Sesamin Research Articles

Sesamin suppresses angiotensin-II-enhanced oxidative stress and hypertrophic markers in H9c2 cells.

Myocardial hypertrophy plays a crucial role in cardiovascular disease (CVD) development. Myocardial hypertrophy is an adaptive response by myocardial cells to stress after cardiac injury to maintain cardiac output and function. Angiotensin II (Ang-II) regulates CVD through the renin-angiotensin-aldosterone system, and its signaling in cardiac myocytes leads to excessive reactive oxygen species (ROS) production, oxidative stress, and inflammation. Sesamin (SA), a natural compound in sesame seeds, has anti-inflammatory and anti-apoptotic effects. This study investigated whether SA could attenuate hypertrophic damage and oxidative injuries in H9c2 cells under Ang-II stimulation. We found that SA decreased the cell surface area. Furthermore, Ang-II treatment reduced Ang-II-increased ANP, BNP, and β-MHC expression. Ang-II enhanced NADPH oxidase activity, ROS formation, and decreased Superoxide Dismutase (SOD) activity. SA treatment reduces Ang-II-caused oxidative injuries. We also found that SA mitigates Ang-II-induced apoptosis and pro-inflammatory responses. In conclusion, SA could attenuate Ang-II-induced cardiac hypertrophic injuries by inhibiting oxidative stress, apoptosis, and inflammation in H9c2 cells. Therefore, SA might be a potential supplement for CVD management.

The Protective Effects of Sesamin against Cyclophosphamide-Induced Nephrotoxicity through Modulation of Oxidative Stress, Inflammatory-Cytokines and Apoptosis in Rats.

Cyclophosphamide is an anticancer drug with a wide spectrum of clinical uses, but its typical side effects are multiple complications, including nephron toxicity. The possible molecular mechanism of the nephroprotective action of sesamin (SM) against cyclophosphamide (CP) induced renal toxicity was investigated in rats by understanding oxidative stress and inflammatory cytokines. In this study, rats were arbitrarily grouped into the following four groups: a normal control group (CNT); a CP-induced toxicity group; a treatment group with two doses of sesamin SM10 and SM20; a group with sesamin (SM20) alone. A single dose of CP (150 mg/kg body, i.p.) was administered on day 4 of the experiments, while treatment with SM was given orally for seven days from day 1. The group treated with SM showed a significant protective effect against CP-induced renal damage in rats. Treatment with SM significantly increased the antioxidant enzymes (GSH, CAT, and SOD) and reduced malondialdehyde (MDA) levels. Thus, SM significantly overcame the elevated kidney function markers (creatinine, blood urea nitrogen, and uric acid) by attenuating oxidative stress. The SM also significantly reduced the elevated cytokines (IL-1β and TNFα) and caspase-3 in the treated group. Histopathological studies confirmed the protective effect of sesamin (SM) on CP-induced nephrotoxicity. In conclusion, the current findings support the nephroprotective effect of sesamin against CP-induced renal injury.

Alleviation of cognitive deficits via upregulation of chondroitin sulfate biosynthesis by lignan sesamin in a mouse model of neuroinflammation

Lignans are plant-derived compounds that act as partial estrogen agonists. Chondroitin sulfate proteoglycans (CSPGs) represent one of the major components of the extracellular matrix. Here we aimed to understand the role of sesamin (SES), a major lignan compound, in the biosynthesis and degradation of CSPGs in the mouse hippocampus because CSPGs play a key role in the regulation of cognitive functions through the promotion of adult neurogenesis. The expression of the pro-inflammatory cytokine interleukin-1β was decreased by SES administration in the hippocampus of lipopolysaccharide (LPS)-treated mice, a model of neuroinflammation-induced cognitive deficits. The expression of genes related to biosynthesis and degradation of CSPGs in the hippocampus of LPS-treated mice was both increased and decreased by SES administration. Further, the diffuse extracellular matrix labeling of CSPGs by Wisteria floribunda agglutinin (WFA) in the hippocampus of LPS-treated mice was increased by SES administration. The densities of neural stem cells, late transit-amplifying cells, and newborn-granule cells in the hippocampus of LPS-treated mice were also increased by SES administration. Moreover, SES-induced alterations in gene expression, WFA labeling, and adult neurogenesis in LPS-treated mice were more evident in the dorsal hippocampus (center of cognition) than in the ventral hippocampus (center of emotion). Neither LPS nor SES administration affected locomotor activity, anxiety-like behavior, and depression-related behavior. However, impairments in contextual memory and sensorimotor gating in LPS-treated mice were recovered by SES administration. Our results show that SES can promote adult hippocampal neurogenesis through the upregulation of CSPGs, which may alleviate cognitive deficits induced by neuroinflammation.

Sesamin protects against DSS-induced colitis in mice by inhibiting NF-κB and MAPK signaling pathways.

To investigate the protective effects and mechanisms of sesamin (SES) on dextran sulfate sodium (DSS)-induced experimental colitis in mice. SES (50, 100, and 200 mg kg-1) were orally administered to C57BL/6 male mice after DSS instillation. The anti-inflammatory effect of SES on colonic damage was assessed by clinical, macroscopic, microscopic, and inflammatory signaling pathways. It could be found that bodyweight and colon length of mice treated with DSS was significantly decreased while that were increased by SES treatment. SES treatment reduced the DAI values and improved the histopathology of the colon in the DSS-treated mice. SES also reduced TNF-α, IL-1β and IL-6 production caused by DSS. We also measured the expression of the phosphorylation of p65, IκB, p38, ERK and JNK protein and found that SES can alleviate colon damage via the NF-κB and MAPK signaling pathways. The findings of this study suggested that SES had anti-inflammatory effects on intestinal inflammation and can be used as a new therapeutic candidate for inflammatory bowel disease.

Sesame lignans suppress age-related disorders of the kidney in mice.

Sesamin is a functional ingredient in sesame (Sesamum indicum) seeds and has many physiological effects. This study investigated whether sesame lignans, sesamin and episesamin (1:1), can suppress age-related disorders of the kidney. Twenty-month-old mice were divided into three groups, and each group received a regular diet (O-C), diet containing sesame lignans (O-SE), and diet containing sesame lignans and α-tocopherol (VE; O-SE+VE), respectively, for 5 months. Six-month-old young mice (Y-C) were compared to the older mice. Renal lipofuscin deposition was increased in the O-C group compared to that in the Y-C group and its deposition with aging was significantly decreased in both O-SE and O-SE+VE groups. Plasma blood urea nitrogen levels in the O-C group increased compared to those in the Y-C group; however, those in both O-SE and O-SE+VE groups did not differ from those in the Y-C group. The number of podocytes in the O-C group decreased compared to that in the Y-C group and this effect was attenuated in the O-SE and O-SE+VE groups. The effect was strongest in the O-SE+VE group. Histological examinations showed that glomerular hypertrophy accompanied by mesangial hyperplasia and renal tubular degeneration was less severe in the O-SE and O-SE+VE groups than in the O-C group. Moreover, age-related increases in the mRNA expression of NADPH oxidase- and inflammation-related genes, including p67phox, p40phox, TNFα, and IL-6, in the kidney were suppressed in the O-SE and O-SE+VE groups. Sesame lignans might be useful to suppress age-related kidney disorders, and these effects could be enhanced with VE.

Flavone/Tertiary Amine as Free Radical Photoinitiator for UV Photopolymerization of Tripropylene Glycol Diacrylate(TPGDA)†

The polymerization kinetics of tripropylene glycol diacrylate(TPGDA) was monitored by real time near infrared(RTIR) with favone(FL) as photosensitizer and different hydrogen donor as coinitiator.The commercial photosensitizer benzophenone(BP) was used as control.The results showed that the molar extinction coefficient(e max) of FL was much higher than that of BP.When FL was used in combination with tertiary amine hydrogen donor ethyl 4-N,N'-dimethylaminobenzoate(EDAB),the rate of polymerization(R p) and final double bond conversion(DC f) could reach 0.58 s-1and 97%,respectively,which was very close to that of commercial BP / EDAB system.However,using sesamin(SM) and benzodioxole(BDO) as coinitiator for FL,the R p and DC f were both very low,which indicated that the excited FL and tertiary amine could generate aminoalkyl free radical species via electron / proton transfer process and initiate the efficient photopolymerization of TPGDA.More importantly,when the co-polymerizable tertiary amines such as EBERYL P115 and dimethylaminoethyl methacrylate(DMEM) are used,the natural component characteristics of FL make it a promising photoinitiator in biomedical and food-packaging fields.

Front cover: Absorption, distribution, metabolism, and excretion of [14C]sesamin in rats

Front cover: Absorption, distribution, metabolism, and excretion of [¹⁴C]sesamin in rats

Development of sesamin-loaded solid dispersion with α-glycosylated stevia for improving physicochemical and nutraceutical properties

The present study aimed to enhance the nutraceutical properties of sesamin (SES) by solid dispersion (SD) approach using α-glycosylated stevia (Stevia-G) as a carrier compound with solubilizing effect. The SD formulations were characterized in terms of physicochemical and pharmacokinetic properties. The skin protective effect was evaluated in a rat model of drug-induced photodermatosis. The SES-loaded SD with Stevia-G (SES/Stevia-G-SD) prepared with spray-drying were uniform and spherical with a diameter of about 3μm, and SES within the formulation was found to be an amorphous state, possibly leading to improved dissolution behavior of SES. SES/Stevia-G-SD provided 190-fold increase in the dissolution amount of SES compared with crystalline SES. The oral bioavailability of SES/Stevia-G-SD (20mg-SES/kg) was 30-fold higher than that of crystalline SES. Orally-dosed SES/Stevia-G-SD (20mg-SES/kg) protected rat skins from drug-induced photodermatosis. Based on these findings, the SES/Stevia-G-SD approach might be efficacious to enhance the nutraceutical potential of SES.

Impact of lignans on the polyunsaturated fatty acid metabolic processing in a rainbow trout (Oncorhynchus mykiss) cell line

In the context of fish oil replacement by alternative plant-derived oils in the fish feed, the influence of lignans, which are phenolic compounds present at significant concentrations in some plant-derived oils, was investigated on the omega-3 (n-3) fatty acid metabolism of the rainbow trout liver cell line RTL-W1 enriched in alpha-linolenic acid (ALA, 18:3n-3). The major linseed oil lignans, namely secoisolariciresinol diglucoside (SDG) and secoisolariciresinol (SECO), as well as the enterolignan enterodiol (END) were evaluated. Moreover, the effects of sesame oil lignans, namely sesamin (SES) and episesamin (EPI), were also investigated and compared to those previously observed in in vivo and in vitro studies which reported favourable effects on the fatty acid bioconversion capacity of salmonids. Cells were incubated with 50μM ALA and 50μM of SES, EPI, SDG, SECO or END for 48h at 19°C. The cells incubated with ALA had significantly higher amounts of 18:4n-3, 20:4n-3 and 20:5n-3 (eicosapentaenoic acid, EPA) as compared to control cells. The supplementation with SES decreased the 18:4n-3, 20:4n-3 and EPA contents, which indicates an inhibition of the desaturation and elongation steps involved in the fatty acid bioconversion pathway. As compared to SES supplementation, EPI supplementation showed a limited impact by only reducing 18:4n-3 and 20:4n-3. Similarly, END supplementation decreased 18:4n-3 and EPA, suggesting an inhibition of the desaturation capacity. Conversely, the supplementation of linseed lignans SDG and SECO had no impact on the fatty acid bioconversion capacity of RTL-W1 liver cells. In conclusion, the present results on the sesame seed lignans SES and EPI contradict the positive effects previously reported on fish lipid metabolism. In contrast, no influence of the linseed lignans SDG and SECO was observed. This suggests that the presence of lignans in linseed oil has no impact on the fish fatty acid bioconversion capacity when the oil is included to the diet.

Anti-inflammatory role of sesamin in STZ induced mice model of diabetic retinopathy

Diabetic retinopathy (DR) is the common cause of diabetic vascular complications that leads to the blindness in the working age population throughout the world. Free radicals mediated oxidative stress and inflammation play a significant role in pathophysiology of DR. To find a new and safe drug to treat DR is still challenging and for that purpose the natural compounds may be therapeutic agents. Here we show that sesamin (SES), which is the main component of sesame seed and its oil, and has been reported as potent antioxidant and neuroprotective, could be a therapeutic agent in DR. In the present study, we investigated protective effect of SES in Streptozotocin (STZ) induced DR in mice. The mice were divided into three groups (Control, DR and DR+SES) for the study. After two weeks post-diabetic establishment, mice were treated with SES (30mg/kg BW, i.p, alternate day) for four weeks. Mice body weight and blood glucose level were measured from each group. The microglial activation of retina was determined by immunohistochemistry analysis by using Iba-1 as a microglia marker. Retinal mRNA levels of Iba-1, tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and Intercellular Adhesion Molecule 1 (ICAM-1) were examined by qRT-PCR. The level of iNOS protein expression was examined by immunoblotting. Together these data demonstrate that SES treatment lowered the progression of diabetic retinal injury by: 1) decreasing blood glucose level, 2) suppressing microglia activation, 3) reducing retinal TNF-α and ICAM-1 levels and 4) quenching iNOS expression. In conclusion, the results suggest that SES treatment may be of therapeutic benefit in reducing the progression of DR by ameliorating hyperglycemia and inflammation in diabetic retina.

Protective effects of the polyphenols (+)-episesamin and sesamin against PDGF-BB-induced activation of vascular smooth muscle cells are mediated by induction of haem oxygenase-1 and inhibition of mitogenic signalling

Activation of vascular smooth muscle cells (VSMCs) represents a key event of atherosclerosis. It is triggered e.g. by the action of platelet-derived growth factor (PDGF). The polyphenol (+)-episesamin (ES) is known to block the TNF-α-induced mitogenic VSMC response. Aiming to develop novel therapeutic options e.g. by dietary supplements, we studied if ES and its stereoisomer sesamin (SE) reduce PDGF-BB-induced growth and migration, which both promote atherosclerosis. ES and SE reduced basal and PDGF-BB-induced proliferation and migration of human, murine and rat VSMC by impaired activation of MAPK and PI3K pathways and reduced oxidative stress by induction of haem oxygenase-1 expression. Moreover, ES and SE blocked PDGF-BB-induced activation of NF-κB with subsequently reduced expression and secretion of the gelatinases matrix-metalloproteinase-(MMP)-2 and MMP-9. In conjunction with their natural origin and well-tolerable properties, these data suggest ES and SE as potential candidates for a complemental treatment of VSMC specific vascular diseases like atherosclerosis.

The promoting effects of sesamin on osteoblast differentiation of human mesenchymal stem cells

Sesamin, a major lignan in sesame seeds and oils, is well known for its health promotion activity. However, its effects on bone cell functions are infrequently observed. In the study, the effects of sesamin on the differentiation of human mesenchymal stem cells (MSCs), osteoblasts, were examined. The differentiation of cells into osteoblasts suggested that sesamin (SE) in combination with osteogenic factors (OS) significantly increased calcium deposition. Although the osteoblastic differentiation markers including bone morphogenetic protein 2 (BMP-2), type I collagen (COL1A1) and alkaline phosphatase (ALP) of each cell donor showed different expressions both in gene type and time point, the increasing trends of COL1A1 and ALP were observed within the condition of OS + SE being compared with OS treatment. Increased ALP activity in OS + SE treatment could mediate the stimulatory effect of sesamin on osteoblast differentiation. Increased phosphorylation of p38 and ERK were related to increasing of ALP activity and mineralization in OS + SE treatment. Hence, it is suggested that sesamin enhanced osteoblast differentiation via activation of those MAPK signalling cascades. All results present that sesamin benefits differentiation of osteoblast progenitors towards functional bone forming cells, osteoblast. Thereby, sesamin would be a potential food supplement promoting bone health.

Recommended Daily Dose of Sesame Lignans Has No Influence on Oral Absorption of P-Glycoprotein Substrates in Rats.

Sesamin (SM) and episesamin (ESM) are constituents of sesame seeds, which are used in health foods and considered to have various beneficial effects in the prevention of lifestyle-related diseases. P-Glycoprotein (P-gp) is an ATP-binding cassette transporter involved in drug absorption in the human gastrointestinal tract. A recent report indicated that SM influences P-gp-mediated drug transport. In the present study, we investigated whether SM and ESM inhibit P-gp in vitro, using Caco-2 cells and the typical P-gp substrates rhodamine123 (Rho123) and fexofenadine. SM and ESM showed no effect on accumulation of these compounds, indicating that SM and ESM do not influence P-gp function. In addition, an in vivo study using Rho123 indicated that SM and ESM do not affect absorption of P-gp substrates. Overall, these results suggest that health foods containing SM and ESM are unlikely to interact with P-gp substrates.

The lignan (+)-episesamin interferes with TNF-α-induced activation of VSMC via diminished activation of NF-ĸB, ERK1/2 and AKT and decreased activity of gelatinases.

Activation of vascular smooth muscle cells (VSMC), a key event in the pathogenesis of atherosclerosis, is triggered by inflammatory stimuli such as tumour necrosis factor-alpha (TNF-α) causing a mitogenic VSMC response. The polyphenol (+)-episesamin (ES) was shown to counteract TNF-α-induced effects, for example in macrophages. Aiming for novel therapeutic options, we here investigated whether ES protects VSMC from TNF-α-induced growth and migration, which both contribute to the onset and progression of atherosclerosis. Human and murine VSMC were treated with combinations of ES and TNF-α. Expressions of mRNA were analyzed by RT-PCR. Enzymatic activities and proliferation were determined by specific substrate assays. Cell signalling was analyzed by Western blot and reporter gene assays. Migration was assessed by wound healing assays. ES at 1-10 μm reduced basal and TNF-α-induced VSMC proliferation and migration due to impaired activation of extracellular signal-regulated kinases (ERK)1/2, Akt (protein kinase B), nuclear factor-kappa B (NF-ĸB) and vascular cell adhesion molecule (VCAM)-1. This was accompanied by reduced expression and secretion of matrix metalloproteinases (MMP)-2/-9, which are known to promote VSMC migration. Specific inhibitors of Akt, NF-ĸB and MMP-2/-9 reduced TNF-α-induced VSMC proliferation, confirming ES-specific effects. Besides, ES reduced TNF-α- and H₂O₂ -induced oxidative stress and in parallel induces anti-inflammatory haem oxygenase (HO)-1 expression. ES interferes with inflammation-associated VSMC activation and subsequent decreased proliferation and migration due to anti-oxidative properties and impaired activation of NF-ĸB, known contributors to atherogenesis. These results suggest ES as a complemental treatment of VSMC specific vascular diseases such as atherosclerosis.

Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke

Stroke is a severe neurological disorder characterized by the abrupt loss of blood circulation into the brain resulting into wide ranging brain and behavior abnormalities. The present study was designed to evaluate molecular mechanism by which sesamin (SES) induces neuroprotection in mouse model of ischemic stroke. The results of this study demonstrate that SES treatment (30mg/kgbwt) significantly reduced infarction volume, lipid per-oxidation, cleaved-caspase-3 activation, and increased GSH activity following MCAO in adult male mouse. SES treatment also diminished iNOS and COX-2 protein expression, and significantly restored SOD activity and protein expression level in the ischemic cortex of the MCAO animals. Furthermore, SES treatment also significantly reduced inflammatory and oxidative stress markers including Iba1, Nox-2, Cox-2, peroxynitrite compared to placebo MCAO animals. Superoxide radical production, as studied by DHE staining method, was also significantly reduced in the ischemic cortex of SES treated compared to placebo MCAO animals. Likewise, downstream effects of superoxide free radicals i.e. MAPK/ERK and P38 activation was also significantly attenuated in SES treated compared to placebo MCAO animals. In conclusion, these results suggest that SES induces significant neuroprotection, by ameliorating many signaling pathways activated/deactivated following cerebral ischemia in adult mouse.

Protective effect of sesamin against myocardial injury induced by cadmium chloride in rats

To investigate the protective effect of sesamin against cadmium chloride (CdCl2)-induced cardiotoxicity in rats. Fifty male Wistar rats were randomly assigned to five groups: control group, CdCl2 group, and low-, middle-, and high-dose sesamin groups. The control group was given normal saline. The CdCl2 group and sesamin groups were intraperitoneally injected with CdCl2 (5 mg/kg×2 d), and the low-, middle-, and high-dose sesamin groups were given 20, 40, and 80 mg/kg sesamin, respectively. All treatments lasted for four weeks. ECG was measured by a physiological recorder, and serum myocardial enzyme levels were determined by biochemical assay. The heart was weighed, and heart tissues were used in histopathological examination and determination of malondialdehyde (MDA) level. Compared with the control group, the CdCl2 group showed significantly higher levels of serum CK and CK-MB, an increased heart coefficient, significant ST-segment elevation, and higher level of MDA in myocardial tissue (P < 0.05). Histopathological analysis showed edema of myocardial tissues and cells, myocardial fibers disorder, karyopyknosis, and uneven or deep staining of nuclear chromatin. Different doses of sesamin relieved the myocardial pathological changes induced by CdCl2, and high-dose sesamin was the most effective. The middle- and high-dose sesamin groups showed significantly reduced serum CK and CK-MB levels compared with the CdCl2 group (P < 0.05). The heart coefficient of the high-dose sesamin group (0.19±0.01%) was significantly lower than that of the CdCl2 group (0.21±0.01%) (P < 0.05). Myocardial MDA levels of the three sesamin groups (42.32±4.65, 36.71±5.34, and 33.12±4.62 nmol/mg pro, respectively) were all significantly lower than that of the CdCl2 group (55.87±3.65 nmol/mg pro) (P < 0.05). Sesamin can relieve myocardial injury induced by CdCl2, and one possible mechanism is the enhancement of antioxidant capacity of myocardial tissue.

Simultaneous Determination of Asaranin and Sesamin in Piper chaba Fruit by using HPTLC-MS Method: Effect of Different Extraction Methods on the Yield of Marker Compounds

A simple, rapid and accurate HPTLC-MS method was developed for the simultaneous quantification of asaranin (AS) and sesamin (SM), the two epimeric furofuran lignans in Piper chaba (Piperaceae) fruit extracts obtained by cold percolation (PER), Soxhlet extraction (SOX), ultrasound assisted extraction (USAE), accelerated solvent extractor (ASE) and microwave assisted extraction (MAE). Separation of AS and SM was achieved on 20×10 cm pre-coated silica gel 60 F254S HPTLC plates with ethyl acetate: hexane (30:70) as mobile phase. Detection and quantification were performed densitometrically at λmax 295 nm. The peak identity was confirmed by electron spray ionization (ESI) mass spectra, which showed the [M + Na]+ ions for both AS and SM at m/z 377. The method was validated according to the ICH guidelines in terms of limit of detection (LOD) and limit of quantification (LOQ), selectivity, linearity, precision, accuracy, and robustness. The results indicate that AS (2.108%) and SM (0.103%) found to present maximum in ASE extract and minimum in PER extract (AS 0.848%; SM 0.048%). By considering the validation results, the method was found to be reproducible and convenient for quantitative analysis of AS and SM in different P. chaba fruit extracts.

Optimization of phenolics extraction from sesame seed cake

Sesame seed cake is considered to be a by-product of the oil industry, being commonly used as cattle feed in several producing countries. However, this residue can be recovered and value added. The main phenolics found in sesame seed are lignans, which are important bioactive compounds of this seed. The main lignans in defatted sesame were identified as sesaminol triglucoside, sesamolinol diglucoside and sesaminol diglucoside. The objective of this study was to optimize the extraction of total phenolics and lignans from sesame seed cake. A second-order polynomial model was set up to predict the responses using response surface methodology (RSM). The independent variables analyzed were temperature (25–90°C), solid/solvent ratio (0.03–0.11g/mL) and ethanol concentration (0–95%). Response variables were the concentrations of total phenolics (TP), sesamin (SES), sesaminol triglucoside (ST) and antioxidant activity (ABTS). The extracted amount of TP ranged between 129.7 and 355.3mgGAE/100g, SES from 3.2 to 25.7mgSES/100g, ST from 208.1 to 537.5mgSE/100g and the ABTS of the extracts was between 8460 and 24311μMTE. Among the analyzed compounds, ST is presented in the highest quantity in sesame cake. Solid to liquid ratio and ethanol concentration were the most important factors affecting extraction, whereas temperature showed reduced influence. The model obtained to describe the effect of these factors on the extraction of ST was satisfactorily validated.

Inhibitory effects of epi-sesamin on endothelial protein C receptor shedding in vitro and in vivo

Endothelial protein C receptor (EPCR) plays a pivotal role in augmenting Protein C activation by the thrombin-thrombomodulin complex. The activity of EPCR is markedly changed by ectodomain cleavage and release as the soluble protein (sEPCR). The EPCR shedding is mediated by the tumor necrosis factor-α converting enzyme (TACE). Epi-sesamin (ESM), from the roots of Asarum siebodlii, is known to exhibit anti-allergic and anti-fungal activities. However, little is known about the effects of ESM on EPCR shedding. We investigated this issue by monitoring the effects of ESM on phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and cecal ligation and puncture (CLP)-mediated EPCR shedding. Data showed that ESM induced potent inhibition of PMA, TNF-α, IL-1β, and CLP-induced EPCR shedding, likely through suppression of TACE expression. In addition, treatment with ESM resulted in a reduction of PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). Given these results, ESM should be viewed as a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of EPCR shedding.

Inhibitory effects of epi-sesamin on HMGB1-induced vascular barrier disruptive responses in vitro and in vivo

Nuclear DNA-binding protein high mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions, such as sepsis and septic shock. Epi-sesamin (ESM), an important component of Asarum sieboldii roots, is known to exhibit anti-allergic, anti-nociceptive, and anti-fungal effects. However, little is known of its effects on HMGB1-mediated inflammatory responses. Here, we investigated this issue by monitoring the effects of ESM on lipopolysaccharide (LPS) or cecal ligation and the puncture (CLP)-mediated release of HMGB1, and on modulation of HMGB1-mediated inflammatory responses. ESM potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ESM resulted in reduced CLP-induced release of HMGB1 and sepsis-related mortality. Of particular interest, ESM inhibition of HMGB1-mediated anti-inflammatory activity was more potent than that by sesamin (SM), likely due to differences between their three-dimensional structures. These results indicate that ESM could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.