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Helmut Sies

Publications and source records attributed to Helmut Sies.

At least 19 recordsLinked to original sources
PubMed2006

Consumption of flavanol-rich cocoa acutely increases microcirculation in human skin.

BACKGROUND: Long term cocoa ingestion leads to an increased resistance against UV-induced erythema and a lowered transepidermal water loss. AIM OF THE STUDY: To investigate the acute effects of a single dose of cocoa rich in flavanols on dermal microcirculation. METHODS: In a crossover design study, 10 healthy women ingested a cocoa drink (100 ml) with high (329 mg) or low (27 mg) content of flavanols. The major flavanol monomer in both drinks was epicatechin, 61 mg in the high flavanol, and 6.6 mg in the low flavanol product per 100 ml. Dermal blood flow and oxygen saturation of hemoglobin were examined by laser Doppler flowmetry and spectroscopically at 1 mm skin depth at t = 0, 1, 2, 4, and 6 h. At the same time points, plasma levels of total epicatechin (free compound plus conjugates) were measured by means of HPLC. RESULTS: Subsequent to the intake of high flavanol cocoa, dermal blood flow was significantly increased by 1.7-fold at t = 2 h and oxygen saturation was elevated 1.8-fold. No statistically significant changes were found upon intake of low flavanol cocoa. Maximum plasma levels of total epicatechin were observed 1 h after ingestion of the high flavanol cocoa drink, 11.6 +/- 7.4 nmol/l at baseline, and 62.9 +/- 35.8 nmol/l at 1 h. No change of total epicatechin was found in the low flavanol group. CONCLUSION: Flavanol-rich cocoa consumption acutely increases dermal blood flow and oxygen saturation.

Adolescent↗
PubMed2006

Rac upregulates tissue inhibitor of metalloproteinase-1 expression by redox-dependent activation of extracellular signal-regulated kinase signaling.

The Rho-like GTPase Rac regulates distinct actin cytoskeleton changes required for adhesion, migration and invasion of cells. Tiam1 specifically activates Rac, and Rac has been shown to affect several signaling pathways in a partly cell-type-specific manner. Recently, we demonstrated that Rac activation inhibits Matrigel invasion of human carcinoma cells by transcriptional upregulation of tissue inhibitor of metalloproteinase-1. The purpose of the present study was to identify key mediators of Tiam1/Rac-induced tissue inhibitor of metalloproteinase-1 expression. Mutational analysis of the human tissue inhibitor of metalloproteinase-1 promoter revealed a major role for a distinct activating protein-1 site at -92/-86 and a minor role for an adjacent polyoma enhancer A3 site. Moreover, Rac activation induced the generation of reactive oxygen species and subsequent reactive oxygen species-dependent activation of extracellular signal-regulated kinase 1,2. In contrast, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activities were not affected. In line with this, Tiam1/Rac-induced tissue inhibitor of metalloproteinase-1 expression as well as Tiam1/Rac-induced binding of nuclear extracts to the activating protein-1 site at -92/-86 were inhibited by catalase and by specific inhibitors of the extracellular signal-related kinase-1,2 activators, mitogen-activated protein kinase kinase-1 and mitogen-activated protein kinase kinase-2 (PD098059, U0126). In conclusion, Rac-induced transcriptional upregulation of tissue inhibitor of metalloproteinase-1 is mediated by reactive oxygen species-dependent activation of extracellular signal-related kinase-1,2 and by transcription factors of the activating protein-1 family.

Antineoplastic Agents↗
PubMed2006

Modulation of FoxO signaling in human hepatoma cells by exposure to copper or zinc ions.

Cells respond to heavy metal stress by activating signaling cascades regulating cellular proliferation and survival. We here demonstrate that the anti-apoptotic kinase Akt is activated in HepG2 human hepatoma cells exposed to copper or zinc ions. Cu2+- and Zn2+-induced phosphorylation of Akt was blocked by phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin and LY294002. Moreover, several endogenous Akt substrates were phosphorylated, including glycogen synthase kinase-3 and transcription factors of the FoxO family, FoxO1a and FoxO4. Exposure to Cu2+ or Zn2+ elicited the subcellular redistribution of an overexpressed FoxO1a-EGFP fusion protein from nucleus to cytoplasm, which was not seen with a mutant FoxO1a form devoid of Akt phosphorylation sites. Both FoxO phosphorylation and nuclear exclusion were blocked by wortmannin. Likewise, the subcellular translocation from nucleus to cytoplasm of the Caenorhabditis elegans FoxO ortholog, DAF-16, was caused in starved worms exposed to copper ions. Activity of the promoter of the human glucose 6-phosphatase gene, known to be regulated by insulin and FoxO1a, was demonstrated in reporter gene assays to be attenuated in hepatoma cells exposed to Cu2+. However, this suppression of glucose 6-phosphatase promoter activity was independent of modulation of the PI3K/Akt pathway. In summary, the PI3K/Akt pathway is activated in human hepatoma cells exposed to Cu2+ or Zn2+, resulting in the phosphorylation and subcellular relocalisation of transcription factor FoxO1a. Furthermore, copper is demonstrated to exert an insulin-mimetic effect also independently of the PI3K/Akt/FoxO pathway.

Animals↗
PubMed2006

Extracellular generation of hydrogen peroxide is responsible for activation of EGF receptor by ultraviolet A radiation.

Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) have been proposed to be activated in cells exposed to ultraviolet A (UVA) radiation (320-400 nm) and to be involved in photocarcinogenesis. Singlet oxygen and hydrogen peroxide are being discussed as mediators of the activation of signal transduction pathways by UVA. It is demonstrated here that EGFR is not activated in cells exposed to UVA in the absence of extracellular photosensitizers. Rather, UVA was capable of activating the EGFR and the related ErbB2 receptor tyrosine kinase in HeLa cells and human keratinocytes only under conditions that allowed for the extracellular photochemical generation of H(2)O(2), such as when cells were covered with cell culture medium during exposure to UVA. Pretreatment of cells with vanadate was required for UVA-induced EGFR activation, pointing to the involvement of protein tyrosine phosphatases. Unlike H(2)O(2), photochemically generated singlet oxygen did not activate EGFR but instead impaired the activation of EGFR by its ligand, EGF. In summary, extracellularly generated H(2)O(2) mediates UVA-induced activation of the EGFR and of ErbB2, whereas intracellular generation of reactive oxygen species upon exposure of cells to UVA is not sufficient for activation of the receptor.

Cells, Cultured↗
PubMed2006

Cytotoxicity of myeloperoxidase/nitrite-oxidized low-density lipoprotein toward endothelial cells is due to a high 7beta-hydroxycholesterol to 7-ketocholesterol ratio.

Oxygenated cholesterols (oxysterols) formed during oxidation of low-density lipoprotein (LDL) are associated with endothelial dysfunction and atherogenesis. We compared the profile of oxysterols in modified human LDL obtained on reaction with myeloperoxidase/H2O2 plus nitrite (MPO/H2O2/nitrite-oxLDL) with that on Cu2+ -catalyzed oxidation. The 7beta-hydroxycholesterol/7-ketocholesterol ratio was markedly higher in MPO/H2O2/nitrite-oxLDL than in Cu2+ -oxidized LDL (7.9 +/- 3.0 versus 0.94 +/- 0.10). Like MPO/H2O2/nitrite-oxLDL, 7beta-hydroxycholesterol was cytotoxic toward endothelial cells through eliciting oxidative stress. Cytotoxicity was accompanied by DNA fragmentation and was prevented by the NADPH oxidase inhibitor apocynin, suggesting stimulation of NADPH oxidase-mediated O2-* formation. 7-Ketocholesterol was only cytotoxic when added alone, whereas a 1:1-mixture with 7beta-hydroxycholesterol surprisingly was noncytotoxic. We conclude from our data that (i) 7beta-hydroxycholesterol is a pivotal cytotoxic component of oxidized LDL, (ii) 7-ketocholesterol protects against 7beta-hydroxycholesterol in oxysterol mixtures or oxLDL, (iii) the 7beta-hydroxycholesterol/7-ketocholesterol ratio is a crucial determinant for cytotoxicity of oxidized LDL species and oxysterol mixtures, and (iv) the low share of 7-ketocholesterol explains the higher cytotoxicity of MPO/H2O2/nitrite-oxLDL than other forms of oxidized LDL. The dietary polyphenol (-)-epicatechin inhibited not only formation but also cytotoxic actions of both oxLDL and oxysterols.

Catechin↗
PubMed2006

Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species.

Myofibroblasts, pivotal for tumor progression, populate the microecosystem of reactive stroma. Using an in vitro tumor-stroma model of skin carcinogenesis, we report here that tumor-cell-derived transforming growth factor beta1 (TGFbeta1) initiates reactive oxygen species-dependent expression of alpha-smooth muscle actin, a biomarker for myofibroblastic cells belonging to a group of late-responsive genes. Moreover, protein kinase C (PKC) is involved in lipid hydroperoxide-triggered molecular events underlying transdifferentiation of fibroblasts to myofibroblasts (mesenchymal-mesenchymal transition, MMT). In contrast to fibroblasts, myofibroblasts secrete large amounts of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), resulting in a significant increase in the invasive capacity of tumor cells. The thiol N-acetyl-L-cysteine, the micronutrient selenite as well as selenoprotein P and the lipid peroxidation inhibitors alpha-tocopherol and butylated hydroxytoluene significantly lower both the number of TGFbeta1-initiated myofibroblasts and the secretion of HGF, VEGF and IL-6, correlating with a diminished invasive capacity of tumor cells. This novel concept of stromal therapy, namely the protection of stromal cells against the dominating influence of tumor cells in tumor-stroma interaction by antioxidants and micronutrients, may form the basis for prevention of MMT in strategies for chemoprevention of tumor invasion.

Acetylcysteine↗
PubMed2006

Activation of ErbB2 by 2-methyl-1,4-naphthoquinone (menadione) in human keratinocytes: role of EGFR and protein tyrosine phosphatases.

Activation of ErbB receptor tyrosine kinases triggers multiple signaling pathways that regulate cellular proliferation and survival. We here demonstrate that ErbB2 is activated via the epidermal growth factor receptor (EGFR) upon exposure of cultured human keratinocytes to 2-methyl-1,4-naphthoquinone (menadione). Both ErbB2 and EGFR are shown to be regulated by protein tyrosine phosphatases that are inhibited by menadione, giving rise to the hypothesis that phosphatase inhibition by menadione may result in a net activation of EGFR and an enhanced ErbB2 phosphorylation. Isolated PTP-1B, a protein tyrosine phosphatase known to be associated with ErbB receptors, is demonstrated to be inhibited by menadione.

Cells, Cultured↗
PubMed2006

Solar-simulated radiation induces secretion of IL-6 and production of isoprostanes in human skin in vivo.

Cytokines represent an integral part of the large group of mediators involved in dermal inflammation. In this in vivo study, ultraviolet light which is one of the major environmental factors affecting cytokine release patterns in the skin was employed. The effects of repeated versus one-time irradiation with solar-simulated ultraviolet light was studied regarding the secretion of proinflammatory cytokines with a Bio-Plex cytokine assay using suction blisters as a model for localized inflammatory processes. The IL-6 concentration increased markedly after 24 h in skin areas irradiated with a twofold minimal erythemal dose (MED) compared to areas challenged repeatedly with 0.3 MED. In addition, we investigated the concentration of 8-isoprostane in the suction blister fluid as a marker of lipid peroxidation due to a UV-induced increase in free radical production. 8-Isoprostane was increased immediately after treatment but declined after 24 h with the exception of the skin area exposed to 2 MED. The differential expression and release of cytokines, and the extent of oxidative damage might therefore depend on the dose and regimen of exposure to solar-simulated radiation.

Adult↗
PubMed2006

(-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans.

Epidemiological and medical anthropological investigations suggest that flavanol-rich foods exert cardiovascular health benefits. Endothelial dysfunction, a prognostically relevant key event in atherosclerosis, is characterized by a decreased bioactivity of nitric oxide (NO) and impaired flow-mediated vasodilation (FMD). We show in healthy male adults that the ingestion of flavanol-rich cocoa was associated with acute elevations in levels of circulating NO species, an enhanced FMD response of conduit arteries, and an augmented microcirculation. In addition, the concentrations and the chemical profiles of circulating flavanol metabolites were determined, and multivariate regression analyses identified (-)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as independent predictors of the vascular effects after flavanol-rich cocoa ingestion. A mixture of flavanols/metabolites, resembling the profile and concentration of circulating flavanol compounds in plasma after cocoa ingestion, induced a relaxation in preconstricted rabbit aortic rings ex vivo, thus mimicking acetylcholine-induced relaxations. Ex vivo flavanol-induced relaxation, as well as the in vivo increases in FMD, were abolished by inhibition of NO synthase. Oral administration of chemically pure (-)-epicatechin to humans closely emulated acute vascular effects of flavanol-rich cocoa. Finally, the concept that a chronic intake of high-flavanol diets is associated with prolonged, augmented NO synthesis is supported by data that indicate a correlation between the chronic consumption of a cocoa flavanol-rich diet and the augmented urinary excretion of NO metabolites. Collectively, our data demonstrate that the human ingestion of the flavanol (-)-epicatechin is, at least in part, causally linked to the reported vascular effects observed after the consumption of flavanol-rich cocoa.

Administration, Oral↗
PubMed2006

Involvement of selenoprotein P in protection of human astrocytes from oxidative damage.

Selenoprotein P (SeP) is a highly glycosylated, selenium-rich plasma protein. Aside from its role as selenium carrier protein, an antioxidative function of SeP has been suggested. Astrocytes, which detoxify reactive oxygen species in the brain, were described as potential target cells of SeP. We investigated the expression of SeP in human astrocytes and its involvement in the protection of these cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage. We show that primary human astrocytes and the human astrocytoma cell line MOG-G-CCM express SeP as an unglycosylated protein, which is not secreted. SeP expression in astrocytes is constitutive. Preincubation of astrocytes with hepatocyte-derived SeP mimicks the protective effect of low-molecular-weight selenocompounds such as sodium selenite or selenomethionine against oxidative damage, shielding astrocytes from t-BHP-induced cytotoxicity. Selenium supplementation of astrocytes counteracts oxidative stress via an increase in expression and activity of the selenoenzyme cytosolic glutathione peroxidase (cGPx). Furthermore, specific downregulation of SeP expression by small interfering RNA decreases cell viability of human astrocytes and makes them more susceptible to t-BHP-induced cytotoxicity. Our results implicate an antioxidant activity of constitutively expressed SeP in selenium-deficient astrocytes, while during adequate selenium supply the enhanced protection against oxidative stress is exerted by cGPx.

Antioxidants↗
PubMed2006

Selenoprotein P protects endothelial cells from oxidative damage by stimulation of glutathione peroxidase expression and activity.

A major fraction of the essential trace element selenium circulating in human blood plasma is present as selenoprotein P (SeP). As SeP associates with endothelial membranes, the participation of SeP in selenium-mediated protection against oxidative damage was investigated, using the human endothelial cell line Ea.hy926 as a model system. Hepatocyte-derived SeP prevented tert-butylhydroperoxide (t-BHP)-induced oxidative cell death of Ea.hy926 cells in a similar manner as did sodium selenite, counteracting a t-BHP-induced loss of cellular membrane integrity. Protection was detected after at least 10 h of SeP supplementation and it peaked at 24 h. SeP time-dependently stimulated the expression of cytosolic glutathione peroxidase (cGPx) and increased the enzymatic activities of glutathione peroxidase (GPx) and thioredoxin reductase (TR). The cGPx inhibitor mercaptosuccinate as well as the gamma-glutamylcysteine synthetase inhibitor buthionine sulfoximine counteracted the SeP-mediated protection, while the TR inhibitors cisplatin and auranofin had no effect. The presented data suggest that selenium supplementation by SeP prevents oxidative damage of human endothelial cells by restoring expression and enzymatic activity of GPx.

Buthionine Sulfoximine↗
PubMed2006

Myeloperoxidase-mediated LDL oxidation and endothelial cell toxicity of oxidized LDL: attenuation by (-)-epicatechin.

Recent data suggest an inverse epidemiological association between intake of flavanol-rich cocoa products and cardiac mortality. Potential beneficial effect of cocoa may be attributed to flavanol-mediated improvement of endothelial function, as well as to enhancement of bioavailability and bioactivity of nitric oxide in vivo. ( - )-Epicatechin is one bioactive flavanol found in cocoa. This review deals with protective actions of ( - )-epicatechin on two key processes in atherogenesis, oxidation of LDL and damage to endothelial cell by oxidized LDL (oxLDL), with emphasis on data from this laboratory. ( - )-Epicatechin not only abrogates or attenuates LDL oxidation but also counteracts deleterious actions of oxLDL on vascular endothelial cells. These protective actions are only partially shared by other vasoprotective agents such as vitamins C and E or aspirin. Thus, ( - )-epicatechin appears to be a pleiotropic protectant for both LDL and endothelial cells.

Antioxidants↗
PubMed2006

Long-term ingestion of high flavanol cocoa provides photoprotection against UV-induced erythema and improves skin condition in women.

Dietary antioxidants contribute to endogenous photoprotection and are important for the maintenance of skin health. In the present study, 2 groups of women consumed either a high flavanol (326 mg/d) or low flavanol (27 mg/d) cocoa powder dissolved in 100 mL water for 12 wk. Epicatechin (61 mg/d) and catechin (20 mg/d) were the major flavanol monomers in the high flavanol drink, whereas the low flavanol drink contained 6.6 mg epicatechin and 1.6 mg catechin as the daily dose. Photoprotection and indicators of skin condition were assayed before and during the intervention. Following exposure of selected skin areas to 1.25 x minimal erythemal dose (MED) of radiation from a solar simulator, UV-induced erythema was significantly decreased in the high flavanol group, by 15 and 25%, after 6 and 12 wk of treatment, respectively, whereas no change occurred in the low flavanol group. The ingestion of high flavanol cocoa led to increases in blood flow of cutaneous and subcutaneous tissues, and to increases in skin density and skin hydration. Skin thickness was elevated from 1.11 +/- 0.11 mm at wk 0 to 1.24 +/- 0.13 mm at wk 12; transepidermal water loss was diminished from 8.7 +/- 3.7 to 6.3 +/- 2.2 g/(h x m2) within the same time frame. Neither of these variables was affected in the low flavanol cocoa group. Evaluation of the skin surface showed a significant decrease of skin roughness and scaling in the high flavanol cocoa group compared with those at wk 12. Dietary flavanols from cocoa contribute to endogenous photoprotection, improve dermal blood circulation, and affect cosmetically relevant skin surface and hydration variables.

Adult↗
PubMed2006

Endothelial function, nitric oxide, and cocoa flavanols.

Endothelial dysfunction is the pathophysiologic principle involved in the initiation and progression of arteriosclerosis, thus endothelial function serves as a "barometer" for cardiovascular health that can be used for the evaluation of new therapeutic strategies. This review provides an introduction to the concept of endothelial dysfunction, and it explores the importance of this prognostic marker in the context of clinical, dietary interventions in humans. Moreover, we summarize and evaluate the findings of various clinical trials that demonstrated an improvement of endothelial dysfunction in subjects with cardiovascular risk factors after the acute and chronic consumption of flavanol-rich foods, including cocoa products, red wine, and tea.

Cacao↗
PubMed2006

Nitrite, a naturally occurring precursor of nitric oxide that acts like a 'prodrug'.

There are enzymatic and non-enzymatic mechanisms that generate NO* from nitrite in blood, stomach, saliva, urine and skin. In blood vessels, nitrite-derived NO* can provide protection via compensatory vasodilation during hypoxia, and in various body fluids it may have antibacterial activity. In the skin, nitrite-derived NO* may contribute to skin tanning, as well as to protection against UV-induced cell damage. Current knowledge on nitrite acting like an NO* 'prodrug' is presented, emphasizing the role of nitrite in skin.

Animals↗
PubMed2005

Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers.

OBJECTIVES: This study was designed to assess the effect of flavanol-rich food on the circulating pool of bioactive nitric oxide (NO) and endothelial dysfunction in smokers. BACKGROUND: Studies suggest that smoking-related vascular disease is caused by impaired NO synthesis and that diets rich in flavanols can increase bioactive NO in plasma. METHODS: In smokers (n = 11), the effects of flavanol-rich cocoa on circulating NO species in plasma (RXNO) measured by reductive gas-phase chemiluminescence and endothelial function as assessed by flow-mediated dilation (FMD) were characterized in a dose-finding study orally administering cocoa containing 88 to 370 mg flavanols and in a randomized double-blind crossover study using 100 ml cocoa drink with high (176 to 185 mg) or low (<11 mg) flavanol content on two separate days. In addition to cocoa drink, ascorbic acid and NO-synthase inhibitor L-NMMA (n = 4) were applied. RESULTS: There were significant increases in RXNO (21 +/- 3 nmol/l to 29 +/- 5 nmol/l) and FMD (4.5 +/- 0.8% to 6.9 +/- 0.9%, each p < 0.05) at 2 h after ingestion of 176 to 185 mg flavanols, a dose potentially exerting maximal effects. These changes correlated with increases in flavanol metabolites. Cocoa-associated increases in RXNO and FMD were reversed by L-NMMA. Ascorbic acid had no effect. CONCLUSIONS: The circulating pool of bioactive NO and endothelium-dependent vasodilation is acutely increased in smokers following the oral ingestion of a flavanol-rich cocoa drink. The increase in circulating NO pool may contribute to beneficial vascular health effects of flavanol-rich food.

Adult↗
PubMed2005

Lycopene-rich products and dietary photoprotection.

Plant constituents such as carotenoids and flavonoids are involved in the light-protecting system in plants and contribute to the prevention of UV damage in humans. As micronutrients they are ingested with the diet and are distributed into light-exposed tissues where they provide systemic photoprotection. beta-Carotene is an endogenous photoprotector, and its efficacy to prevent UV-induced erythema formation has been demonstrated in intervention studies. Lycopene is the major carotenoid of the tomato and is a very efficient singlet oxygen quencher in the group of carotenoids. Following ingestion of lycopene or tomato-derived products rich in lycopene, photoprotective effects have been demonstrated. After 10-12 weeks of intervention a decrease in the sensitivity towards UV-induced erythema was observed in volunteers. Dietary carotenoids may contribute to life-long protection against harmful UV radiation.

Carotenoids↗