinoresinol di-O-Glc (384.15+/-19.67μg/g)^[10]
• Chlorogenic acid (26.3-46.9mg/g)^[11][12][17]
• Ferulic and caffeic acid^[11]

The bark and leaves tend to possess both lignans and irioid glycosides as the active components, which are likely what set this plant out from others. The other phenolics in the plants are quite general to most plants and not in remarkable quantities in this plant

The water extract of the leaves is a relatively potent antioxidant with an IC₅₀ of 18.9+/-0.2μg/mL in a DPPH assay (albeit weaker than the reference drugs of vitamin c at 5.9+/-0.1μg/mL and vitamin e at 9.7+/-0.2μg/mL)^[11] The unique bioactive, geniposidic acid, does not appear to have significant antioxidant properties^[11] and the total flavonoid content is 9.5-21.3mg/g of the leaves.^[12]

There is a polysaccharide content of this plant (leaf or bark not specified) at around 23.6-24.1% of total weight^[18] and the content of irioid glycosides appears to be less in this plant when directly compared to plantago asiatica (a plant related to psyllium).^[19] While the irioid glycosides can also be found in the seeds,^[20] these parts of the plant are not commonly used as supplements nor functional foods.

The irioid glycoside geniposide and its aglycone (genipin) have been detected in plasma and in organs (kidneys) following oral ingestion of the bark^[7] and aucubin at 50mg/kg oral intake (rats) in isolation has been noted to peak in the blood at a T_max of 1.08h and a C_max of 4016+/-2394ng/mL and a fairly prolonged half-life of 7.38+/-2.9 hours.^[21]

The lignan (+)-pinoresinol-di-β-D-glucopyranoside has been noted to be absorbed in rats with a T_max of 1.56+/-0.87 hours and a half-life of 3.66 hours, being detected at a C_max of 18.57+/-8.09ng/mL at an oral intake of 10mg/kg.^[22]

Both the irioid glycosides as well as the lignans seem to have the potential to be absorbed, although pharmacokinetic data is somewhat limited as it is not sure what the active ingredient(s) is/are

Both irioid glycosides of genipin (geniposide and geniposidic acid) can be hydrolyzed into free genipin in intestinal bacteria.^[23]

Lignans in Eucommia ulmoides may have phosphodiestease (PDE) inhibiting properties, with IC₅₀ values between 63.5-123.8µM and two (of seven tested) lignans having an IC₅₀ greater than 200µM;^[9] this has been noted previously against cAMP-related PDE enzymes^[24] but an in-depth evaluation of which subsets of the PDE enzyme are inhibited and the selectivity of the lignans is not yet conducted.

May inhibit PDE enzymes, but due to the lack of research on selectivity and moderate potency (paired with unknown amounts of lignans in the plant) it is not sure how practically relevant this information is

The bioactive asperuloside has been found to inhibit PI3K with an IC₅₀ of 2µM, being less potent than uttronin A (1.1µM) and hypericin (180nM)^[25] while being more effective than emodin (3.3µM) and quercetin.^[26]

May inhibit PI3K

Eucommia ulmoides stem bark extract appears to have acetylcholinesterase inhibiting properties in vitro (IC₅₀ of 172μg/mL)^[27] and is able to exert neuroprotective effects against beta-amyloid proteins (as assessed by memory formation and normalizing the increase in acetylcholinesterase)^[27] and hydrogen peroxide with 5-20μg/mL preventing 30-70% of cytotoxicity, with 2.5μg/mL showing some efficacy in reducing oxidative biomarkers.^[2] In isolation, both chlorogenic acid and geniposidic acid show protective effects.^[28]

In rats given intracerebral injections of beta-amyloid proteins (induces Alzheimer's-like cognitive dysfunction), 5-20mg/kg of the stem bark extract noted that the higher range of intake (10-20mg/kg) protected from memory dysfunction.^[27]

Appears to have neuroprotective properties, which have at least once been confirmed to occur in a living model at fairly reasonable oral dosages

Mechanistically, eucommia ulmoides appears to possess beta-blocking potential as assessed by a lipolysis assay with isoproterenol.^[29]

Eucommia ulmoides bark can also cause vasorelaxation in a concentration dependent manner in a way that is fully dependent on nitric oxide^[30][31] and thought to be related to potassium channels.^[31]

May have beta-blocking potential (thought to be related to the lignans) and may be vasorelaxant

Eucommia ulmoides appears to have antihypertensive effects due to its activating effects on the parasympathetic nervous system^[32] and can work in a dose-dependent manner in spontaneously hypertensive rats.^[33] In fructose overfed rats that develop insulin resistance and hypertension, 500-1000mg/kg of eucommia ulmoides can reduce blood pressure in a dose dependent manner but cannot completely normalize it.^[34][35][36]

In prehypertensive humans, while supplementation of 500mg eucommia ulmoides (8% pinoresinol) daily for eight weeks only caused marginal reductions in blood pressure that faded with time a higher dose (1,000mg thrice daily) for two weeks has resulted in a reduction in both systolic and diastolic blood pressure by 7.5/3.9mmHg.^[29]

Eucommia ulmoides appears to be reliably antihypertensive in rats, and a daily dose of 3g of the leaves has been shown at least once to be effective in humans

Ingestion of eucommia ulmoides daily for 90 days in rats appears to reduce the expression of the GLUT4 transporter in rats given a high fat diet, yet increased expression in rats on a normal diet (not obesogenic) and increased expression in skeletal muscle.^[15]

Appears to modify GLUT4 transporters in a somewhat unreliable manner

In fructose drinking rats (a research model for fatty liver) given 500-1000mg/kg of eucommia ulmoides leaf extract over four weeks, the supplementation was able to fully normalize the changes in insulin and insulin sensitivity (HOMA-IR) without affecting blood glucose which was unaffected by fructose treatment initially.^[34]

In streptozotocin-induced diabetic mice given eucommia ulmoides orally for four weeks (1,400mg/kg) was able to reduce blood glucose and normalize oxidative parameters such as SOD and MDA.^[37]

Mechanistically, it has been noted that ingestion of Eucommia ulmoides is associated with increases in protein content of some intermediates of energy metabolism (isocitrate dehydrogenase 3, citrate synthase, pyruvate kinase, GLUT4, and H⁺ transporting mitochondrial F1 complex)^[15] and in rat liver increases in the activity of genes involved in fat oxidation has been noted in the range of 1.21-1.88 fold (300-1,600mg/kg leaf extract intake)^[38] which is thought to explain the increases in fat oxidation seen in the liver.^[38][39][15] The increase was noted on the rate-limiting stages of β-oxidation (Cpt1a, Acox1, and Acadvl), α-Oxidation, and ω-oxidation (Cyp4a1).^[38]

Differential effects have been noted on UCPs, with an increase in UCP3 seen in normal rats and an increase in UCP2 seen in high fat fed rats,^[15] and PPARγ mRNA has been found to be increased.^[15] The aforementioned genetic changes in liver enzymes also appear to be targets of PPARα and PPARδ, suggesting they may play a role.^[38]

It is hypothesized that the above changes are due in part to geniposide and geniposidic acid as well as their aglycone (genipin) as they consist of most of the plant's phytochemicals by weight^[38] and since geniposide has shown lipid reducing properties in isolation.^[40]

Eucommia ulmoides appears to modify the levels of proteins involved in energy metabolism and expenditure and in particular the uncoupling proteins (mediates heat production and 'wastes' energy), but the exact mechanism of action underlying these observations is not yet clear

A study in anaethesized rats given an intraduodenal injection of eucommia ulmoides (1-5mg or 4-20mg/kg) noted an increase in sympathetic nerve activity in both white and brown adipose tissue, and in concious rats there was an increase in plasma fatty acids (154.5-156.6% at 1-5mg of the leaf extract) and body temperature.^[41]

An increase in heat expenditure following a single dose has been noted in rats, following fairly reasonable oral dosages as well

At least one study, in assessing its mechanisms on blood pressure, has found beta-blocking properties in human fat cells able to reduce the effects of isoproterenol.^[29] This suggests that eucommia ulmoides can suppress the effects of fat burners that signal via these receptors, namely ephedrine or synephrine.

It's beta-blocking potential, while beneficial to blood pressure, may antagonize the effects of other fat burner

In mice given a high fat diet with 3% or 9% of either the leaf powder or water extract of eucommia ulmoides (corresponds to human doses of 0.99g and 2.35g respectively), the weight gain observed is abolished over 90 days of ingestion.^[15] In normal mice on a normal diet, the addition of 9% eucommia ulmoides is associated with a nonsignificant trend to lose body weight (12%) and a significant reduction in triglycerides and NEFA with an increase in adiponectin,^[15] and the high fat and normal diet groups given 9% were similar weights at the end of the trial.^[15] The leaf powder and the water extract from the leaves are comparable in potency^[15][42] and other studies tested have noted a failure for high doses (3-6g/kg) to affect body mass over 35 days in rats (despite a reduction in white adipose tissue mass)^[43] and a failure for low doses (15.5mg daily) to reduce body mass in hamsters.^[39] One study comparing 3% leaf extract against 10% found only the latter effective at reducing body weight,^[41] although the degree of fat loss was less drastic and partially confounded with a reduction in food intake.^[41]

In osteoporotic mice, 5% of the diet as the water extract of eucomia ulmoides leaves is able to attenuate the rate of fat gain.^[44]

For rat studies that measure weight as a secondary data point, 500-1000mg/kg of the leaf extract over 4 weeks has failed to cause a significant fat reducing effect in fructose-overfed rats.^[34]

Longterm ingestion of eucommia ulmoides in rats appears to cause minor fat loss and is more potently an anti-obese agent, there are a lack of human studies on this herb at this point in time

It is possible that the antioxidant properties of Eucommia ulmoides leaf extract can preserve bone cell integrity in periods of oxidative stress, and is active in a concentration dependent manner as low as 6.25µg/mL (EC₅₀ being around 25µg/mL).^[45] There has also been a noted inhibitory effect on osteoclastic formation attributed to the irioid glycosides.^[46]

The enhancement of signalling via the estrogen receptor alpha^[1] may also contribute to enhanced bone growth properties, but is unlikely to be the only mechanism at play (as there is still protection for bone in instances of estrogen deficiency such as rat ovarectomy^[44][47]).

In ovarectomized rats, 5% of the diet as eucommia ulmoides appears to reduce the rate of bone loss in this menopausal research model^[44] and the cortex in doses of 300-500mg/kg (but not 100mg/kg) appears to reduce the loss in bone mass over 16 weeks with a potency not significantly different than the reference drug estradiol.^[47]

Both genipin and geniposide have been noted to inhibit nitric oxide release from LPS-stimulated macrophages at a concentration of 12.5μM (7-10%), with genipin increasing in potency with near absolute suppression at 100μM^[7] and both the cortex itself has shown similar properties (antiinflammatory properties against LPS-stimulated macrophages) between 0.05-0.5mg/mL to near half of control^[48] and the bark has reported an IC₅₀ against COX2 induction of 9.92μg/mL (meloxicam as reference drug was more potent at 0.18μM).^[19]

The androgen receptor is the receptor by which androgens (testosterone and DHT mostly, to a lesser degree DHEA) exert most of their biological effects.^[49] Binding of a ligand (be it a hormone or plant) to the receptors is enough to induce effects,^[50] and it appears that Eucommia ulmoides possesses phytoandrogens capable of this.^[1]

In mammalian COS-7 cells, an ethanolic extract of the bark from Eucommia ulmoides is able to bind to and weakly activate the androgen receptor with enough affinity to displace testosterone with efficacy at a 5-25ng/mL range.^[1] The addition of the extract to a medium containing DHT noted that even at saturating levels of DHT, Eucommia ulmoides augmented signalling in the range of 112-204% of baseline.^[1] While this was found with the fractions containing triterpenoids, the caprylic acid content of Eucommia ulmoides and caprylic acid isolated from coconut oil both mimicked this augmentation.^[1]

While oral intake of 1-50mg of the ethanolic extract in rats has failed to modify prostatic weights (suggesting weak androgenicity), it was able to increase the testosterone (5000mcg injection) induced prostatic growth by approximately 20%.^[1]

Eucommia ulmoides appears to be androgenic, although weakly on its own. This plant appears to augment signalling of other androgens through the androgen receptor (thus increasing their efficacy) which is currently thought to be due to the caprylic acid content

Similar to the effects on the androgen receptor, Eucommia ulmoides (50ng/mL) strongly binds to and weakly activates the estrogen receptor (ERα) while augmenting the signalling of estradiol.^[1]

Similar to its effects on the androgen receptor, this herb appears to augment signalling through the estrogen receptor (alpha confirmed, beta isoform not tested)

The augmenting effects of Eucommia ulmoides on the androgen and estrogen receptor do not appear to extend to the cortisol receptor nor the progesterone receptor.^[1]

Does not appear to significantly modify signalling through the cortisol receptor

In isolated rat pituitary cells incubated with 20µg/mL of the n-hexane, chloroform, or ethyl acetate fractions, there appears to be a stimulation of growth hormone release.^[46]

May stimulate growth hormone release, requires studies in living models to assess whether this is relevant or not

The polysaccharides from this plant, at 300-600mg/kg for 15 days, appear to have protective effects in the kidneys as assessed by MDA and glutathione concentrations after renal ischemia reperfusion; this was attributed to antioxidant properties (Protective effects were confirmed by histological examination, and although 600mg/kg was close to normalization it was not fully protective)^[18] and the overall bark extract (70% ethanolic) itself also has protective effects against cadmium at 125-500mg/kg.^[7]

A mixture of panax pseuodoginseng and eucommia uloides (50% and 25% of weight respectively) at 10mg daily (35.7-41.6mg/kg) for six weeks after nephrectomy noted a mild protective effect on glomerular filtration rate and histological examination.^[51]