5 research outputs found
Selective Inhibition of Human AKR1B10 by n-Humulone, Adhumulone and Cohumulone Isolated from Humulus lupulus Extract
Hop-derived compounds have been subjected to numerous biomedical studies investigating their impact on a wide range of pathologies. Isomerised bitter acids (isoadhumulone, isocohumulone and isohumulone) from hops, used in the brewing process of beer, are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies. However, the closely related reductases AKR1A1 and AKR1B1, which fulfil important roles in the detoxification of endogenous and xenobiotic carbonyl compounds oftentimes crossreact with inhibitors designed to target AKR1B10. Accordingly, there is an ongoing search for selective AKR1B10 inhibitors that do not interact with endogeneous AKR1A1 and AKR1B1-driven detoxification systems. In this study, unisomerised α-acids (adhumulone, cohumulone and n-humulone) were separated and tested for their inhibitory potential on AKR1A1, AKR1B1 and AKR1B10. Also AKR1B10-mediated farnesal reduction was effectively inhibited by α-acid congeners with Ki-values ranging from 16.79 ± 1.33 ”M (adhumulone) to 3.94 ± 0.33 ”M (n-humulone). Overall, α-acids showed a strong inhibition with selectivity (115â»137 fold) for AKR1B10. The results presented herein characterise hop-derived α-acids as a promising basis for the development of novel and selective AKR1B10-inhibitors
Kombinierte Effekte von CO2 und Temperatur auf Wachstum und Photosynthese der marinen Gezeitenrotalge Mastocarpus stellatus (Rhodophyta) (Combined effects of CO2 and temperature on growth and photosynthesis of the marine intertidal red alga Mastocarpus stellatus (Rhodophyta))
Zusammenfassung
In stÀndiger Wechselwirkung begriffen, ergÀnzen sich die Ozeane mit der ErdatmosphÀre zu
einem komplexen, wie hochsensiblen System, welches auf VerÀnderungen verschiedener Art
empfindlich reagiert und dessen Einfluss auf die Lebensbedingungen ĂŒber und unter Wasser
erheblich ist. Steigende Treibhausgasemissionen und der einhergehende Klimawandel sind
aktuelle Herausvorderungen, die unsere Ozeane in ihrer Funktion als Ăkosysteme grundlegend
verĂ€ndern. Seit Beginn der Industrialisierung gelangt ĂŒber den atmosphĂ€rischen Austausch und
mit stetiger steigender Tendenz CO2 in das OberflÀchenwasser der Ozeane, wo es in der Reaktion
mit Wasser KohlensĂ€ure bildet â Ein Prozess der als Ozenversauerung beschrieben wird. Effekte
dieses Vorgangs insbesondere in Kombination mit tiefgreifenden TemperaturverÀnderungen
können vielseitige Folgen fĂŒr einzelne Meeresorganismen, sowie gesamte Ăkosysteme haben.
Oftmals sind ökophysiologische Antworten einzelner Organismengruppen jedoch unbekannt,
ebenso wie ihre Reaktion im Gesamtkontext ihres Lebensraumes. Ein Beispiel hierfĂŒr sind
Makroalgen, die in ihrer Funktion als natĂŒrlicher Lebensraum, Laichgrund und als
Nahrungsgrundlage vieler Meereslebewesen einen essentiellen Bestandteil der
Lebensgemeinschaften im Ozean darstellen. Durch die Simulation unterschiedlicher CO2-
Szenarien in optimalen bzw. subletalen Temperaturbereichen wurden im Kontext dieser Arbeit
physiologische Reaktionen in Form von Wachstum, Photosynthese und Pigmentgehalt auf
kombinierte Effekte von Ozeanversauerung und Temperatur an der marinen Gezeitenrotalge
Mastocarpus stellatus untersucht.
In dieser Studie konnte gezeigt werden, dass M. stellatus insensitiv auf steigende CO2-
Konzentrationen sowohl innerhalb optimaler als auch in subletalen Temperaturbereichen reagiert.
Eine Steigerung von Photosynthese und Wachstum, wie sie insbesondere an thermischen
Grenzbereichen in einer Ausgangshypothese dieser Studie erwartet wurde, konnte nicht
festgestellt werden. Auch im Bereich der Pigmentkonzentrationen konnten durch simulierte
Effekte der Ozeanversauerung keine signifikanten bzw. bei optimalen Kulturtemperaturen nur
marginale Unterschiede nachgewiesen werden. Interaktive Effekte von CO2 und Temperatur
wurden in Form einer reduzierten Photosyntheseleistung bei subletalen Temperaturbedingunen
beobachtet.
Abstract
Since the beginning of the Industrial Revolution 200 years ago, atmospheric CO2-concentrations
have been increasing dramatically. As the worldâs oceans and its atmosphere stand in a constant
equilibrium, diffusing CO2 forms a weak carbonic acid within the upper ocean layers leading to a
change in the composition of dissolved inorganic carbon. This process is often referred to as
ocean acidification, which in combination with increasing temperatures due to climate change
can have considerable effects on marine flora and fauna as well as on entire ecosystems.
Ecophysiological responses to an increasing pCO2 and rising temperatures can be manifold as
they vary between different groups of organisms. Hence reactions to a change of these parameters
within organism groups and ecosystems are individual, difficult to predict and not seldom
unknown.
Macroalgae in their function as natural habitats, spawning grounds and food source to a great
variety of marine organisms play an important and essential role in marine environments.
Previous studies have shown diverse responses of macroalgae to effects of ocean acidification
with a majority indicating enhanced rates of growth and photosynthesis.
Simulating different CO2-sceanrios under optimum and sublethal temperature conditions, this
study targets to investigate physiological responses of the intertidal red algae Mastocarpus
stellatus to combined effects of CO2 and temperature in terms of growth, photosynthesis and
pigment content.
This study could show an insensitivity of M. stellatus to rising pCO2 under optimum as well as
under sublethal temperature conditions. Against the leading Hypothesis assuming increased pCO2
could enhance growth and photosynthesis, M. stellatus did not show any of these effects. Pigment
extraction of algal material which has been cultivated under sublethal conditions could not reveal
any significant effects that ocean acidification could have had on pigment content. In case of the
optimum temperature treatment marginal effects were visible but cannot necessarily be attributed
to ocean acidification. Interactive effects were evident in terms of reduced photosynthetic
performance at sublethal temperatures and low CO2-concentrations
Selective inhibition of human AKR1B10 by n-humulone, adhumulone and cohumulone isolated from Humulus lupulus extract
Hop-derived compounds have been subjected to numerous biomedical studies investigating their impact on a wide range of pathologies. Isomerised bitter acids (isoadhumulone, isocohumulone and isohumulone) from hops, used in the brewing process of beer, are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies. However, the closely related reductases AKR1A1 and AKR1B1, which fulfil important roles in the detoxification of endogenous and xenobiotic carbonyl compounds oftentimes crossreact with inhibitors designed to target AKR1B10. Accordingly, there is an ongoing search for selective AKR1B10 inhibitors that do not interact with endogeneous AKR1A1 and AKR1B1-driven detoxification systems. In this study, unisomerised α-acids (adhumulone, cohumulone and n-humulone) were separated and tested for their inhibitory potential on AKR1A1, AKR1B1 and AKR1B10. Also AKR1B10-mediated farnesal reduction was effectively inhibited by α-acid congeners with Ki-values ranging from 16.79 ± 1.33 ”M (adhumulone) to 3.94 ± 0.33 ”M (n-humulone). Overall, α-acids showed a strong inhibition with selectivity (115â137 fold) for AKR1B10. The results presented herein characterise hop-derived α-acids as a promising basis for the development of novel and selective AKR1B10-inhibitors.PeerReviewe