(+)-Episesamin inhibits adipogenesis and exerts anti-inflammatory effects in 3T3-L1 (pre)adipocytes by sustained Wnt signaling, down-regulation of PPARγ and induction of iNOS
Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany. The Journal of nutritional biochemistry
(Impact Factor: 3.79).
07/2012; 24(3). DOI: 10.1016/j.jnutbio.2012.02.004
Obesity and its associated health risks still demand for effective therapeutic strategies. Drugs and compositions derived from Oriental medicine such as green tea polyphenols attract growing attention. Previously, an extract from the Japanese spice bush Lindera obtusiloba (L. obtusiloba) traditionally used for treatment of inflammation and prevention of liver damage was shown to inhibit adipogenesis. Aiming for the active principle of this extract (+)-episesamin was identified, isolated and applied in adipogenic research using 3T3-L1 (pre)adipocytes, an established cell line for studying adipogenesis. With an IC(50) of 10μM (+)-episesamin effectively reduced the growth of 3T3-L1 preadipocytes and decreased hormone-induced 3T3-L1 differentiation as shown by reduced accumulation of intracellular lipid droplets and diminished protein expression of GLUT-4 and vascular endothelial growth factor. Mechanistically, the presence of (+)-episesamin during hormone-induced differentiation provoked a reduced phosphorylation of ERK1/2 and β-catenin along with a reduced protein expression of peroxisome proliferator-activated receptor γ and a strongly increased protein expression of iNOS. Treatment of mature adipocytes with (+)-episesamin resulted in a reduction of intracellular stored lipid droplets and induced the proapoptotic enzymes caspases-3/-7. Besides interfering with adipogenesis, (+)-episesamin showed anti-inflammatory activity by counteracting the lipopolysaccharide- and tumor necrosis factor α-induced secretion of interleukin 6 by 3T3-L1 preadipocytes. In conclusion, (+)-episesamin seems to be the active drug in the L. obtusiloba extract being responsible for the inhibition of adipogenesis and, thus, should be evaluated as a novel potential complementary treatment for obesity.
Available from: Anil Gaikwad
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ABSTRACT: Obesity is a result of adipocyte hypertrophy followed by hyperplasia. It is a risk factor for several metabolic disorders such as dyslipidemia, type-2 diabetes, hypertension, and cardiovascular diseases. Coagulanolides, particularly coagulin-L isolated from W. coagulan has earlier been reported for anti-hyperglycemic activity. In this study, we investigated the effect of coagulin-L on in vitro models of adipocyte differentiation including 3T3-L1 pre-adipocyte, mouse stromal mesenchymal C3H10T1/2 cells and bone marrow derived human mesenchymal stem cells (hMSCs). Our results showed that, coagulin-L reduces the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), the major transcription factors orchestrating adipocyte differentiation. Detailed analysis further proved that early exposure of coagulin-L is sufficient to cause significant inhibition during adipogenesis. Coagulin-L inhibited mitotic clonal expansion (MCE) by delayed entry in G1 to S phase transition and S-phase arrest. This MCE blockade was caused apparently by decreased phosphorylation of C/EBPβ, modulation in expression of cell cycle regulatory proteins, and upregulation of Wnt/β-catenin pathway, the early stage regulatory proteins of adipogenic induction. Taken together all evidences, a known anti-hyperglycemic agent coagulin-L has shown potential to inhibit adipogenesis significantly, which can be therapeutically exploited for treatment of obesity and metabolic syndrome.
Phytomedicine: international journal of phytotherapy and phytopharmacology 11/2013; 21(4). DOI:10.1016/j.phymed.2013.10.009 · 3.13 Impact Factor
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ABSTRACT: AimActivation of vascular smooth muscle cells (VSMC), a key event in the pathogenesis of atherosclerosis, is triggered by inflammatory stimuli such as tumor necrosis factor alpha (TNF-) causing a mitogenic VSMC response. The polyphenol (+)-episesamin (ES) was shown to counteract TNF--induced effects e.g. in macrophages. Aiming for novel therapeutic options, we here investigated whether ES protects VSMC from TNF--induced growth and migration, which both contribute to the onset and progression of atherosclerosis.Methods
Human and murine VSMC were treated with combinations of ES and TNF-. Expressions of mRNA were analyzed by RT-PCR. Enzymatic activities and proliferation were determined by specific substrate assays. Cell signaling was analyzed by western blot and reporter gene assays. Migration was assessed by wound healing assays.ResultsES at 1-10 μM reduced basal and TNF--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--induced VSMC proliferation, confirming ES-specific effects. Besides, ES reduced TNF-- and H2O2-induced oxidative stress and in parallel induces anti-inflammatory heme oxygenase (HO)-1 expression.ConclusionES 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.This article is protected by copyright. All rights reserved.
Acta Physiologica 09/2014; 213(3). DOI:10.1111/apha.12400 · 4.38 Impact Factor
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ABSTRACT: For many years, research related to atherosclerosis has generated numerous scientific studies; pharmacological treatment for this multifactorial disease however continues generating controversy. In this context, Freise & Querfeld 2014 made an important contribution investigating the antioxidant effects of (+) -Episesamin (ES) upon cultured cells, demonstrating its ability to inhibit the mitogenic effects induced by tumor necrosis factor alpha (TNF-α) on vascular smooth muscle cell (VSMC) proliferation and migration. They also evaluated ES effect upon intracellular oxidative stress induced by TNF-α and hydrogen peroxide (H2O2) in VSMC, performing an extensive description of the experimental results. This study shows ES as a promising strategy as antioxidant therapy for human atherogenic process.This article is protected by copyright. All rights reserved.
Acta Physiologica 01/2015; 213(3). DOI:10.1111/apha.12453 · 4.38 Impact Factor
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