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Biomedical subjects

Helmut Sies

Publications and source records attributed to Helmut Sies.

At least 55 records · Page 3Linked to original sources
PubMed2004

Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia.

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of beta-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature-vascular or degenerative-dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.

Aged↗
PubMed2004

Paracrine effect of TGF-beta1 on downregulation of gap junctional intercellular communication between human dermal fibroblasts.

Disruption of gap junctional intercellular communication (GJIC) is associated with tumor progression during multistage carcinogenesis. A coordinated interaction of epithelial tumor cells with the stromal environment via growth factors is a prerequisite for tumor invasion. Here, the involvement of growth factors in downregulation of homologous GJIC of dermal fibroblasts, used as model for stromal cells, was examined. Tumor cell derived transforming growth factor-beta1 (TGF-beta1), having oncogenic activities at late stages of carcinogenesis, was identified as being responsible for downregulation of GJIC via an increase in the level of reactive oxygen species in stromal fibroblasts. Lowering the level of reactive oxygen species by antioxidants, such as the cell-permeable N-acetyl-L-cysteine, prevented TGF-beta1-mediated downregulation of intercellular communication between confluent fibroblasts.

Cell Communication↗
PubMed2004

Carotenoids and UV protection.

Photooxidative processes play a role in the pathobiochemistry of various disorders of light-exposed tissue. After irradiation of skin with UV light, erythema (sunburn) is an initial effect suitable for monitoring the direct biological response. Carotenoids are efficient in photoprotection, scavenging singlet oxygen and peroxyl radicals. Intervention studies with supplements or a carotenoid-rich diet documented efficiency in systemic photoprotection, measuring a decreased sensitivity against UV-induced erythema. For successful intervention, treatment with carotenoids is needed for a period of at least ten weeks. An increased consumption of carotenoids may contribute to life-long protection against UV-induced damage.

Animals↗
PubMed2004

Thioredoxin secreted upon ultraviolet A irradiation modulates activities of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in human dermal fibroblasts.

Regulation of the balance of matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-2) by thioredoxin (Trx) was investigated in human dermal fibroblasts. Expression and secretion of Trx and Trx reductase 1 (TR1) was increased after ultraviolet (UV) A irradiation. A significant increase in proMMP-2 activity and a decrease of TIMP-2 activity in supernatants of UVA-irradiated fibroblasts were observed in gelatin and reverse zymography compared to non-irradiated fibroblasts. Removal of Trx or TR1 by immunoprecipitation diminished these changes in proMMP-2 activity. Incubation with 5, 5'-dithio-bis-2-nitrobenzoic acid (DTNB) also suppressed these changes. Incubation with recombinant Trx or TR decreased TIMP-2 activity and increased MMP-2 activity. UVA-irradiated fibroblasts, transiently transfected with a dominant-negative mutant or wild-type Trx, showed down- or upregulation of proMMP-2 activities, respectively, without significant change of protein amount. In conclusion, thioredoxin secreted by UVA irradiation is involved in the regulation of MMP-2 and TIMP-2 activities through its redox activity in human dermal fibroblasts.

Fibroblasts↗
PubMed2004

Contribution of UVB and UVA to UV-dependent stimulation of cyclooxygenase-2 expression in artificial epidermis.

Both UVB (280-320 nm) and UVA (320-400 nm) radiation lead to an enhanced expression of cyclooxygenase-2 (COX-2) in epidermal cells in various in-vitro and in-vivo models. It is demonstrated here that the expression of COX-2 is induced in artificial human epidermis exposed to simulated solar light (>290 nm). Employing filters eliminating specified regions from the simulated solar spectrum, the UVB and UVA-2 (320-350 nm) regions are shown to fully account for induction of COX-2 mRNA and protein as well as the enhanced production of prostaglandin E(2) after irradiation. At the protein level, approximately 70% of the total induction by solar light is due to light in the UVA-2 region. UVA-1 (350-400 nm), visible light and IR radiation are practically ineffective. COX-2 induction by simulated solar light is attenuated in the presence of inhibitors of p38(MAPK) or of c-Jun-N-terminal kinases (JNK), whereas COX-2 induction by UVA is blocked only by inhibition of JNK. UV-induced COX-2 expression is not affected by inhibition of the MEK 1,2/ERK 1,2 pathways.

Cyclooxygenase 2↗
PubMed2004

Selenoprotein P protects low-density lipoprotein against oxidation.

Selenoprotein P (SeP) is an extracellular glycoprotein with 8-10 selenocysteines per molecule, containing approximately 50% of total selenium in human serum. An antioxidant function of SeP has been postulated. In the present study, we show that SeP protects low-density lipoproteins (LDL) against oxidation in a cell-free in-vitro system. LDL were isolated from human blood plasma and oxidized with CuCl2, 2,2'-azobis(2-amidinopropane) (AAPH) or peroxynitrite in the presence or absence of SeP, using the formation of conjugated dienes as parameter for lipid peroxidation. SeP delayed the CuCl2- and AAPH-induced LDL oxidation significantly and more efficiently than bovine serum albumin used as control. In contrast, SeP was not capable of inhibiting peroxynitrite-induced LDL oxidation. The protection of LDL against CuCl2- and AAPH-induced oxidation provides evidence for the antioxidant capacity of SeP. Because SeP associates with endothelial membranes, it may act in vivo as a protective factor inhibiting the oxidation of LDL by reactive oxygen species.

Amidines↗
PubMed2004

Nutritional protection against skin damage from sunlight.

The concept of systemic photoprotection by dietary means is gaining momentum. Skin is continuously exposed to ultraviolet (UV) radiation, the major cause of skin disorders such as sunburn, photodamage, and nonmelanoma skin cancer. Most of the erythemal annual UV dose is encountered under nonvacation conditions, when no sunscreen is applied. In the absence of topically added compounds, skin protection depends solely on endogenous defense. Micronutrients can act as UV absorbers, as antioxidants, or can modulate signaling pathways elicited upon UV exposure. UV-induced erythema is a suitable parameter to assess photoprotection. Dietary protection is provided by carotenoids, tocopherols, ascorbate, flavonoids, or n-3 fatty acids, contributing to maintenance resistance as part of lifelong protection.

Antioxidants↗
PubMed2004

Induction of MMP-10 and MMP-1 in a squamous cell carcinoma cell line by ultraviolet radiation.

Ultraviolet radiation may cause non-melanoma skin cancer by genetic and epigenetic events. In this study, we investigated in a squamous cell carcinoma cell line, SCL-1, whether UV irradiation modulates the expression of matrix metalloproteinases, known to be involved in tumor progression and metastasis by degradation of extracellular matrix components. UVA or UVB irradiation of SCL-1 resulted in a rapid transcriptional up-regulation and increased secretion of two members of the matrix metalloproteinase family, MMP-10 (stromelysin-2) and MMP-1 (interstitial collagenase). The increase in MMP-10 steady-state mRNA levels was detected 1 hour after UVA and 4 h after UVB irradiation, whereas MMP-1 was upregulated 4 h after UVA and 16 h after UVB irradiation of tumor cells. UV-induced phosphorylation of extracellular regulated kinases (ERK-1/2) and p38 stress kinase and increased binding of AP-1 transcription factor preceded the rapid stimulation of MMPs in SCL-1 cells. Incubation of cells with the MEK1/2 inhibitor U0126 or the p38 inhibitor SB202190 abolished the UVA and UVB mediated induction of MMP-1 and MMP-10. In conclusion, this study shows that UV irradiation of squamous cell carcinoma results in a rapid up-regulation of MMPs. Our results suggest that the time course of induction of target genes, like MMPs, differs between cell types depending on the stimulus.

Animals↗
PubMed2004

Oxidative modification of low-density lipoprotein: lipid peroxidation by myeloperoxidase in the presence of nitrite.

Oxidative modification of low-density lipoprotein (LDL) is a pivotal process in early atherogenesis and can be brought about by myeloperoxidase (MPO), which is capable of reacting with nitrite, a NO metabolite. We studied MPO-mediated formation of conjugated dienes in isolated human LDL in dependence on the concentrations of nitrite and chloride. This reaction was strongly stimulated by low concentrations (5-50 microM) of nitrite which corresponds to the reported concentration in the arterial vessel wall. Under these conditions no protein tyrosine nitration occurred; this reaction required much higher nitrite concentrations (100 microM-1 mM). Chloride neither supported lipid peroxidation alone nor was its presence mandatory for the effect of nitrite. We propose a prominent role of lipid peroxidation for the proatherogenic action of the MPO/nitrite system, whereas peroxynitrite may be competent for protein tyrosine nitration of LDL. Monomeric and oligomeric flavan-3-ols present in cocoa products effectively counteracted, at micromolar concentrations, the MPO/nitrite-mediated lipid peroxidation of LDL. Flavan-3-ols also suppressed protein tyrosine nitration induced by MPO/nitrite or peroxynitrite as well as Cu2+-mediated lipid peroxidation of LDL. This multi-site protection by (-)-epicatechin or other flavan-3-ols against proatherogenic modification of LDL may contribute to the purported beneficial effects of dietary flavan-3-ols for the cardiovascular system.

Dose-Response Relationship, Drug↗
PubMed2003

Evaluation of sulfur, selenium and tellurium catalysts with antioxidant potential.

Oxidative stress is implicated, either directly or indirectly, in the pathology of a range of human diseases. As a consequence, the development of efficient antioxidants for medical use has become increasingly important. We have synthesised a range of structurally related organo-sulfur, -selenium and -tellurium agents and demonstrated that a combination of electrochemical methodology, in vitro assays and cell culture tests can be used to rationalise the antioxidant activity of these catalytic agents. Based on its exceptionally low anodic oxidation potential (Epa) and high activity against the representative oxidative stressors tert-butyl hydroperoxide and peroxynitrite, 4,4'-dihydroxydiphenyltelluride is predicted to be a potent antioxidant. This compound exhibits a correspondingly high activity with a remarkably low IC50 value of 20 nM, when tested in PC12 cell culture using a bioassay indicative of the early stages of Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

Sulfur and selenium: the role of oxidation state in protein structure and function.

Sulfur and selenium occur in proteins as constituents of the amino acids cysteine, methionine, selenocysteine, and selenomethionine. Recent research underscores that these amino acids are truly exceptional. Their redox activity under physiological conditions allows an amazing variety of posttranslational protein modifications, metal free redox pathways, and unusual chalcogen redox states that increasingly attract the attention of biological chemists. Unlike any other amino acid, the "redox chameleon" cysteine can participate in several distinct redox pathways, including exchange and radical reactions, as well as atom-, electron-, and hydride-transfer reactions. It occurs in various oxidation states in the human body, each of which exhibits distinctive chemical properties (e.g. redox activity, metal binding) and biological activity. The position of selenium in the periodic table between the metals and the nonmetals makes selenoproteins ideal catalysts for many biological redox transformations. It is therefore apparent that the chalcogen amino acids cysteine, methionine, selenocysteine, and selenomethionine exhibit a unique biological chemistry that is the source of exciting research opportunities.

Cysteine↗
PubMed2003

The presence of nitrite during UVA irradiation protects from apoptosis.

Nitrite occurs ubiquitously in biological fluids such as blood and sweat, representing an oxidation product of nitric oxide. Nitrite has been associated with a variety of adverse effects such as mutagenicity, carcinogenesis, and toxicity. In contrast, here we demonstrate that the presence of nitrite, but not nitrate, during irradiation of endothelial cells in culture exerts a potent and concentration-dependent protection against UVA-induced apoptotic cell death. Protection is half-maximal at a concentration of 3 mM, and complete rescue is observed at 10 mM. Nitrite-mediated protection is mediated via inhibition of lipid peroxidation in a similar manner as seen with butylated hydroxytoluene, a known inhibitor of lipid peroxidation. Interestingly, nitrite-mediated protection is completely abolished by coincubation with the NO scavenger cPTIO. Using electron paramagnetic resonance (EPR) spectroscopy or Faraday modulation spectroscopy, we directly prove UVA-induced NO formation in solutions containing nitrite. In conclusion, evidence is presented that nitrite represents a protective agent against UVA-induced apoptosis due to photodecomposition of nitrite and subsequent formation of NO.

Apoptosis↗
PubMed2003

UVA-mediated downregulation of MMP-2 and MMP-9 in human epidermal keratinocytes.

While human dermal fibroblasts increase the expression and secretion of distinct matrix metalloproteinases (MMPs) in response to ultraviolet (UV) irradiation, much less is known about regulation of MMPs with regard to normal human epidermal keratinocytes (NHEK). In this in vitro study, the effect of ultraviolet A (UVA) irradiation on gelatinase expression and secretion by NHEK was investigated. Irradiation of NHEK with non-toxic doses of UVA resulted in a dose-dependent downregulation of MMP-2 (gelatinase A) and MMP-9 (gelatinase B). A single dose of 30JUVA/cm(2) lowered MMP-2 activity to 26% and MMP-9 activity to 33% compared with mock-irradiated cells at 24h after irradiation. Downregulation of MMP-2 and MMP-9 steady-state mRNA levels was observed at 4h after UVA irradiation. The inhibitory effect of UVA on gelatinases was mediated by UVA-generated singlet oxygen (1O(2)). These findings suggest an inverse response to UVA irradiation in NHEK than in fibroblasts.

Cells, Cultured↗
PubMed2003

Modulation of homologous gap junctional intercellular communication of human dermal fibroblasts via a paracrine factor(s) generated by squamous tumor cells.

Loss of gap junctional intercellular communication (GJIC) is a characteristic of cancer cells. Since a coordinated interaction of epithelial tumor cells with stromal cells is a prerequisite for tumor invasion and metastasis, the present study was designed to test the hypothesis that skin-derived tumor cells may modulate homologous and heterologous GJIC. While homologous GJIC of human dermal fibroblasts as well as epidermal keratinocytes was detected, no communication was measured between SCL-1 cells derived from squamous cell carcinoma of human skin. Interestingly, co-cultures of dermal fibroblasts and SCL-1 tumor cells in serum-containing medium resulted in a 52-70% lowering of the number of communicating fibroblasts. Furthermore, incubation of confluent fibroblast cultures with serum-free supernatant fractions (20-30 kDa) from tumor cells, termed the 20/30 fraction, lowered the homologous gap junction communication of fibroblasts by >90%. This novel aspect of down-regulated homologous GJIC of dermal fibroblasts, which is reversible, was neither mediated by alteration of the expression of connexin43, the major gap junctional protein of dermal fibroblasts, nor by aberrant localization of connexin43 in the plasma membrane. Furthermore, post-translational modifications of connexins, such as phosphorylation, was not measured by mobility shift studies. Tumor cell-mediated GJIC down-regulation between fibroblasts was suppressed using EGTA-containing serum-free tumor cell-derived supernatants suggesting that calcium ions (Ca2+) might mediate the transduction of this effect. The involvement of Ca2+ in down-regulation of homologous GJIC of fibroblasts was supported by an increase in fluorescence intensity of the intracellular calcium-sensitive indicator Fura-2 upon treatment of fibroblasts with the active 20/30 fraction. In conclusion, these data establish homologous GJIC of (stromal) fibroblasts as a parameter modulated by a paracrine acting factor(s) of epithelial tumor cells during tumor-stroma interaction of skin cells.

Base Sequence↗