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Ecklonia Cava is a brown seaweed with a rich polyphenolic content (this particular subset being known as eckols or phlorotannins) that confers anti-oxidant properties, it is being investigated for health properties.

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Discussion

Summary Things To Know How To Take Human Effect Matrix Scientific Research Citations Summary

All Essential Benefits/Effects/Facts & Information

Ecklonia Cava is a type of seaweed which is known to be one of the highest sources of phloroglucinols, a type of antioxidant compound that appears to be unique to sea plants. The phloroglucinols appear to be very potent anti-oxidants, and these benefits have been noted after oral ingestion as well.

That being said, the potency of Phloroglucinols being anti-oxidants seems to be a bit separate from the magnitude of benefit one gets from ingesting these compounds. Benefits have been noted on Blood Pressure, Blood Glucose, and Inflammation but for the most part these are statistically sound but practically small benefits. The current human evidence is unconvincing for the most part, although these compounds and seaweed are undoubtedly 'healthy' as a general statement.

Other effects that seem interesting for Ecklonia Cava are an apparently anti-allergic potential that is not highly explored, and there appears to be some anti-cancer properties as well (mostly tested in regards to melanoma). Topical application of Ecklonia is one of a few compounds that can enhance hair growth, and it appears to be novel in the sense that it both inhibits androgen-induced hair loss and also directly enhances hair growth (so it, by itself, appears to be some form of combination therapy). How to Take Recommended dosage, active amounts, other details

Ecklonia Cava products appear to benefit the body in relatively low doses, with weak health benefits on blood pressure and glucose in the range of 100mg; higher doses (which would be expected when consuming the seaweed itself as a food product) confer dose-dependent responses.

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The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects ecklonia cava has on your body, and how strong these effects are.

Grade Level of Evidence Robust research conducted with repeated double-blind clinical

trials Multiple studies where at least two are double-blind and placebo

controlled Single double-blind study or multiple cohort studies

Uncontrolled or observational studies only

Level of Magnitude Consistency of Evidence Outcome of effect research results Notes ? ? ? Blood Very High See May reduce blood glucose levels,

Glucose Minor study not overly potent in doing so A possible reduction in blood Blood Very High See pressure in overweight persons

Pressure Minor 2 studies with supplementation of ecklonia cava Very High See

LDL-C Possible reductions in LDL-C Minor 2 studies Total Very High See A possible reduction in total

Cholesterol Minor 2 studies cholesterol concentrations No significant influence on Very High See

Triglycerides - triglycerides noted with ecklonia study cava Appears to reduce C-reactive C-Reactive Very High See protein, with the degree of

Protein Notable study reduction being noted almost a halving Very High See No significant influence on

HDL-C - study HDL-C detected Scientific Research

Table of Contents:

1. 1 Sources and Summary 1. 1.1 Sources 2. 1.2 Composition 3. 1.3 Patents 2. 2 Neurology 1. 2.1 Alzheimer's 2. 2.2 Neuroprotection 3. 2.3 Sedation 3. 3 Cardiovascular Health 1. 3.1 Blood Pressure 2. 3.2 Lipoproteins 3. 3.3 Artherosclerosis 4. 4 Interactions with Glucose Metabolism 1. 4.1 Absorption 2. 4.2 Pancreas 3. 4.3 Interventions 5. 5 Interactions with Obesity 1. 5.1 Mechanisms 2. 5.2 Interventions 6. 6 Inflammation and Immunology 1. 6.1 Mechanisms 2. 6.2 Lymphocytes 7. 7 Interactions with Oxidation 1. 7.1 Mechanisms 8. 8 Cytology 1. 8.1 Mitochondria 9. 9 Joint and Skeletal Health 1. 9.1 Mechanisms 10. 10 Muscles and Performance 1. 10.1 Mechanisms 2. 10.2 Interventions 11. 11 Interactions with Organ Systems 1. 11.1 Liver 12. 12 Interactions with Cancer Metabolism 1. 12.1 Angiogenesis 2. 12.2 Melanoma 3. 12.3 Breast 13. 13 Interactions with Aesthetics 1. 13.1 Hair 2. 13.2 Skin 14. 14 Safety and Toxicology 1. 14.1 General

1Sources and Summary

1.1. Sources

Ecklonia Cava (family Phaeophyceae) is a brown seaweed that had usage as a food product, similar to Fucus vesiculosus (Bladderwrack), it is currently being explored for its health promoting properties due to its high Polyphenolic content of 18.3% dry weight.[1] Beyond the polyphenolics, carbohydrates consist of up to 44.9% of Ecklonia while protein is 28.2% by weight (with the remaining coming from an ash content of 7.5% and a lipid content of 1.2%).[1] They are mostly collected from Islands in the Jeju Province of Korea (highest concentration of Ecklonia Cava for subsequent sales) although they can be found in a variety of places.[2]

1.2. Composition

Ecklonia Cava contains, in the polyphenolic (phlorotannin) fraction which constitutes up to 18.3% of Ecklonia dry weight:[1]

Eckol, as well as both 2-phloroeckol[3] and 7-phloroeckol[4] at 1.19% Ecklonia by dry weight[5] Phloroglucinol, the simplest phlorotannin structure (1,3,5-trihydroxybenzene)[4] Dieckol Phlorofucofuroeckol 6,6'-Bieckol at 1.28% Ecklonia dry weight,[5] 8,8'-Bieckol, and Pyrogallol- phloroglucinol-6,6'-bieckol[6] Eckstolonol[7] 2-O-(2,4,6-trihydroxyphenyl)- -bieckol[3] 1-(3',5'-dihydroxyphenoxy)-7-(2'',4'',6-trihydroxyphenoxy)-2,4,9-trihydroxydibenzo- 1,4-dioxin[8] Phlorotannin A,[3] phlorofucofuroeckol A,[5] and Fucodiphloroethol G[5] Dioxinodehydroeckol[4][9] Fucoidan,[10] a sulfated polysaccharide[11]

Phlorotannins are a subclassification of polyphenolic compounds that are identified by dibenzo-1,4-dioxin backbone, and do not exist in terrestrial (land originating) plants;[12] Phlorotannins are found in various species of brown seaweeds.

In general, Ecklonia Cava just appears to be a vessel for Phlorotannin structures (common to seaweeds, but no other source possesses them). It does possess Phloroglucinol which is common to all seaweeds, but it seems to possess a higher Eckol and Dieckol content (which seem to be more prominent in the Ecklonia species)

1.3. Patents

'Ventol' is a term used to refer to an extraction of Ecklonia Cava rich in phlorotannin compounds,[12] with enzymatic extractions in general increasing the content of phloroglucinols (polyphenolics) on a weight basis sometimes exceeding 50%.[11]

'Viscozyme' is a polysaccharide from Ecklonia Cava that is fermented by the bacteria Lactobacillus brevis, and produced by Novozyme corporation.[13] This fermentation was found in a Master's Thesis study where Ecklonia was fermented by said bacteria as well as Candida utilis and Saccharomyces cerevisiae with the Viscozyme fermentation showing greatest subsequent Nitric Oxide suppression in a macrophage cell line (indicative of anti- inflammatory properties).[13]

Fermentation in general is known to increae anti-oxidant properties of Ecklonia Cava,[14] this study was fermented using a separate Bacteria species than Viscozyme (Candida utilis) and the degree of improvement may not be accurate.

2Neurology

2.1. Alzheimer's

In HEK293 cells overexpressing amyloid precursor protein (APP), the butanolic extract of -protein oligermization, fibrillization, -induced neuronal cell death.[15] This was replicated elsewhere, where 40 protein secretion from HEK293 cells to 42.6+/-6.6% of control -42 to 28.3+/-4.9% (with dose-dependence showing at lower doses, but not statistically significance).[16] When assessing secretase enzymes decreases were noted in the alpha secretases of ADAM10 and ADAM17 and the gamma secretase PSEN1, but not PSEN2; mRNA levels of both BACE1 and BACE2 were unaffected although the protein content of BACE1 was reduced.[16] When assessing activity of secretases, a slight increase of alpha secretase inhibitory is met with a reduction in gamma secretase activity (correlating with PSEN1 reduction) with no significant changes to beta-secretase activity.[16]

Additionally, Dieckol and phlorofucofuroeckol may possess anti-cholinesterase properties.[17]

May have anti-Alzheimer's properties, but no living models have been assessed so far

2.2. Neuroprotection

Injections of 50mg/kg Ecklonia Cava into rats prior to experimental infarct induction via middle cerebral artery occlusion was able to exert neuroprotective effects as assessed by less brain edema, neural apoptosis, and infarct size after injury.[18]

In HT22 hippocampal cells, various phlorotannins showed anti-oxidant properties at 50uM and reduced Reactive Oxygen Species (ROS) induced by hydrogen peroxide by 75.22% (phloroglucinol), 69% (eckol), 67.32% (triphlorethol-A), 77.63% (eckstolonol), and 77.73% (dieckol), although a tenth the concentration of dieckol (5uM) reduced ROS by 50.42%.[19] TBARS (measure of lipid peroxidation) was reduced with similar potency, and these effects occured with a preservation of cell viability and prevention of calcium influx.[19]

Anti-inflammatory may also be present in microglia cells, where isolated Dieckol exerts anti- inflammatory effects against LPS-induced microglia and suppresses COX-2, iNOS, PGE(2) and NO production in response to LPS at 50-300mcg/mL.[20] The highest concentration (300mcg/mL) was associated with normalizing PGE(2) and NO, suggesting that the dose- dependent responses can ultimately result in potent effects; these effects were thought to be through NF-kB inhibition, but also existed alongside a potent reduction in ROS and MAPK inhibition;[20] similar results have been noted elsewhere.[21]

General anti-oxidant and antiinflammatory properties confer neuroprotection against stressors, but nothing appears to be overly novel or potent

2.3. Sedation

An enyzmatic extract of Ecklonia (98.4+/-1.6mg/g Phloroglucinol equivalents and 630.2+/- 11.3mg/g phlorotannin content) appears to possess sedative properties in a dose dependent manner, with 1000mg/kg being slightly less sedative than 2mg/kg Diazepam in augmenting a phenobarbitol-induced sleep.[22] The observed effect was due to phloroglucinols in Ecklonia, and were fully antagonized with flumazenil (and thus were mediated via GABA(A)- Benzodiazepine receptors).[22]

In regards to anti-convulsant properties, Ecklonia showed dose-dependent anti-convulsant properties but 1000mg/kg failed to outperform Diazepam at 2mg/kg as active control.[22]

Weak sedative properties at high doses

3Cardiovascular Health

3.1. Blood Pressure

Ecklonia is thought to reduce blood pressure as phlorotannins in Ecklonia possess ACE inhibitory properties.[23] Dieckol appears to be the most potent noncompetitive inhibitor of ACE with an IC50 of 1.47+/-0.02mM, with other inhibitors being Phloroglucinol (2.57+/- 0.03mM), Triphlorethol-A (2.01+/-0.36mM), Eckol (2.27+/-0.08mM), and Eckstolonol (2.95+/-0.28mM).[23]

In overweight adults given either 72mg or 144mg of Ecklonia polyphenols daily for 12 weeks, only the higher dose was associated with a reduction in systolic blood pressure (2.6%) and no significant change in diastolic blood pressure.[24] This reduction in blood pressure was not replicated in a pilot study using 200mg Ecklonia for 12 weeks in hypercholesterolemics.[3]

May reduce blood pressure, but appears to be pretty weak at it

3.2. Lipoproteins

An increase in HDL-C has been noted in overweight but otherwise healthy adults given 72mg or 144mg of Ecklonia polyphenols daily for 12 weeks, with the former dose increasing HDL- C by 8.6% and the latter by 13%.[24] This study also noted decreases in LDL-C (10-14.3%) and Total Cholesterol (6.1-9.3%), but the decline in triglycerides was not significant.[24] Another study selectively using persons with high cholesterol or LDL-C using 200mg Ecklonia polyphenols (same supplier, Livechem Inc.) in a non-blinded study where total cholesterol was reduced by 8% and LDL-C by 9.5%, where triglycerides and HDL-C were unaffected.[3] The benefits are noted to be greater during subgroup analysis when only factoring in persons who had metabolic syndrome.[3]

Tends to improve the lipid profile, but the potency nothing impressive

3.3. Artherosclerosis

Ecklonia Cava extract has been found to suppress LPS-induced inflammatory responses in endothelial cells (those lining the arteries) and reduce immune cell adhesion, the expression of three select adhesion factors (VCAM-1, ICAM-1 and E-selectin) were abolished in vitro with hydroalcoholic and butanol extracts of Ecklonia Cava (attenuated with other extracts) at 200mcg/mL.[25] The potency correlated with and was thought to be due to NF-kB inhibition.[25] Protective effects in endothelial cells (HUVECs) have been noted elsewhere associated with the phloroglucinols, and associated with anti-inflammatory and anti-oxidant effects;[26] this study is duplicated in Medline.[27]

Improvements in the artherogenic index have been noted following ingestion of 72mg and 144mg of Ecklonia Cava daily for 12 weeks,[24] which may be related to inflammation as a 45.1% reduction in C-Reactive protein (indicative of inflammation) has been noted following oral ingestion of Ecklonia Cava.[3] The effects of Ecklonia Cava on lipids themselves are relatively subpar, as mentioned in the previous section. May protect the endothelium due to anti-inflammatory properties, and thus be anti- artherogenic

4Interactions with Glucose Metabolism

4.1. Absorption

Ecklonia Cava appears to be able to inhibit intestinal glucose uptake via SGLT1 with an IC50 value of 345+/-54ug/mL when assessing the methanolic extract, and this was accompanied by a downregulation of SGLT1 protein content reaching a 31.5% reduction with 200ug/mL Ecklonia Cava after 1 hour.[28] These effects were shown in vivo, where in normal mice glucose uptake was reduced 14.8% (not significant) and in diabetic mice by 39.7%, which correlated with the reductions in SGLT1 expression (17% and 34%) following Ecklonia at 3% of feed intake.[28] These effects go well with Dieckol, which per se appears to be a - -amylase with IC50 values of 0.24 and 0.66mM, with 0.67mM i - -amylase.[29] In this study, these IC50 values were more potent than Arcabose, and Dieckol was confirmed to reduce circulating glucose following a test meal in mice (47% following 100mg/kg Dieckol).[29]

Can inhibit glucose absorption. Kind of nice as many compounds that inhibit carbohydrate absorption act on enzymes (alpha-amylase, sucrase) and inhibit polymers of sugars but not glucose itself

4.2. Pancreas

In isolated pancreatic cells, 50ug/mL Ecklonia Cava was able to augment glucose-induced insulin secretion by 2.8-fold[28] and increased basal insulin has been found in diabetic mice (75%) with 3% Ecklonia in the feed with no significant influence on normal mice.[28] Increases to insulin secretion have been replicated in mice given 3-5% Ecklonia Cave.[30]

In instances of damage to the pancreatic cells, glucotoxicity (toxicity via excessive glucose) appears to be attenuated under the influence of Ecklonia extract; this particular study used an enzymatic hydrolysis of Ecklonia,[31] but a reduction of beta-cell losses during diabetes (experimental type II) has been noted with oral consumption of standard Ecklonia extract.[30]

4.3. Interventions

In type II diabetic rats (genetic) fed 0.5% Dieckol (a component of Ecklonia) daily for 6 weeks noted improvements relative to control on all measured parameters of lipid and glucose metabolism.[32] In comparison to the active control of rosiglitazone, at 0.005% of the diet, the improvements in lipid parameters were either of equal magnitude (triglycerides, HDL-C) or lesser with Dieckol (total cholesterol, FFA) and all glucose parameters were lesser in magnitude.[32]

144mg of Ecklonia Cava polyphenols daily for 12 weeks in overweight adults without diabetes or metabolic syndrome was associated with a slight reduction of fasting blood glucose (4.9%) with no significant effect observed with 72mg; subjects in this study lost body fat, which may have influenced the results.[24]

Weak but beneficial effects on glucose metabolism in persons with impaired glucose metabolism (metabolic syndrome, pre-diabetes, diabetes type II; etc.)

5Interactions with Obesity

5.1. Mechanisms

Polyphenols are associated with suppressing diacylglycerol acyltransferase-1 (DGAT-1) with [24] an IC50 of 25ug/mL (unpublished results noted here )

One phloroglucinol derivative was able to decrease lipid accumulation into adipocytes in a concentration-dependent manner up to 50uM; a suppression of PPARy activity was also observed in a concentration-dependent manner alongside other proteins involved in adipogenesis.[8] A similar effect has been seen with Dioxinodehydroeckol (in differentiating

FAS, LPL) all of which were mediated via activation of AMPK at a concentration of 5- 20uM, as an AMPK inhibitor abolished all the aforementioned effects.[9]

5.2. Interventions

In rats, 200mg/kg of an butanolic-ethanolic extract of Ecklonia Cava (6.9-8% polyphenolics) given to diet-induced obese mice for 8 weeks noted reduced body weight as well as reduced appetite (as measured by food intake, thought to be causative of weight loss).[33] This study also noted that one extract (higher in phloroglucinols) was more potent than another source of Ecklonia Cava, implicating eitehr phloroglucinols or another currently unidentified agent for appetite reduction.[33]

One study in overweight adults with no significant morbidities noted that consumption of 72mg or 144mg of Ecklonia polyphenols daily for 12 weeks was associated with a reduction of body weight by 0.9kg (1.3%) and 1.3kg (1.9%) from baseline; placebo did not experience any loss of weight, while food intake (via 24-hour dietary recall) did not show any significant differences.[24] A reduction in waist circumference was seen elsewhere with 200mg of Ecklonia polyphenols over 12 weeks in persons with high cholesterol, but this study did not have a placebo group and the reduction in waist circumference was not significant (nor was there a reduction in overall weight).[3]

Either weak or non-existent effects on body fat loss

6Inflammation and Immunology

6.1. Mechanisms 6,6'-Bieckol, when incubated in peritoneal macrophages and RAW 264.7 macrophages, is able to dose-dependently reduce Nitric Oxide release from activated macrophages with most efficacy at 100-200uM (around 30% suppression; value derived from graph) and attenuated IL- -10 release, a more potent suppression was noted on PGE(2) levels at more than 80%.[34] Protein levels of iNOS and COX2 were attenuated with 6,6'-Bieckol, and these were thought to be via preventing TNF- and IL-6 genomic activity by preventing NF-kB from acting on its promoters (exact mechanism of inhibition not known).[34]

A polysaccharide in a bacterial fermented version of Ecklonia (Viscozyme) also shows these effects, where 12.5-100mcg/mL of this polysaccharide dose-dependently reduced LPS- stimulated NO release to a maximal 20% of control at 100mcg/mL without significantly affecting PGE(2) levels (80% of control at 100mcg/mL only, other concentrations insignificant).[13] Secondary to these effects, less TNF- -6 release was noted but no influence on IL- [13]

Components of Ecklonia appear to be anti-inflammatory on macrophages, and are oddly additive in regards to PGE(2) and NO suppression (probably pure chance)

Phloroglucinol may protect immune cells (lymphocytes and splenocytes) from radiation- induced apoptosis.[35] Interestingly, this study noted that Phloroglucinol increased cell viability in a concentration dependent manner between 25-100mcg/mL to 165% (relative to control) before radiation was introduced, induced proliferation of splenocytes, and prevented 12.2%, 35.3% and 37.4% of Reactive Oxygen Species (ROS) at 25, 50, and 100mcg/mL.[35] These effects were confirmed in vivo following injections of 10mg/kg into irradiated mice.[35] Similar radioprotective properties are seen with Dieckol, where lethally irradiated mice experienced prolonged survival with Dieckol secondary to preventing immune cell apoptosis and increasing some parameters of oxidant defense[36] and with Phloroglucinol, where the anti-oxidant propertie preserved glutathoine and reduced apoptosis in response to radiation.[37]

General protective effects may exist for the immune cells themselves in response to stressors (studies have investigated protection from radiation induced damage, using UVB rays at times)

One novel mechanism by which Ecklonia Cava can interact with the immune system is via Immunoglobulin E (IgE) on basophils and mast cells.[38] This study used a methanolic extract of Ecklonia and noted that expression of % at 50mcg/mL and 11.3% at 100mcg/mL; these effects were coupled with less antigen binding to the receptor at the highest concentration approximately a halving of histamine release.[38] These mechanisms may underlie the results seen in a previous study where mice who exhibited allergic asthma reactions to an antigen had significantly reduced allergic responses (assessed by immune cell infiltration into lungs) following injections of 20mg/kg Ecklonia Cava extract daily for 4 days prior to testing;[39] A decrease in antigen-specific IgE was also noted with Ecklonia, being 67% less than control after exposure to the antigen.[39]

Limited evidence, but appears to work in rats after injections and does appear to possess anti- allergic properties 6.2. Lymphocytes

The polyphenolics appear to induce proliferation of Lymphocytes in a concentration dependent manner in vitro between 5-100mcg/mL with 500mcg/mL increasing lympcyte count 6-fold over 48 hours.[1] This is mediated via inducing NF-kB activity via the p65 subunit (as NF-kB inhibition blocks this effect).[1]

7Interactions with Oxidation

7.1. Mechanisms

Various studies using isolated phloroglucinols note potent anti-oxidant properties against Reactive Oxygen Species (ROS) in particular, with either around 70% inhibition (triphlorethol-A, eckol, phloroglucinol, dieckol, and eckstolonol),[19] or have been implicated in abolishing the increase in ROS in response to toxins[40] or stressors.[7] A reduction in lipid peroxidation is also noted in some studies (assessed by TBARS) which may be secondary to reducing ROS production.[19]

Additionally, the Nrf2 gene (known to induce anti-oxidant defenses) may be induced by Eckol, where a concentration and time dependent increase in HO-1 is noted V79-4 cells in vitro at 1-10mcg/mL over 48 hours.[41] This induction of HO-1 was prevented by inhibiting Nrf2, which Eckol was found to promote activity of secondary to activating ERK and PI3K/Akt.[41] Interestingly, Eckol appeared to exert all anti-oxidant protection due to HO-1, as inhibiting HO-1 normalized cell death in response to oxidation[41] and these mechanisms are shared by Triphlorethol-A.[42]

Dieckol has also been noted to not sequester free radicals directly, but instead prevents binding of a protein (WAVE2) to the P47phox subunit of NADPH oxidase (a pro-oxidative enzyme) and thus prevents a degree of NADPH oxidase activity.[43]

Appears to be a potent anti-oxidant compound, but its potency in vitro appears to be more pronounced than the benefits it seems to exert after oral ingestion Eckol and Dieckol have been noted to not directly sequester free radicals, but work through interacting with pro-oxidative or anti-oxidative enzymes

8Cytology

8.1. Mitochondria

Triphlorethol-A from Ecklonia has been tested in vitro against formaldehyde-induced cytotoxicity, Triphlorethol-A appears to reduce free radicals (ROS) and enhanced cellular survival from 53% (control) to 74% at 30uM;[44] this appeared to be secondary to attenuating DNA damage and mitochondrial membrane potential loss in response to formaldehyde.[44]

9Joint and Skeletal Health

9.1. Mechanisms

In vitro using murine macrophages (to test inflammation in response to an antigen) noted that a phlorotannin-rich extract of Ecklonia Cava (SEANOL) was able to attenuate the increase in PGE2 by 61%, 85%, 92%, and 99% at 10, 30, 60, and 100ug/mL; a potency similar to Celecoxib at all doses and similar to Aspirin at 60-100ug/mL (underperforming at the lower concentrations).[45] Similar results have been noted elsewhere yet connected to a reduction in IL-1a induced proteoglycan degradation (implicating benefit for osteoarthritis)[12] and at least in an osteosarcinoma cell line an increase in collagen synthesis has been noted with phloroglucinol compounds (alongside anti-inflammatory properties, such as a reduction in MMP1, 3, and 13).[46]

Attenuating an increase in PGE(2) is reflective of COX2 inhibition, and the increase in COX2 expression has been noted with isolated Dieckol[20] and 6,6'-Bieckol;[34] one study looking at the polysaccharide fragment noted rather lacklustre inhibition of PGE(2) induction,[13] suggesting that the benefits associated with Ecklonia are due to the phloroglucinols (polyphenolics). At least Dieckol has been demonstrated to be an indirect suppressor of COX-2, preventing its increase in response to pro-inflammatory stimuli (albeit in microglia) rather than possessing direct inhibitory potential like Celecoxib.[20]

The phloroglucinols appears to be suppressors of COX-2 activity (may not be direct inhibitors) and thus may have a role in attenuating joint pain; direct interventions have not been undertaken

10Muscles and Performance

10.1. Mechanisms

In a small animal study of type I diabetic animals given Ecklonia Cava (300mg/kg methanolic extract; 116.8mg/g polyphenolics) where a reduction in serum glucose was noted, subsequent in vitro testing with C2C12 myocytes was able to induce Akt phosphorylation independent of insulin as well as inducing AMPK activity in a dose-dependent manner up to 300mcg/mL concentration.[47]

10.2. Interventions

Ecklonia Cava polyphenols (40mg of polyphenols; mostly phlorofucofuroeckol, dieckol, and two bieckols) is associated with a prolonged time to voluntary exhaution in endurance exercise (2.19 minutes; from approximately 8m to 10:30m) and a nonsignificant increase in VO2 max in non-sedentary persons.[48] This study did not find an alteration in RER (indicative of whether energy is derived from fat or glucose) and no significant alterations in blood lactate.[48]

11Interactions with Organ Systems

11.1. Liver

Isolated Dieckol from Ecklonia Cava was given at 5 or 25mg/kg alongside a dose of Alcohol able to induce liver toxicity was able to increase survival rates over 14 days at 25mg/kg only (66% in control, 82% with 25mg/kg) and slightly protected the liver as assessed by enzyme release (GOT and GPT, almost normalized at 25mg/kg) and histology.[49] Mixed Ecklonia polyphenols at 0.02% or 0.2% of the rat diet when the drinking water was spiked with alcohol and CCL4 (hepatotoxin) was able to outright normalize the expected increase in plasma AST and ALT seen with both hepatotoxins (AST being suppressed 99% and 97% in response to [40] ethanol and CCL4, ALT being suppressed 98% and 100%). The downside to this latter study was that it used doses of either alcohol or CCL4 that were subactive in isolation (whereas Ecklonia fully protected against the combination, which synergistically induced liver injury) and no group on Ecklonia against ethanolic toxicity in isolation was used.[40]

Mechanistically, the observed effects are thought to be through preserving cellular concentrations of glutathione due to direct anti-oxidant properties (at 12.5mcg/mL).[40]

Appears to be quite potent in protecting the liver form Alcohol in rats

In regards to hepatic stellate cell activation (which precedes fibrosis), Ecklonia Cava extract in general may have protective effects against high glucose concentrations.[50]

12Interactions with Cancer Metabolism

12.1. Angiogenesis

Phloroglucinol (1,3,5-trihydroxybenzene) appears to inhibit angiogenesis and wound healing secondary to the growth factor VEGF, and oral administration of 0.94mg/kg Phloroglucinol to mice who were injected with a tumor appeared to reduce the rate of tumor growth over 24 subsequent days and thought to be secondary to inhibiting angiogenesis (demonstrated in vivo).[51]

Phlorotannins in general have weak to moderate ability to inhibit Metalloproteinases (MMPs),[52] and in particular Dieckol has been tested in a HT1080 cell line in vitro on invasiveness of tumor cells and Dieckol dose-dependently reduced invasion to about 10% of control at 100ug/mL.[53] This was thought to be through suppressing MMP2 and MMP9 transcription secondary to suppressing NF-kB activity (via increasing p- no influence on MAPK, ERK, TIMP-1/2 nor AP-1,[53] and similar effects have also been noted with 6,6'-bieckol (to a less potent degree).[54]

12.2. Melanoma Ecklonia Cava is investigated for its interactions on Melanoma due to its inhibitory potential on Tyrosinase and Melanogenesis (initially investigated due to whitening properties for cosmetics), due to the compounds of Phloroglucinol, 7-phloroeckol, and dioxinodehydroeckol;[4] 7-phloroeckol being a noncompetitive inhibitor of Tyrosinase in this cell line.[4] Dieckol appears to be more potent than the other Phloroglucinols.[55]

Most Phloroglucinols appear to inhibit melaogenesis, with Dieckol being the most potent

In cultured mouse melanoma cells, Dieckol (a component of Ecklonia) was able to suppress migration and invasiveness of Melanoma cells to 23% of control cells (assessed by invasion into Matrigel chambers) at 25mcg/mL.[43] This was thought to be secondary to Dieckol inhibiting ROS-mediated invasiveness (as adding ROS increased migration potential of control cells in this study, and ROS derived from Rac1 of NADPH Oxidase has previously been linked to migration potential[56][57]) and Dieckol appears to prevent WAVE2 binding to the p47phox subunit of NAPDH, thus preventing the increase in ROS via the Ras1/ROS independent of direct anti-oxidant properties.[43] The subsequent inhibition of this pathway is a decrease in FAK-dependent migration, and has also been noted in sarcoma cells.[58]

Appears to interfere with NADPH oxidase function, and Dieckol can exert anti-oxidant properties in that manner rather than direct sequestering of radicals

12.3. Breast

Two phloroglucinols from Eckolnia (dioxinodehydroeckol and a longer IUPAC named one) have been tested for their ability to induce apoptosis breast cancer cells, and dioxinodehydroeckol appeared to inhibit proliferation by 25-64% between 1-100uM (MCF-7) and 13-55% between 1-100uM (MDA-MB-231) as well as increasing apoptosis, thought to be secondary to preventing NF-kB translocation and thus inhibiting the subsequent antiapoptotic proteins (XIAP, Cox-2 and iNOS).[59] Despite the higher potency in estrogen- responsive breast cancer cells (MCF-7), interactions with the estrogen receptor were not assessed.[59]

13Interactions with Aesthetics

13.1. Hair

An ecklonia cava enzymatic extract (35% Dieckol) appears to promote hair growth when the solution is applied to rats (0.5% of solution) and in vitro where 0.05% Dieckol promoted proliferation of Dermal Papillae cells by 113.5% of control.[60] This hair promoting effect was abolished when incubated with tolbutamide (an inhibitor of potassium channels), which establishes that Ecklonia Cava has similar mechanisms to Minoxidil.[60]

100ug/mL was able to -reductase activity by 66.1%, which was not significantly different than Finasteride (despite the latter, at 2nM, inhibiting 94.6% activity) yet isolated - reductase activity when Finasteride was at 2nM and Dieckol at 100ug/mL).[60] Appears to have dual inhibitory potential on 5-alpha reductase enzymes and can also promote hair regrowth with a mechanism similar to Minoxidil (although comparative potency is unknown)

13.2. Skin

The phlorotannin Eckstolonol from Ecklonia Cava is able to prevent UV-B induced skin cell damage in a concentration dependent manner in a range of 5-200uM,[7] which validates previous studies noting anti-oxidant effects of Eckstonolol.[61][62] The potency was that while UV-B was able to reduce cell viability to 43.5% of control, 200uM Eckstolonol increased viability to 72.2% while decreasing a 50% increase in DNA damage to 21.5%; a weak- moderate efficacy despite abolishing the increase in Reactive Oxygen Species and attenuating the decrease in SOD and Catalase.[7] Eckol (another constituent) also exhibits similar potency at 27uM, and this appeared to reduce lipid peroxidation greatly (normalization of 8- isoprostane), but also failed to normalize cell viability.[63]

Potent anti-oxidantive effects in skin cells in vitro, but surprisingly less protection than would be expected secondary to the potent anti-oxidant effects

[64] Dieckol also appears to have anti-tyrosinase properties, inhibiting tyrosinase with an IC50 of 20uM in a non-competitive manner.[65]

14Safety and Toxicology

14.1. General

One human intervention using 72-144mg Ecklonia polyphenols daily failed to find any difference in serum blood markers (white or red blood cells, hematocrit or platelets) and noted a slight reduction of liver enzymes in overweight adults over 12 weeks.[24] Albumin and urinary proteins appeared to be reduced slightly with no alteration in serum creatinine.[24] Although another safety analysis also failed to find toxic effects, the benefit effects on liver enzymes were not replicated in hypercholesterolemic persons.[3] Scientific Support & Reference Citations

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(Common misspellings for Ecklonia cava include eklonia, eclonia, ecklona, eclona, eklona, kava)