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Mechanism of action of Rhodiola, salidroside, tyrosol and triandrin in isolated neuroglial cells: an interactive pathway analysis of the downstream effects using RNA microarray data.

ABSTRACT

Aim: The aim of this study was to identify the targets (genes, interactive signaling pathways, and molecular networks) of Rhodiola rosea extract in isolated neuroglia cells and to predict the effects of Rhodiola extract on cellular functions and diseases. In addition, the potential mechanism of action of Rhodiola rosea extract was elucidated, and the "active principle" among the three isolated constituents (salidroside, triandrin, and tyrosol) was identified.

Methods: Gene expression profiling was performed using the T98G human neuroglia cell line after treatment with the Rhodiola rosea SHR-5 extract and several of its individual constituents (salidroside, triandrin and tyrosol). An interactive pathway analysis of the downstream effects was performed using datasets containing significantly up- and down-regulated genes, and the effects on cellular functions and diseases were predicted.

Results: In total, the expression of 1062 genes was deregulated by the Rhodiola extract (631 analyzed, 336 --up-regulated, 295--down-regulated), and 1052,1062, and 1057 genes were deregulated by salidroside, triandrin, and tyrosol, respectively. The analysis of the downstream effects shows that the most significant effects of Rhodiola are associated with cardiovascular (72 deregulated genes), metabolic (63 genes), gastrointestinal (163 genes), neurological (95 genes), endocrine (60 genes), behavioral (50 genes), and psychological disorders (62 genes).

The most significantly affected canonical pathways across the entire dataset, which contains the 1062 genes deregulated by Rhodiola, were the following: (a) communication between innate and adaptive immune cells, (b) eNOS signaling, (c) altered T and B cell signaling in rheumatoid arthritis, (d) axonal guidance signaling, (e) G-protein coupled receptor signaling, (f) glutamate receptor signaling, (g) ephrin receptor signaling, (h) cAMP-mediated, and (i) atherosclerosis signaling pathways.

Genes associated with behavior and behavioral diseases were identified within intracellular signaling pathways (d) through (h). The analysis of the downstream effects predicted decreases in emotional and aggressive behavior, which corroborates the results from preclinical and clinical studies of the use of Rhodiola for the treatment of depression and anxiety. Of the 17 genes that regulate emotional behavior, nine exhibit expression patterns that are consistent with decreases in emotional behavior (z-score -2.529), and all five relevant genes are expressed in a manner consistent with decreases in aggressive behavior (z-score -2.197). A decrease in seizures and infarct sizes and an increase in the chemotaxis of cells were predicted to accompany the decrease in emotional and aggressive behaviors.

Conclusions: Rhodiola exhibits a multi-targeted effect on transcription to regulate the cellular response, affecting the various signaling pathways and molecular networks associated with beneficial effects on emotional behavior, particularly aggressive behavior, and with psychological, neurological, cardiovascular, metabolic, endocrine, and gastrointestinal disorders. Each of the purified compounds has its own pharmacological profile, which is both similar to and different from that of the total Rhodiola extract. In general, several compounds contribute to the specific cellular or/and physiological function of the extract in various diseases.

Keywords:

Pharmacogenomics

Rhodiola rosea

Salidroside

Triandrin

Tyrosol

Introduction

Rhodiola rosea is an 'adaptogen' indicated 'for temporary relief from symptoms of stress such as fatigue and the sensation of weakness' [EMEA, 2102]. Numerous clinical trials have demonstrated that repeated administrations of Rhodiola rosea extract SHR-5 exert anti-fatigue effects that increase mental performance, particularly the ability to concentrate [Darbinyan et al., 1999; Spasov et al., 2000a; Shevtsov et al., 2003], and reduce burnout in patients with fatigue syndrome [Olsson et al., 2009]. Encouraging results have been found for the use of Rhodiola against mild to moderate depression [Darbinyan et al., 2007] and generalized anxiety [Spasov et al., 2000b; Bystritsky et al., 2008]. These data agree with the results of in vitro studies using isolated cells [Asea et al., 2013; Panossian et al., 2012, 2013], nematodes [Wiegant et al., 2008, 2009], and animal models [Panossian et al., 2007, 2008a,b, 2009]. Collectively, the evidence supports the use of Rhodiola for the treatment of mental and behavioral disorders [Panossian and Wikman, 2009, 2010], which are usually treated with synthetic drugs targeting serotonergic, noradrenergic, glutamatergic, and GABA-ergic transmission (Nutt et al., 2002); these synthetic drugs, which have many adverse effects, include selective serotonin reuptake inhibitors (SSRIs), selective serotonin and noradrenalin reuptake inhibitors (SNRIs), and benzodiazepines (Tyrer and Baldwin, 2006).

The pathophysiology of mental and behavioral disorders is a multistaged and complex process that is not limited to the canonical pathways mentioned above. The beneficial stress-protective activity of Rhodiola is associated with several levels of regulation for homeostasis, the hypothalamic-pituitary-adrenal axis [Panossian, 2013], and the key mediators of intracellular communications. These key mediators include molecular chaperons, particularly Hsp70 [Prodius et al., 1997; Panossian et al., 2009; Lishmanov et al., 1996; Wiegant et al., 2008], stress-activated c-Jun N-terminal protein kinase 1 (JNK) [Panossian et al., 2007], forkhead box O (FOX-O) transcription factor DAF-16 [Wiegant et al., 2009], cortisol [Lishmanov et al., 1987; Panossian et al., 2007; Olsson et al., 2009], nitric oxide (NO) [Panossian et al., 2007], and [beta]-endorphin [Lishmanov et al., 1987; Maslov et al., 1997; Maimeskulova et al., 1997] and the biosynthesis of ATP, which changes the energy source [Abidov et al., 2003]. Studies on the anti-depressive and anxiolytic activity of Rhodiola rosea suggest that several of its mechanisms of action may contribute to (i) monoamine-oxidase A inhibition [van Diermen et al., 2009], (ii) monoamine modulation [Stancheva and Mosharrof, 1987], (iii) normalization of 5-HT (7), (iv) HPA-axis modulation (inhibition of cortisol, stress-induced protein kinases, and nitric oxide) (1, 6), and (v) anti-stress effects in animal depression models [Panossian et al., 2008a,b; Perfumi and Mattioli, 2007; Mattioli et al., 2009].

Initially, rhodioloside (syn. salidroside) was discovered to be an active principle in Rhodiola rosea root extract [Aksenova et al., 1968], Further pharmacological studies identified many other active constituents [Panossian et al., 2008a; van Diermen et al., 2009]. Consequently, the total extract is considered an active pharmaceutical ingredient in various Rhodiola rosea extracts, such as SHR-5 and FB300A, which may differ based on their phytochemical and pharmacological profiles. In this study, we tested the effects of the Rhodiola SHR-5 extract and three isolated compounds, specifically salidroside, triandrin, and tyrosol, on the gene expression profiles of isolated human neuroglia cells, which were measured using m-RNA arrays.

This study aimed to identify all of the molecular pathways and networks affected by Rhodiola at the transcriptional level for the regulation of cell responses. Therefore, we analyzed the microarray-based transcriptome-wide mRNA expression profiles of the T98G neuroglial cell line after exposure to Rhodiola rosea SHR-5 extract and three individual active compounds isolated from this plant: salidroside, tyrosol, and triandrin. The T98G neuroblastoma cell line was chosen based on a previous publication [Panossian et al., 2013], An interactive pathway downstream analysis was performed using datasets containing significantly up- or down-regulated genes, and the effects on relevant cellular functions and diseases were predicted and identified.

Materials and methods

Drugs and chemicals

Salidroside and tyrosol were purchased from Chromadex (Irvine, CA). Triandrin was isolated by the Swedish Herbal Institute (SHI) Research and Development (Goteborg, Sweden) and identified through comparison (HPLC, TLC, and UV) with an authentic reference sample that was kindly provided by Prof. Zapesoznaya (Institute of Officinal and Aromatic plants VILAR, Moscow, Russia). Pharmaceutical-grade standardized extracts of R. rosea L. roots were manufactured in accordance with the ICH Q7A and EMEA guidelines for Good Agricultural and Collecting Practice (GACP) and Good Manufacturing Practice (GMP) of active pharmaceutical ingredients (API). The working samples used during the experiments were prepared using diluted stock solutions (5mg/ml) of genuine Radix Rhodiola extract or 10mM solutions of purified analytical markers, specifically salidroside (3 mg/ml), triandrin (3.1 mg/ml), or tyrosol (1.4 mg/ml), in the appropriate volumes of phosphate buffered saline solution (PBS). Aliquots of the working solutions (200 [micro]L) were added to 3 ml of the cell culture to obtain final concentrations of the active markers and genuine extract equal to those obtained in the incubation media containing Rhodiola SHR-5 (Table 1 and Fig. 1).

The 40 [micro]g/ml dose (final concentration of Rhodiola SHR-5 in the incubation media) was chosen based on a recent pharmacokinetic study of Rhodiola rosea-derived salidroside in human blood plasma; we measured concentrations of approximately 1 [micro]g/ml, which equals 3 [micro]M (Panossian et al., 2010).

The concentrations of the total extracts of the three herbal ingredients and their active constituents are compatible in all of the test samples: the final concentration of salidroside was maintained at 3 [micro]M (900 [micro]g/l) across all of the test samples containing salidroside, including the Rhodiola extract. Similarly, the triandrin and tyrosol concentrations were calculated based on an HPLC analysis of their contents in genuine extracts and combinations thereof. The concentration of the genuine Rhodiola extract was calculated using specification to ensure that it corresponds to the therapeutically effective doses.

Cell culture

The T98G human neuroglial cell line was purchased from the American Type Culture Collection (ATCC, CRL-1690). The cells were grown in DMEM + GlutaMAX-1 (Gibco, Darmstadt, Germany) with 10% fetal bovine serum (Gibco, Darmstadt) and 1% penicillin/streptomycin (Gibco, Darmstadt). The cells were passaged twice a week and maintained in a 37[degrees]C incubator under a humidified atmosphere containing 5% C[O.sub.2]. All of the experiments were conducted using cells in the logarithmic growth phase.

Drug treatment

The T98G cells were seeded 24 h before treatment on six-well plates at a density of 150,000 cells per well. The next day, the medium was removed, and the cells were treated in a final volume of 3 ml (Table 1).

The ethanol content of the media of the cells treated with the isolated compounds and the vehicle (control cells) was 0.8%. Two technical replicates were performed for each sample. The cells were incubated with the test substances for 24 h at 37[degrees]C prior to RNA isolation.

mRNA isolation and quality control

The cells were harvested after 24 h of treatment. The total RNA was isolated using the InviTrap Spin Universal RNA Mini kit (Stratec Molecular, Berlin, Germany) and dissolved in RNAse-free water. The RNA from the two technical replicates was combined (1:1) to generate one treatment sample and one control sample. The quality of the total RNA was assessed via gel analysis using the Total RNA Nano chip assay on an Agilent 2100 Bioanalyzer (Agilent Technologies GmbH, Berlin, Germany). All of the samples were of the highest quality and had RIN values of 10.

Gene expression profiling

The microarray hybridizations were performed at the Institute of Molecular Biology (Mainz, Germany). Whole Human Genome RNA chips (8 x 60K Agilent) were used to profile the gene expression. The probe labeling and hybridization procedures were carried out according to the one-color microarray-based gene expression analysis protocol (http://www.chem.agilent.com/Library/ usermanuals/Public/G414090040_GeneExpression.One-color.v6. 5.pdf). Briefly, the total RNA was labeled and converted to cDNA, and fluorescent cRNA (cyanine 3-CTP) was then synthesized. The resulting material was purified using a QIAgen RNeasy Kit. After the cRNA was fragmented, the samples were hybridized for 17 h at 65[degrees]C. The microarray slides were washed and scanned with an Agilent Microarray Scanning system. The images were analyzed, and the data were extracted. The background was subtracted, and the data were normalized using the standard procedures included in the Agilent Feature Extraction Software.

Microarray data analysis

The expression data were analyzed further using the Chipster software (http://chipster.csc.fi/) to filter genes based on their expression and significance. These steps include the filtering of genes to isolate those that were up- or down-regulated between one- and three folds of the standard deviation (depending on the total number of extremely up- or down-regulated genes). A subsequent assessment of the significance of the genes using an empirical Bayes t-test narrowed the pool of genes further. All of the genes that were considered in the subsequent analysis were significantly different (p-value<0.05) compared with the control unless noted otherwise. The filtered data were then subjected to an Ingenuity pathway (Core) analysis to reveal the networks and pathways influenced by the treatments (http://www.ingenuity.com/).

Real-time RT-PCR

The microarray data were validated using real-time RT-PCR as previously described [Panossian et al., 2013].

Interactive pathway analysis (IPA) of complex omics data

The signaling pathways related to the deregulated genes identified via the microarray analyses were determined as previously described (http://www.ingenuity.com/).

Results

A microarray-based transcriptome-wide mRNA expression analysis was performed to identify the possible targets of the tested substances in T98G cells. The T98G cells were treated with the test substances for 24 h in two technical replicates, and the total RNA was then isolated and pooled for microarray hybridization. The significantly deregulated genes were identified relative to the untreated controls (p < 0.05) through an analysis using the Chipster software.

Ingenuity pathway analyses were performed using datasets containing the significantly up- or down-regulated genes: 1062 genes were deregulated by treatment with the Rhodiola extract (631 analyzed, 336 up-regulated, 295 down-regulated), and 1052, 1062, and 1057 genes were deregulated by treatment with salidroside, triandrin, and tyrosol, respectively.

Supplementary Table 1 lists the genes deregulated by more than twofold, as well as their magnitude of change, type, and location within the cell. Table 2 and Fig. 2 show the canonical pathways that were most strongly affected and their associated genes. The most significantly affected canonical pathways across the entire dataset containing the 1062 genes deregulated by Rhodiola were the following: (a) communication between the innate and adaptive immune cells, (b) eNOS signaling, (c) altered T and B cell signaling in rheumatoid arthritis, (d) axonal guidance signaling, (e) G-protein coupled receptor signaling, (f) glutamate receptor signaling, (g) ephrin receptor signaling, (h) cAMP-mediated signaling, and (i) atherosclerosis signaling pathways. Of these pathways, pathways (d) through (h) are associated with behavior and behavioral diseases.

The analysis of the downstream effects shows that the most significant effects of Rhodiola are associated with cardiovascular (72 genes), metabolic (63 genes), gastrointestinal (163 genes), neurological diseases (95 genes), endocrine (60 genes), behavioral (50 genes), and psychological disorders (62 genes). Fig. 3 displays the cellular functions and diseases associated with the genes and genetic networks that showed significant differences in expression after treatment with the test sample.

The analysis of the downstream effects predicted decreases in emotional and aggressive behavior and in neurological and cardiovascular diseases, as shown in Table 3.

The downstream effect analysis of the behavioral cluster showed that 50 genes involved in the regulation of behavior were affected by Rhodiola, as shown in Table 4. Among these, the effects on emotional and aggressive behaviors were predictable. This conclusion agrees with the results of preclinical and clinical studies on the use of Rhodiola for the treatment of depression and anxiety.

Of the 17 genes that regulate emotional behavior, nine exhibited expression levels consistent with decreases in emotional behavior. Therefore, decreases in emotional (z-score -2.529, overlap p-value 4.57E-06) and aggressive behavior were predicted (Tables 3 and 4), and all five relevant genes presented expression levels consistent with decreases in aggressive behavior (z-score -2.197, overlap p-value 5.74E-03), as shown in Table 5.

Fig. 4 shows the molecular network associated with emotional function and the effects of Rhodiola on the related gene expression.

Fig. 5 displays the most significantly affected canonical pathways associated with behavior and behavioral diseases, specifically behavioral disorders. The affected pathways include neuronal signaling pathways, intracellular pathways, and second messenger signaling pathways (Figs. 6-8).

The most significantly influenced pathways are the axonal guidance (Fig. 6 and Table 6), G-protein coupled receptor (Fig. 7 and Table 7), glutamate receptor (Fig. 8 and Table 8), ephrin receptor, and cAMP-mediated pathways.

Table 9 shows the effects of Rhodiola on the genes involved in psychological disorders, and Table 10 shows the effects of this extract on the genes involved in depression.

Of the 14 deregulated genes associated with depressive disorders, 11 encode various proteins located on the cell membrane, particularly receptor proteins (Fig. 9)

ADRAB (associated with alpha2-adrenergic Gi protein-coupled receptor) is one of the up-regulated genes. These sites play an essential role during numerous diseases, including attention deficit hyperactivity disorder, hypertension, cardiovascular disorder, multiple sclerosis, heart disease, post-traumatic stress disorder, stroke, major depression, bipolar disorder, Parkinson's disease, attention deficit disorder, psychomotor agitation, insomnia, mood disorder, anxiety disorder, social anxiety disorder, Alzheimer's disease, panic disorder, depressive disorder, and psychosis.

In addition to decreases in emotional and aggressive behaviors, decreases in seizures (8 of 17 affected genes exhibit a change in expression direction consistent with decreases in seizures, as shown in Table 11, overlap p-value 6.66E-03, activation z-score -2.2) and infarct sizes (7 of 9 affected genes exhibit a change in expression direction consistent with decreases in size of infarct sizes, as shown in Tables 12 and 13, overlap p-value 1.72E-03, activation z-score -2.157) were predicted.

An increase in cell chemotaxis (p-value 8.05E-04, activation z-score -2.206) was also predicted because 16 of 23 affected genes exhibited a change in expression direction consistent with an increase in chemotaxis.

Among affected genes in total of 256 genes are involved in cancer; however only for 27 genes, (Table 14) relationship between increased expression and tumor growth is known (Table 14). Based on gene expression direction of 14 genes, namely CCR2, CXCL6, DACT2, ELF5, ENAH, ESR1, FLT1, LIN28B, NCAM1, NOX4, SERPINA1, TLE1, TLR7, XRCC5, it can be concluded that Rhodiola may have beneficial effect in cancer, that is in line with growing body of evidence about antitumor activity of Rhodiola and salidroside [Cai et al., 2012; Zhang et al., 2013; Liu et al., 2012; Bocharova et al., 1995; Dement'eva and laremenko, 1987]. However effects on expression of 5 other genes, CDKN2C, FHL1, HGF, IL1RL1, CD53, are associated with tumor growth and carcinogenesis. Therefore, at this stage of knowledge it is not possible to predict overall effect of Rhodiola in cancer, based on the data available from this study and indirect literature data.

Tables 15-19 demonstrate the similarities and differences between the effects of the Rhodiola extract and those of the purified compounds isolated from the extract (salidroside, triandrin, and tyrolsol) on the following:

--gene expression profiles (Table 15) of isolated neuroglia cells,

--canonical pathways (Table 19),

--molecular and cellular functions (Table 17),

--physiological system functions (Table 18), and

--diseases and disorders (Table 16) associated with these effects.

Discussion

The mechanisms utilized by the Rhodiola extract have been studied extensively. The mechanisms through which SHR-5 and its active constituents act on human emotion and behavior have been studied using isolated cells and through analyses of hormones and stress markers in animals. These studies have shown that the anti-depressive effects of SHR-5 and salidroside presumably operate in tandem with their effects on the following:

--the NPY-Hsp70-mediated effects on glucocorticoid receptors, including the expression and release of neuropeptide Y (NPY) and stress-activated proteins (Hsp70 and JNK); the activation of neuropeptide Y expression (Panossian et al., 2012), which is low during depression: and the activation of Hsp72 expression (Panossian et al., 2012), which inhibits stress-activated protein kinase JNK, a protein that plays an important role during the suppression of glucocorticoid receptors and consequently induces increases in cortisol expression during stress and depression (Panossian et al., 2007), the down-regulation of some G-protein coupled receptors, particularly the serotonin receptors in isolated neuroglia cells (Panossian et al., 2013), and

--the down-regulation of the estrogen alpha receptors in isolated neuroglia cells (Panossian et al., 2013).

The proposed mechanisms underlying the effect of Rhodiola on cognitive function, memory, learning, and attention are the following;

* the partial deregulation of GPCR, including the down-regulation of serotonin 5-HT3 GPCR,

* the deregulation of cAMP followed by the closure of hyperpolarization-activated channels,

* the up-regulation of P13K, which is required for the long-term potentiation of neurons,

* the up-regulation of IP3, which is important for inducing plasticity in cerebellar Purkinje cells,

* the up-regulation of the SERPINIi gene (serpin peptidase inhibitor, neuroserpin), which plays an important role in synapse development and regulates synaptic plasticity, and

* the normalization of cortisol homeostasis (Panossian et al., 2013).

In this study, we found many other intracellular targets for Rhodiola and its active constituents. Fig. 10 shows the scope and limitations of the conclusions based on this study.

During our study, we assessed gene expression in isolated neuroglia cells exposed to Rhodiola extract or one of its active constituents (salidroside, triandrin, and tyrosol) by analyzing mRNA arrays. An additional interactive pathway downstream analysis of the mRNA microarray data predicted the effects of Rhodiola on cellular functions, biological processes, and pharmacological activity. These effects exclude any possible interactions between Rhodiola at the metabolomics level of cellular response regulation and posttranslational steps, including agonistic or antagonistic effects on the receptors and effects on the allosteric regulation of enzymes that bind with cofactors.

The mechanisms of action (MOA) discussed above are related to a substance that consists of many compounds; this substance is extracted from dry roots and is called the "total extract". Total extracts are usually characterized using content marker compounds; these compounds, including salidroside, are found to be active toward some isolated cells, animals, and humans through some/various bioassays.

Initially, rhodioloside (syn. salidroside) was discovered to be an active principle of Rhodiola rosea root extract [Aksenova et al., 1968]. Further pharmacological studies identified many other active constituents; however, there is limited information regarding their activity and clinical importance [Panossian et al., 2008a,b; van Diermen et al., 2009] because these compounds lack sufficient scientific scrutiny. Consequently, the total extract is as an active pharmaceutical ingredient in various Rhodiola Rosea extracts, such as SHR-5 and FB300A; this substance may vary depending on its phytochemical and pharmacological profiles. In this study, we tested the effects of Rhodiola SHR-5 extract and three isolated compounds (salidroside, triandrin, and tyrosol) on the gene expression profile of isolated human neuroglia cells using an n-RNA array.

Furthermore, we analyzed the similarities and differences between the effects of the Rhodiola extract and those of the compounds isolated from the extract (salidroside, triandrin, and tyrosol):

--gene expression profiles (Table 15) in isolated neuroglia cells,

--canonical pathways (Table 19),

--molecular and cellular functions (Table 17),

--physiological system functions (Table 18), and

--diseases and disorders (Table 16) associated with these effects.

Fig. 11 shows Venn diagrams depicting the deregulated genes, and these reveal the common and unique aspects of each individual compound relative to the genes. Therefore, 265 (!) target genes are shared by the three compounds (Fig. 11a). Notably, only 153 of these 265 genes are targeted by the Rhodiola total extract, whereas 112 remain unaffected due to the antagonistic interactions of molecular networks, as discussed in a previous publication [Panossian et al., 2013], Therefore, the biological activity of the Rhodiola total extract differs from the activity of the purified compounds; however, some pharmacological features associated with these 112 inactive genes that are associated with the pure substances cannot be observed with the extract.

Consequently, each purified compound exhibited its own pharmacological profile, which presents with similarities to and differences from the profile obtained after treatment with the total Rhodiola extract. In general, several compounds contribute to the specific cellular or/and physiological functions associated with various diseases. The results of this study support both the principles of pharmacognosy based on the "magic bullet" model and the concept of multi-targeted therapy. Both of these concepts are relevant depending on the application, which is to develop a new specific drug from a complex or to develop a drug with a novel MOA.

Based on the results obtained during this study, we can draw some additional conclusions. Rhodiola has a multi-targeted effect at the transcriptional level on cell response regulation, affecting various signaling pathways and molecular networks associated with beneficial effects on emotional behavior, particularly aggressive behavior, as well as psychological, neurological, cardiovascular, metabolic, endocrine, and gastrointestinal disorders.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.phymed. 2014.07.008.

Conflict of interest

R.H., T.E., and A.P. declare no competing financial interests. G.W. is a stockholder in the Swedish Herbal Institute (SHI).

ARTICLE INFO

Article history:

Received 6 May 2014

Accepted 10 July 2014

Acknowledgements

This work was supported in part by the Swedish Herbal Institute (A.P., G.W.). We are indebted to Dr. Tolga Eichhorn (Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Mainz Germany) for his scientific discussions.

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Alexander Panossian (a), *, Rebecca Hamm (b), Georg Wikman (a), Thomas Efferth (b)

(a) Swedish Herbal Institute Research and Development, Goteborg, Sweden

(b) Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany

* Corresponding author at: Swedish Herbal Institute Research and Development, Grondalsgatan 11 A, SE-412 62 Goteborg, Sweden. Tel.: +46 702818171.

E-mail addresses: alexander.panossian@shi.se, ap.phytomedicine@telia.com, ap@shi.se (A. Panossian).

http://dx.doi.org/10.1016/j.phymed.2014.07.008

Table 1
Concentrations used to treat T98G neuroglial cells during the
microarray experiments.

Drug               Concentration    Designation

Rhodiola extract   40 [micro]g/ml   Test sample F
Salidroside (I)    3 [micro]M       Test sample I
Triandrin (II)     1.5 [micro]M     Test sample J
Tyrosol (III)      3 [micro]M       Test sample K

Table 2
Most significantly affected canonical pathways across the dataset
containing the 1094 genes deregulated by Rhodiola.

Ingenuity canonical pathways         -log (p-value) (a)   Ratio (b)

Communication between innate and     3.6E00               7.14E-02
adaptive immune cells

eNOS signaling                       3.18E00              5.81E-02

Altered T cell and B cell            3.01E00              7E-02
signaling in rheumatoid
arthritis

Dendritic cell maturation            2.8E00               4.74E-02

Axonal guidance signaling            2.64E00              3.52E-02

G-protein coupled receptor           2.55E00              4.35E-02
signaling

Stearate biosynthesis 1 (animals)    2.44E00              8.16E-02

Glutamate receptor signaling         2.36E00              6.94E-02

Ephrin receptor signaling            2.32E00              4.29E-02

Atherosclerosis signaling            2.18E00              5.07E-02

cAMP-mediated signaling              2.14E00              4.42E-02

Maturity onset diabetes of young     2.09E00              9.09E-02
(MODY) signaling

NF-[kappa]B signaling                1.95E00              4.6E-02

Ephrin A signaling                   1.95E00              7.41E-02

1L-12 signaling and production in    1.94E00              4.46E-02
macrophages

Leptin signaling in obesity          1.93E00              5.88E-02

Intrinsic prothrombin activation     1.86E00              8.11E-02
pathway

Primary immunodeficiency             1.83E00              6.25E-02
signaling

Cytokines in communication           1.75E00              7.27E-02
between immune cells

Thiamin salvage 111                  1.74E00              2E-01

TR/RXR activation                    1.71E00              4.59E-02

LXR/RXR activation                   1.63E00              4.32E-02

Coagulation system                   1.59E00              7.89E-02

tRNA splicing                        1.59E00              6.52E-02

Cellular effects of viagra           1.51E00              3.87E-02

Estrogen biosynthesis                1.5E00               6.12E-02

Ingenuity canonical pathways         Molecules/genes

Communication between innate and     TLR10,CD40LG,IL12B,HLA-B,TLR8,
adaptive immune cells                TLR7,IGHA1,TNFRSF17

eNOS signaling                       ADCY2,PRKGI,FLTI,PIK3C2G,CHRNB4,
                                     CNGB3,AQP4,ESR1,AQP2

Altered T cell and B cell            IL21,TLR10,CD40LG,IL12B,TLR8,
signaling in rheumatoid              TLR7,TNFRSF17
arthritis

Dendritic cell maturation            CD1D,CD40LC,IL12B,LEPR,ZBTB12,
                                      HLAB,COL2A1,PIK3C2G,CD1C ,PLCD4

Axonal guidance signaling            EPHA7,RGS3,PIK3C2G,WNT16,EPHA3,
                                     NTNG1,EPHA6,EPHB1, ADAM30,
                                     SEMA6D,SEMA3D,GNAT1,MMP8,UNC5D,
                                     PAK7,ADAM29,PLCD4

G-protein coupled receptor           ADRA2B,ADCY2,RGS18,PDE3A,CNR1,
signaling                            TAAR1,CALCR,PIK3C2G,PDE11A,
                                     PDE4D,AVPR1A,MC4R

Stearate biosynthesis 1 (animals)    SLC27A2,CYP2E1,ELOVL2,ACOT4

Glutamate receptor signaling         SLC17A8,GRIN1,SLC17A6,GRIK2,GRIA3

Ephrin receptor signaling            EPHA7,EPHA6,GRIN1,EPHB1,RGS3,
                                     GNAT1,PIK3C2G,PAK7,EPHA3

Atherosclerosis signaling            CD40LG,APOA2,LPL,COL2A1,ALOX12,
                                     SERPINA1,CCR2

cAMP-mediated signaling              ADRA2B,ADCY2,RGS18,PDE3A,CNR1,
                                     TAAR1,CNGB3,PDE11A,PDE4D,MC4R

Maturity onset diabetes of young     SLC2A2,FABP1,HNF1A
(MODY) signaling

NF-[kappa]B signaling                TLR10,CD40LC,FLT1,TLR8,TLR7,
                                     PIK3C2G,BMPR1B,TNFRSF17

Ephrin A signaling                   EPHA7,EPHA6,PIK3C2G,EPHA3

1L-12 signaling and production in    CD40LG,IL12B,APOA2,IFNA7,PIK3C2G,
macrophages                          ALOX12,SERPINA1

Leptin signaling in obesity          ADCY2,LEPR,PDE3A,PIK3C2G,PLCD4

Intrinsic prothrombin activation     F10,CO2A1,FGB
pathway

Primary immunodeficiency             CD40LG,IGHM,IGHA1,AICDA
signaling

Cytokines in communication           IL21,IL20,IL12B,IFNA7
between immune cells

Thiamin salvage 111                  TPK1

TR/RXR activation                    F10,RXRG,DIO1,UCP1,PIK3C2C

LXR/RXR activation                   RXRG,IL1RL1,APOA2,LPL,SERPINA1,
                                     CETP

Coagulation system                   F10,SERPINA1,FGB

tRNA splicing                        PDE3A,PDE11A,PDE4D

Cellular effects of viagra           ADCY2,PRKG1,GPR37,PDE3A,PDE4D,
                                     PLCD4

Estrogen biosynthesis                HSD17B13,CYP2E1,CYP4X1

(a) Fisher's exact test.

(b) The ratio was calculated as follows: # of genes in a given
pathway that meet the cutoff criteria divided by total # of genes
that make up that pathway.

Table 3
Predicted effects of Rhodiola on behavioral disorders and
neurological and cardiovascular diseases. The effects were determined
using data of the deregulated genes and downstream effects.

Category         Disease or function   p-Value    Predicted
                 annotation                       activation state

Behavior         Emotional behavior    4.57E-06   Decreased

Behavior         Aggressive behavior   5.74E-03   Decreased

Neurological     Seizures              6.66E-03   Decreased
disease

Cardiovascular   Size of infarct       1.72E-03   Decreased
disease

Category         Activation   Molecules                     #
                 z-score (a)                                molecules

Behavior         -2.529       AVPRIA,CCR2,CNR1,ESR1,GCN     17
                              T4,GRIK2,GRIN1,IRS4,LEPR,NP
                              S,PAK7,RIMSI,SLCI7A6,SLC17
                              A8,SLC9A1,TACR3,XRCC5

Behavior         -2.197       CNR1,ESR1,GCNT4,LEPR,PAK7     5

Neurological     -2.203       CA9,CHRNB4,CNR1,GRIK2,GRI     17
disease
                              N1,KAL1,KCNK2,NCAM1,NR4A
                              3,PIK3C2G,RIMS1,SCN10A,SCN
                              11A,SCN2B,SLC17A8,SLC9A1,T
                              IPARP

Cardiovascular   -2.157       CCR2,CD40LG,CNR1,FGB,GP6,H    9
disease                       GF,HLA-B,NOX4,PPP1R1A

(a) The z-score measures how much a particular value, such as x,
differs from the mean value, denoted m. This difference (x-m) is
then divided by the standard deviation (SD) to provide the z-score;
z=(x-m)/SD; z<-2 or z> 2 implies significance.

The z-score (normal scores, standardized variable) is the number of
standard deviations that an observation is above the mean; z =
(x-m)/SD, where: x--is the raw score, m--is the mean, and SD--is the
standard deviation. The absolute value of z represents the distance
between the raw score and the mean in units of the standard
deviation.

Table 4
Predicted effects of Rhodiola on behavioral disorders. The effects
were determined based on the deregulated genes and data from the
downstream effect analysis.

Disease or function     p-Value    Predicted          Activation
annotation                         activation state   z-score

Behavior                7.69E-07                      -0.240

Emotional behavior      4.57E-06   Decreased          -2.529

Locomotion              3.08E-04                      0.820

Licking behavior        3.12E-04

Nurture                 6.69E-04

Active avoidance        1.49E-03
response

Social behavior         1.71E-03

Self-administration     3.18E-03
of cocaine

Conditioning            4.12E-03                      0.728

Sexual receptivity      4.72E-03
of female organism

Maternal nurturing      4.87E-03

Aggressive              5.74E-03   Decreased          -2.197
behavior

Ingestion of            5.87E-03                      0.415
ethanol

Aggressive              6.22E-03
behavior toward males

Abnormal circadian      7.11E-03
phase

Appetite                1.02E-02

Maternal behavior       1.02E-02

Disease or function     Molecules                          # Molecules
annotation

Behavior                AQP4,AVPR1A,BMPR1B,CCKBR,CCR2,     45
                        CHRNG,CNR1,CYP2E1,CYP46AI,DDC,
                        EPHA,ESR1,FABP1,GCNT4,GNAT3,
                        GRIK2,GRIN1,HNF4G,IRS4,LEPR,
                        MC4R,MTM1,MTNR1A,NCAM1,NPS,
                        NR4A3,PAK7,PDE11A,PRKG1,RIMSI,
                        RXRG,SCN11A,SCN2B,SLC17A6,
                        SLC17A8,SLC9A1,SMTNL1,SNRPN,
                        TAAR1,TACR3,TAS1R2,TAS1R3,
                        TAS2R4,TBX1,XRC5

Emotional behavior      AVPR1A,CCR2,CNR1,ESR1,GCNT4,GRl    17
                        K2,GRIN1,IRS4,LEPR,NPS,PAK7,
                        RIMS1,SLCl76,SLC17A8,SLC9A1,
                        TACR3,XRCC5

Locomotion              ALK,CCKBR,CHRNB4,CNR1,DAB1,        17
                        ESR1,GPR7,GRlA3,GRIN1,HNF4G,
                        MC4R,NCAM1,NPS,PDE11A,RIMS1,
                        RXRG,SLC17A6

Licking behavior        ESRI,TAS1R2,TAS1R3                 3

Nurture                 ESRI,GRIN1,IRS4,RIMS1,XRCC5        5

Active avoidance        CNR1,PAK7,TACR3                    3
response

Social behavior         AVPR1A,CNR1,GRIN1,PDE11A,RIMS1,    6
                        TBX1

Self-administration     NPS,SLC17A6                        2
of cocaine

Conditioning            ALK,BMPR1B,CCR2,CNR1,EPHA6,        10
                        ESR1,GR,GRIN1,NCAM1,SLC17A6

Sexual receptivity      AVPR1A,ESR1                        2
of female organism

Maternal nurturing      ESR1,IRS4,RIMS1,XRCC5              4

Aggressive              CNR1,ESR1,GCNT4,LEPR,PAK7          5
behavior

Ingestion of            CCR2,CNR1,GRIA3,NPS                4
ethanol

Aggressive              ESR1,GCNT4,PAK7                    3
behavior toward males

Abnormal circadian      MC4R,MTNR1A,NCAM1                  3
phase

Appetite                LEPR,MC4R,SLC17A6                  3

Maternal behavior       AVPR1A,ESR1,IRS4                   3

Table 5
Effect of Rhodiola on genes associated with emotional and aggressive
behavior.

Gene ID   Entrez Gene Name and summary-target protein;
          http://www.ncbi.nlm.nih.gov/gene/

ESR1      Estrogen receptor 1
          This gene encodes an estrogen receptor, specifically a
          ligand-activated transcription factor composed of several
          domains that are important for hormone binding, DNA
          binding, and transcription activation. The protein
          localizes at the nucleus. Estrogen and its receptors are
          essential for sexual development, reproductive function,
          and the development of other tissues, such as bone.
          Estrogen receptors are also involved in pathological
          processes, including breast cancer, endometrial cancer, and
          osteoporosis.

CNR1      This gene encodes one of two guanine-nucleotide-binding GPCR
          proteins, which inhibit adenylate cyclase activity and are
          involved in the cannabinoid-induced CNS effects (including
          alterations in mood and cognition) experienced by users of
          marijuana.

LEPR      Leptin receptor. This protein is a receptor for leptin (an
          adipocyte-specific hormone that regulates body weight) and
          is involved in the regulation of fat metabolism and of a
          novel hematopoietic pathway required for normal
          lymphopoiesis.

GRIK2     Glutamate receptor--the predominant excitatory
          neurotransmitter receptor inthe brain activated during
          various normal neurophysiologic processes. It is involved
          in the following: the negative regulation of synaptic
          transmission and glutamatergic and neuron apoptotic
          processes; the positive regulation of neuron apoptotic
          process and synaptic transmission; and the regulation of
          action potentials in a neuron, the JNK cascade, and the
          long-and short-term neuronal synaptic plasticity and
          transmission. Mutations in this gene have been associated
          with autosomal recessive mental retardation.

PAK7      The protein encoded by this gene is a member of the PAK
          family of Ser/Thr protein kinases that regulate
          cytoskeletal dynamics, proliferation, and cell survival
          signaling. This kinase is predominantly expressed in the
          brain; it can promote neurite outgrowth and thus might
          affect neurite development, learning, locomotor behavior,
          and memory;

AVPR1A    The protein encoded by this gene acts as a GPC receptor for
          arginine vasopressin. Its activity is mediated by
          G-proteins that stimulate a phosphatidylinositol-calcium
          second messenger system. The receptor mediates cell
          contraction and proliferation, platelet aggregation,
          release of coagulation factor, and glycogenolysis. It is
          involved in social behavior, maternal aggressive behavior,
          negative regulation of transmission of nerve impulse,
          regulation of corticotropin secretion, penile erection,
          sperm ejaculation, etc.

SLC17AS   This gene encodes a vesicular glutamate transporter. The
          encoded protein transports glutamate into the synaptic
          vesicles before it is released into the synaptic cleft.

GCNT4     This gene encodes an enzyme called N-acetyl lactosaminide
          beta-1,6-N-acetylglucosaminyl-transferase, which is
          involved in the regulation of carbohydrates, proteins, and
          thyroid hormone metabolism, post-translational protein
          modification, protein 0-linked glycosylation, inter-male
          aggressive behavior, etc.

NPS       This gene encodes a neuropeptide that is involved in the
          regulation of the action potential, the positive regulation
          of GABAergic synaptic transmission, the positive regulation
          of synaptic transmission, and visual learning.

GRIN1     Glutamate receptor, ionotropic, N-methyl D-aspartate 1.
          The protein encoded by this gene is a critical subunit of
          the N-methyl-D-aspartate receptors, which are members of
          the glutamate receptor channel superfamily. These
          heteromeric protein complexes have multiple subunits
          arranged to form a ligand-gated ion channel. These subunits
          are critical for the plasticity of synapses, which supports
          memory and learning.

CCR2      The receptors encoded by this gene mediate the
          agonist-dependent calcium mobilization and the inhibition
          of adenylyl cyclase.

SLC17A6   This gene encodes a glutamate transporter that is involved
          in the regulation of neurotransmitter transport and uptake.

IRS4      IRS4 encodes the insulin receptor substrate 4, which is a
          cytoplasmic protein that contains many potential tyrosine
          and serine/threonine phosphorylation sites. The
          tyrosine-phosphorylated IRS4 protein associates with
          cytoplasmic signaling molecules that contain SH2 domains.
          The IRS4 protein is involved in insulin-like growth factor
          receptor and insulin receptor-mediated signal transduction.

RIMS1     The protein encoded by this gene is a RAS gene superfamily
          member that regulates synaptic vesicle exocytosis. This
          gene regulates the voltage-gated calcium channels during
          neurotransmitter and insulin release, glutamate secretion,
          long-term synaptic potentiation, neuronal synaptic
          plasticity, neurotransmitter secretion and transport, the
          positive regulation of synaptic vesicle fusion to the
          presynaptic membrane, and visual perception.

XRCC5     The protein encoded by this gene is the 80-kilodalton
          subunit of the ATP-dependent DNA helicase II or DNA repair
          protein XRCC5 and is involved in the repair of
          double-stranded DNA breakage. It is involved in brain
          development, DNA recombination, DNA repair, the positive
          regulation of neurogenesis, etc.

SLC9A1    The encoded protein is a plasma membrane transporter that
          plays a central role in regulating pH homeostasis. It is
          involved in neuronal death, the positive regulation of the
          action potential, apoptotic processes, the positive
          regulation of cell growth, mitochondrial membrane
          permeability, protein oligomerization, proton transport,
          transmembrane transport, etc.

TACR3     This gene belongs to a family of genes that function as
          GPCR receptors for tachykinins. These genes regulate aging,
          the neuropeptide signaling pathway, dopamine metabolic
          processes, feeding behavior, the response to morphine,
          signal transduction, synaptic transmission, etc.

Gene ID   Prediction (based on change in             Fold change
          expression direction)

ESR1      Decreased                                  -7.516
          ESR1 is known to increase emotional
          behavior and is down-regulated by
          Rhodiola; therefore, it is predicted to
          decrease emotional behavior.

CNR1      Decreased                                  3.182
          CNRI is known to decrease emotional
          behavior and is up-regulated by
          Rhodiola; therefore, it is predicted to
          decrease emotional behavior.

LEPR      Decreased                                  2.676
          LEPR is known to decrease emotional
          behavior and is up-regulated by
          Rhodiola; therefore, it is predicted to
          decrease emotional behavior.

GRIK2     Decreased                                  -3.182
          GRIK2 is known to increase emotional
          behavior and is down-regulated by
          Rhodiola; therefore, it is predicted to
          decrease emotional behavior.

PAK7      Decreased                                  -3.095
          PAK7 is known to increase emotional
          behavior and is down-regulated by
          Rhodiola; therefore, it is predicted to
          decrease emotional behavior.

AVPR1A    Decreased                                  -3.482
          AVPR1A is known to increase
          emotional behavior and is
          down-regulated by Rhodiola; therefore,
          it is predicted to decrease emotional
          behavior.

SLC17AS   Decreased                                  4.317
          SLC17A8 is known to decrease
          emotional behavior and is
          up-regulated by Rhodiola; therefore, it
          is predicted to decrease emotional
          behavior.

GCNT4     Decreased                                  2.809
          GCNT4 is known to decrease emotional
          behavior and is up-regulated by
          Rhodiola; therefore, it is predicted to
          decrease emotional behavior.

NPS       Decreased                                  2.848
          NPS is known to decrease emotional
          behavior and is up-regulated by
          Rhodiola; therefore, it is predicted to
          decrease emotional behavior.

GRIN1     Increased                                  3.864
          GRIN1 is known to increase emotional
          behavior and is up-regulated by
          Rhodiola; therefore, it is predicted to
          increase emotional behavior.

CCR2      Affected                                   -3.010
          The literature indicates that this gene
          is involved in emotional behavior but
          does not indicate whether it increases
          or decreases the function.

SLC17A6   Affected                                   -2.751

IRS4      Affected                                   -3.555

RIMS1     Affected                                   4.532

XRCC5     Affected                                   4.627

SLC9A1    Affected                                   3.340

TACR3     Affected                                   -2.676

Gene ID   Findings and references

ESR1      Increases (Ogawa et al., 1997)

CNR1      Decreases (Martin et al., 2002)

LEPR      Decreases (O'Rahilly et al., 2003)

GRIK2     Increases (Ko et al., 2005)

PAK7      Increases (Nekrasova et al., 2008)

AVPR1A    Increases (Bielsky et al., 2004)

SLC17AS   Decreases (Stone et al., 2009)

GCNT4     Decreases (Amilhon et al., 2010)

NPS       Decreases (Rizzi et al., 2008)

GRIN1     Increases

CCR2      Affects

SLC17A6   Affects

IRS4      Affects

RIMS1     Affects

XRCC5     Affects

SLC9A1    Affects

TACR3     Affects

Table 6
Genes involved in axonal guidance pathway that are deregulated by
Rhodiola.

Symbol    Entrez gene name

WNT16     Wingless-type MMTV integration site family, member 16

PLCD4     Phospholipase C, delta 4

ADAM29    ADAM metallopeptidase domain 29

MMP8      Matrix metallopeptidase 8 (neutrophil collagenase)

EPHA6     EPH receptor A6

PAK7      p21 protein (Cdc42/Rac)-activated kinase 7

EPHA7     EPH receptor A7

EPHA3     EPH receptor A3

SEMA6D    Serna domain, transmembrane domain
          (TM), and cytoplasmic domain, (semaphorin) 6D

ADAM30    ADAM metallopeptidase domain 30

UNC5D     Unc-5 homolog D (C. elegans)

SEMA3D    Serna domain, immunoglobulin domain
          (Ig), short basic domain, secreted.
          (semaphorin) 3D

GNAT1     Guanine nucleotide binding protein (G-protein), alpha
          transducing activity polypeptide 1

NTNG1     Netrin G1

RGS3      Regulator of G-protein signaling 3

PIK3C2G   Phosphatidylinositol-4-phosphate 3-kinase, catalytic
          subunit type 2 gamma

EPHB1     EPH receptor B1

Symbol    Fold change   Location              Type(s)

WNT16     -7.781        Extracellular space   Other

PLCD4     -5.098        Cytoplasm             Enzyme

ADAM29    -4.993        Plasma membrane       Peptidase

MMP8      -3.227        Extracellular space   Peptidase

EPHA6     -3.095        Plasma membrane       Kinase

PAK7      -3.095        Nucleus               Kinase

EPHA7     -2.888        Plasma membrane       Kinase

EPHA3     -2.868        Plasma membrane       Kinase

SEMA6D    -2.751        Plasma membrane       Other

ADAM30     2.848        Plasma membrane       Peptidase

UNC5D      3.272        Plasma membrane       Other

SEMA3D     3.605        Extracellular space   Other

GNAT1      3.681        Plasma membrane       Enzyme

NTNG1      4.056        Extracellular space   Other

RGS3       5.134        Nucleus               Other

PIK3C2G    6.589        Cytoplasm             Kinase

EPHB1      6.821        Plasma membrane       Kinase

Table 7
Genes involved in GPCR signaling pathways that are deregulated by
Rhodiola.

Symbol    Entrez gene name

PDE3A     Phosphodiesterase 3A, cGMP-inhibited

PIK3C2G   Phosphatidylinositol-4-phosphate 3-kinase, catalytic
          subunit type 2 gamma

PDE11A    Phosphodiesterase 11A

MC4R      Melanocortin 4 receptor

PDE4D     Phosphodiesterase 4D, cAMP-specific

TAAR1     Trace amine associated receptor 1

CNR1      Cannabinoid receptor 1 (brain)

RGS18     Regulator of G-protein signaling 18

ADRA2B    Adrenoceptor alpha 2B

CALCR     Calcitonin receptor

AVPR1A    Arginine vasopressin receptor 1A

ADCY2     Adenylate cyclase 2 (brain)

Symbol    Fold change   Location          Type(s)

PDE3A      9.000        Cytoplasm         Enzyme

PIK3C2G    6.589        Cytoplasm         Kinase

PDE11A     5.776        Cytoplasm         Enzyme

MC4R       4.659        Plasma membrane   G-protein Coupled Receptor

PDE4D      4.028        Cytoplasm         Enzyme

TAAR1      3.945        Plasma membrane   G-protein Coupled Receptor

CNR1       3.182        Plasma membrane   G-protein Coupled Receptor

RGS18      3.053        Cytoplasm         Other

ADRA2B     2.928        Plasma membrane   G-protein Coupled Receptor

CALCR      2.713        Plasma membrane   G-protein Coupled Receptor

AVPR1A    -3.482        Plasma membrane   G-protein Coupled Receptor

ADCY2     -3.681        Plasma membrane   Enzyme

Table 8
Genes associated with the glutamate receptor signaling
pathway that are deregulated by Rhodiola.

Symbol    Entrez gene name

SLC17A8   Solute carrier family 17 (vesicular glutamate transporter),
          member 8

GRIN1     Glutamate receptor, ionotropic, N-methyl-D-aspartate 1

GRIA3     Glutamate receptor, ionotropic, AMPA 3

SLC17A6   Solute carrier family 17 (vesicular glutamate transporter),
          member 6

GRIK2     Glutamate receptor, ionotropic, kainate 2

Symbol    Fold change   Networks   Location          Type(s)

SLC17A8    4.317        17         Plasma membrane   Transporter

GRIN1      3.864        7          Plasma membrane   Ion channel

GRIA3      3.031        7          Plasma membrane   Ion channel

SLC17A6   -2.751        12,14      Plasma membrane   Transporter

GRIK2     -3.182        7          Plasma membrane   Ion channel

Table 9
Effect of Rhodiola on genes involved in psychological diseases.

Disease or          p-Value    Molecules                   # Molecules
function
annotation

Substance-related   6.98E-06   ADRA2B,APOA2,AVPR1A,CA9,    13
disorders                      CHRNA1,CHRNB4,CHRNG,
                               CNR1,DDC,GRIN1,PDE4D,
                               SCN11A,SCN2B

Addiction           1.62E-04   ADRA2B,APOA2,CA9,CHRNA1,    10
                               CHRNB4,CHRNG,CNR1,DDC,
                               SCN11A,SCN2B

Mood disorders      3.73E-04   ADRA2B,ALOX12,AQP4,CA9,     22
                               CACNB2,CCKBR,CHRNA1,CHR
                               NB4,CHRNG,DDC,ESR1,GRIA3,
                               GRIK2,GRIN1,KCNK2,MTNR1A,
                               MYOM1,NCAM1,NDUFS7,
                               PDE11A,SCN11A,SCN2B

Depressive          7.90E-04   ADRA2B,AQP4,CACNB2,         14
disorder                       CCKBR,CHRNA1,CHRNB4,
                               CHRNG,ESR1,CRIA3,GRIN1,
                               KCNK2,MYOM1,NCAM1,PDE11A

Tauopathy           8.33E-04   ADRA2B,APOA2,CETP,CNR1,     24
                               CYP46A1,DCX,DDC,ESR1,GNR
                               HR,GRIA3,GRIN1,IGHM,LPL,
                               MRC1,MTNR1A,PARP15,PDE3A,
                               RAB6A,REG1A,SCN10A,
                               SCN11A,SCN2B,SERPINA1,
                               SLC2A2

Tobacco-related     1.36E-03   CHRNA1,CHRNB4,CHRNG,DDC      4
disorder

Alcoholism          1.95E-03   ADRA2B,APOA2,CA9,CHRNA1,     8
                               CHRNB4,CHRNG,SCN11A,SCN2B

Alzheimer's         4.51E-03   ADRA2B,APOA2,CETP,CNR1,     21
disease                        CYP46A1,DCX,DDC,ESR1,GNR
                               HR,GRIA3,GRIN1,IGHM,LPL,
                               MRC1,MTNR1A,PARP15,
                               PDE3A,RAB6A,REG1A,
                               SERPINA1,SLC2A2

Bipolar disorder    6.13E-03   ADRA2B,ALOX12,CA9,CACNB2,   14
                               DDC,ESR1,CRIA3,CR1K2,
                               GRIN1,MTNR1A,NCAM1,
                               NDUFS7,SCNUA,SCN2B

Schizoaffective     6.32E-03   ADRA2B,CHRNA1,CHRNB4,        6
disorder                       CHRNG,ESR1,MTNR1A

Pervasive           6.55E-03   ADRA2B,DCX,GRIN1,SNRPN,      5
developmental                  TCF7L2
disorder

Delirium            7.91E-03   ADRA2B,CHRNA1,CHRNB4,        5
                               CHRNG,GRIN1

Disorder of the     9.49E-03   ADCY2,ADRA2B,AP1S2,AQP4,    28
basal ganglia                  BBOX1,CCKBR,CNR1,DDC,
                               GPR88,GRIK2,GRIN1,HLA-B,
                               KCNJ4,KCNK2,LPL,MTNR1A,
                               PDE4D,PFKFB1,PPP1R1A,
                               RAB6A,RXRG,SCN10A,SCN11A,
                               SCN2B,SERPINA1,SLC17A4,
                               SLC19A3,TMED10

Schizophrenia       1.07E-02   ADRA2B,ALK,CHRNA1,CHRNB4,   20
                               CHRNG,CNR1,CYP2E1,DAB1,
                               ESR1,GPR37,GRIK2,GRIN1,
                               MTNR1A,NCAM1,NTNG1,
                               PIK3C2G,RXRG,SLC15A1,
                               TCF7L2,TNXB

Table 10
Effect of Rhodiolo on genes involved in depression.

Symbol   Entrees gene name and summary-target protein;         Fold
         http://www.ncbi.nim.nih.gov/gene/                     change

ADRA2B   Adrenoceptor alpha 2B.                                 2.928
         Alpha-2-adrenergic receptors are members of the
         G-protein-coupled receptor superfamily. These
         receptors are critical for regulating the
         neurotransmitter release from sympathetic nerves
         and adrenergic neurons in the central nervous
         system

AQP4     Aquaporin 4                                            3.01
         This gene encodes a member of the aquaporin family
         of intrinsic membrane proteins that function as
         water-selective channels in the plasma membranes of
         many cells. The encoded protein is the predominant
         aquaporin found in the brain

CACNB2   Calcium channel, voltage-dependent, beta 2 subunit.   -3.387
         This gene encodes a subunit of a voltage-dependent
         calcium channel protein that is a member of the
         voltage-gated calcium channel superfamily

CCKBR    Cholecystokinin B receptor.                           -2.621
         This gene encodes a G-protein coupled receptor for
         gastrin and cholecystokinin (CCK), regulatory
         peptides of the brain and gastrointestinal tract

CHRNA1   Cholinergic receptor, nicotinic, alpha I (muscle)     -2.77
         The muscle acetylcholine receptor consists of five
         subunits of four different types: two alpha
         subunits and one beta, gamma, and delta subunit.
         This gene encodes an alpha subunit that
         participates in acetylcholine binding/channel
         gating

CHRNB4   Cholinergic receptor, nicotinic, beta 4 (neuronal)     5.464

CHRNG    Cholinergic receptor, nicotinic, gamma (muscle)       -5.028
         The mammalian acetylcholine receptor is a
         transmembrane glycoprotein with several subunits.
         This gene encodes the gamma subunit, which
         participates in neuromuscular organogenesis and
         ligand binding.

ESR1     Estrogen receptor 1                                   -7.516
         This gene encodes an estrogen receptor, which is a
         ligand-activated transcription factor composed of
         several domains that are important for hormone
         binding, DNA binding, and transcription activation.
         The protein localizes to the nucleus, and estrogen
         and its receptors are essential for sexual
         development and reproductive function, as well as
         the development of other tissues, such as bone.
         Estrogen receptors are also involved in
         pathological processes including breast cancer,
         endometrial cancer, and osteoporosis

GRIA3    Glutamate receptor, ionotropic, AMPA 3                 3.031
         Glutamate receptors are the predominant excitatory
         neurotransmitter receptors in the mammalian brain
         and are activated during various normal
         neurophysiologic processes. These receptors are
         heteromeric protein complexes composed of multiple
         subunits that are arranged to form ligand-gated ion
         channels

GRIN1    Glutamate receptor, ionotropic, N-methyl-D-            3.864
         aspartate 1 The protein encoded by this gene is a
         critical subunit of the N-methyl-D-aspartate
         receptors. These members of the glutamate receptor
         channel superfamily are heteromeric protein
         complexes with multiple subunits arranged to form a
         ligand-gated ion channel. These subunits are
         critical for the plasticity of synapses, which is
         believed to support memory and learning

KCNK2    Potassium channel, subfamily K, member 2               3.411
         This gene encodes one of the members of the
         two-pore-domain background potassium channel
         protein family. This type of potassium channel is
         formed by two homodimers that create a channel that
         releases potassium from the cell to control the
         resting membrane potential.

MYOM1    Myomesin 1                                             2.732

NCAM1    Neural cell adhesion molecule 1                        2.657
         This gene encodes a cell adhesion protein that is
         involved in cell-to-cell interactions and
         cell-matrix interactions during development and
         differentiation. The encoded protein is involved in
         the development of the nervous system and cells
         involved in the expansion ofT cells and dendritic
         cells, which are critical for immune surveillance

PDE11A   3',5'-cyclic-nucleotide phosphodiesterase (PDE)        5.776
         The 3',5'-cyclic nucleotides CAMP and cGMP are the
         second messengers among numerous signal
         transduction pathways. The 3',5'-cyclic nucleotide
         phosphodiesterases (PDEs) catalyze the hydrolysis
         of CAMP and cGMP to form the corresponding
         5'-monophosphates and provide a mechanism for
         dawn-regulating CAMP and cGMP signaling. This gene
         encodes a member of the PDE protein superfamily

Symbol   Depression-related biological process and role in cell

ADRA2B   Activation of MAPK cascade; activation of protein kinase B
         activity; adrenergic receptor signaling pathway; cell-cell
         signaling; GPCR-signaling pathway; negative regulation of
         epinephrine and norepinephrine secretion; positive
         regulation of neuron differentiation; signal transduction

AQP4     Nervous system development; protein
         homooligomerization; renal water absorption; response to
         glucocorticoid stimulus; response to radiation; sensory
         perception of sound; transmembrane transport; regulation
         of dopamine and t-glutamic acid

CACNB2   Axon guidance; calcium ion import; calcium ion transport;
         neuromuscular junction development; synaptic
         transmission; visual perception

CCKBR    Behavioral defense response; feeding behavior;
         phospholipase C-activating G-protein coupled receptor
         signaling pathway; GABAergic; positive regulation of
         synaptic transmission, glutamatergic; sensory perception;
         signal transduction; regulation of alpha catenin

CHRNA1   Ion transmembrane transport; musculoskeletal
         movement; neuromuscular synaptic transmission; neuron
         homeostasis; signal transduction; synaptic transmission

CHRNB4   Behavioral response to nicotine; ion transport; locomotor
         behavior; regulation of membrane potential; regulation of
         neurotransmitter secretion; smooth muscle contraction;
         synaptic transmission; synaptic transmission

CHRNG    Acetylcholine-activated cation-selective channel activity;
         acetylcholine receptor activity; cation transport; ion
         transmembrane transport; muscle contraction; regulation
         of membrane potential; signal transduction; synaptic
         transmission

ESR1     Cellular response to estradiol stimulus; elevation of
         cytosolic calcium ion concentration; gene expression;
         intracellular steroid hormone receptor signaling pathway;
         male gonad development; negative regulation of the
         1-kappaB kinase/NF-kappaB cascade; phospholipase
         C-activating G-protein coupled receptor signaling
         pathway; positive regulation of the nitric oxide
         biosynthetic process; signal transduction; transcription

GRIA3    Glutamate receptor signaling pathway; ion
         transmembrane transport; ion transport; regulation of
         receptor recycling; synaptic transmission; long-term
         potentiation, long-term depression, plasticity, excitatory
         postsynaptic potential, depolarization, depotentiation,
         depression,

GRIN1    Apoptosis, plasticity, synaptic transmission, long-term
         potentiation, cell death, transmembrane potential,
         excitotoxicity, cytotoxicity, communication, homeostasis

KCNK2    G-protein coupled receptor signaling pathway; ion
         transport; potassium ion transmembrane transport;
         potassium ion transport; regulation of ion transmembrane
         transport; stabilization of membrane potential; synaptic
         transmission

MYOM1    Muscle contraction

NCAM1    Aging; axon guidance; cell surface receptor signaling
         pathway; learning or memory; multicellular organismal
         response to stress; negative regulation of cell death;
         neuron development; neuron projection development;
         organ regeneration; peripheral nervous system axon
         regeneration; positive regulation of calcium-mediated
         signaling; regulation of the sensory perception of pain;
         thalamus development

PDE11A   CAMP catabolic process; cGMP catabolic process;
         metabolic process; signal transduction

Symbol   Related disease

ADRA2B   Attention deficit hyperactivity disorder, hypertension,
         cardiovascular disorder, multiple sclerosis, heart disease,
         post-traumatic stress disorder, stroke, major depression,
         bipolar disorder, Parkinson's disease, attention deficit
         disorder, psychomotor agitation, insomnia, mood disorder,
         anxiety disorder, social anxiety disorder, Alzheimer's
         disease, panic disorder, depressive disorder, psychosis

AQP4     Major depression, Huntington's disease, Parkinson's
         disease

CACNB2   Hypertension, hype rcholesterolemia, hyperlipidemia,
         mania, depressive disorder, migraines, short-QT syndrome
         4, Brugada syndrome, bipolar disorder, Alzheimer's disease

CCKBR    Withdrawal syndrome, hypergastrinemia, Huntington's
         disease, major depression, hyperphagia

CHRNA1   Depressive disorder, seizures, psychomotor agitation,
         schizophrenia, stroke, coronary disease, etc.

CHRNB4   Seizures, psychomotor agitation, schizophrenia,
         schizoaffective disorder, depressive disorder

CHRNG    Psychomotor agitation, schizophrenia, depressive disorder,
         Escobar syndrome, lethal multiple pterygium syndrome

ESR1     Breast cancer, weight gain, atherosclerosis, obesity,
         depressive disorder, Alzheimer's disease, etc.

GRIA3    Tremor, X-linked mental retardation, major depression,
         Alzheimer's disease, bipolar disorder

GRIN1    Schizophrenia, Alzheimer's disease, Parkinson's disease,
         bipolar disorder, major depression, obsessive-compulsive
         disorder, multiple sclerosis, frontal lobe dementia, Lewy
         body disease, bipolar depression, binge eating disorder,
         opioid dependence, morbid obesity, autosomal dominant
         mental retardation type 8, attention deficit hyperactivity
         disorder, drug abuse, Down's syndrome, ataxia,
         frontotemporal dementia, anxiety disorder, autism,
         open-angle glaucoma, cognition disorder, postoperative
         pain, delirium, Huntington's disease, depressive disorder,
         dementia, breast cancer, partial seizure, tuberculosis,
         urinary tract infection, Lennox-Gastaut syndrome,
         epileptic seizure, hypophagia, starvation,
         neurodegeneration, bipolar I disorder

KCNK2    Seizures, major depression, prostatic carcinoma,
         Huntington's disease

MYOM1    Major depression

NCAM1    Major depression, bipolar disorder

PDE11A   Physical disability, cardiovascular disorder, diabetes
         mellitus, major depression

Table 11
Predicted effects of Rhodiola on seizures. The effects were
determined based on the deregulated genes and the downstream effect
analysis data.

Genes in   Prediction (based on   Fold change   Findings (number
dataset    change in expression                 of supporting
           direction)                           publications)

CNR1       Decreased               3.182        Decreases (4)
GRIN1      Decreased               3.864        Decreases (3)
NCAMI      Decreased               2.657        Decreases (2)
SLC9A1     Decreased               3.340        Decreases (2)
RIMS1      Decreased               4.532        Decreases (1)
SCN2B      Decreased               3.605        Decreases (4)
SLC17A8    Decreased               4.317        Decreases (1)
KCNK2      Decreased               3.411        Decreases (1)
CHRNB4     Increased               5.464        Increases (2)
NR4A3      Affected               -3.272        Affects (1)
GRIK2      Affected               -3.182        Affects (2)
KAL1       Affected                2.657        Affects (1)
CA9        Affected                4.959        Affects (16)
SCN10A     Affected                5.856        Affects (6)
TIPARP     Affected               -3.411        Affects (1)
PIK3C2G    Affected                6.589        Affects (1)
SCN11A     Affected                3.411        Affects (3)

Table 12
Predicted effect of Rhodiola on genes involved in cardiovascular
diseases and disorders.

Disease or function      p-Value    Activation z-score
annotation

Size of Infarct          1.72E-03   -2.157 (a)

Infarction               1.28E-03   -1.961

Vascular Disease         3.37E-09   -1.342

Cardiomyopathy           6.95E-03   -1.128

Heart Disease            6.05E-08   -0.994

Vascular Lesion          4.72E-04   -0.988

Atherosclerotic Lesion   7.43E-04   -0.843

Disorder of Artery       2.67E-08   -0.821

Ischemic Injury of the   9.29E-06   -0.816
Brain

Cerebrovascular          1.24E-05   -0.816
Dysfunction

Ischemia of the Brain    6.30E-04   -0.816

Arteriosclerosis         3.21E-08   -0.552

Atherosclerosis          7.19E-08   -0.293

Heart Dysfunction        6.98E-03   -0.228

Heart Failure            2.31E-03    0.246

Coronary Disease         2.20E-07

Hypertension             1.69E-06

Coronary Artery          7.85E-06
Disease

Ischemic                 2.11E-04
Cardiomyopathy

Hyper-triglyceridemia    6.93E-04

Pulmonary Hypertension   9.83E-04

Intermittent             2.31E-03
Claudication

Peripheral Vascular      2.59E-03
Disease

Atherogenesis            2.78E-03

Venoocclusion            2.80E-03

Congestive Heart         2.91E-03
Failure

Preeclampsia             3.19E-03

Stroke                   4.13E-03

Pulmonary Hypertensive   4.42E-03
Arterial Disease

Formation of Vascular    4.84E-03
Lesion

Arrhythmia of Heart      5.36E-03
Ventricle

Malignant Hypertension   5.41E-03

Growth of                6.52E-03
Atherosclerotic Lesion

Angina Pectoris          6.55E-03

Heart Septa1 Defect      6.98E-03

Arrhythmia               7.37E-03

Hypotension              8.40E-03

Familial Combined        8.59E-03
Hyperlipidemia

Hypercholesterol emia    9.62E-03

Cardiac Fibrillation     9.88E-03

Disease or function      Molecules                         # Molecules
annotation

Size of Infarct          CCR2,CD40LG,CNR1,FGB,GP6,HGF,     9
                         HLA-B,NOX4,PPPR1A

Infarction               ADRA2B,CCR2,CD40LG,CNR1,ESR1,     15
                         F10,FGB,GP6,GRIN1,HGF,HLA-B,
                         NOX4,PDE3A,PPP1R1A,REG1A

Vascular Disease         ADRA2B,ALOX12,APOA2,AQP4,         49
                         BMPR1B,CACNB2,CCR2,CD1D,CD40LG,
                         CL-FP,CHRNA1,CHRNB4,CHRNG,
                         CNGB3,CNR1,CNTN5,COL2A1,DDC,
                         EPHA3,ESR1,F10,FHL1,FLT1,GP6,
                         GRIK2,GRIN1,IL1RL1,IL20,KCNK2,
                         KL,KLF6,LPL,MCF2L,MGAM,MMP8,
                         MTNR1A,MYO3B,NKX26,NOX4,PDE11A,
                         PDE3A,PDE4D,PRKG,RASGRF2,
                         SCN10A,SLC9A1,TBX1,TLR7,VWA3B

Cardiomyopathy           CACNB2,CCR2,CHRNA1,CHRNB4,        13
                         CHRNG,FHL1,LDB3,LEPR,PDE11A,
                         PDE3A,PDE4D,PPP1R1A,TBX20

Heart Disease            ADRA2B,AQP2,BMPR1B,CA9,CACNB2,    49
                         CCR2,CD40LG,CHRNA1,CHRNB4,
                         CHRNG,CNGB3,CNR1,CNTN5,DDC,
                         DPP6,EN04,EPHA3,ESR1,F10,FHL1,
                         FLT1,GP6,HGF,HHEX,IGHM,IL1RL1,
                         KCN2,KL,LDB3,LEFTY2,LEPR,LPL,
                         MCF2L,MGAM,MY03B,NHLH1,NKX26,
                         NOX4,PDE11A,PDE3A,PDE4D,PFKFB1,
                         PPP1R1A,SCN10A,SLC9A1,TBX,
                         TBX20,UBE4B,VWA3B

Vascular Lesion          APOA2,CCR2,CD1D,CD40LG,CETP,      13
                         ESR1,FLT1,IL1RL1,LPL,MMP8,
                         MTNR1A,PCSK5,PRKG1

Atherosclerotic Lesion   APOA2,CCR2,CD1D,CD40LG,CETP,      10
                         ESR1,FLT1,IL1RL1,LPL,PRKG1

Disorder of Artery       ADRA2B,APOA2,BMPR1B,CACNB2,       35
                         CCR2,CD1D,CD40LG,CETP,CNGB3,
                         CNR1,CNTN5,COL2A1,ESR1,F10,
                         FLT1,GRIN1,IL1RL1,IL20,KL,
                         KLF6,LPL,MCF2L,MGAM,MMP8,
                         MTNR1A,MYO3B,NKX26,PDE11A,
                         PDE3A,PDE4D,PRKG1,SLC9A1,TBX1,
                         TLR7,VWA3B

Ischemic Injury of the   AQP4,CD1D,CNR1,KCNK2,NOX4,        6
Brain                    RASGRF2

Cerebrovascular          ADRA2B,AQP4,CD1D,CHRNA1,CHRNB4,   14
Dysfunction              CHRNG,CNR1,DDC,F10,KCNK2,NOX4,
                         PDE3A,PDE4D,RASGRF2

Ischemia of the Brain    AQP4,CD1D,CNR1,F10,KCNK2,NOX4,    7
                         RASGRF2

Arteriosclerosis         ADRA2B,APOA2,BMPR1B,CACNB2,       31
                         CCR2,CD1D,CD40LG,CETP,CNGB3,
                         CNR1,CNTN5,COL2A1,ESR1,F10,
                         FLT1,GRIN1,IL1RL1,IL20,KL,
                         KLF6,LPL,MCF2L,MGAM,MMP8,
                         MY03B,PDE11A,PDE3A,PDE4D,
                         PRKG1,SLC9A1,VWA3B

Atherosclerosis          ADRA2B,APOA2,BMPR1B,CACNB2,       30
                         CCR2,CD1D,CD40LG,CETP,CNGB3,
                         CNR1,CNTN5,ESR1,F10,FLT1,
                         GRIN1,IL1RL1,IL20,KL,KLF6,LPL,
                         MCF2L,MGAM,MMP8,MYO3B,PDE11A,
                         PDE3A,PDE4D,PRKG1,SLC9A1,VWA3B

Heart Dysfunction        CACNB2,FLT1,LPL,NOX4              4

Heart Failure            ADRA2B,AQP2,CA9,CACNB2,ENO4,      12
                         EPHA3,IL1RL1,PDE11A,PDE3A,
                         PDE4D,SLC9A1,UBE4B

Coronary Disease         ADRA2B,BMPR1B,CACNB2,CHRNA1,      22
                         CHRNB4,CHRNG,CNGB3,CNR1,CNTNS,
                         ESR1,F10,FLT1,KL,LPL,MCF2L,
                         MGAM,MYO3B,PDE11A,PDE3A,PDE4D,
                         SLC9A1,VWA3B

Hypertension             ADRA2B,ALOX12,BMPR1B,CA9,         22
                         CACNB2,CHRNA1,CHRNB4,CHRNG,
                         ESR1,F10,FHL1,FLT1,LPL,MYO3B,
                         NOX4,PDE11A,PDE3A,PDE4D,PRKG1,
                         SCN10A,SLC9A1,VWA3B

Coronary Artery          ADRA2B,BMPR1B,CACNB2,CNGB3,       18
Disease                  CNR1,CNTN5,F10,FLT1,KL,LPL,
                         MCF2L,MGAM,MY03B,PDE11A,PDE3A,
                         PDE4D,SLC9A1,VWA3B

Ischemic                 CHRNA1,CHRNB4,CHRNG,PDE11A,       7
Cardiomyopathy           PDE3A,PDE4D,PPP1R1A

Hyper-triglyceridemia    APOA2,CA9,CETP,LEPR,LPL,RP1       6

Pulmonary Hypertension   ADRA2B,BMPR1B,FHL1,PDE11A,        6
                         SCN10A,SLC9A1

Intermittent             PDE11A,PDE3A,PDE4D                3
Claudication

Peripheral Vascular      F10,LPL,PDE3A,SLC9A1              4
Disease

Atherogenesis            APOA2,CD1D,CD40LG,CETPESR1,LPL    6

Venoocclusion            EPHA3,F10,LPL                     3

Congestive Heart         ADRA2B,AQP2,CACNB2,EPHA3,         7
Failure                  PDE3A,PDE4D,UBE4B

Preeclampsia             ADRA2B,ESR1,F10,FLT1,SCN10A       5

Stroke                   ADRA2B,CHRNA1,CHRNB4,CHRNG,       8
                         DDC,F10,PDE3A,PDE4D

Pulmonary Hypertensive   BMPR1B,FHL1,PDE11A,SCN10A         4
Arterial Disease

Formation of Vascular    APOA2,CD1D,CD40LG,CETP,ESR1,      7
Lesion                   LPL,PCSK5

Arrhythmia of Heart      ADRA2B,CACNB2,DPP6,NHLH1,         5
Ventricle                SCN10A

Malignant Hypertension   CHRNA1,CHRNB4,CHRNG               3

Growth of                CCR2,FLT1                         2
Atherosclerotic Lesion

Angina Pectoris          CACNB2,GP6,PDE11A,PDE3A,PDE4D     5

Heart Septa1 Defect      ADRA2B,LEFTY2,TBXl,TBX20          4

Arrhythmia               ADRA2B,CACNB2,CNTN5,DPP6,F10,     9
                         KCNK2,NHLH1,PDE4D,SCN10A

Hypotension              ADRA2B,AVPR1A,CNR1,DDC,F10        5

Familial Combined        LPL,RXRG                          2
Hyperlipidemia

Hypercholesterol emia    APOA2,CD40LG,FABP1,LPL            4

Cardiac Fibrillation     ADRA2B,CNTN5,DPP6,F10,KCNK2,      6
                         NHLH1

(a) Predicted activation state.

Table 13
Effects of Rhodiola on infarct size.

Genes in   Prediction (based   Fold change   Findings (number
dataset    on change in                      of supporting
           expression                        publications)
           direction)

NOX4       Decreased           -4.000        Increases (1)
CP6        Decreased           -3.227        Increases (1)
HCF        Decreased            3.580        Decreases (2)
CNR1       Decreased            3.182        Decreases (2)
FGB        Decreased            2.908        Decreases (1)
CD40LC     Decreased           -3.053        Increases (1)
CCR2       Decreased           -3.010        Increases (1)
HLA-B      Increased            3.182        Increases (1)
PPP1R1A    Affected             3.531        Affects (1)

Table 14
Predicted effect of Rhodiola in cancer, deregulated genes and
downstream effect analysis data.

Genes in   Prediction (based   Fold change   Findings (number
dataset    on expression                     of supporting
           direction)                        publications)

CCR2       Decreased           -3.010        Increases (12)
CXCL6      Decreased            3.117        Decreases (3)
DACT2      Decreased            2.504        Decreases (2)
ELF5       Decreased            4.757        Decreases (2)
ENAH       Decreased           -8.877        Increases (9)
ESRl       Decreased           -7.516        Increases (206)
FLT1       Decreased           -2.657        Increases (224)
LIN28B     Decreased           -3.010        Increases (6)
NCAM1      Decreased            2.657        Decreases (30)
NOX4       Decreased           -4.000        Increases (7)
SERPINA1   Decreased           12.729        Decreases (6)
TLE1       Decreased           -4.469        Increases (3)
TLR7       Decreased            2.676        Decreases (46)
XRCC5      Decreased            4.627        Decreases (9)
AICDA      Increased           10.126        Increases (3)
CD53       Increased            3.732        Increases (1)
CDKN2C     Increased           -2.990        Decreases (27)
FHL1       Increased           -8.398        Decreases (8)
HCF        Increased            3.580        Increases (42)
IL1RL1     Increased            3.891        Increases (16)

Table 15
Top up-and down-regulated genes by Rhodiola, salidroside, triandrin
and tyrosol in T98C cells. The values show the fold changes compared
with the control.

 Rhodiola rosea        Slaidroside

Gene       Fold      Gene      Fold
Symbol     Change    Symbol    Change

SERPINA1   12.729    KCNK10    13.086
AICDA      10.126    CHIT1     9.918
PDE3A      9.000     FETUB     9.918
GJB5       8.877     NMNAT3    9.646
K1R2DS3    8.574     OR51L1    9.646
OR51L1     7.516     EOMES     8.754
TNXB       7.013     AKR1D1    8.225
APOBEC2    6.821     PLA2G4D   8.225
EPHB1      6.821     DNAJC16   7.413
PPIP5K1    6.727     SLC15A1   6.916
SLC17A4    6.727     SMTNL1    6.916
UBXN10     6.727     BAI3      6.364
GALNT14    6.681     VN1R4     6.021
GCNT3      6.589     KCNK10    13.086
PIK3C2G    6.589     EPHB1     5.979
SF3B2      6.453     CHN2      5.938
SLC6A15    -5.938    CTNNA2    -6.589
HHEX       -5.979    HTR3D     -6.589
PDLIM2     -6.681    MCF2L     -6.589
APLF       -6.727    P2RY13    -6.589
DNAH7      -6.821    MTNR1A    -6.916
PARP15     -7.210    GPR83     -7.210
ESB1       -7.516    POLN      -7.210
TBX20      -7.674    TRDN      -7.210
WNT16      -7.781    LRRC25    -7.464
GSTA3      -8.168    LILRB5    -7.890
FHL1       -8.398    NTN3      -8.574
ENAH       -8.877    AGXT2     -8.754
UGT2A3     -9.254    PLCD4     -10.126
CETP       -9.781    SLC6A15   -10.483
HNF4G      -11.551   AKAP14    -11.236

    Triandrin            Tyrosol

Gene       Fold      Gene      Fold
Symbol     Change    Symbol    Change

KCNH7      36.002    OR51L1    13.086
FETUB      10.853    PCDH8     10.483
DNAJC16    10.703    HS3ST5    9.918
SUCNR1     10.126    APOBEC2   9.849
TKTL2      9.781     CHIT1     9.514
CHIT1      9.318     K1R2DS3   8.515
ACTG2      8.815     SMTNL1    8.515
KIR2DS3    8.168     KLF6      8.056
OR51L1     7.89      FETUB     7.413
TLR8       7.413     DNAH2     6.774
PDE3A      7.062     XRCC5     6.727
SMTNL1     7.013     PHACTR3   6.364
APOBEC2    6.589     SGPP2     6.364
COL21A1    6.589     SLC15A1   6.364
KLF6       6.589     TCF7L2    6.364
SGPP2      6.589     AKR1D1    6.32
HFE        -5.736    USP45     -22.785
EPHA6      -6.148    E2F2      -23.264
NPBWR2     -7.311    EFEMP2    -26.355
NTRK2      -7.362    NFIL3     -28.641
THNSL2     -9.254    DARS2     -29.857
CETP       -9.514    KHDRBS1   -32.672
RAD9B      -9.849    RB1CC1    -33.825
LPAR5      -9.918    LAP3      -35.753
ANP32A     -11.236   HERC3     -41.355
UNC13A     -16.45    TYMP      -47.177
HFE        -5.736    ETNK1     -57.282
EPHA6      -6.148    ZNF516    -245.572
NPBWR2     -7.311    NDUFAF1   -380.038
NTRK2      -7.362    CD151     -630.346
THNSL2     -9.254    ICTI      -680.287

The gene symbols are color coded to indicate up-regulation (red) or
down-regulation (green).

Table 16
Top five diseases and disorders affected by Rhodiola, salidroside,
triandrin, and tyrosol in T98G cells.

Rhodiola extract

                                       p-Value             # Genes

Cardiovascular disease                 3.37E-11-9.88E-03   72
Endocrine system disorders             3.35E-10-3.02E-03   60
Gastrointestinal disease               3.35E-10-8.69E-03   163
Metabolic disease                      3.35E-10-9.62E-03   63
Organismal injury and abnormalities    1.24E-08-1.09E-02   62

Salidroside

                                       p-Value             # Genes

Cardiovascular disease                 6.97E-05-1.91E-02   50
Neurological disease                   9.37E-05-1.91E-02   83
Endocrine system disorders             9.57E-05-7.25E-04   40
Gastrointestinal disease               9.57E-05-1.91E-02   151
Metabolic disease                      9.57E-05-1.91E-02   46

Tyrosol

                                       p-Value             # Genes

Neurological disease                   2.93E-04-3.73E-02   33
Ophthalmic disease                     2.93E-04-3.73E-02   15
Endocrine system disorders             3.35E-04-3.73E-02   34
Metabolic disease                      3.35E-04-3.73E-02   41
Gastrointestinal disease               8.67E-04-4.19E-02   32

Triandrin

                                       p-Value             # Genes

Metabolic disease                      2.46E-03-4.98E-02   37
Developmental disorder                 4.09E-03-4.22E-02   18
Hereditary disorder                    4.09E-03-4.22E-02   27
Neurological disease                   4.09E-03-4.73E-02   20
Psychological disorders                4.09E-03-3.74E-02   3

Table 17
Top five molecular and cellular functions affected by Rhodiola,
salidroside, triandrin and tyrosol in T98G cells.

Rhodiola extract

                                          p-Value             # Genes

Cell-to-cell signaling and interaction    3.76E-07-1.06E-02   78
Cellular movement                         4.24E-06-1.04E-02   74
Molecular transport                       9.21E-06-1.04E-02   89
Cell morphology                           2.39E-05-1.09E-02   63
Cellular assembly and organization        2.39E-05-6.52E-03   14

Salidroside

                                          p-Value             # Genes

Cell-To-Cell Signaling and Interaction    8.36E-06-1.91E-02   70
Nucleic Acid Metabolism                   3.40E-05-1.91E-02   36
Small Molecule Biochemistry               3.40E-05-1.91E-02   60
Cellular Compromise                       6.96E-05-1.91E-02   23
Cell Death and Survival                   1.14E-04-1.91E-02   102

Tyrosol

                                          p-Value             # Genes

Lipid metabolism                          1.39E-03-5.00E-02   19
Molecular transport                       1.39E-03-5.00E-02   14
Small molecule biochemistry               1.39E-03-5.00E-02   30
Nucleic acid metabolism                   2.50E-03-3.73E-02   4
Cellular assembly and organization        4.06E-03-4.19E-02   13

Triandrin

                                          p-Value             # Genes

Lipid Metabolism                          1.40E-03-4.22E-02   14
Molecular Transport                       1.40E-03-3.74E-02   8
Small Molecule Biochemistry               1.40E-03-4.22E-02   19
Cell-To-Cell Signaling and Interaction    2.53E-03-3.74E-02   16
Carbohydrate Metabolism                   7.97E-03-3.74E-02   4

Table 18
Top five physiological system functions affected by Rhodiola,
salidroside, triandrin, and tyrosol in T98G cells.

Rhodiola extract

                                            p-Value            # Genes

Behavior                                    7.69E-07-1.02E-02  50
Nervous system function                     3.60E-06-1.00E-02  65
Humoral immune response                     2.39E-05-6.52E-03  28
Hematological system function               8.50E-05-1.06E-02  64
Organ morphology                            9.59E-05-1.09E-02  61

Salidroside

                                            p-Value            # Genes

Behavior                                    2.14E-06-1.83E-02  40
Nervous system function                     6.77E-05-1.91E-02  60
Cardiovascular system function              1.13E-04-1.91E-02  24
Hematological system function               2.16E-04-1.91E-02  68
Tissue morphology                           2.92E-04-1.91E-02  71

Tyrosol

                                            p-Value            # Genes

Hair and skin development and function      1.29E-02-3.73E-02  6
Hematological system function               1.29E-02-3.73E-02  10
Hematopoiesis                               1.29E-02-3.73E-02  4
Lymphoid tissue structure and development   1.29E-02-3.73E-02  3
Nervous system function                     1.88E-02-1.88E-02  2

Triandrin

                                            p-Value            # Genes

Tissue development                          2.53E-03-3.74E-02  14
Cardiovascular system function              6.86E-03-3.74E-02  4
Organismal development                      6.86E-03-3.74E-02  8
Cell-mediated immune response               7.97E-03-3.74E-02  2
Hematological system function               7.97E-03-3.74E-02  8

Table 19
Top Canonical Pathways affected by Rhodiola, salidroside, triandrin,
and tyrosol in T98G cells.

Rhodiola extract

Ingenuity canonical pathways              Ratio

Communication between                     7.14E-02

innate and adaptive immune cells
eNOS signaling                            5.81E-02

Altered Tcell and B ceil                  7E-02

signaling in rheumatoid
arthritis

Dendritic cell maturation                 4.74E-02

Axonal guidance signaling                 3.52E-02

G-protein coupled receptor                4.35E-02
signaling

Stearate biosynthesis I                   8.16E-02

Glutamate receptor signaling              6.94E-02

Ephrin receptor signaling                 4.29E-02

Atherosclerosis signaling                 5.07E-02

Salidroside

Ingenuity canonical pathways              Ratio

cAMP-mediated signaling                   14/226 (0.062)

B cell development                        5/36 (0.139)

Phototransduction pathway                 5/67 (0.075)

eNOS signaling                            8/155 (0.052)

Protein ubiquitination pathway            12/270 (0.044)

G-protein coupled receptor                4.35E-02
signaling

tRNA splicing                             8.7E-02

Cardiac [beta]-adrenergic signaling       5.06E-02

Altered T cell and B cell signaling in    6E-02
rheumatoid arthritis

Protein kinase A signaling                3.69E-02

Tyrosol

Ingenuity canonical pathways              Ratio

G-protein coupled receptor signaling      32/515 (0.062)

cAMP-mediated signaling                   15/213 (0.07)

Hematopoiesis from pluripotent stem       5/55 (0.091)
cells

Primary immunodeficiency signaling        5/55 (0.091)

PPARa/RXRa activation                     11/169 (0.065)

Phototransduction pathway                 9.09E-02

Aminosugars metabolism                    8.45E-02

Estrogen-mediated S-phase entry           1.11E-01

LPS/IL-1 mediated inhibition of RXR       5.5E-02
function

Starch and sucrose metabolism             7.94E-02

Triandrin

Ingenuity canonical pathways              Ratio

B cell development                        5/29 (0.172)

G-protein coupled receptor signaling      30/515 (0.058)

Dopamine-DARPP32 feedback in cAMP         11/164 (0.067)
signaling

Netrin signaling                          4/45 (0.089)

Communication between innate and          6/93 (0.065)
adaptive immune cells

Neuropathic pain signaling in dorsal      6.6E-02
horn neurons

nNOS signaling in neurons                 8.7E-02

Phenylalanine, tyrosine and               1.33E-01
tryptophan biosynthesis

Chondroitin sulfate biosynthesis          8E-02

Parkinson's signaling                     1.25E-01
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Author:Panossian, Alexander; Hamm, Rebecca; Wikman, Georg; Efferth, Thomas
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Sep 25, 2014
Words:12543
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