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Significance Statement
Panossian A, Seo EJ, Wikman G, Efferth T. Synergy assessment of fixed combinations of Herba Andrographidis and Radix Eleutherococci extracts by transcriptome-wide microarray profiling. Phytomedicine. 2015 Oct 15;22(11):981-92
The reductionist method of fractionating herbal extracts to isolate an active principle has been the core of drug development strategies for centuries. The method is based on the assumption that herbal extracts contain one or two active principles, but it underestimates the complexity of the pathogenesis of disease and has reached its limit. In contrast, the holistic approach of multi-target therapy using multicomponent plant extracts, based on network interactions and synergy concepts, may be effective. The novel method of assessing synergistic and antagonistic interactions of combinations of herbal extracts by transcriptome-wide microarray-based mRNA expression profiling of isolated cell lines is a valuable tool for understanding the mechanisms of action of herbal drugs and their possible clinical benefits. Isolated brain cells were separately incubated with plant extracts or a fixed combination. The total number of more than two-fold deregulated genes from all experiments were compared in a Venn diagram. The number of genes deregulated by the combination, but not by any constituent alone, provided evidence of synergistic interactions between the ingredients in the fixed combination. Thus, the combination of plant extracts may not exhibit some effects of the single ingredients and may exert some new and unique features. The combination is a new biologically active substance, a hybrid of “parent” ingredients. Furthermore, downstream analysis of significantly up- or down-regulated genes in interactive pathways predicted effects on cellular and physiological functions and disease. For example, the predicted effectiveness of the combination of Herba Andrographis Radix Eleutherococci in autoimmune diseases via inhibition of the -IFN signalling pathway and encephalitis, or the combination of Radix Rhodiola, Fructus Shizandrae, and Radix Eleutherococci in ageing-associated disorders.
Journal Reference
Phytomedicine. 2015;22(11):981-92.
Panossian A1, Seo EJ2, Wikman G3, Efferth T2.
[expand title=”Show Affiliations”]- Swedish Herbal Institute Research and Development, Askloster, Sweden. Electronic address: [email protected].
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
- Swedish Herbal Institute Research and Development, Askloster, Sweden. [/expand]
Abstract
BACKGROUND:
Generally accepted, but insufficiently proved, the concept of synergy is based on an assumption that combining of two biologically active substances is justified because the combination is more active and less harmful than the ingredients.
HYPOTHESIS:
Analysis of RNA microarray of isolated neuroglia cells and the comparison the number of genes deregulated by plant extracts and their fixed herbal formulation might be a useful tool/method for assessment of synergistic and antagonistic interactions of herbal extracts in human organism.
AIM:
The primary aim of this study was to extend a new method of assessment of synergistic and antagonistic interactions of herbal extracts in isolated human neuroglia cells when they applied in the form of fixed combinations. The secondary aim of the study was to predict possible effects of Herba Andrographidis (APE), Radix Eleutherococci (ESE) genuine extracts and their fixed combination Kan Jang (KJ) on cellular and physiological functions and associated diseases. The third task of the study was to find evidences that justify the hypothesis that these plants extracts in combination are more useful than the monodrugs.
METHODS:
Gene expression profiling was performed on the human neuroglia cell line T98G after treatment with Herba Andrographis, Radix Eleutherococci, Kan Jang and total number of more than two fold-deregulated genes from all experiments were compared by Venn diagram. Interactive pathways downstream analysis was performed with data sets of significantly up- or down-regulated genes and predicted effects on cellular functions and diseases were identified by Ingenuity IPA database software.
RESULTS:
ESE and APE significantly deregulate 207 and 211 genes correspondingly; 36 deregulated genes were common for both extracts. In total of 382 deregulated genes was expected to be deregulated by their fixed combination Kan Jang. However, it was found only 250 genes deregulated by KJ. Among these 250 genes, 111 genes were unique for the Kan Jang combination and not affected by ESE and APE. This is presumably due to synergistic interactions of molecular networks affected by Radix Eleutherococci and Herba Andrographis. Meanwhile, 170 genes deregulated by Radix Eleutherococci, and 55 genes deregulated by Herba Andrographis when tested alone, were not up- or downregulated by Kan Jang. That is the result of antagonistic integrations of ESE and Herba Andrographidis extracts when applied in the combination. Fold change of expression of 18 common genes deregulated by Herba Andrographis, ESE and Kan Jang was not additive when APE and Radix Eleutherococci are combined in Kan Jang herbal formula. However, a qualitative difference is observed in the fingerprint of deregulated genes of daughter substance (KJ) compared to fingerprints/signatures of deregulated genes of parent substances (Herba Andrographis and Radix Eleutherococci). Specific for Kan Jang and predictable (z-score > 2) were the effects on pathways and networks associated with infectious and chronic inflammatory disorders, namely encephalitis or neurological movement disorders. Noteworthy, Eleutherococcus alone has no effect on those networks, particularly on encephalitis network, while Kan Jang deregulates 11 genes which have predictable inhibitory effect on infection, while Herba Andrographis regulates only 5 genes which are activated in encephalitis. It can be speculated that Herba Andrographidis in combination with Radix Eleutherococci may have better therapeutic effect, since more targets are affected. Similar suggestion is justified regarding neurological movement, which is associated with chronic inflammation, like arthritis and osteoarthrosis. Though, microarray analysis did not provide final proof that the genes induced by the Kan Jang, Herba Andrographis and Radix Eleutherococci are responsible for the physiological effects observed in humans following their oral administration. It provided insights into putative genes and directions for future research and possible implementation into practice. The most significantly affected canonical pathways deregulated by Kan Jang and Herba Andrographidis was interferon signaling pathway, indicating the possible effectiveness of Kan Jang and Herba Andrographidis in the treatment of severe sepsis, systemic lupus erythematosus and other autoimmune diseases
CONCLUSION:
Analysis of RNA microarray data from isolated neuroglia cells and the comparison the number of genes deregulated by plant extractsand their fixed herbal formulation might be a useful tool/method for assessment of synergistic and antagonistic interactions of herbal extracts in human organism. Combination of APE and ESE in KJ formulation is most likely justified.
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