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Yoni Freedhoff, MD, is an assistant professor of family medicine at the University of Ottawa, where he’s the founder and medical director of the Bariatric Medical Institute. Dr. Freedhoff is considered to be Canada’s most outspoken obesity expert, and is the author of "The Diet Fix," a #1 national Canadian bestseller.
Sesamin is the most prominent lignan compound found in sesame seeds, one of the two highest sources of lignans in the human diet (the other being flax). Sesamin is catered to be a nutritional supplement that confers antioxidant and antiinflammatory effects (if touting its health properties) or possibly being an estrogen receptor modulator and fat burner (if targeting atheltes or persons wishing to lose weight).
Sesamin has a few mechanisms, and when looking at it holistically it can be summed up as a fatty acid metabolism modifier. It appears to inhibit an enzyme known as delta-5-desaturase (Δ5-desaturase) which is a rate-limiting enzyme in fatty acid metabolism; inhibiting this enzyme results in lower levels of both eicosapentaenoic acid (EPA, one of the two Fish Oil fatty acids) as well as Arachidonic acid, and this mechanism appears to be relevant following oral ingestion. The other main mechanism is inhibiting a process known as Tocopherol-ω-hydroxylation, which is the rate limiting step in the metabolism of Vitamin E; by inhibiting this enzyme, sesamin causes a relative increase of vitamin E in the body but particularly those of the gamma subset (γ-tocopherol and γ-tocotrienol) and this mechanism has also been confirmed to be active following oral ingestion.
There are some other mechanisms in place which seem promising (protection against Parkinson's Disease as well as promotion of bone mass) but most of the mechanisms including estrogen receptor modulation, fat burning from the liver, and activation of the antioxidant response element (ARE) have not been confirmed in humans and have their reasons to suspect that they do not occur; this includes either a concentration that is too high to matter for oral supplementation, or in the case of fat burning it being a process that seems to be exclusive to rats.
In the end, sesamin serves a pretty interesting role as having the potential to augment γ-tocopherol and γ-tocotrienol metabolism by preventing their degradation; increasing the levels of these vitamin E vitamers has a lot of therapeutic benefits in and of itself, and since they are quite expensive to purchase as supplements then sesamin could be a cheap workaround or something used to 'cut' the vitamin E.
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Sesame Seeds, Sesame Oil
Known to interact with Drug Metabolizing enzymesExamine.com Medical Disclaimer
There are limited human studies on sesamin, but it appears that oral ingestion of around 100-150mg of sesamin is sufficient to raise bodily sesamin stores to the level where it can preserve Vitamin E in the body; this indirect antioxidative effect may be the most practical reason to supplement sesamin.
If using sesame seeds to get your sesamin from, human studies have used 50-75g of sesame seeds with some success and rat studies tend to use 100-fold the oral dose of sesame seeds relative to sesamin (which would make the aforemented dose of 100-150mg as minimum being 10-15g of sesame seeds).
The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Sesamin has in your body, and how strong these effects are.
|Grade||Level of Evidence|
|A||Robust research conducted with repeated double blind clinical trials|
|B||Multiple studies where at least two are double-blind and placebo controlled|
|C||Single double blind study or multiple cohort studies|
|D||Uncontrolled or observational studies only|
|Level of Evidence ||Effect||Change||Magnitude of Effect Size ||Scientific Consensus||Comments|
A small decrease in blood pressure has been noted with sesamin supplementation
Sesamin is a molecule known as a lignan, and while it is prevalent in many food sources it is named after the first food source it was discovered in (Sesame seed oil, or the oil from Sesamum indicum) alongside a related structure, sesamolin, in 1951. Sesamum indicum (sesame seeds) have more lignans than just sesamin of which include sesaminol, sesamolin, and sesamol as well as many lignan glycosides and catabolites; there are 16 distinct lignans in sesame seeds but sesamin appears to be the most well researched in part because it is the most prominent lignan in the seed oil.
Sesame seeds are actually one of the few sources of dietary lignans in appreciable quantities, as although most food products are below 2mg/100g sesame significantly exceeds this (estimated average of total lignans being 373mg/100g) as does flax (335mg/100g); no other common food product appears to come close except maybe chickpeas (35mg/100g) and peas (8mg/100g), and flax is not a significant source of sesamin in particular and is instead a source of mostly secoisolariciresinol diglucoside.
When isolated sesame seed oil, approximately 1-2% of said oil is considered a 'nonfat' fragment which contains the sesame lignans.
Sesamin is a standard lignan that has been isolated from sesame seed oil; it is not the only lignan in the oil, but it is the most well researched of them due to being present in highest amounts (relative to the other lignans)
Since then, it has been isolated from a variety of foods and supplemental herbs including:
Despite being named after sesame seeds, sesamin is very widespread in nature and its presence in plants is not limited to a specific plant family nor genera. Sesame seeds are still the best source of sesamin with the except of what seems to be a lone toxic plant (Virola venosa)
Sesamin is a lignan (unlike pinoresinol, matairesinol, and syringaresinol) that does not allow conjugation in its natural form, instead initially requiring metabolism into its catechol metabolites. Despite the lack of conjugation, it is known to occur as sesamin and episesamin (its more well known epimer) as well as asarinin (the lesser known epimer).
The catechol metabolite are simply when the methylenedioxyphenyl groups (pentagons with two oxygen structures) are converted into 3,4-dihydroxyphenol groups (the catechol group, visually appears to be two OH- groups on the hexagon) and these metabolites are referred to as either sesamin monocatechol or sesamin dicatechol (depending on whether one or two groups have been turned into catechols).
Sesamin is a lignan structure, and it is metabolized into two lignan byproducts (enterodiol and enterolactone) which may also mediate some of the biological effects of sesamin supplements
There are some alternate names for the aforementioned molecules. Sesamin monocatechol is referred to as SC-1 at times, and when it is methylated (via COMT) it is sometimes just referred to as 'derivative of sesamin monocatechol' despite its common name being 'Piperitol'. Due to piperitol also being a common molecule, sesamin monocatechol (literally piperitol before it gets the methyl group) is sometimes referred to as demethylated piperitol.
Piperitol refers to is sesamin monocatechol gets methylated, and if only one side of sesamin dicatechol gets methylated then the resulting molecule is known as 3'-O-demethylpinoresinol; this is because if both ends become methylated, the lignan that results is actually just pinoresinol (found in food products and a parent lignan itself).
Sesamin metabolites are shared with the metabolites of other lignans, so at times the names that they are called are synonymous and some confusion may exist
Oral ingestion of 0.2% of the rat diet as sesamin (240-280mg/kg) has resulted in serum levels of sesamin, sesamin monocatechol, and sesamin dicatechol all at over 200ng/mL with no alterations in serum concentrations seen with the addition of 1% Vitamin E to the diet.
In humans fed sesame seeds (50g of seeds, 183mg sesamin) it appears sesamin is absorbed with a Cmax of 105+/-11.7nM at a Tmax of one hour and an absorption half-life of 15 minutes and elimination half-life of 2.08+/-0.58 hours; overall, the AUC was 362+/-92.0nM/h/L. One study has referenced unpublished research noting a Tmax value of 4.7+/-0.2 hours with sesamin (dosage unspecified), but slightly longer values with episesamin and sesamolin.
Sesamin appears to be absorbed following oral ingestion in rats and humans, and standard oral servings appear to reach a low to moderate nanomolar range
Sesamin appears to get metabolized into sesamin monocatechol (SC-1) via P450 enzymes (CYP2C9), which then has the capacity to be further metabolized via CYP2C9 into into sesamin dicatechol (SC-2); Sesamin catechols can then either be glucuronidated (via UGT enzymes) from where it is excreted in the urine, or it can be further methylated via the COMT enzyme into monomethylated variants (SC-1 turning into SC-1m which is also known as piperitol, and SC-2 into SC-2m); both SC-1 and SC-2 have the ability to active Nrf2/ARE whereas sesamin and their methylated metabolites (via the COMT enzyme) do not suggesting that intervening at the level of COMT may preserve antioxidant effects of sesamin metabolites.
Sesamin monocatechol (SC-1) and sesamin dicatechol (SC-2) have been detected in the urine of humans following sesamin ingestion (508μM/180mg sesamin and 192μM/71mg sesaminol) and SC-1 has accounted for 22.2-38.6% of the total ingested sesamin.
Episesamin goes through a similar metabolic pathway as sesamin does.
Sesamin is initially metabolized (via CYP2C9) into sesamin monocatechol, and it can be metabolized by the same enzyme again on the other side to form sesamin dicatechol. These catechol derivatives can either by tagged with a glucuronide and be urinated out, or they can be further converted via COMT into methylated derivatives
Sesamin can take a metabolic route that does not involve sesamin monocatechol formation. Rather than initial metabolism by human CYP2C9, sesamin can be metabolized by intestinal microflora to produce enterolactone and enterodiol which are general byproducts of intestinal microflora from dietary lignans known as enterolignans. That being said, at least in rats the conversion rate of sesamin into these enterolignans is low (1.1%) and is significantly less than the lignan seen in flax seed (secoisolariciresinol at 57.2%) but conversion has been noted to either be fairly even (rats) or weightet heavily towards enterodiol, with this latter study (mice) with 0.1% of the diet as sesamin reaching 6.5-8nM enterolactone in serum and 388-569nM enterodiol.
Conversion of sesamin into enterolignans has been confirmed with orally ingested sesamin, and it does appear to be less of an enterolignan source than an equal dosage of flax and in rats, Tahini.
Similar to most lignans, sesame is known to be metabolized by intestinal bacteria to produce the enterolignans (enterodiol and enterolactone). However, sesame doesn't have the best conversion into these enterolignans but may still reach the low nanomolar range
Sesamin appears to inhibit CYP3A4 activity in a concentration dependent manner with 15.6-55.8% inhibition at 10-40µM yet it appears to prevent induction of CYP3A4 by interfering with the coregulators of PXR; when coinbuated at these concentrations with a known inducer of CYP3A4, sesamin is able to attenuate the induction by 21.3-77.3% (relative to induced control without sesamin).
Sesamin is known to inhibit CYP3A4 activity, but it also appears to be able to prevent the induction of CYP3A4 in response to drugs that would normally upregulate the activity of this enzyme
10-100µM sesamin appears to inhibit P-glycoprotein as assessed by Rhodamine 123 accumulation in LS-180V cells, reaching 2.2-fold accumulation with the highest tested dose (which was similar to 300µM piperine), but after 48 hours of incubation sesamin has lost its effect.
Sesamin appears to increase the mRNA levels of multidrug resistance proteins MDR1 and MDR3 (with the increase in MDR2 being nonsignificant).
Sesamin appears to be a P-glycoprotein inhibitor yet a Multidrug Resistance Protein inducer, with unclear effects on this set of drug efflux transporters acutely but they seem to be a nonissue after prolonged incubation
Δ5-desaturase is an enzyme that catalyzes the conversion of eicosatetraenoic acid into EPA (one of the fatty acids called Fish Oil) for omega-3 fatty acids and it mediates the conversion of dihomo-γ-linolenic acid into Arachidonic acid for the omega-6 fatty acids. It is a rate limiting step, and its inhibition should reduce both EPA (and subsequently, DHA) as well as arachidonic acid while causing a backlog (ie. relative increase) of both dihomo-γ-linolenic acid and eicosatetraenoic acid.
Sesamin is a noncompetitive inhibitor of Δ5-desaturase with a Ki of 155µM without significantly influencing Δ6, Δ9, or Δ12-desaturase enzymes and not influencing transcription of any enzyme; while it is said to be potent it appears Curcumin is moreso while both molecules seemed to inhibit omega-6 synthesis more than omega-3 synthesis. This 'selective' inhibition of omega-6 rather than omega-3 desaturation by this enzyme has not been noted in rats given sesamin at 0.5% of the diet (known to cause liver concentrations of 1.32µg/g and serum concentrations of 0.17µg/mL) and in otherwise healthy postmenopausal women given 50g sesame seeds there have been reductions in both EPA (12%) and arachidonic acid (8%).
Sesamin appears to be able to inhibit the Δ5-desaturase enzyme which results in reduced circulating levels of EPA and arachidonic acids. It is said to be a potency inhibitor of Δ5-desaturase yet curcumin outperforms it, and it appears to be inhibited at a concentration significantly higher than should occur in the body (yet it seems to work in humans)
CYP3A is also involved in metabolizing tocopherols into carboxychroman metabolites which have been confirmed to be relevant to human metabolism of vitamin E and 1µM of sesamin is able to reduce tocopherol metabolism mediated by CYP3A (90% inhibition over 48 hours) in isolated HepG2 cells; a potency comparable to 1µM ketoconazole and has been replicated elsewhere at 2µM and may be related to a CYP3A-type cytochrome which initiates ω-hydroxylation of tocopherol.
This is sometimes said to selectively increase preservation of the Vitamin E vitamers of the gamma variant (γ-tocoperhol and γ-tocotrienol) since the aforementioned metabolism is less active on α-tocopherol and rat studies that measure plasma vitamin E vitamers do note selective increases of γ-tocopherol and γ-tocotrienol rather than α-tocopherol.
Sesamin inhibits a particular CYP3A enzymes that is involved in vitamin E metabolism, where the enzyme initially ω-hydroxylates vitamin E (required step) and then the rest of vitamin E is subject to fat oxidation. By inhibiting this step, sesamin causes an increase in circulating and organ concentrations of vitamin E
Secondary to preventing the metabolism of vitamin E, sesamin at 0.2% of the diet is known to increase circulating vitamin E when in addition to a standard diet and when ingested alongside additional vitamin E (α-tocopherol, δ-tocopherol, and γ-tocopherol tested) it is able to augment the increase in serum and tissue levels of vitamin E. Things that vitamin E inherently does, like reducing cholesterol, are augmented alongside the increase in circulating vitamin E.
This mechanism essentially results in more activity of dietary or supplemental vitamin E sources, and whatever vitamin E does in the body it can do better under the influence of sesamin
In rats fed an 0.5% sesamin diet (known to cause liver concentrations of 1.32µg/g and serum concentrations of 0.17µg/mL) over 15 days is associated with a near doubling of mitochondrial activity in the liver and peroxisomal fatty acid oxidation 10-fold (via a genomic mechanism); a response known to occur in rats but neither mice nor hamsters and to a larger degree with sesamolin and episesamin than with sesamin itself.
The above changes towards lipid oxidation are thought to be reflective of PPARα activation which reliably induces fatty acid oxidation in the liver when activated. They also seem to be somewhat synergistic with dietary EPA supplementation, but not so much arachidonic acid.
Sesamin is thought to have PPARα activating potential in the liver, but it is uncertain how much practical relevance this has in humans due to this being a mechanism that differs between species
Sesamin has been found to inhibit NF-kB activation in a dose and time dependent manner by a variety of inflammatory agents, affecting constitutive and inductive NF-kB with an IC50 in the range of 40.1-60.2μM depending on cell type tested. Sesamin also prevented TNF-α induced degradation of the inhibitory subunit IκBα, and both inhibited TNF-α induced activation of IKK and IKK-induced NF-kB activation.
Sesamin has been found to inhibit NF-kB in cancer cells, which is thought to underlie the chemotheraputic effects of sesamin via augmenting anti-cancer drugs
While sesamin and episesamin are technically inactive, the metabolites SC-1 and EC-1 (formed from P450) appeared to activate Nrf2/ARE signalling while the metabolites SC-1m, EC-1m, and EC-2 (formed from COMT) were also inactive. SC-1 (the tested molecule) at 1-10µM increased activity of Nrf2/ARE in a concentration dependent manner with the highest tested concentration reaching 6-fold enhancement and induction of γ-GCSc and NQO-1 were confirmed.
It seems that p38 MAPK is somewhat involved as an intermediate for the following, but N-Acetylcysteine was able to abolish the increase in Nrf2/ARE seen with sesamin (which suggests hormetic effects and involvement of Keap1) and blocking Nrf2 itself will prevent sesamin from saving cells from H2O2.
Sesamin is able to activate the antioxidant response element (ARE) via Nrf2, and this appears to be due to a hormetic response. This will underlie some of the antioxidant properties of sesamin, although the direct antioxidant effects and the superoxide dismutase induction are likely mediated by other mechanisms
Superoxide dismutase (SOD) is an antioxidative enzyme that sequesters the superoxide radical (O2-), and sesamin appears to be able to induce this enzyme activity 3-fold at a concentration of 1pM (0.001nM) which seems to underlie the protective effects in neuronal PC12 cells seen at 1pM concentration. This occurs at a concentration significantly lower than the Nrf2/ARE induction (the lowest active concentration, 1µM, is 1,000,000 times higher than 1pM) suggesting an independent mechanism of action.
There is some currently unknown mechanism of action associated with sesamin that occurs potently and at a remarkably low concentration (one picomole), and this doesn't seem to be at all related to the other mechanisms due to being uniquely potent
0.2% sesamin included in the fruit fly diet appears to extend maximal lifespan by around 12% and while 0.1% sesamin was associated with a smaller increase (5%) this failed to reach statistical significance. This was associated with increased levels of superoxide dismutase (SOD) isozymes SOD1 and SOD2 and their mRNA, whereas some other enzymes (Catalase and Rpn11) showed increased mRNA but not protein content.
The authors suspected that an upregulation of Rpn11 (known to promote lifespan) since Mth (a gene known to promote lifespan) was unaffected by sesamin. Interestingly, this exact same overall profile of effects (upregulation of Rpn11 and antioxidant enzymes without Mth) is seen with both Blueberry extract and apple polyphenols.
Sesamin has once been linked to increased longevity, and this appears to be somewhat associated with an increase in antioxidant enzymes and is similar to some other antioxidants in mechanisms
Sesamin (500-2,000nM) can protect PC12 cells from kainate induced cell death in a concentration dependent manner, but BV-2 cells seem more resistant (requiring 10-50µM); this was associated with reduced ROS and lipid peroxidation.
15-30mg/kg of a sesamin extract (90% sesamin and 10% sesamolin) fed to rats for three days, the higher dose fully protected against mortality from kainate (22% death down to zero).
Sesamin appears to be able to protect cells from excitotoxicity from kainate at a very low concentration, which is likely due to the antioxidative effect of sesamin in these neuronal cells. This has been confirmed in rats following oral ingestion of sesamin
Higher concentrations of sesamin (1-50µM) appear to attenuate the activation of p38 and ERK1/2 (MAPKs) from kainate, with 50µM nearly normalizing the difference; JNK was unaffected.
Kainate induced MAPK activation (which mediates neurotoxicity from kainate) may also be reduced from sesamin, but this occurs at a higher concentration
Microglia are neuronal support cells (glial cells) that respond to inflammatory signals (ie. activation) and secrete cytokines that, while serving a vital physiological role, may cause neurodegeneration is stimulated to an excessive level for a prolonged period of time. Activated microglia are known to accumulate in Parkinson's Disease and suppressing their activation is thought to be therapeutic.
Sesamin appears to reduce the inflammatory response of microglia (assessed via IL-6, IL-1β, and TNF-α secretion) in response to MPP+ with a potency comparable or lesser than 0.1µM (100nM) Quercetin, which was due to suppressing O2- (superoxide) production ultimately suppressing cytotoxicity from 20% to 1.9% and abolishing DNA fragmentation. This potency has been replicated elsewhere where 1pM of sesamin protected dopaminergic PC12 neurons from MPP+ induced oxidative damage (60% protection relative to control) associated with inducing SOD and attenuating the increase in catalase (which may have just been indicative of less oxidation in the cells).
Sesamin appears to be very potent in protecting cells from the main dopaminergic research toxin, and this occurs at a very low concentration. It is unsure why, but this may be related to the cell line tested (PC12)
Sesamin does not appear to alter the levels of the dopamine transporter (DAT) either inherently nor in response to the MPP+ toxin despite this toxin being able to reduce DAT levels and sesamin being protective.
Does not appear to influence levels of the dopamine transporter
In isolated PC12 cells, sesamin at 20-75µM (but not 150-200μM) appears to enhance intracellular dopamine production associated with an induction of tyrosine hydroxylase (TH; the rate limit step of dopamine synthesis) to the degree of 106.3–128.2% at 50µM and is synergistic with L-DOPA in increasing dopamine concentrations. AADC (catalyzes conversion of L-DOPA to dopamine) was unaffected.
TH is positively regulated by cyclic AMP-dependent protein kinase (PKA) which is a target of sesamin as it could increase intracellular cAMP in a time and concentration dependent manner from 136.5% (10 minutes of 20µM) to 321.6% (60 minutes of 100µM).
Additionally, sesamin (50μM) is able to attenuate L-DOPA induced cytotoxicity in a manner that does not involve superoxide dismutase (unaffected) but is related to attenuating the negative effects of L-DOPA on ERK1/2.
Sesamin appears to, at least in vitro, augment dopamine synthesis by increasing the rate limit step and protect from dopamine induced cell death. This may occur at higher concentrations than other actions of sesamin
Sesamin (100µM) can reduce micrglial activation (BV-2 cells) from LPS as assessed by nitrite concentrations to around 20% of control, whereas sesaminol is less potent than sesamin yet active to similar levels from 20-100µM.
Sesamin has been shown to attenuate LPS induced p38 MAPK activation (reducing the inflammatory effects of LPS) yet activate Nrf2/ARE to exert protective effects which is known to be downstream of p38 MAPK activation; this can somewhat be rationalized since the 'p38 MAPK' tends to refer to both p38 and p42/p44 (the latter of which is selectively inhibited by sesamin.) but requires further investigation.
Sesamin appears to reduce neuroinflammation at higher than normal concentrations, and this appears to involve MAPK signalling somehow. The exact mechanisms are not known
Sesamin monocatechol and episedamin monocatechol (10µM) appear to induce neuronal differentiation via activating ERK1/2 (downstream of the TrkA receptor) without influencing the receptor itself, and this concentration is 62-66% as effective as 30ng/mL NGF; agonists of this receptor, including low concentrations of NGF, are synergistically enhanced in the presence of sesamin monocatechols at 5-10µM by 45-68%.
Sesamin itself, as well as sesamin dicatechol and the COMT deriviates, are ineffective or weakly effective at the same concentration and it is thought that ERK1/2 underlies the effects since Akt is not activated and blocking ERK1/2 prevented seasmin from acting.
Appears to augment the signalling of the TrkA receptor, which NGF works upon, which is thought to be due to inhibiting ERK1/2
Sesamin, when fed to gerbils at 20mg/kg, is able to reduce infact size from induced ischemia (a model for stroke) by 56% while a mixture (90% sesamin and 10% sesaminol) reduces infarct size by 49%. In a rat model of intracerebral hemorrhage, selective inhibition of p44/42 (in the MAPK family and closely related to p38) from an intracerebrovascular injection of 30nM sesamin appears to underlie neuroprotective effects.
There appear to be neuroprotective effects of sesamine following oral ingestion, and this oral dose seems to correlate to a human dose of around 2.5mg/kg
Sesamin appears to inhibit cholesterol absorption from the intestines when fed to rats at 0.5% of the diet due to interfering with micelle formation, but failed to influence fatty acid absorption and did not bind to nor interfere with bile acids; the lack of inhibition on fatty acids has been noted elsewhere.
This may underlie hypocholesterolemic effects of Sesamin after consumption in humans.
Sesamin is known to inhibit cholesterol absorption from the intestines in rats, and the oral intake that it occurs at is fairly reasonable
As assessed by temporal ESR (a way to measure antioxidant effects in vivo using an injection of TEMPOL) 250mg/kg sesamin (equal mixture of sesamin and episesamin) with 10mg/kg α-tocopherol has failed to reduce the reducing potential of the inferior vena cava, suggesting that over the course of 24 hours after oral ingestion there was no modification of antioxidant effects.
In LDL receptor deficient mice (LDLR-/-), sesamin at 0.1% of the diet failed to reduce serum cholesterol either alone of in combination with 0.7% stanol ester (which was effective but not additive with sesamin).
A pilot study using six weeks of daily ingestion of 40g roasted sesame seeds in persons with high cholesterol (no placebo control) has noted a failure to reduce LDL-C and total cholesterol significantly, but there was a significant reduction of HDL-C (5%) relative to baseline.
Sesamin at 0.1% of the diet in LDL receptor deficient mice (LDLR-/-) did not modify triglycerides levels, although they were not increased from the test diet either.
Six weeks of 40g roasted sesame seeds in persons with high cholesterol (pilot study with no placebo group) failed to reduce plasma triglycerides.
When looking at oxidized LDL (oLDL) induced endothelial dysfunction, Sesamin was able to reduce the oxidative effects of oLDL (and indirectly preserve the Superoxide dismutase (SOD) enzyme) which was thought to be secondary to an attenuation of NF-kB activation; a pro-inflammatory response.
Dietary sesamin at 63.7+/-0.4mg/kg in both wild type and ApoE-/- mice (prone to artherosclerosis) trended (40%) but failed to significantly reduced aortic/thoracic lesion size after 26 weeks (whereas Quercetin and Theaflavin were effective) while the induction of eNOS was lesser than that of the aforementioned two molecules.
Sesamin is though to enhance bloodflow secondary to inhibiting superoxide radical production which may be secondary to reducing the levels of NADPH oxidase (p22(phox) and p47(phox) proteins) seen in hypertensive rats, as inhibiting NADPH will reduce superoxide production in endothelial cells and result in a preservation of eNOS activity and a relatively increased production of Nitric Oxide since superoxide would normally convert nitric oxide into the peroxynitrate radical.
Secondary to antioxidant effects, sesamin may preserve nitric oxide functions in the endothelium
0.1-1% of the diet as Sesamin in spontaneously hypertensive rats was effectively able to normalize deoxycorticosterone acetate (DOCA) induced oxidation (although it only attenuated the increase in systolic blood pressure by 29-55%) while not significantly influencing oxygen radical levels in control while 40-160mg/kg sesamin to rats for 16 weeks is able to improve arterial function in hypertensive rats.
Animal evidence supports the idea of oral sesamin ingestion being able to promote blood flow in instances of hypertension
One intervention in middle-aged women with mild hypertension following 60mg Sesamin over 4 weeks in a double-blind crossover manner noted significant reductions in systolic blood pressure (137.6+/-2.2 to 134.1+/-1.7mmHg; 2.6% reduction) and diastolic blood pressure (87.7+/-1.3 to 85.8+/-1.0mmHg; 2.2% reduction).
Elsewhere, sesamin has once been implicated in improving blood flow in otherwise healthy humans with under average blood flow (albeit confounded with Schisandra chinensis) and sesame oil at 35g has been noted to increase blood flow in hypertensives.
A small but statistically significant reduction in blood pressure may exist following low dose Sesamin consumption in humans, which has been seen with isolated sesamin and with sesame oil
Sesamin (2% of diet, around 200mg/kg) appears to suppress lipogenic genes in the liver of rats after 15 days of ingestion, with significantly more suppression on all mRNAs when the diet consisted of Arachidonic acid rather than maize or DHLA oil. Similar changes were seen in the mRNA of genes involved in fatty acid oxidation, particularly peroxisomal oxidation.
Appears to mediate its benefits through increasing fatty acid oxidation in the liver via peroxisomes and acting as a PPARα agonist
When looking at the isomers, 0.2% of the diet containing either Sesamin, Episesamin, or Sesamolin was able to modify gene expression of various fatty acid regulatory genes in the range of 1.5 to 2-fold that of the control diet. Notable changes were that increases in enzymes of fatty acid oxidation (n=22) increased 10-280% with Sesamin, 60-1200% with Episesamin, and 50-1100% with Sesamolin (relative to control diet). Similar changes were seen with mitochondrial biogenesis genes (n=3) while no significant differences existed with lipogenesis or lipid transport gene suppression.
This study noted that Episesamin and Sesamolin were able to increase hepatic weight (22-27%) while reducing the weight of epididymal white adipose tissue (19-20%), with Sesamin not affecting either parameter. In vitro, Sesamin appears to be weaker than both Episesamin and Sesamolin at inducing genetic expression
Sesamin and related sesame lignans appear to influence a variety of genomic responses that suggest it may be a fat burning compound
50g of Sesame seeds, when compared to either a control of rice powder at the same weight or their own baseline when caloric intake was controlled, failed to influence body mass over 4 weeks in post-menopausal women.
Insufficient evidence to support Sesamin as a fat burning supplement
Sesamin appears to increase the expression of COL1 (7-fold), ALP (15-fold), OCN, BMP-2 (20-fold) and Runx2, as well as upregulate OGN and downregulate RANKL, in osteoblastic (hFOB1.19) cells at a concentration of 10μg/mL, with some statistically significant effects at 1μg/mL. These changes are indicative of differentiation of osteoblasts, and were thought to be related to the observed activation of ERK and p38 signalling (not confirmed to be required) as these two MAPKs are beneficial for osteoblast growth.
Appears to, at least in cell cultures, promote osteoblastic growth which is though to be beneficial for bone mass
12.5-50μM sesmain in THP-1 monocytes is able to reduce N-formyl-methionyl-phenylalanine induced chemotaxis (fMLF being a chemoattractant that produces an inflammatory response via the FP receptor) in a concentration dependent manner with 50μM effectively normalizing chemotaxis. This was observed following injections of 12mg/kg sesamin (mice) where chemotaxis was abolished and was thought to be due to inhibition of ERK1/2 signalling and NF-kB activation in monocytes.
Higher concentrations of sesamin appear to have antiinflammatory effects against chemotaxis, or the tissue infiltration of immune cells
Episesamin appears to prevent Endothelial protein C receptor (EPCR) 'shedding' induced by inflammatory signalling molecules (TNF-α, IL-1β, and PMA), which is thought to be secondary to tumor necrosis factor-α converting enzyme (TACE) inhibition.
In a DPPH assay, sesamin metabolites at 5µM show direct antioxidant effects including sesamin monocatechol (11.4%), sesamin dicatechol (70.5%), piperitol (1.2%), and 3'-O-demethylpiperitol (43.2%) whereas sesamin itself is pretty much inactive.
Sesamin metabolites, but not sesamin itself, show direct free radical scavenging properties in vitro as assessed by a DPPH assay
CYP3A is also involved in metabolizing tocopherols into carboxychroman metabolites which have been confirmed to be relevant to human metabolism of vitamin E and 1µM of sesamin is able to reduce tocopherol metabolism mediated by CYP3A (90% inhibition over 48 hours) in isolated HepG2 cells; a potency comparable to 1µM ketoconazole and has been replicated elsewhere at 2µM and may be related to a CYP3A-type cytochrome which initiates ω-hydroxylation of tocopherol.
30mg/kg of sesamin has been noted to increase circulating vitamin E vitamers by 50-55.8% of baseline. In rats fed exclusively γ-tocopherol, sesamin at 0.2% appears to augment organ accrual of γ-tocopherol to a similar level as 20% sesame seeds and reduced urinary excretion to 20% of control and 0.2% sesamin elsewhere to increase plasma α and γ-tocopherol (albeit sesamol was more potent) and can synergistically suppress the lipid peroxidation induced by a diet excessive in DHA (from Fish Oil).
Sesame seeds do not inhibit vitamin E excretion into bile acids.
Secondary to inhibiting the degradation of Vitamin E vitamers (which has been confirmed in living models following oral ingestion of sesamin), sesamin can prolonged their effects in the body and exert antioxidant effects secondary to the effects of vitamin E
Superoxide can be directly scavenged by sesamin metabolites at 5µM including sesamin monocatechol (55.5%), sesamin dicatechol (73.7%), piperitol (2.5%), and 3'-O-demethylpiperitol (53.6%). The effects of the monocatechols and dicatechols (sesamin and episesamin) are slightly lesser than that of catechin yet greater than that of ellagic acid.
Sesamin appears to be able to directly sequester superoxide radicals, and is fairly decent at doing so since it is between two reference molecules in potency
Sesamin can induce the expression of SOD in PC12 neurons to about three-fold of control levels at a concentration of 1pM and can preserve SOD expression during toxic stressors.
In rats subject to kainate-induced seizures, the drop in SOD levels to 55% of baseline is attenuated to 81% with oral ingestion of 30mg/kg sesamin extract (90% sesamin and 10% sesamolin); 15mg/kg was ineffective.
Remarkably effective at inducing the superoxide dismutase enzyme in vitro
Hydroxyl radicals can be directly scavenged by sesamin metabolites at 5µM including sesamin monocatechol (5.4%), sesamin dicatechol (59.2%), piperitol (5.7%), and 3'-O-demethylpiperitol (11.9%). The potency of episesamin monocatechol seems similar to catechin itself, and both sesamin and episesamin dicatechols are as potent as ellagic acid.
Appears to directly scavenge free hydroxyl radicals, and actually seems to be quite potent at this (similar potency to a reference compound known as ellagic acid)
In PC12 cells exposed to H2O2, the active sesamin metabolites at 2-10μM appears to reduce cytotoxicity secondary to Nrf2/ARE activation.
Lipid peroxides (TBARS assay) can be directly scavenged by sesamin metabolites at 5µM including sesamin monocatechol (37.9%), sesamin dicatechol (71.3%), piperitol (6.7%), and 3'-O-demethylpiperitol (42.0%).
Despite the interactions with vitamin E metabolism, sesamin metabolites appear to be able to directly sequester lipid peroxides
In rats subject to kainate induced seizures, 30mg/kg sesamin appears to be able to reduce the increase in lipid peroxidation (serum MDA) from 145% of control down to 117%, and this was associated with an increase in plasma Vitamin E to 50% and 55.8% of baseline (control and kainate group, respectively). There was no influence of 15mg/kg sesamin, and while sesamin itself is able to reduce lipid peroxidation in rats the addition of vitamin E appears to be synegistic in doing so.
Sesamin does appear to inhibit lipid peroxidation directly with somewhat respectable potency, but the majority of its benefits against lipid peroxidation are likely occurring secondary to its ability to increase Vitamin E concentrations in living systems
In mice subject to nickel toxicity, dietary sesamin (60-120mg/kg) alongside said nickel for 20 days was able to reduce the elevation in liver enzymes and damage which was associated with less oxidative damage, and this lesser oxidative damage was associated with less oxidative DNA damage as assessed by 8-OHdG. Sesamin added to a diet without nickel was not different than control.
The antioxidative effects of sesamin extend to the genome, where they can reduce oxidative damage to DNA. There does not appear to be a reduction of DNA damage in animals not subject to oxidative toxins
When looking at the estrogen receptor, in PC12 neurons sesamin at one of the active concentrations (1pM) does not modify protein content of either the ERα nor ERβ.
Sesamin is not known to alter the estrogen receptor itself (quantity thereof in a cell)
500-4,000nM (0.5-4µM) sesamin in Ishikawa cells has failed to exert estrogenic effects and failed to alter the estrogenic signalling from 1nM estradiol. Higher concentrations of 10µM in T47D breast cancer cells note that sesamin has weak estrogenic properties and while it was additive with a subeffective level of estradiol (1pM) it was suppressive of estrogen signalling at 1nM; this also applied to sesamol and enterolactone while both enterolactone and enterodiol are known to be estrogens (although enterodiol does not hinder the signalling of 1nM estradiol).
Despite the relatively high concentrations mentioned above (10µM), oral ingestion of 1% sesamin in the diet of mice with high circulating estrogen appears to reduce the size of their estrogen responsive tumors which suggests an estrogen antagonistic effect.
When looking at the estrogen receptor, it is plausible that sesamin and some metabolites act as selective estrogen receptor modulators (SERMs) but this has not been fully confirmed in living models yet
One study conducted in post-menopausal women following consumption of Sesame Seeds at 50g for 4 weeks failed to find any influence on urinary estrone or estradiol (two estrogen compounds) while serum sulfated DHEA declined by 22%. A nonsignificant (P=0.065) increase in SHBG was noted at 15%; these effects could not be attributed to Sesamin per se due to other lignans in sesame.
Sesame seeds do not appear to influence circulating estrogen levels in otherwise healthy postmenopausal women
As assessed by temporal ESR (a way to measure antioxidant effects in vivo using an injection of TEMPOL) 250mg/kg sesamin (equal mixture of sesamin and episesamin) with 10mg/kg vitamin E appears to increase reducing capacity of the liver (indicative of antioxidant effects) by 10-15% relative to control which is then normalized within one day following oral ingestion.
While sesamin does not appear to increase γ-tocotrienol accumulation in the liver (since it isn't stored there anyways) it does appear to slightly increase α-tocopherol concentrations.
In immortalized pancreatic β-cells (NIT-1) subject to streptozotocin induced toxicity, 100-400µg/mL sesamin was able to concentration dependently protect these β-cells associated with antioxidant effects (normalizing changes in lipid peroxidation and antioxidant enzymes).
May have protective effects on pancreatic β-cells at high concentrations
As assessed by temporal ESR, 250mg/kg sesamin paired with 10mg/kg α-tocopherol failed to modify reducing capcity of kidney tissue when measured over the course of a day following oral ingestion.
In vitro, Sesamin has been shown to suppress proliferation of various cell lines. The cell lines suppressed and their respective IC50 values (umol/L) are leukemic KBM-5(42.7), leukemic K562(48.3), myeloma U266(51.7), prostatic DU145(60.2), colon HCT116(57.2), Pancreatic MiaPaCa-2(58.3), Lung adenocarcinoma H1299(40.1), and BreastMDA-MB-231(51.1). An augmented TNF-a mediated apoptosis was noted in KBM-5 and U266 cell (no others tested) ranging from 4.7 to 7.2-fold increased apoptosis, thought to be from Sesamin preventing TNF-a induction of Bcl-2 and Survivin which can preserve cancer cells.
TNF-a induced expression of cell-proliferative (cyclin D1, COX-2) and invasive (ICAM-1, MMP-9, VEGF) gene products was prevented with Sesamin, all of which was thought to be from preventing NF-kB translocation at 100umol/L. An attenuation of TNF-a induced ICAM-1 expression has been noted elsewhere in human endothelial cells.
Appears to augment TNF-a induced chemotherapy in vitro, and prevent TNF-a from enhancing cell survival
When comparing a diet containing 50mg/kg α-tocopherol in mice against a diet containing 229mg/kg Vitamin E (conferring 50mg/kg α-tocopherol alongside 37.4% γ-tocotrienol) over six weeks prior to a week of UVB-induced skin damage noted that the latter group was more protected, associated with γ-tocotrienol accumulation in skin. The further addition of 0.2% sesamin to the latter diet was able to augment γ-tocotrienol accumulation in the skin and synergistically increase the protective effects.
Sesamin appears to augment the skin accumulation of γ-tocotrienol, and secondary to that increases its protective effects
Secondary to one of the main mechanisms of action (Tocopherol-ω-hydroxylase inhibition) sesamin can increase vitamin E concentrations in the body either with or without additional supplementation of vitamin E; due to this, there is some apparent synergism by sesamin augmenting things that vitamin E can normally due.
At least one study noting the interactions between γ-tocopherol and sesamin in humans noted that while urinary d2-γ-CEHCs decreased (urinary metabolite of γ-tocopherol) appeared to occur in both groups, it occurred to a larger degree to men (halving the urinary metabolite over 72 hours with sesame muffins conferring 93.8mg sesamin and 42mg sesamolin). Women are known to have a faster γ-tocopherol disappearance rate then men while men may have higher γ-tocopherol due to higher blood lipids, and although it is not ascertaine what underlies the gender difference it may be related to higher plasma γ-tocopherol.
In short, sesamin appears to augment the actions of all vitamin E vitamers simply because it allows more vitamin E to bioaccumulate in your body and exert their effects
Vitamin K is a fat-soluble quinone vitamin, and can be found in either the K1 vitamer (phylloquinone) or any of the K2 vitamers (menaquinones); its pathway of elimination in the body is somewhat similar to vitamin E, and thus it is thought that sesamin may also preserve vitamin K levels.
Oral ingestion of sesamin to rats (0.2% of the diet) appears to increase phylloquinone levels in the liver, and this was also seen with 1-10% of the diet as sesame seed (no differences between doses); menaquinone 4 (MK-4) was not affected by the aforementioned conditions, but 20% of the diet as sesame seeds increased tissue levels of MK-4 in all measured tissues alongside increases in phylloquinone (Kidney, heart, lung, testis, and brain).
Preliminary evidence suggests that sesamin ingestion can also increase vitamin K retention in the body
Although it increases synthesis of vitamin C in rats, this cannot happen in humans and does not apply to supplementation of sesamin; there may still be interactions vicariously though vitamin E, but these synergisms would be more accurately said to be due to vitamin E rather than sesamin
Sesamin at 0.5% of the diet is known to induce hepatic fat oxidation and when sesamin (albeit 0.2%) is ingested alongside dietary fish oil (1.5-3%) in rats this induction of fat oxidation is synergistically enhanced, reaching a level seen with 8-10% fish oil alone and the addition of either fish oil to sesamin being able to make a half dose of sesamin as potent as the initial dose. This synergism appears to persist even in studies where an antagonistic effect of sesamin on liver content of EPA is seen, which is thought to be a result of Δ5-desaturase inhibition.
One of the mechanisms of sesamin is thought to be related to PPARα activation (the sequelae of PPARα are seen with sesamin ingestion) and the addition of fish oil to sesamin synergistically increases these effects
Sesamin at 2% of the diet in rats and Alpha-Lipoic Acid at 2.5% of the diet for 22 days exerts additive effects in reducing serum Triglycerides, despite inducing relatively similar gene expression.
There was no benefit to combining the compounds on liver triglyceride concentrations. Although the combination decreased lipogenesis in an additive fashion ALA partially negated the effects of Sesamin on increasing fatty acid oxidation.
One study suggests additive effects on reducing triglyceride synthesis, and antagonistic effects on fatty acid synthesis
One bioactive of Schisandra, known as Schisandrin B, has been tested alongside Sesamin at either 43mg/kg or 215mg/kg and had hepatoprotective effects against CCL4-induced toxicity with similar efficacy to 7.5mg/kg Silymarin (from Milk Thistle).
Schisandra chinensis has been tested (65mg of the extract) with Sesamin (2.5mg) with a small amount of Vitamin E (3.75IU) in regards to blood viscosity, and in a small sample of 10 persons with subaverage blood flow noted that two of the above tablets daily for 2 weeks was associated with 9% faster blood flow at week 1 and 9.7% increased blood flow relative to baseline at week 2.
Schisandra and Sesamin has also been tested in a proper double-blind trial in persons with borderline liver enzymes, and combination therapy at double the dose in the above blood flow study decreased elevated ALT and AST without influencing Bilirubin levels; anti-oxidative parameters were increased after 5 months.
Has been tested in conjunction with Sesamin, no synergism has been tested
Conjugated Linoleic Acid (CLA) is a fatty acid mixture that is touted to increase fat loss via acting to similar mechanisms as Sesamin. One study has been conducted in rats where one group fed 1% CLA was compared to another group fed 1% CLA with 0.2% Sesamin (some Episesamin in the mixture) in addition to CLA for 8 weeks failed to find any additive or synergistic benefits. A lack of synergistic effects have been found with CLA and Sesamin at the same doses in a previous rat study, although both trended towards additive effects being statistically significant.
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