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Anxiety reflects the anticipation of future threats and is a normal emotional experience; however, when this emotion is severe enough to affect behavior or cause distress, it can develop into an anxiety disorder 1. Anxiety disorders are one of the most common mental problems in the adults, with a prevalence rate of 7. Thus, it has become a social problem that cannot be ignored. The COVID pandemic, which was first identified in December , has been found to be associated with high incidences of psychological symptoms, such as anxiety and depression, which has raised public concern about mental health 5. Another study has shown that patients can be plagued by sleep disturbances, anxiety, or depression even 6 months after being discharged from the hospital with a cure 6. Antianxiety drugs often only have single-action targets, require long-term use, and are associated with many adverse reactions and dependencies 7. In contrast, guided by the traditional Chinese medicine TCM holistic concept, the TCM prescriptions can be used to treat diseases with their multiple compounds, multiple targets of action, and multiple pathways, and share the advantages of fewer adverse reactions and higher patient compliance 8. Similarly, TCM has certain characteristics. Many TCM drugs have shown efficacies in reducing the negative effects of anxiety symptoms and in enhancing mental health 9. The ancient Chinese formula Renshu Powder initially seen in the Introduction to Medicine , Li Ting, Ming dynasty has long been used to treat mental and physical symptoms caused by anxiety and fear. The combination of prepared Rehmannia root and Chinese arborvitae kernel is the core drug pair in the formula. Based on the theories of system biology, network pharmacology affords a powerful and practical research method By utilizing multidisciplinary theories, it predicts the mechanism of action of a specific compound in treating a specific disease by screening the potential bioactive components, targets, and pathways. The principles of network pharmacology are consistent with TCM theories. Recent studies have shown that the possible mechanisms of COVID treatment by the five recommended prescriptions are regulation of immune system, anti-inflammatory, antiviral, regulation of cell apoptosis, anti-pulmonary fibrosis, myocardial protection, etc. Here we predicted the potential pharmacological mechanisms of the action of the herb pair of prepared Rehmannia root and Chinese arborvitae kernel, especially the targets and their compounds, in the treatment of anxiety disorders by using network pharmacology approaches, with a view to promote the global use of TCM-based antianxiety medications. The main active compounds of the herb pair and their targets were imported into the Cytoscape software 3. The study was conducted in accordance with the Declaration of Helsinki as revised in The targets of the main active compounds in the herb pair were mapped to the disease-related targets, and the intersecting genes i. After 3 sessions of filtering criteria: parameter values higher than the medians , the core targets were obtained. Receptor-ligand docking simulations were performed using Autodock Vina 1. The predicted anxiety-intervening targets were filtered using the Metascape database The main active ingredients, diseases, predicted targets, and major pathways of the herb pair were imported into the TCM drugs-ingredients-diseases-targets-pathways network, in order to more visually demonstrate the multitarget and multipathway characteristics of the prepared pair of Rehmannia root-Chinese arborvitae kernel for intervention of anxiety disorders. The selected targets obtained in this study were analyzed by rigorous statistics. We analysed the topological data by Cytoscape version 3. The topology analysis was performed by using the Network Analyzer tool. Among them, there were 2 active compounds in prepared Rehmannia root and 5 in Chinese arborvitae kernel. Beta-sitosterol was a shared active compound in these 2 herbs Table 1. After gene normalization and removal of duplicate values, action targets were obtained. The main active compounds of the herb pair and their targets were imported into the Cytoscape software to construct a visual network of TCM drugs-ingredients-targets Figure 1. The network topology analysis using the Network Analyzer plug-in showed that there were nodes and edges, with an average degrees of freedom of 3. Among these active compounds, arachidonic acid, stigmasterol, and beta-sitosterol had the highest Degree values, suggesting they were the key active compounds in the herb pair. The drug pair targets were mapped to the disease targets, and 70 predicted targets were obtained. The data were imported into Cytoscape for topological analysis, and the PPI network yielded from this is presented in Figure 2. The top 3 active compounds ranked by Degree value were selected to dock with the top 3 core targets, and sertraline hydrochloride was used as a positive control. Thus, the proper core targets and ligands were selected. Stigmasterol and beta-sitosterol had the optimal binding energies to NOS3, as shown in Table 2 and Figures 4 and 5 , in which the red dashed lines represent hydrogen bonds, indicating that stigmasterol forms hydrogen bonding with NOS3 at the active site ARG and beta-sitosterol forms hydrogen bonding with NOS3 at the active site TRP A total of 53 GO terms were obtained, consisting of 20 biological process BP terms, 14 cell composition CC terms, and 19 molecular functions MF terms, as shown in Figure 6. The herb pair and its main active compounds, diseases, predicted targets, and main pathways were imported into Cytoscape software to draw the TCM drugs-ingredients-diseases-targets-pathways network, with an attempt to demonstrate the multicompound, multitarget, and multipathway characteristics of the herb pair. The results are shown in Figure 8. Experimental and clinical studies have demonstrated that both genetic and environmental factors contribute to the risk of developing an anxiety disorder The common triggers for anxiety disorders include neurotransmitters, neuroendocrine function, neuroanatomy, immune disorders, stressful psychological events, and drug addiction and withdrawal These influencing factors are also involved in the targets and pathways by which prepared Rehmannia root and Chinese arborvitae kernel treat anxiety disorders. Filtering in our current study revealed that arachidonic acid, stigmasterol, and beta-sitosterol were the key active compounds in the herb pair prepared Rehmannia root and Chinese arborvitae kernel. Arachidonic acid AA is one of the most abundant and widely distributed polyunsaturated fatty acids PUFA in mammals and also one of the essential fatty acids in humans. It is catalyzed by phospholipase A2 PLA2 and can generate various metabolites through cyclooxygenase COX , lipoxygenase LOX , and cytochrome P CYP pathways, playing a wide range of important physiological roles; in particular, it has unique biological activities in lowering blood lipids; inhibiting platelet aggregation; fighting against inflammation, cancer, and lipid oxidation; and promoting the development of brain tissue Research has shown that stigmasterol exerts its neuroprotective effects by downregulating GluN2B-mediated excitotoxicity and reducing oxidative stress, showing therapeutic promise for cerebrovascular and neurodegenerative diseases The nitric oxide synthase 3 NOS3 gene is located in chromosome region 7pp NOS is mainly expressed in neurons and differentially distributed in different regions of the brain; abnormal NOS3 gene expression induces neuronal and glial degeneration in the brain Malformations of the cerebral vasculature are associated with reduced NOS3 expression. Decreased NOS3 expression in cerebral vasculature is associated with the risk of vascular lesions, vascular smooth muscle cell apoptosis, and amyloid plaque formation As a physiologically active low-molecular-weight polypeptide, epidermal growth factor EGF plays a special role in regulating cell growth, proliferation, and differentiation. Its pathophysiological roles in various diseases have increasingly been recognized. EGF is closely related to cognitive function, as it is a potent mitogen that promotes the growth and development of the nervous system while protecting and nourishing neurons and dopamine when oxidative damage to neurons occurs PTGS2 may increase the production of inflammatory chemokines and cytokines by activating its downstream pathways e. Mitogen-activated protein kinase 1 MAPK1 , an effector kinase of the MAP kinase signaling pathway, is controlled by cell proliferation, differentiation, apoptosis, and angiogenesis Anxiety disorder comorbidity, as a risk factor for suicide, was found to be significantly associated with variations in MAPK1 polymorphisms High levels of peroxisome proliferator-activated receptors PPAR have been found in the hippocampus and amygdala of the brains of patients with anxiety disorders. Estrogen is thought to play a key role in anxiety. Estrogen receptor 1 ESR1 polymorphisms are associated with the risk of anxiety disorders 42 , and there is a strong association between ESR1 variants and cognitive outcomes Alterations in serotonin 5-hydroxytryptamine 5-HT neurotransmission and peripheral immune activation have been shown to be strongly associated with a variety of psychiatric disorders SLC6A4 is a serotonin transporter gene. Studies have shown that there are many predisposing factors for affective disorder, such as epigenetic processes including SLC6A4 promoter methylation and microRNA silencing. PTEN plays an important role in the development of neurons. In addition, it also plays a role in synaptic plasticity in adulthood. Studies have shown that the synaptic function of PTEN in amygdala is closely related to specific behavioral characteristics In our current study, GO enrichment analysis was performed to describe the intracellular properties of core target proteins, where biological processes, including blood circulation, synaptic signaling, cellular response to organic cyclic compound, response to toxic substance, cellular response to nitrogen compound, response to nutrient levels, and organic hydroxy compound metabolic process, were found to be involved in the therapeutic effects of prepared Rehmannia root and Chinese arborvitae kernel on anxiety disorders. The related molecular functions, including oxidoreductase activity, protein kinase binding, G protein—coupled amine receptor activity, nuclear receptor activity, amide binding, protein homodimerization activity, neurotransmitter receptor activity, and ammonium ion binding, might enable the herb pair to exert its antianxiety activity. Furthermore, cellular localization showed that the mechanism sites were the membrane raft, synaptic membrane, receptor complex, cyptoplasmic vesicle membrane, side of membrane, perinuclear region of the cytoplasm, and other cellular environments. KEGG enrichment pathways mainly involved signaling pathways e. Neuroactive ligand-receptor interaction signaling pathways are closely related with learning and memory and play key roles in neuronal processes, such as neural plasticity and synaptic function It is widely present in neuronal cells and plays an important role in the regulation of cell division, differentiation, and survival, as well as tumorigenesis. It is closely associated with a variety of mood disorders and neurological diseases. The mTOR signaling pathway involves the proliferation of neural stem cells, regulation of neural circuits, and regulation of circadian rhythms. It regulates memory and learning behaviors through synaptic plasticity Recent studies have confirmed that ketamine is a glutamatergic N-methyl-D-aspartate receptor NMDA-R antagonist, which has the characteristics of fast onset and lasting effect in the process of antidepressant. It is therefore assumed that depression is closely associated with the mTOR pathway, and the mTOR pathway may play a key role in depression treatment Another experiment confirmed that early-life stress alters synaptic plasticity by inhibiting the hippocampal mTOR pathway, which may result in increased anxiety-like behaviors and impaired cognitive function 55 ; anxiety disorders are associated with inflammation. Long-term stress environment can destroy the function of hypothalamus pituitary adrenal axis and the autonomic nervous system, which may induce systemic proinflammatory diseases. Systemic inflammation can enter the brain and increase levels of pro-inflammatory cytokines, which have been shown to promote both direct and indirect neurotoxic effects It affects the emotional function, social behavior, and spatial memory in humans and is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases Acute local blockade of this MAPK signaling pathway in hypothalamic paraventricular nucleus PVN may cause a profound anxiogenic phenotype Phosphodiesterase 2 PDE2 is involved in cGMP PKG signal transduction, which is highly expressed in limbic brain regions including hippocampus and amygdala , which may become a breakthrough in the treatment of depression and anxiety 59 , Alterations in various behaviors including appetite, mood, sleep, and cognitive function in patients with anxiety disorders have been associated with the serotonergic system, and a growing body of research supports a role for dysfunction of serotoninergic, noradrenergic, and dopaminergic systems in the neurobiological processes involved in major depression disorder and anxiety disorders Estrogen promotes synapse formation, induces growth factor production, protects against oxidative stress, regulates cognition- and mood-related neurotransmitters such as 5-HT, norepinephrine NE , and acetylcholine, and is associated with learning-, memory-, and anxiety-related behaviors The amygdala is an important structure for anxiety and fear responses; research has confirmed that oxytocin can influence anxiety levels by regulating amygdala activation Thyroid hormones can facilitate intracellular pathways of signaling and affect the neurotransmission of 5-HT and norepinephrine, thus participating in mood and behavior regulation processes In summary, our current study preliminarily predicted that the mechanism of action of the herb pair of prepared Rehmannia root-Chinese arborvitae kernel in treating anxiety disorders involves multiple ingredients, multiple targets, and multiple pathways. The authors have no conflicts of interest to declare. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Table 1 The main active compounds of the herb pair of prepared Rehmannia root and Chinese arborvitae kernel Full table. Figure 1 TCM drugs-ingredients-targets network. Figure 2 PPI network. PPI, protein-protein interaction. Figure 3 Core targets. Table 2 Docking of the main active compounds with the core target protein molecules Full table. Figure 4 Molecular docking of stigmasterol with NOS3. Figure 5 Molecular docking of beta-sitosterol with NOS3. Figure 6 Gene Ontology enrichment analysis-biological process. Figure 7 KEGG pathway enrichment analyses. Figure 8 The TCM drugs-ingredients-diseases-targets-pathways network. Network pharmacology study on the mechanism of the herb pair of prepared Rehmannia root-Chinese arborvitae kernel for anxiety disorders. Ann Palliat Med ;10 3