Abstract
Products derived from Noni fruit (MORINDA CITRIFOLIA) have been commercialised in the USA since the 1990s and are increasingly distributed all over the world. A large number of beneficial ...effects have been claimed for Noni. Fruit juice of Noni has been approved as a Novel Food by the European Commission in 2003. This article reviews current knowledge on the phytochemistry, pharmacology, safety aspects of Noni fruit and Noni-derived products, and health-related claims and benefits. The knowledge on the chemical composition of Noni fruit has considerably increased over recent years. A number of IN VITRO and, to a certain extent, IN VIVO studies demonstrate a range of potentially beneficial effects. However, clinical data are essentially lacking. To what extent the findings from experimental pharmacological studies are of potential clinical relevance is not clear at present. Based on a toxicological assessment, Noni juice was considered as safe. Due to recent reports of cases of hepatotoxicity, the safety issue has been re-examined in Europe. While the European Food Safety Authority sees no link between adverse effects on liver and consumption of Noni juice, a continuing monitoring of the situation is desirable and some vigilance advised.
The herbal medicine Bryophyllum pinnatum has been used as a tocolytic agent in anthroposophic medicine and, recently, in conventional settings alone or as an add-on medication with tocolytic agents ...such as atosiban or nifedipine. We wanted to compare the inhibitory effect of atosiban and nifedipine on human myometrial contractility in vitro in the absence and in the presence of B. pinnatum press juice (BPJ).
Myometrium biopsies were collected during elective Caesarean sections. Myometrial strips were placed under tension into an organ bath and allowed to contract spontaneously. Test substances alone and at concentrations known to moderately affect contractility in this setup, or in combination, were added to the organ bath, and contractility was recorded throughout the experiments. Changes in the strength (measured as area under the curve (AUC) and amplitude) and frequency of contractions after the addition of all test substances were determined. Cell viability assays were performed with the human myometrium hTERT-C3 and PHM1-41 cell lines.
BPJ (2.5 μg/mL), atosiban (0.27 μg/mL), and nifedipine (3 ng/mL), moderately reduced the strength of spontaneous myometrium contractions. When BPJ was added together with atosiban or nifedipine, inhibition of contraction strength was significantly higher than with the tocolytics alone (p = 0.03 and p < 0.001, respectively). In the case of AUC, BPJ plus atosiban promoted a decrease to 48.8 ± 6.3% of initial, whereas BPJ and atosiban alone lowered it to 70.9 ± 4.7% and to 80.9 ± 4.1% of initial, respectively. Also in the case of AUC, BPJ plus nifedipine promoted a decrease to 39.9 ± 4.6% of initial, at the same time that BPJ and nifedipine alone lowered it to 78.9 ± 3.8% and 71.0 ± 3.4% of initial. Amplitude data supported those AUC data. The inhibitory effects of BPJ plus atosiban and of BPJ plus nifedipine on contractions strength were concentration-dependent. None of the test substances, alone or in combination, decreased myometrial cell viability.
BPJ enhances the inhibitory effect of atosiban and nifedipine on the strength of myometrial contractions, without affecting myometrium tissue or cell viability. The combination treatment of BPJ with atosiban or nifedipine has therapeutic potential.
Women diagnosed with breast cancer frequently seek complementary and alternative (CAM) treatment options that can help to cope with their disease and the side effects of conventional cancer therapy. ...Especially in Europe, breast cancer patients use herbal products containing mistletoe (Viscum album L.). The oldest and one of the most prescribed conventional drugs for the treatment of estrogen receptor positive breast cancer is tamoxifen. Aside from positive clinical experience with the combination of tamoxifen and mistletoe, little is known about possible herb-drug interactions (HDIs) between the two products. In the present in vitro study, we investigated the effect of standardized commercial mistletoe preparations on the activity of endoxifen, the major active metabolite of tamoxifen.
The estrogen receptor positive human breast carcinoma cell line MCF-7 was treated with (E/Z)-endoxifen hydrochloride in the presence and absence of a defined estradiol concentration. Each concentration of the drug was combined with fermented Viscum album L. extracts (VAE) at clinically relevant doses, and proliferation, apoptosis and cell cycle were analyzed. In parallel, possible inhibition of CYP3A4/5 and CYP2D6 was investigated using 50-donor mixed gender pooled human liver microsomes (HLMs).
VAE did not inhibit endoxifen induced cytostasis and cytotoxicity. At higher concentrations, VAE showed an additive inhibitory effect. VAE preparations did not cause inhibition of CYP3A4/5 and CYP2D6 catalyzed tamoxifen metabolism.
The in vitro results suggest that mistletoe preparations can be used in combination with tamoxifen without the risk of HDIs.
Herbal extracts are complex multi-component mixtures; adequate characterization and quality control of herbal products is thus challenging. Recent technologies and tools enable new approaches to be ...applied. These include, among others, HPLC-based on-line spectroscopy, chemometric analysis of LC-MS and NMR datasets, expression profiling with microarrays, and HPLC-based activity profiling. We have applied some of these technologies for selected problems related to herbal extract characterization.
For phytochemical profiling of herbal extracts, we combine HPLC with various on-line detectors (PDA, ELSD, ESI, APCI, and TOFMS) and off-line NMR with a 1mm microprobe. This approach will be illustrated with the example of the ancient European dye and medicinal plant
Isatis tinctoria
1. From the anti-inflammatory extract, more than 70 compounds were unambiguously identified and a series of additional compounds tentatively assigned, corresponding altogether to an estimated 90% weight of the extract. We have used genome-wide expression profiling to investigate possible estrogen-like properties of
Cimicifuga racemosa
extracts. Findings from microarray experiments were confirmed by quantitative RT PCR 2. HPLC-based activity profiling has been initially developed for lead discovery purposes 3, but is equally suitable to identify pharmacologically relevant constituents in herbal extracts. This will be illustrated by characterization of GABA
A
receptor modulators in sedative TCM herbs.
References:
1 Mohn T, Plitzko I, Hamburger M (2009) Phytochem., 70: 924–934. 2 Hamburger M (2002) Phytochem. Rev., 1: 333–344. 3 Potterat O, Hamburger M (2006) Cur. Org. Chem., 10: 899–920.
A dense network of continuous single‐ and dual‐frequency GPS receivers at Taal Volcano, Philippines, reveals four major stages of volcanogenic deformation: deflation, from installation in June 1998 ...to December 1998; inflation, from January to March 1999; deflation, from April 1999 to February 2000; and inflation, from February to November 2000. The largest displacements occurred during the February–November 2000 period of inflation, which was characterized by ∼120 mm of uplift of the center of Volcano Island relative to the northern caldera rim at average rates up to 216 mm/yr. Deformation sources were modeled using a constrained least squares inversion algorithm. The source of 1999 deflation and inflation in 2000 were modeled as contractional and dilatational Mogi point sources centered at 4.2 and 5.2 km depth, respectively, beneath Volcano Island. The locations of the inflationary and deflationary sources are indistinguishable within the 95% confidence estimates. Modeling using a running 4‐month time window from June 1999 to March 2001 reveals little evidence for source migration. We suggest that the two periods of inflation observed at Taal result from episodic intrusions of magma into a shallow reservoir centered beneath Volcano Island. Subsequent deflation may result from exsolution of magmatic fluids and/or gases into an overlying, unconfined hydrothermal system.
Phonological priming effects were examined in an auditory single-word shadowing task. In 6 experiments, target items were preceded by auditorily or visually presented, phonologically similar, word or ...nonword primes. Results revealed facilitation in response time when a target was preceded by a word or nonword prime having the same initial phoneme when the prime was auditorily presented but not when it was visually presented. Second, modality-independent interference was observed when the phonological overlap between the prime and target increased from 1 to 3 phonemes for word primes but not for nonword primes. Taken together, these studies suggest that phonological information facilitates word recognition as a result of excitation at a prelexical level and increases response time as a result of competition at a lexical level. These processes are best characterized by connectionist models of word recognition.
We have recently implemented a technology platform for a miniaturized activity-based approach in natural products discovery. The platform includes 2D-barcoded liquid extract libraries, HPLC-based ...micro-fractionation for bioactivity and simultaneous on-line spectroscopy (PDA, TOFMS, and MS/MS), and off-line NMR spectroscopy with a 1mm microprobe. This platform is generally applicable with mechanism-based and functional assays in the 96-well MTP format 1 and serves as a turntable for collaborative projects in various therapeutic areas.
γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain, and subunit-selective GABA
A
receptor agonists would have important therapeutic applications. The issue of sound validation and dereplication of profiling protocols will be discussed with a functional assay for GABA
A
receptor modulators using an automated two-microelectrode voltage-clamp assay with
Xenopus
oocytes expressing GABA
A
receptors of desired subunit composition 2. Identification of GABA
A
receptor ligands with scaffolds new for the target will be presented, such as Diels-Alder adducts from
Morus alba
.
Aberrant phosphatidylinositol 3-kinase (PI3K) activity has been linked to the formation of cancer chronic inflammation and other diseases. We are screening for PI3K class III inhibitors using a mutated yeast for Vps43p. A library of >700 plant and fungal extracts for inhibitors provided very few hits, among these, a lipophilic extract from
Citrus medica
var.
sarcodactylis
pericarp. HPLC-based activity profiling of the extract, and cell-culture-based confirmatory testing of compounds will be described.
In a co-operation with the Swiss Tropical Institute, we screen for compounds active against malaria, leishmaniasis and trypanosomiasis. The validation of our profiling approach, and compounds identified from TCM plants will be discussed.
Acknowledgements: Swiss National Science Foundation, Steinegg Foundation, Freiwillige Akademische Gesellschaft.
References: 1. Potterat, O., Hamburger, M. (2006) Curr Org Chem 10:899–920, 2. Kim, HJ. et al. (2008) Planta Med 74: in press
Glucosinolates have attracted significant interest due to the chemopreventive properties of some of their transformation products. Numerous protocols for the extraction and analysis of glucosinolates ...have been published, but limited effort has been devoted to optimize and validate crucial extraction parameters and sample preparation steps. We carried out a systematic optimization and validation of a quantitative assay for the direct analysis of intact glucosinolates in Isatis tinctoria leaves (woad, Brassicaceae). Various parameters such as solvent composition, particle size, temperature, and number of required extraction steps were optimized using pressurized liquid extraction (PLE). We observed thermal degradation of glucosinolates at temperatures above 50°C, and loss of >60% within 10min at 100°C, but no enzymatic degradation in the leaf samples at ambient temperature. Excellent peak shape and resolution was obtained by reversed-phase chromatography on a Phenomenex Aqua column using 10mM ammonium formate as ion-pair reagent. Detection was carried out by electrospray ionisation mass spectrometry in the negative ion mode. Analysis of cruciferous vegetables and spices such as broccoli (Brassica oleracea L. var. italica), garden cress (Lepidium sativum L.) and black mustard (Sinapis nigra L.) demonstrated the general applicability of the method.
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