Synergy and Antagonism of Active Constituents of ADAPT-232 on Transcriptional Level of Metabolic Regulation of Isolated Neuroglial Cells

Abstract

Gene expression profiling was performed on the human neuroglial cell line T98G after treatment with adaptogen ADAPT-232 and its constituents – extracts of Eleutherococcus senticosus root, Schisandra chinensis berry, and Rhodiola rosea root as well as several constituents individually, namely, eleutheroside E, schizandrin B, salidroside, triandrin, and tyrosol. A common feature for all tested adaptogens was their effect on G-protein-coupled receptor signaling pathways, i.e., cAMP, phospholipase C (PLC), and phosphatidylinositol signal transduction pathways. Adaptogens may reduce the cAMP level in brain cells by down-regulation of adenylate cyclase gene ADC2Y and up-regulation of phosphodiesterase gene PDE4D that is essential for energy homeostasis as well as for switching from catabolic to anabolic states and vice versa. Down-regulation of cAMP by adaptogens may decrease cAMP-dependent protein kinase A activity in various cells resulting in inhibition stress-induced catabolic transformations and saving of ATP for many ATP-dependant metabolic transformations. All tested adaptogens up-regulated the PLCB1 gene, which encodes phosphoinositide-specific PLC and phosphatidylinositol 3-kinases (PI3Ks), key players for the regulation of NF-κB-mediated defense responses. Other common targets of adaptogens included genes encoding ERα estrogen receptor (2.9–22.6 fold down-regulation), cholesterol ester transfer protein (5.1–10.6 fold down-regulation), heat shock protein Hsp70 (3.0–45.0 fold up-regulation), serpin peptidase inhibitor (neuroserpin), and 5-HT3 receptor of serotonin (2.2–6.6 fold down-regulation). These findings can be reconciled with the observed beneficial effects of adaptogens in behavioral, mental, and aging-associated disorders. Combining two or more active substances in one mixture significantly changes deregulated genes profiles: synergetic interactions result in activation of genes that none of the individual substances affected, while antagonistic interactions result in suppression some genes activated by individual substances. These interactions can have an influence on transcriptional control of metabolic regulation both on the cellular level and the level of the whole organism. Merging of deregulated genes array profiles and intracellular networks is specific to the new substance with unique pharmacological characteristics. Presumably, this phenomenon could be used to eliminate undesirable effects (e.g., toxic effects) and increase the selectivity of pharmacological intervention.

Rhodiola species: A comprehensive review of traditional use, phytochemistry, pharmacology, toxicity, and clinical study

“…To investigate its effects on the transcriptional level of metabolic regulation, gene expression profiling of T98G cells was performed after treatment with ADAPT‐232 (3 and 300 μg/mL). It has been suggested that targets of ADAPT‐232 include G‐protein‐coupled receptor pathways (ie, cAMP, PLC, and PI3K), ERα receptor, CEPT, Hsp70, neuroserpin, and 5‐HT3 receptor, which provides molecular mechanisms of its beneficial effects . Meanwhile, gene expression profiling of T98G cells treated with SHR‐5 (Extract 38 , 40 μg/mL) has been performed, which showed part of results in consistent with ADAPT‐232 .…”

Network pharmacology of cancer: From understanding of complex interactomes to the design of multi-target specific therapeutics from nature

“…We performed gene expression profiling in human T98G neuroglial cells with and without treatment of the herbal mixture ADAPT-232 and its constituents. ADAPT-232 is a herbal mixture consisting of Eleutherococcus senticosus root, Schisandra chinensis berry, and Rhodiola rosea root, which contain several bioactive natural products such as eleutheroside E, schizandrin B, salidroside, triandrin, and tyrosol (148).…”

Application of multi-target phytotherapeutic concept in malaria drug discovery: a systems biology approach in biomarker identification

“…Combination dose response in in vitro antiplasmodial assays over combined dose ranges provide critical information on how different compounds act together to affect different Plasmodium infection outcomes [81]. The method used in combining these plant extracts is known as the fixed ratio method [59] and a modified method of combining them at equipotencies and variable potencies in antiplasmodial assays have been reported to give reproducible results [82, 83]. …”