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.

The activity of the tumor suppressor p53 is induced in response to DNA-damaging agents such as UV and g radiation. Phosphorylation is one of the key regulatory steps for activating p53 function. Recent reports have shown that p53 is phosphorylated at both serines 15 and 392 in response to UV radiation. Phosphorylation at serine 15 prevents the binding of HDM2, a negative regulator of p53. Phosphorylation at serine 392 induces the DNA-binding function of p53. We examined the requirement for phosphorylation at both serines and show that both these modi®cations occur on the same molecule of p53. In vitro assays demonstrate that phosphorylation at either one of these sites is not sucient to yield an active p53. Phosphorylation by DNA-PK, that modi®es serines 15 and 37, inhibits HDM2 binding to p53 but does not induce the DNA-binding activity of p53. Phosphorylation at serine 392, on the other hand, stimulates the DNA-binding ability of p53 but does not make it immune to binding and inhibition by HDM2. Thus, our results demonstrate that multiple sites need to be modi®ed to yield a functional p53. Oncogene (2000) 19, 358 ± 364.

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