Irmgard Merfort

Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin.

Luteolin is a flavone which occurs in medicinal plants as well as in some vegetables and spices. It is a natural anti-oxidant with less pro-oxidant potential than the flavonol quercetin, the best studied flavonoid, but apparently with a better safety profile. It displays excellent radical scavenging and cytoprotective properties, especially when tested in complex biological systems where it can interact with other anti-oxidants like vitamins. Luteolin displays specific anti-inflammatory effects at micromolar concentrations which are only partly explained by its anti-oxidant capacities. The anti-inflammatory activity includes activation of anti-oxidative enzymes, suppression of the NFkappaB pathway and inhibition of pro-inflammatory substances. In vivo, luteolin reduced increased vascular permeability and was effective in animal models of inflammation after parenteral and oral application. Although luteolin is only a minor component in our nutrition (less than 1 mg/day) epidemiological studies indicate that it has the potential to protect from diseases associated with inflammatory processes such as cardiovascular disease. Luteolin often occurs in the form of glycosides in plants, but these are cleaved and the aglycones are conjugated and metabolized after nutritional uptake which has to be considered when evaluating in vitro studies. Some data for oral and topical bioavailability exist, but more quantitative research in this field is needed to evaluate the physiological and therapeutical potential of luteolin.

Anti-carcinogenic effects of the flavonoid luteolin.

Luteolin is a flavonoid which is part of our daily nutrition in relatively low amounts (less than 1 mg/day). Nevertheless, some epidemiological studies suggest an inverse correlation between luteolin intake and the risk of some cancer types. Luteolin displays specific anti-inflammatory and anti-carcinogenic effects, which can only partly be explained by its anti-oxidant and free radical scavenging capacities. Luteolin can delay or block the development of cancer cells in vitro and in vivo by protection from carcinogenic stimuli, by inhibition of tumor cell proliferation, by induction of cell cycle arrest and by induction of apoptosis via intrinsic and extrinsic signaling pathways. When compared to other flavonoids, luteolin was usually among the most effective ones, inhibiting tumor cell proliferation with IC50 values between 3 and 50 µM in vitro and in vivo by 5 to 10 mg/kg i.p., intragastric application of 0.1–0.3 mg/kg/d, or as food additive in concentrations of 50 to 200 ppm. Luteolin has been shown to penetrate into human skin, making it also a candidate for the prevention and treatment of skin cancer.

Perspectives on sesquiterpene lactones in inflammation and cancer.

Sesquiterpene lactones are a large group of secondary plant metabolites mostly known from the Asteraceae family. They exert a broad variety of different biological activities. This review attempts to critically summarise the knowledge on the anti-inflammatory and cytotoxic activity of SLs, with a special focus on parthenolide and helenalin. Recent advances on their molecular modes of action, allergic potential and also QSAR studies with SLs are presented. Therapeutic areas are highlighted in which SLs may play a role in the future. Thus, SLs may possess therapeutic relevance as single components for the local treatment of inflammation, such as rheumatoid complaints. In cancer therapy, SLs may be favourable in dual therapy or in the inhibition of leukaemia cell growth. In each case, native SLs serve as leads that have to be optimised in terms of their specificity, pharmacokinetics and absorption, distribution, metabolism and excretion (=ADME) properties. Finally, appropriate in vivo studies will decide whether SLs will become therapeutics or remain interesting research compounds.

ON/OFF and Beyond - A Boolean Model of Apoptosis

Apoptosis is regulated by several signaling pathways which are extensively linked by crosstalks. Boolean or logical modeling has become a promising approach to capture the qualitative behavior of such complex networks. Here we built a large-scale literature-based Boolean model of the central intrinsic and extrinsic apoptosis pathways as well as pathways connected with them. The model responds to several external stimuli such as Fas ligand, TNF-α, UV-B irradiation, interleukin-1β and insulin. Timescales and multi-value node logic were used and turned out to be indispensable to reproduce the behavior of the apoptotic network. The coherence of the model was experimentally validated. Thereby an UV-B dose-effect is shown for the first time in mouse hepatocytes. Analysis of the model revealed a tight regulation emerging from high connectivity and spanning crosstalks and a particular importance of feedback loops. An unexpected feedback from Smac release to RIP could further increase complex II formation. The introduced Boolean model provides a comprehensive and coherent description of the apoptosis network behavior. It gives new insights into the complex interplay of pro- and antiapoptotic factors and can be easily expanded to other signaling pathways.

NMR spectral analysis of polyphenols from Punica granatum

Abstract Brevifolin carboxylic acid, brevifolin, corilagin, 3,6-( R )-hexahydroxydiphenoyl-(α/β)- 1 C 4 -glucopyranose, 1,2,6-tri- O -galloyl-β- 4 C 1 -glucopyranose, 1,4,6-tri- O -galloyl-β- 4 C 1 -glucopyranose, ellagic acid, 3,4,8,9,10-pentahydroxydibenzo[ b,d ]pyran-6-one, granatin-B and punicafolin were isolated from the leaves of Punica granatum . 1 H and 13 C NMR spectra of brevifolin carboxylic acid and brevifolin have been recorded and assigned for the first time. A new interpretation of the NMR data or related compounds is discussed. The structure of the new natural polyphenol-1,2,3- tri- O -galloyl-β- 4 C 1 -glucopyranose has been established.

Determination of the wound healing effect of Calendula extracts using the scratch assay with 3T3 fibroblasts

UNLABELLED PHARMACOLOGICAL RELEVANCE: Presentation of the scratch assay as a convenient and inexpensive in vitro tool to gain first insights in the wound healing potential of plant extracts and natural compounds. AIM OF THE STUDY The present study deals with the optimization of the scratch assay which can be used as an in vitro model for quantification of fibroblast migration to and proliferation into the wounded area. It is suitable for the first evaluation of the wound re-epithelialization potential of crude herbal extracts, isolated compounds and pharmaceutical preparations. As a proof of concept three preparations from traditional medicinal plants were investigated. MATERIALS AND METHODS Swiss 3T3 albino mouse fibroblasts were used in monolayers and platelet derived growth factor as positive control. Hexane and ethanolic extracts from Calendula officinalis and Matricaria recutita, Hypericum oil as well as the triterpenoids faradiol myristate and palmitate were studied. To differentiate between proliferation and migration antimitotic mitomycin C was added. RESULTS Both extracts of Calendula officinalis stimulated proliferation and migration of fibroblasts at low concentrations, e.g. 10 microg/ml enhanced cell numbers by 64.35% and 70.53%, respectively. Inhibition of proliferation showed that this effect is mainly due to stimulation of migration. Faradiol myristate and palmitate gave comparable stimulation rates at an almost 50 microg/ml concentration, indicating that they contribute partially, but not most significantly to the wound healing effects of Calendula preparations. Extracts from Matricaria recutita were only moderately active. Hypericum oil was cytotoxic at concentrations higher than 0.5 microg/ml. CONCLUSIONS The scratch assay in the present form can be used as a promising scientific approach and platform to differentiate between plant extracts known for their wound healing and their anti-inflammatory properties.

Botanicals in Dermatology: An Evidence-Based Review

Botanical extracts and single compounds are increasingly used in cosmetics but also in over-the-counter drugs and food supplements. The focus of the present review is on controlled clinical trials with botanicals in the treatment of acne, inflammatory skin diseases, skin infections, UV-induced skin damage, skin cancer, alopecia, vitiligo, and wounds. Studies with botanical cosmetics and drugs are discussed, as well as studies with botanical food supplements. Experimental research on botanicals was considered to a limited extent when it seemed promising for clinical use in the near future.In acne therapy, Mahonia, tea tree oil, and Saccharomyces may have the potential to become standard treatments. Mahonia, Hypericum, Glycyrrhiza and some traditional Chinese medicines appear promising for atopic dermatitis. Some plant-derived substances like dithranol and methoxsalen (8-methoxypsoralen) [in combination with UVA] are already accepted as standard treatments in psoriasis; Mahonia and Capsicum (capsaicin) are the next candidates suggested by present evidence. Oral administration and topical application of antioxidant plant extracts (green and black tea, carotenoids, coffee, and many flavonoids from fruits and vegetables) can protect skin from UV-induced erythema, early aging, and irradiation-induced cancer. Hair loss and vitiligo are also traditional fields of application for botanicals.According to the number and quality of clinical trials with botanicals, the best evidence exists for the treatment of inflammatory skin diseases, i.e. atopic dermatitis and psoriasis. However, many more controlled clinical studies are needed to determine the efficacy and risks of plant-derived products in dermatology. Safety aspects, especially related to sensitization and photodermatitis, have to be taken into account. Therefore, clinicians should not only be informed of the beneficial effects but also the specific adverse effects of botanicals used for dermatologic disorders and cosmetic purposes.

Anti-inflammatory effects of glycyrol isolated from Glycyrrhiza uralensis in LPS-stimulated RAW264.7 macrophages

The anti-inflammatory effects of glycyrol, a benzofuran coumarin isolated from Glycyrrhizae Radix, were studied. Glycyrol of 5, 25 and 50 microM dose-dependently inhibited nitric oxide (NO) production by down-regulating inducible nitric oxide synthase (iNOS), and alleviated cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 macrophages, in both the mRNA and the protein. Furthermore, glycyrol dose-dependently decreased the mRNA of the pro-inflammatory cytokines IL-1beta and IL-6. LPS-induced NF-kappaB activation was prevented in RAW264.7 macrophages by inhibition of I-kappaBalpha phosphorylation. In addition, administration of glycyrol (30 and 100 mg/kg, i.p) reduced the thickness of carrageenan-induced mouse-paw edema swelling. Taken together, our results indicate that glycyrol is an important anti-inflammatory constituent of Glycyrrhizae Radix, and that its anti-inflammatory effect is attributed to the inhibition I-kappaBalpha phosphorylation.

Anti-inflammatory activity of two different extracts of Uncaria tomentosa (Rubiaceae)

We assessed in vivo the anti-inflammatory activity of two Cats claw bark extracts, by comparing a spray-dried hydroalcoholic extract against an aqueous freeze-dried extract, to determine which extract was more effective. We used the carrageenan-induced paw edema model in mice. In addition, to assess the molecular mechanism of action, we determined the inhibition of NF-kappa B through the Electrophoretic Mobility Shift Assay (EMSA) and the effects on cycloxygenase-1 and -2. Results showed that the anti-inflammatory activity was significantly higher using the hydroalcoholic compared with the aqueous extract (P<0.05). The extracts also showed little inhibitory activity on cyclooxygenase-1 and -2. It cannot be excluded that the slight inhibitory activity on DNA binding of NF-kappa B is due to cytotoxic effects.

Caffeoylquinic acids from flowers of Arnica montana and Arnica chamissonis

Abstract Two caffeoylquinic acids were isolated from flowers of Arnica montana and three from A. chamissonis ssp. foliosa var. incana . Their structures were established on the basis of spectral data (UV, 1 H NMR, 13 C NMR, FABMS) as 1,4,5-tri- O -caffeoylquinic acid, 1,5-di- O -caffeoylquinic acid and 3,4,5-tri- O -caffeoylquinic acid methyl ester. The first compound is a new natural product.