Evolutionary advantage and molecular modes of action of multi-component mixtures used in phytomedicine

Heidelberg University, Institute of Pharmacy and Molecular Biotechnology, INF 364, 69120 Heidelberg, Germany.
Current Drug Metabolism (Impact Factor: 2.98). 01/2009; 9(10):996-1009.
Source: PubMed


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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    • "Majority of thoroughly studied medicinal plants contain broad spectrum of bioactive compounds (Efferth and Koch, 2011) with each phytochemicals have different antimicrobial mode (Simoes et al., 2009). Multitarget effects of phytochemicals include alteration in structure and function of proteins, interference with synthesis of DNA or RNA or proteins, disruption of the cell membrane and change in its function, inhibition of cytochrome P450 or enhanced absorption and thus bioavailability of active metabolites (Efferth and Koch, 2011; Wink, 2008). It has been shown that extracts of different plants contain inhibitors of efflux pumps in bacteria (Garvey et al., 2011; Hsieh et al., 1998), therefore can help fighting multidrug resistance by inhibiting the action of efflux pumps. "
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    Asian Journal of Animal and Veterinary Advances 10/2015; 10(9):443-460. DOI:10.3923/ajava.2015.443.460 · 0.87 Impact Factor
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    • "Natural molecules and products reemerge as promising sources of complex multitarget mixtures that are used as alternative therapeutic agents for various conditions, including infections and chronic diseases [1] [2], such as oral diseases [3] [4] [5] or digestive cancers [6]. Amphipterygium adstringens Schiede ex Schlecht (Julianaceae ) is an endemic species in Mexico commonly known as " cuachalalate. "
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    ABSTRACT: Amphipterygium adstringens is a plant widely used in Mexican traditional medicine for its known anti-inflammatory and antiulcer properties. In this work, we evaluated the in vitro antimicrobial and antiproliferative activities of the methanolic extract of A. adstringens against oral pathogens such as Streptococcus mutans, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Candida albicans, and Candida dubliniensis, using microdilution (MIC) and agar diffusion methods (MBC), and the antiproliferative activity evaluating total growth inhibition (TGI) by staining the protein content with sulforhodamine B (SRB), using nine human cancer cell lines. Crude extract (CE) of A. adstringens showed some degree of activity against one or more of the strains with a MIC from 0.125 mg/mL to 63 mg/mL and MBC from 1.6 to 6.3 mg/mL and cytotoxic activity, particularly against NCI-ADR/RES, an ovarian cell line expressing multiple resistance drugs phenotype. The CE is a complex mixture of possible multitarget metabolites that could be responsible for both antimicrobial and antiproliferative activities, and further investigation is required to elucidate the identity of active compounds. Nevertheless the CE itself is useful in the development of new antimicrobial treatment based on natural products to prevent oral diseases and as alternative natural source for cancer treatment and prevention.
    Evidence-based Complementary and Alternative Medicine 10/2015; 2015(4):175497. DOI:10.1155/2015/175497 · 1.88 Impact Factor
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    • "Direct interaction of secondary plant compounds with proteins by the formation of ionic bonds is known to induce changes in conformation and bioactivity. Moreover, it has to be taken into account that green tea contains a complex mixture of catechins and other polyphenolic compounds that could synergistically affect the aforementioned mechanisms [29]. Although the catechins are chemical antioxidants which can quench free radical species and have been demonstrated to increase the resistance to oxidative stress in C. elegans [30], we have previously shown that the prevention of glucose-induced lifespan-reduction by the polyphenol quercetin is independent of antioxidant activities [31]. "
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    ABSTRACT: Hyperglycemia is a hallmark of diabetes mellitus which leads to the onset of complications in the long term. Green tea through its high content of polyphenolic catechins, on the other hand, is suggested to prevent or at least delay such detrimental complications. In the present study we fed the nematode Caenorhabditis elegans on a liquid medium supplemented with 10mM glucose in the absence or presence of a catechin-enriched green tea extract (CEGTE). After exposure of young adults for 48h survival was subsequently measured under heat stress at 37°C. Whereas CEGTE at 0.01% did not affect the survival of wild type nematodes, it completely reversed the glucose-induced survival reduction. Those effects were not achieved through the monomeric catechins included in CEGTE. RNA interference (RNAi) for sir-2.1 not only prevented the survival extension by CEGTE under simultaneous glucose exposure but caused a further reduction of survival. Likewise, the knockdown of uba-1, encoding the only E1-ubiquitin-activating enzyme in C. elegans, proved that UBA-1 is essential for the survival extension by CEGTE and that its loss of function changes CEGTE from a survival extending into a survival reducing extract. Stimulation of the proteasome by CEGTE was finally proven through measurements of the proteolytic cleavage of a fluorogenic peptide substrate. To conclude, our studies provide evidence that CEGTE reverses glucose-induced damage in C. elegans through activation of adaptive responses mediated by SIR-2.1 and proteasomal degradation. The hormetic mode of action is revealed by a reduction of survival once the adaptive processes were blocked. Copyright © 2015. Published by Elsevier B.V.
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