Micronutrients in signalling and disease prevention (Group Stahl)

Prof. Dr. rer. nat. Wilhelm Stahl

Universitätsstr. 1
22.03.04
40225 Düsseldorf

Primary and secondary antioxidant defense

Reactive oxygen species (ROS) such as superoxide or hydrogen peroxide are intentionally generated under physiological conditions to promote an oxidative tone important for redox signaling. The term oxidative Eustress (eu- greek – proper) was coined in context with these signaling pathways. External stressors and/or excessive endogenous ROS production may increase the oxidative burden leading to cellular damage. Specific enzymes and antioxidant compounds including dietary polyphenols and carotenoids provide a primary network of defense. Adaptation to oxidative stress comprises a secondary defense line which is responsive to endogenous and exogenous stimuli. Reactive dietary constituents, UV-irradiation, or electrophilic agents trigger the expression of the cellular defense systems thus fostering ROS scavenging or repair of molecular damage.

In this context our research is focused on the stimulatory effects of specific dietary polyphenols (chalcones) and metabolites of lipids (apo-carotenals and lipid-aldehydes) on the Nrf2/Keap1 system. Prevention of damage by micronutrients comprises primary defense due to their antioxidant activity and secondary defense mediated by the stimulation of an adaptive response.

Photoprotection

Exposure to UV-light is the major cause for skin cancer and responsible for skin aging. In addition to the use of topical sunscreens endogenous photoprotection was suggested as an additional measure. This concept comprised delivery of suitable micronutrients with the diet which are absorbed and transported to skin where they develop their photoprotective properties.

We investigate UV-protective activities of several classes of micronutrients including carotenoids and flavonoids at the molecular and cellular level. In human intervention studies we have shown that dietary products rich in photoprotective compounds provide protection against UV-induced erythema (sun burn) and modulate skin properties related to skin health and aging. Tomato-, green tea-, and cocoa-derived food proved to be active in this context. The biological activities are attributed to UV-absorbing and antioxidant properties of specific constituents like ß-carotene, lutein, lycopene, phytoene, phytofluene, epicatechin, or naringenin.

CO-dependent signaling

Among the enzymes which are induced as secondary response to oxidative stress is the hemeoxygenase-1 (HO-1) which metabolizes heme to biliverdin, ferrous iron and carbon monoxide. The redox system biliverdin/bilirubin is thought to contribute to antioxidant defense. HO-1 is also induced by electrophilic substances such as dietary polyphenols like naringenin-chalcone, cardamonin or isoliquiretigenin which address the Nrf2-Keap1 system. Molecular basis of activation is an electrophilic reaction of alpha-beta unsaturated structures with thiol groups in the sensitizing protein. 

In addition to the mechanism of HO-1 activation by dietary chalcones and the studies on the bioavailability of these compounds in humans we are interested in signaling effects of the coproduct carbon monoxide (CO). In this context we study intracellular formation of CO, its production from CO-releasing molecules and biological effects resulting from the interaction of CO with heme-carrying structures within the cell. Especially, regulatory effects on the respiratory chain with consequences on basic energy metabolism are of interest.

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