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We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for processing in flow which allowed harnessing of O2 as a benign reagent for late-stage photocatalytic N-CH3 oxidation of natural products and active pharmaceutical ingredients. These substrates bear functional groups which are not tolerated by previous methods. The organophotocatalytic process benefited from the flow parameters, affording cleaner reactions in short residence time of 13.5 mins and productivities of up to 0.65 g / day. Mechanistic studies found that catalyst derivatization not only enhanced solubility of the new catalyst compared to DCA, it profoundly diverted the photocatalytic reaction mechanism from singlet electron transfer (SET) reductive quenching with amines to energy transfer (EnT) with O2.

Recent clinical evidence suggests the efficacy of a traditional herbal medicinal product containing myrrh (Commiphora molmol Engl.), coffee charcoal (Coffea arabica L.) and chamomile flower dry extract (Matricaria chamomilla L.) in the therapy of inflammatory bowel diseases (IBD). However, the mechanisms of action in this context have not been entirely elucidated. The present study aimed to evaluate the effects of myrrh, coffee charcoal and chamomile flower extract on the inflammatory cross talk between immune and intestinal epithelial cells together with the resulting intestinal barrier disorders. A complex co-culture cell model consisting of intestinal epithelial cell (IEC) monolayers (Caco-2, HT29-MTX-E12) and macrophages (THP-1) was established for the simultaneous investigation of these two IBD characteristics. The lipopolysaccharide (LPS) activation of the macrophages led to a pro-inflammatory mediator release and thereby an inflammatory stimulation of IECs with chemokine release and reduced barrier function. The effects of the individual plant extracts and a ternary combination on inflammatory mediator release (IL-6, TNF, IL-8, MCP-1, PGE2) was quantified by ELISA. The transepithelial electrical resistance (TEER) of IEC monolayers was measured to evaluate the effects on the barrier function. Budesonide served as a positive control. All three plant extracts exhibited anti-inflammatory properties via the inhibition of the inflammatory mediator release to a varying extent. An intestinal barrier stabilising effect was observed for myrrh and coffee charcoal. Myrrh exerted the most distinct pharmacological activity. Dose reducing and synergistic interactions emerged within the threefold combination. Thus, our results provide a mechanistic basis for the use of the herbal combination of myrrh, coffee charcoal and chamomile flower extract in IBD treatment and underline the potential benefits of the phytotherapeutic multi-component/multi-target approach in this complex pathogenesis.

The deployment of onshore wind power involves spatial sustainability trade-offs, e.g., between the minimization of energy system costs, the mitigation of impacts on humans and biodiversity, and equity concerns. We analyze challenges arising for decision-making if wind power generation capacity has to be allocated spatially in the presence of such trade-offs. The analysis is based on a game developed for and played by stakeholders in Germany. The results of the game illustrate that there is no unanimously agreed ranking of sustainability criteria among the participating stakeholders. They disagreed not only on the weights of different criteria but also their definition and measurement. Group discussions further revealed that equity concerns mattered for spatial allocation. Yet, stakeholders used quite different concepts of equity. The results support the importance of transparent, multi-level and participatory approaches to take decisions on the spatial allocation of wind power generation capacity.

Blick in die Wissenschaft, Bd. 27 Nr. 38 (2018): Blick in die Wissenschaft 38

Sixty-three extracts obtained from 18 plants traditionally used in the South Pacific archipelago Vanuatu for the treatment of infectious diseases were screened for antimicrobial and antiprotozoal activities. In addition, the extracts were subjected to a detailed analysis on cytotoxic effects toward a panel of human cancer cell lines, designed as a smaller version of the NCI60 screen. Intriguingly, 15 plant extracts exhibited strong cytotoxic effects specific for only one cancer cell line. Extracts of the leaves of Acalypha grandis Benth. significantly affected Plasmodium falciparum without showing obvious effects against the other protozoa tested. The leaves of Gyrocarpus americanus Jacq. displayed significant activity against Trypanosoma b. brucei and the leaves of Tabernaemontana pandacaqui Lam. I as well as the stems of Macropiper latifolium (L.f.) against Trypanosoma cruzi. In contrast none of the extracts showed relevant antibacterial or antifungal activity.

Die derzeit in der Planungspraxis vorzufindende Ausweisung von Siedlungsflächen führt zu einer erheblichen Änderung der bisherigen Siedlungsstrukturen. Weiterhin tritt verstärkt das Problem des Bevölkerungsrückgangs und der Alterung auf. Sowohl im bundesdeutschen Durchschnitt, insbesondere aber in Ostdeutschland, sinkt damit die Nutzungsdichte. Die höhere Inanspruchnahme von Flächen für Siedlungs- und Verkehrszwecke führt außerdem zu einem Verlust einer nicht erneuerbaren Gutes und verändert das Landschaftsbild. Sowohl im Wohn- als auch im gewerblichen Bereich werden die vorhandenen Potenziale zu wenig genutzt. Während innerstädtische Flächen brachfallen, erfolgt die Ausweisung neuer Baugebiete im Außenbereich. Mit einem nachhaltigen regionalen Flächenmanagement sollen der Flächenverbrauch reduziert und eine zukunftsfähige Raumstruktur entwickelt werden. Vor der Diskussion geeigneter Instrumente ist eine kritische Auseinandersetzung mit den gegenwärtigen flächenpolitischen Zielen und deren Optimierung erforderlich. In diesem fünften Band der KoReMi-Schriftenreihe werden daher die flächenpolitischen Ziele unter Schrumpfungsbedingungen diskutiert. Dabei wird zunächst ein theoretischer flächenpolitischer Zielkatalog erarbeitet, der Handlungsziele und Maßnahmen enthält und eine Ableitung flächenpolitischer Strategien ermöglicht. Diesem Katalog werden die gegenwärtigen normativen Aussagen der Landes- und Regionalplanung in der Kernregion Mitteldeutschland gegenübergestellt. Die gewonnenen Erkenntnisse liefern eine wertvolle Grundlage für die Auseinandersetzung mit den gemeindlichen Entwicklungsperspektiven, die als Band 06 dieser Schriftenreihe veröffentlicht werden.

Therapeutic effects of dietary flavonoids have been attributed mainly to their antioxidant capacity. Xanthohumol (1), a prominent flavonoid of the hop plant, Humulus lupulus, was investigated for its antioxidant potential and for its effect on NF-κB activation. To examine the biological relevance of 1, a hepatic ischemia/reperfusion model was chosen as a widely accepted model of oxidative stress generation. The impact of 1 on endogenous antioxidant systems, on the NF-κB signal transduction pathway as well as on apoptotic parameters, and on hepatic tissue damage was evaluated. Compound 1 markedly decreased the level of reactive oxygen species in vitro. Furthermore, levels of enzymatic and nonenzymatic antioxidants were restored after pretreatment in postischemic hepatic tissue, and lipid peroxidation was attenuated. NF-κB activity was reduced in vitro as well as in hepatic tissue after ischemia/reperfusion upon pretreatment with 1. In addition, the phosphorylation of Akt was markedly inhibited. Surprisingly, 1 decreased the expression of the antiapoptotic protein Bcl-X and increased caspase-3 like-activity, a proapoptotic parameter. Moreover, hepatic tissue damage as well as TNF-R levels increased in xanthohumol-pretreated liver tissue after ischemia/reperfusion. In summary, xanthohumol did not protect against ischemia/reperfusion injury in rat liver, despite its antioxidant and NF-κB inhibitory properties.

Drug development from natural products, such as herbal extracts and compounds, is a promising research strategy for the identification of new drug candidates. Incessant identification of new lead compounds is imperative to overcome the limitations of many modern treatment options. This holds especially true in immunological diseases, such as chronic inflammation and autoimmune disorders, as current immunosuppressive treatments come with severe side effects and efficacy loss over time. The value of natural products in this endeavour has been impressively demonstrated by compounds like cyclosporin A and tacrolimus. To address this challenge, a multidisciplinary project was initiated. A library of 600 herbal extracts from Panama was screened for efficacy against the proliferation of lymphocytes, a hallmark feature of autoimmune diseases. An extract of Hyptis brachiata emerged as a highly effective preparation. Subsequent chemical analysis lead to the isolation and characterization of multiple constituents. The main inhibitory potential was later attributed to the antimitotic properties of the isolated aryltetralin lignans, including the well-known podophyllotoxin. The additional weak cytokine suppression by the extract was evaluated via flow cytometric immunophenotyping. However, no specific compound with corresponding efficacy could be identified. In the second, main project of this dissertation, the safety of herbal products was evaluated in the context of the treatment of nonpsychotic mental disorders in pregnancy. The herbal preparations included in this project were St. John´s wort (Hypericum perforatum), California poppy (Eschscholzia californica), Valerian (Valeriana officinalis), Lavender (Lavandula angustifolia) and Hops (Humulus lupulus). All of these are commonly used in the treatment of nonpsychotic mental disorders; however, due to their traditional use, they have been only poorly characterised for their safety. In a major effort, a multi-centre, multidisciplinary project aimed at providing the crucially required data on the safety of these preparations was undertaken. As part of this effort, the toxic and modulatory properties of the extracts and the corresponding constituents were assessed in a variety of assays (cytotoxicity, genotoxicity, and functional) in a placental cell line and primary human immune cells. These two model systems were chosen for their crucial functions in all stages of pregnancy. None of the extracts exhibited genotoxic, cytotoxic or functional effects, at physiologically relevant concentrations in both models. Only in the artificially high concentration of 100 µg/mL statistically significant cytotoxicity was identified for the extracts from St. Johnʼs wort, California poppy (very weak effect), valerian, and hops in placental cells. At concentrations of ≥ 30µg/mL the extracts of St. John´s wort and Valerian also induced significant inhibition of lymphocyte proliferation. Additional testing of the corresponding compounds supported these findings. Protopine (California poppy), valerenic acid (valerian), and linalool (lavender) were essentially ineffective in all placental and immunological assays. Meanwhile, hyperforin and hypericin (St. John´s wort), and valtrate (valerian) induced cytotoxicity, in placental cells, in concentrations higher than 1 µM. In the ex vivo lymphocyte model, these three constituents affected viability and proliferation in concentrations ≥ 3 µM. Immunophenotyping of cells treated with these three compounds exhibited varying results on cytokine production and surface marker expression. Overall, the two St. John´s wort compounds showed a more inhibitory phenotype compared to valtrate which induced stimulation on all the cytokines. Genotoxicity was reported to be of no concern for all tested substances in both model systems.

The identification of new lead compounds, and the development of novel drugs for the treatment of autoimmune diseases, are of great importance, since today’s available pharmaceuticals often have substantial limitations. Glucocorticoids and drugs that inhibit the deoxyribonucleic acid (DNA) synthesis (e.g. cyclophosphamide) often cause severe side effects, while state-of-the-art biologicals usually impose a heavy financial burden. Plant extracts are a good starting point for the development of immunosuppressive leads, since they are evolutionarily optimized to serve numerous biological functions. The track record of natural product drug discovery for immunosuppressive leads has been distinguished by blockbuster drugs, such as cyclosporin A or tacrolimus; however, a well-planned, multidisciplinary research approach is required for screening plant extracts, characterizing their effects, clarifying targets, and isolating bioactive compounds. Enhanced T cell proliferation is a feature of autoimmune diseases such as rheumatoid arthritis or multiple sclerosis; therefore, as a starting point, this study investigated the T cell proliferation inhibitory potential of a library of 435 extracts, prepared from plants used in traditional Chinese medicine (TCM). The immunosuppressive activity of the extracts was assessed by a proliferation-based assay utilizing physiologically-relevant anti-CD3 and anti-CD28 stimulated primary human T lymphocytes. It showed that an Artemisia argyi (Asteraceae, A. argyi) ethyl acetate extract and a Boswellia carteri (Burseraceae, B. carteri) dichloromethane (DCM) extract were active, reflected by a half maximal inhibitory concentration (IC50) of 16.2 µg/mL for the A. argyi extract and 27.0 µg/mL for B. carteri extract. The observed inhibitory effect on T cell proliferation was based on a specific intervention of T cell signaling via an interleukin-2 (IL-2)-dependent mechanism, rather than induced apoptosis or necrosis. Further characterizations revealed a reduced expression of the T cell activation markers CD25 and CD69, as well as a decreased production of IL-2 and interferon-γ (IFN-γ), by the A. argyi extract; the B. carteri extract also suppressed the IL-2 and IFN-γ secretion. Moreover, treatment with B. carteri extract resulted in a reduced degranulation capacity of stimulated T cells. Both extracts were subjected to high-performance liquid chromatography (HPLC)-mass spectrometry (MS)-based activity profiling. A T cell proliferation assay identified 8-acetyl-artanomaloide, arteglasin A, jaceosidin, 1R-canin, and (4S,5S,6S,7S)- and (4R,5R,6S,7S)-seco-tanapartholides as active constituents of A. argyi. The proliferation assay showed that for B. carteri, 3-O-acetyl-8,24-dienetirucallic acid, 3-O-acetyl-7,24-dienetirucallic acid, 3-oxo-8,24-dienetirucallic acid and 3-O-acetyl-α-boswellic acid suppressed the proliferation of stimulated T lymphocytes. To validate the target of the active A. argyi and B. carteri compounds, monitoring of the T cell signaling cascade was performed, starting with the IL-2 transcription factor activator protein 1 (AP-1), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and the nuclear factor of activated T cells (NFAT). Suppression of the NF-κB and NFAT activity, with IC50 values between 2.0 and 9.3 µM for NF-κB and 1.6 and 9.3 µM for NFAT, was detected for the A. argyi sesquiterpene lactones. 3-O-acetyl-alpha-boswellic acid was found to be the most promising candidate among the B. carteri compounds, as reflected by an IC50 value of 5.6 µM for NFAT activity suppression. For A. argyi the T cell signaling cascade monitoring was extended to the calcium flux in anti-CD3 stimulated Jurkat T cells. The results indicated a suppression of the calcium flux by 30 µg/mL A. argyi extract; however, no influence on the calcium flux of stimulated Jurkat T cells could be shown for the A. argyi compounds, suggesting that the crude plant extract may affect the signaling on a more upstream level than the single compounds, isolated thus far. This study also evaluated the potential wound healing and immune modulating capacities of extracts from nine plants that are traditionally used in Nepal to improve wound healing. An ethyl acetate extract of Gmelina arborea (Lamiaceae, G. arborea) positively influenced the wound-healing capacity of human keratinocytes and fibroblasts. For satisfactory wound healing, a balance between pathogen clearance by inflammatory feedback loops, and regulatory mechanisms to prevent fatal inflammatory responses, is essential; thus, the influence of the extracts on inflammation parameters was addressed. The G. arborea ethyl acetate extract, and an ethyl acetate extract from Bassia longifolia (Sapotaceae, B. longifolia), concentration-dependently inhibited the proliferation of stimulated T cells. This proliferation inhibition was not related to induced apoptosis or necrosis. The observed suppression of T cell proliferation could be linked to a decreased secretion of IL-2, which is essential for the proliferation and differentiation of T lymphocytes. Furthermore, the degranulation capacity of stimulated T cells was shown to decrease in response to treatment with either B. longifolia or G. arborea extract, emphasizing the anti-inflammatory potential of both extracts. Dendritic cells (DCs) play an important role in wound closure, since they increase the cell migration rate of keratinocytes by secreting interleukin-8 (IL-8). A slightly enhanced IL-8 secretion by DCs was detected after treatment with ethyl acetate extracts of either G. arborea or B. longifolia.

Dieser Band gibt einen Einblick, welche flächenpolitischen Themen in den Gemeinden der Kernregion Mitteldeutschland mit welcher Intensität auf der Tagesordnung stehen. Es zeigt sich, dass die Herausforderungen durch den demographischen Wandel oder finanzielle Ressourcenknappheit erkannt wurden, dies sich aber derzeit nach Meinung des Projektverbundes noch nicht ausreichend in den gemeindlichen Handlungen widerspiegelt. Nachdem in Band 05 dieser Schriftenreihe die theoretischen flächenpolitischen Ziele unter Schrumpfungsbedingungen diskutiert wurden und eine Gegenüberstellung mit den gegenwärtigen normativen Aussagen der Landes- und Regionalplanung in der Kernregion Mitteldeutschland erfolgte, werden in diesem sechsten Band die gemeindlichen Entwicklungsperspektiven abgebildet. Grundlage für diese Auseinandersetzung ist eine schriftliche Befragung der Gemeinden, die Anfang 2008 durchgeführt wurde. Neben dieser quantitativen Erhebung erfolgten Vor-Ort-Gespräche mit Gemeindevertretern, die einige Aussagen des Fragebogens ergänzend erklärten. Mit den Ergebnissen in diesem Band wurde das Arbeitsmodul II des Projektes 'REFINA KoReMi' abgeschlossen. Wir danken an dieser Stelle allen Gemeindevertretern, die sich die Zeit genommen haben, den Fragebogen umfassend auszufüllen bzw. für ein persönliches Gespräch zur Verfügung zu stehen. Durch diese engagierte Mitarbeit war es möglich, vertiefend in das Thema der gemeindlichen Sichtweisen zu flächenpolitischen Themen einzutauchen und den erarbeiteten theoretischen Zielen gegenüberzustellen.