Evolutionary advantage and molecular modes of action of multi-component mixtures used in phytomedicine.
ABSTRACT Plants use complex mixtures of secondary compounds (SM) of different structural classes to protect themselves against herbivores, bacteria, fungi and viruses. These complex mixtures may contain SM, which are specific for a single target (monotarget SM). A majority of SM, however, can interfere with several targets (multitarget SM) in a pleiotropic fashion. The composition of such extracts appears to be optimised, since the components are not only additive but apparently synergistic in their bioactivity. Synergism can be achieved by inhibiting the xenobiotics inactivating activities of animals and microbes (MDR, CYP), by facilitating the uptake of polar SM across biomembranes and/or by affecting several important organs in animals concomitantly. Phytotherapy employs equally complex extracts of medicinal plants. Arguments were put together that the utilisation of complex mixtures with pleiotropic agents presents a unique therapeutic approach with many advantages over monotarget compounds. Mixtures of multitarget SM, used in phytotherapy include phenolics, tannins, mono- and sequiterpenes, saponins, iridoid glucosides and anthraquinones, but only few of them alkaloids or other toxic monotarget SM.Multitarget effects are caused by SM, which can modulate the three-dimensional structure of proteins (and thus their function), by interfering with DNA/RNA (especially gene expression) or membrane permeability. In addition, complex extracts may contain synergists, which can inhibit MDR, cytochrome P450 or enhance absorption and thus bioavailability of active metabolites. The molecular modes of action are reviewed for the main groups of secondary metabolites.
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ABSTRACT: Background Impaired 5-HT3 receptor function is likely involved in the pathogenesis of functional gastrointestinal disorders (FGID) and 5-HT3 receptor antagonists are effective treatments for chemotherapy-induced nausea and vomiting (CINV) and irritable bowel syndrome (IBS). The monoterpene alcohol menthol and the aporphine alkaloid boldine combat symptoms of gastrointestinal diseases; both interact with other members of the Cys-loop ligand-gated ion channel family and may therefore also act on 5-HT3 receptors.Methods The impact of boldine and menthol on human recombinant homomeric 5-HT3A- and heteromeric 5-HT3AB receptors in HEK293 cells was determined by radioligand binding, a luminescence-based Ca2+ assay, and a membrane potential assay. 5-HT3 protein and mRNA expression was assessed in human colon tissue.Key ResultsBoldine and menthol inhibited the 5-HT-induced activation of 5-HT3 receptors in the low and middle micromolar range, respectively. Boldine was a competitive antagonist of both receptors being 6.5- to 10-fold more potent at 5-HT3A- vs 5-HT3AB receptors. Menthol non-competitively and stereoselectively inhibited both receptors: In contrast to (+)-menthol, (−)-menthol was significantly more potent toward 5-HT3A- vs 5-HT3AB receptors. We show co-expression of 5-HT3A and 5-HT3B subunits in the human gut epithelium, the lamina propria, the myenteric plexus, and the muscular cell layer.Conclusions & InferencesThe demonstrated 5-HT3 inhibitory effects may be relevant for boldine's and menthol's alleviating properties on FGID and may encourage clinical studies with the compounds or the plant extracts for CINV and IBS treatment. The found receptor-discriminative properties make boldine and (−)-menthol to potentially useful tools for analyzing structural differences between these receptor subtypes.Neurogastroenterology and Motility 04/2014; · 2.94 Impact Factor
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ABSTRACT: The essential oils isolated from the fresh flowers, fresh leaves, and both fresh and air-dried stems of Eremophila maculata (Scrophulariaceae) were characterized by GC-FID and GC/MS analyses. Sabinene was the major component in most of the oils, followed by limonene, α-pinene, benzaldehyde, (Z)-β-ocimene, and spathulenol. The leaf and flower essential oils showed antibacterial and antifungal activity against five Gram-positive and four Gram-negative bacterial strains, multi-resistant clinical isolates from patients, i.e., methicillin-resistant Staphylococcus aureus (MRSA), as well as two yeasts. Minimum inhibitory concentrations (MICs) and minimum microbicidal concentrations (MMCs) were between 0.25 and 4 mg/ml.Chemistry & Biodiversity 05/2014; 11(5). · 1.81 Impact Factor
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ABSTRACT: The chemical compositions of essential oils from cumin and coriander fruits were investigated using GLC and GLC/MS. Forty six compounds were identified in both oils. The major constituents of cumin oil were identified as γ-terpinene (22.7%), β-pinene (19.2%), cuminaldehyde (18.0%), p-cymene (11.5%), whereas linalool (70.43%) is the most abundant component in coriander oil. The antioxidant and anti-inflammatory activity and cytotoxicity of the essential oils were assessed. Cumin oil exhibited stronger antioxidant activity (IC 50 values, 2.37 mg/ml for DPPH • assay and 27.7 µg/ml for OH • assay) as compared to the coriander oil. Both oils inhibited the PGE 2 production in lipopolysaccharide (LPS) stimulated HepG-2 cells. They also inhibited soybean lipoxygenase (5-LOX). Cumin oil (20 µg/ml) caused a 22.44% reduction in PGE 2 level after treatment of the cells. IC 50 values for lipoxygenase inhibition were 35.8 and 38.6 µg/ml for cumin and coriander oils, respectively. Cumin oil exhibited substantial antiproliferative activity against HepG-2 with an IC 50 value of 31.4 µg/ml, whereas coriander was less active (IC 50 120.4 µg/ml).The natural Products Journal. 06/2014; 4(1):63-69.