Peter Maria ECKL started his scientific career in the late 1970s at the Paris-Lodron University of Salzburg working in the field of radiation research [...]

Summary Freie Radikale sind Atome oder Moleküle mit mindestens einem ungepaarten Valenzelektron.Radikale, etwa Sauerstoff-Radikale oder auch reaktive Sauerstoffspezies (ROS) genannt, spielen bei einer Vielzahl biologischer Prozesse eine wichtige Rolle. Liegen sie im Übermaß im Körper vor, kommt es zu oxidativem Stress. Hierbei werden die Zellen und Gewebe im Körper durch freie Radikale zerstört. Dies kann verschiedene Erkrankungen mit begünstigen, wie zum Beispiel Krebserkrankungen oder Typ-2-Diabetes mellitus. Freie Radikale entstehen durch Belastungen aus der Umwelt, zum Beispiel Chemie- oder Strahlenexposition, aber auch durch zu viel Stress, Nikotin- und Alkoholkonsum. Antioxidantien neutralisieren freie Radikale und können so Zellschäden vorbeugen. Sie finden sich zum Beispiel in verschiedenen Obst- und Gemüsesorten. Durch Bewegung und Kaltreize lässt sich zudem die Produktion körpereigener Antioxidantien ankurbeln.

SummaryBaden und Wasseranwendungen haben für den Menschen seit langer Zeit kulturelle und gesundheitliche Bedeutung. Dabei spielen Kältereize wie bei der Kneipp-Therapie oder das Winterbaden eine besondere Rolle für die Durchblutung, die Immunabwehr, aber auch speziell zur Bildung von Antioxidantien.

Rationale: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to impaired pancreatic function and therefore reduced intestinal absorption of lipids and fat-soluble vitamins especially in patients with CF developing pancreatic insufficiency (PI). Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown. Objectives: To investigate the course of plasma vitamin A and E in patients with CF under LUM/IVA therapy. Methods: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy. Results: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p < 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p < 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p < 0.01). Conclusions: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF.

Evidence suggests that the increased production of free radicals and reactive oxygen species lead to cellular aging. One of the consequences is lipid peroxidation generating reactive aldehydic products, such as 4-hydroxynonenal (HNE) that modify proteins and form adducts with DNA bases. To prevent damage by HNE, it is metabolized. The primary metabolic products are the glutathione conjugate (GSH-HNE), the corresponding 4-hydroxynonenoic acid (HNA), and the alcohol 1,4-dihydroxynonene (DHN). Since HNE metabolism can potentially change during in vitro aging, cell cultures of primary human dermal fibroblasts from several donors were cultured until senescence. After different time points up to 30 min of incubation with 5 µM HNE, the extracellular medium was analyzed for metabolites via liquid chromatography coupled with electrospray ionization mass spectrometry (LC/ESI-MS). The metabolites appeared in the extracellular medium 5 min after incubation followed by a time-dependent increase. But, the formation of GSH-HNL and GSH-DHN decreased with increasing in vitro age. As a consequence, the HNE levels in the cells increase and there is more protein modification observed. Furthermore, after 3 h of incubation with 5 µM HNE, younger cells showed less proliferative capacity, while in older cells slight increase in the mitotic index was noticed.

There exists a multitude of pharmaceutical drugs which effects include the formation of oxidants and, therefore increased lipid peroxidation or which at least deteriorate the redox balance within cells, tissues or organs. In many of those cases, the generated oxidants are an important part of the drug efficiency. Well known examples of those drugs and xenobiotics are anticancerogenic drugs (chemotherapeutics), antihelminthics, dermatics, tuberculostatics and various antibiotics. In anticholinergics and spasmolytics an increased generation of oxidants and lipid peroxides seems to be rather a side effect than a specific pharmacological effect. That seems true also for all xenobiotics stimulating the catecholamine formation. The increased free radical generation and lipid peroxidation by chemotherapeutic drugs and cytostatics, by many antibiotics, tuberculostatics, and dermatics contributes to therapy of different types of cancer, microbially induced infectious diseases – by bacteria, viruses, or fungi – autoaggression, or psoriasis. Doxorubicin/daunorubicin is an example for anthracyclin-antibiotics used in the therapy of malignant tumors such as breast and lung tumors, gynecological sarcomas, lymphomas, and hepatocellular carcinoma (HCC). Within its fine mechanisms of this substance one finds intercalant transcription inhibiting effectivity, inhibition of topoisomerase II activity, and promoting an overwhelming formation of oxidants and lipid peroxidation products. Last mechanism leads also to strong side effects of doxorubicin such as depression of the bone marrow and cardiotoxicity. In contrast other pharmaceutical drugs reduce the concentration of oxidants or even directly deliver antioxidants, such as antiallergics, nootropics (antidementives), geriatrics, antiphlogistics, prostaglandins and prostacyclins such as iloprost, drugs influencing gout or hyperuricemia such as inhibitors of purine degradation, roborantia and vitamine preparatives, also anticoagulative acting drugs, and hypnotics. The use of GSH can be useful, since the dysfunction of the GSH redox system appears to cause a variety of diseases including neurodegenerative disorders. However, the effectiveness of GSH as therapeutic agent is limited because of its low bioavailability. Another aspect of the formation of oxidants and increased lipid peroxidation during and after application of pharmaceutical drugs is the detoxification of drugs preferably by the liver. The metabolic reactions involved in the detoxification of drugs and further xenobiotics present one of the main sources for the generation of oxidants in humans and animals treated with pharmaceutical drugs. The cytochrome P450 systems plays an important role within total oxygen radical and oxidant generation in human body.

4-Hydroxynonenal (HNE) is one of the quantitatively most important products of lipid peroxidation. Due to its high toxicity it is quickly metabolized, however, a small share of HNE avoids enzymatic detoxification and reacts with biomolecules including proteins. The formation of HNE-protein-adducts is one of the accompanying processes in oxidative stress or redox disbalance. The modification of proteins might occur at several amino acids side chains, leading to a variety of products and having effects on the protein function and fate. This review summarizes current knowledge on the formation of HNE-modified proteins, their fate in mammalian cells and their potential role as a damaging agents during oxidative stress. Furthermore, the potential of HNE-modified proteins as biomarkers for several diseases are highlighted.

4-Hydroxynonenal (HNE) is one of the quantitatively most important products of lipid peroxidation. Due to its high toxicity it is quickly metabolized, however, a small share of HNE avoids enzymatic detoxification and reacts with biomolecules including proteins.

Background: Aging and chronic kidney disease (CKD) are associated with bone mineral metabolism disorders, in addition to disarrangement of trabeculae structure and bone architecture. Increased alkaline phosphatase (ALP) and parathyroid hormone (PTH) have been related with abnormal bone turn over. Lycopene, a plant derived micronutrient, has strong quenching and free radical scavenging attitude. Objectives: This study aimed to evaluate the effects of lycopene and calcifediol (25 OH D3) based Integrated Medicine on ALP, PTH and oxidative stress. Methods: In octogenarians, nonagenarians and centenarians with chronic kidney disease (GFR :45 ±10,4 ml/min/1,73 m2), vitamin D deficiency and abnormal ALP, PTH blood values, the effects of daily lycopene supplementation on blood oxysterols and on 4-hydroxy-2,3-trans- nonenal (4-HNE) as markers of oxidative stress were evaluated. The effects of calcifediol administration together with daily lycopene supplementation on PTH and ALP blood concentrations were also investigated. Results: Daily lycopene supplementation induced a reduction of oxysterols (α-triol: 0.40 ± 0.07 μg / L vs 0.32 ± 0, 04 μg / L and β-epoxi cholesterol: 5.3 ± 1.3 μg / L vs 3.7 ± 0.6 μg / L) but not of 4-HNE (0.27 ± 0.18 nmol / L vs 0.25 ± 0.20 nmol / L). Vitamin D added to lycopene for two weeks decreased the blood values of ALP (106 ± 40 U / L vs 69 ± 19 U / L) and PTH (108 ±42 pg/ml vs 66± 21 pg/ml). Conclusion: Tomato derived lycopene, with daily supplements, decreased cholesterol oxidation products. Calcifediol and vegetable derived antioxidant daily supplementations were associated to normalization of ALP and PTH. Keywords: oxysterols; 4-hydroxynonenal; lycopene; alkaline phosphatase; parathyroid hormone; chronic kidney disease (CKD)

Patients with cystic fibrosis (CF) show decreased plasma concentrations of antioxidants due to malabsorption of lipid soluble vitamins and consumption by chronic pulmonary inflammation. β-Carotene is a major source of retinol and therefore is of particular significance in CF. The aim of this study was to investigate the effect of daily intake of red palm oil (RPO) containing high amounts of β-carotene on the antioxidant levels in CF patients. Sixteen subjects were recruited and instructed to enrich their food with 2 to 3 tablespoons of RPO (~1.5 mg of β-carotene) daily over 8 weeks. Carotenoids, retinol, and α-tocopherol were measured in plasma at baseline and after intervention. In addition β-carotene, lycopene, α-tocopherol, and vitamin C were measured in buccal mucosa cells (BMC) to determine the influence of RPO on antioxidant tissue levels. Eleven subjects completed the study properly. Plasma β-carotene, retinol, and α-carotene of these patients increased, but plasma concentrations of other carotenoids and α-tocopherol as well as concentrations of β-carotene, lycopene, α-tocopherol, and vitamin C in BMC remained unchanged. Since RPO on a daily basis did not show negative side effects the data suggest that RPO may be used to elevate plasma β-carotene in CF.

This review on recent research advances of the lipid peroxidation product 4-hydroxy-nonenal (HNE) has four major topics: I. the formation of HNE in various organs and tissues, II. the diverse biochemical reactions with Michael adduct formation as the most prominent one, III. the endogenous targets of HNE, primarily peptides and proteins (here the mechanisms of covalent adduct formation are described and the (patho-) physiological consequences discussed), and IV. the metabolism of HNE leading to a great number of degradation products, some of which are excreted in urine and may serve as non-invasive biomarkers of oxidative stress.

Oxidative stress is often considered as a causative factor in carcinogenesis. In addition, current knowledge recognizes oxidative stress as a mechanism by which various cancer therapies act against cancer. To ameliorate the side effects of cancer therapy, many of the patients suffering from cancer are subject to adjuvant therapy, which often implies antioxidant supplementation. Yet, the benefits of such adjuvant treatments are still uncertain owing to the lack of appropriate integrative and personalized medical approach. In particular, reactive oxygen species formed during oxidative stress and products of lipid peroxidation are not only cytotoxic, but can modulate signal transduction in cells, which also behave similar to individuals under stress. Accordingly, pro-oxidants and antioxidants might be considered as modifiers of specific cellular redox signaling. Therefore, there is a need to evaluate the potential benefits of antioxidant supplements in healthy persons, and in particular in cancer patients during therapy. Our review will present a summary of the existing knowledge regarding the effects of various antioxidants in cancer therapies, focusing on cellular adaptation to oxidative stress interacting with redox signaling transduction pathways thereby influencing cell growth.

The aspects of Kneipp therapy and of classical natural medicine are characterized by a wide spectrum of effects and efficacy. We suggest that the basic mechanisms of such classical types of therapy are elementary and unique being based on ubiquitous substances and biochemical reactions. In this regard, we investigated the reactive oxygen species (ROS), lipid peroxidation (LPO) products, and antioxidative protective mechanisms. The balance between prooxidative and antioxidative mechanisms - characterizing the so-called oxidative stress - exerts high impact on the status of health, disease, wellbeing, and fitness. The review on all five parts of Kneipp therapy - hydrotherapy, phytotherapy, nutritional therapy, exercise therapy, and regulatory therapy - supplies distinct arguments for improved coping with oxidative stress by means of all forms of Kneipp therapy. It is clearly demonstrated that the reduced formation of free oxygen radicals and/or the increased removal of these potentially toxic substances is a combining element in natural medicine.

Die Kneipp'schen Therapieverfahren und damit zentrale Inhalte der klassischen Naturheilverfahren zeichnen sich durch ein breites Wirkungsspektrum aus. Es ist naheliegend, dass diesen Verfahren auch gemeinsame Wirkungsmechanismen auf der Basis ubiquitärer Substanzen und Reaktionsmechanismen zugrunde liegen. Hier wurden die Wirkungen von reaktiven Sauerstoffspezies (ROS), von Lipid peroxidations(LPO)-Produkten und von antioxidativen Schutzmechanismen untersucht. Die Bilanz von prooxidativen und antioxidativen Prozessen, die das Mass für einen oxidativen Stress angibt, hat eine immense Auswirkung auf Gesundheit, Krankheit, Wohlbefinden und Leistungsfähigkeit. Die Übersicht über Resultate zu allen fünf Säulen der Kneipp-Therapie - Hydrotherapie, Phytotherapie, Ernährungstherapie, Bewegungstherapie und Ordnungstherapie - liefert klare Hinweise auf die bessere Bewältigung von oxidativem Stress durch die Kneipp'schen Therapieformen. Es wird deutlich aufgezeigt, dass eine verminderte Bildung freier Radikale und/oder deren bessere Bewältigung ein verbindendes Element der klassischen Naturheilverfahren ist.