Eucommia ulmoides Oliver (E. ulmoides) is a monotypic genus Eucommia, also known as tuchong in Japanese and tu-chung in Korean, and was recorded in Shen Nong Ben Cao, a classic Chinese medical book [1]. It is characterized by being resistant to cold (−40 °C) and hot (44 °C) conditions [2]. Generally, E. ulmoides is cultivated in the southern area of Qingling in China, including the Guizhou, Sichuan, Hubei, Shaanxi, Hunan, Gansu, Yunnan, Anhui, Guangxi, Henan, Zhejiang, and Jiangxi provinces (Figure 1A) ^[3][4][5][3,4,5]. E. ulmoides has been utilized for at least 2000 years according to ancient Chinese medical records [6]. In 1955, the first global conference on the pharmacological effects of E. ulmoides was organized in Leningrad, and the scientists there suggested that E. ulmoides was effective in decreasing blood pressure [7]. From then on, E. ulmoides has attracted intensive attention worldwide and a great deal of scientific research and clinical trials have been undertaken to study its biological functions and pharmacological effects (Figure 1B).

Recently, the barks and leaves of E. ulmoides have been listed separately in the Chinese Pharmacopoeia (2020 version), with different quality control criteria, but identical functions, including nourishing the liver and kidney, and strengthening bones and muscles [8]. Additionally, Eucommia ulmoides Oliver barks (EUE) were recorded in the European Pharmacopoeia (9th Edition), Japanese Pharmacopoeia (17th Edition, English Version), Hong Kong Chinese Materia Medica Standards (Volume 3), and Taiwan Herbal Pharmacopeia (3rd Edition). In particular, among the 200 standard formulations in the Taiwan Herbal Pharmacopeia, 5 prescriptions involve EUE [9]. Traditionally, E. ulmoides has been considered to have the properties of tonifying the kidney and liver, strengthening bones and muscles, and fixing meridians from ancient records [6]. While in modern pharmacology, 204 chemical constituents have been identified from the leaves, barks, seeds, and flowers of E. ulmoides, and these compounds are divided into phenols, iridoids, lignans, flavonoids, terpenoids, sterols, gutta-percha, polysaccharides, unsaturated fatty acids, amino acids, and mineral elements [10]. Several components display vital biological functions both in vivo and in vitro, such as hypolipidemic, antihypertensive, antidiabetic, anti-inflammatory, antioxidative, neuroprotective, hepatoprotective, bone-metabolic, renoprotective, anti-aging, anti-fatigue, antidepressant, hypnotic-sedative, immune regulation, cognitive improvement, uterine smooth relaxation muscles, and erectile function enhancement ^{[11][12][13][14][15]}[11,12,13,14,15]. Apart from being a medicine, E. ulmoides has also been employed as a health supplement popular in China, Japan, and Korea [16]. In short, E. ulmoides has great economic value and the potential for being used in novel drugs.

The neuroendocrine–immune (NEI) regulatory network (Figure 2) is a complex system, incorporating the nervous system, endocrine system, and immune system, to maintain homeostasis and plays a pivotal role in the treatment of complicated diseases, with the involvement of bioregulatory signals such as neurotransmitters, hormones, and cytokines/chemokines ^[17][18][19][17,18,19]. RThis researchers view aims to systematically summarize the chemical components, biological activities, and pharmacological effects of E. ulmoides on NEI diseases, which will provide a reference for research, development, and application of the active components of E. ulmoides.

Besedobsky first proposed the NEI network in 1997. The interactions among the NEI system represent a complete communication circuit by sharing common signaling ligands and their receptors. In general, the nervous system regulates the immune system in two ways. One is through the release of neurotransmitters or neuropeptides such as acetylcholine, 5-HT, and opioid peptides from the endings of autonomic nerves, which act on immune cells and organs (bone marrow, thymus, lymph nodes, and gut) [20]. The second regulatory mechanism is through the hypothalamic–pituitary–adrenocortical (HPA), hypothalamic–pituitary–thyroid (HPT), hypothalamic–pituitary–gonadal (HPG), and hypothalamic–pituitary–somatotropic (HPS) axes to regulate the immune system. The release of neurohormones such as corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus can stimulate the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH acts on the adrenal cortex and promotes the secretion of glandular hormones (e.g., glucocorticoids) to mediate the immune response [21]. On the other hand, immune cells can generate various immune mediators to trigger the activation of the nervous system in response to inflammatory and invasive stimuli. For example, IL-1 can upregulate the secretion of CRH [22], IL-1β, and TNF-α, which are regarded as potential neurotoxic substances [23], while the proinflammatory cytokine induction of interferon-γ (IFN-γ) provides neuroprotection during acute neuroinflammation by inducing the secretion of IL-6 [24].

The secretion of hormones also has a role in the nervous system. For example, thyroxine is important for the development of the brain [25], oxytocin can improve the learning and memory of mice by regulating the hippocampus [26], and vasopressin can also enhance memory [27]. As for the immune system, hormones such as glucocorticoids secreted by the adrenal cortex have both anti-inflammatory and proinflammatory effects [28]. As gonadal hormones, both androgens and estrogens can improve immunity ^[29][30][29,30]. In particular, estrogen can alter the immune response by binding to specific receptors on immune cells, resulting in their proliferation, and they play a feedback regulatory role on the hypothalamic–pituitary axis ^[29][31][29,31].

The NEI network is involved in multidirectional functions and multiple systems. Once the imbalance or alteration of the NEI network occurs, various diseases may follow, such as multiple sclerosis, fatigue, inflammation, psoriatic arthritis, systemic lupus erythematosus, depression, anxiety, cancer, and obesity ^{[32][33][34][35][36][37][38][39][40][41]}[32,33,34,35,36,37,38,39,40,41]. From a holistic perspective, E. ulmoides has a “multi-components, multi-targets” profile for the treatment of various diseases. Hence, it is valuable to understand the pharmacological effects of E. ulmoides in the NEI network and fill this research gap.

3. Pharmacological Effects of E. ulmoides on NEI Network-Associated Diseases

The NEI network mediators and their end products have widespread effects at the systemic and cellular levels. They are responsible for disease behavior, such as cancer, neurodegenerative diseases (Alzheimer’s disease (AD) and Parkinson’s disease (PD) which are explained in Figure 34A), metabolic disorders including obesity, insulin resistance, diabetes, cardiovascular disease, and dyslipidemia, as well as osteoporosis, fatigue, depression, and anxiety ^{[32][33][34][35][36][37][38][39][40][41][42][43][44]}[32,33,34,35,36,37,38,39,40,41,48,49,50] (Figure 34B). Thus, maintaining the balance of the NEI network may bring benefits for the treatment of these diseases. Through reviewing the literature on E. ulmoides, rwesearchers found that the herb does affect these diseases, as discussed in the following sections and summarized in Table 1.