Medicinal Plant Research 2024, Vol.14, No.4 http://hortherbpublisher.com/index.php/mpr © 2024 HortHerb Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved.
Medicinal Plant Research 2024, Vol.14, No.4 http://hortherbpublisher.com/index.php/mpr © 2024 HortHerb Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Publisher HortHerb Publisher Edited by Editorial Team of Medicinal Plant Research Email: edit@mpr.hortherbpublisher.com Website: http://hortherbpublisher.com/index.php/mpr Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada Medicinal Plant Research (ISSN 1927-6508) is an open access, peer reviewed journal published online by HortHerb Publisher. The journal publishes all the latest and outstanding research articles, letters and reviews in all aspects of medicinal plant research, including plant growth and development, plant biology, plant nutrition, medicinal properties, phytochemical constituents, fitoterapia, pharmacognosy, essential oils, ethno- pharmacology agronomic management, and phytomedicine, as well as chemistry, pharmacology and use of medicinal plants and their derivatives. HortHerb Publisher is an international Open Access publisher specializing in horticulture, herbal sciences, and tea-related research registered at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. All the articles published in Medicinal Plant Research are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. HortHerb Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
Medicinal Plant Research (online), 2024, Vol. 14, No.4 ISSN 1927-6508 http://hortherbpublisher.com/index.php/mpr © 2024 HortHerb Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Ethnobotanical Uses and Phytochemistry of Eucommia ulmoides: A Comprehensive Review Honglin Wang, Bida Zhu, Degang Zhao Medicinal Plant Research, 2024, Vol. 14, No. 4, 180-195 Comprehensive Review of Bioactive Compounds in Loquat and Their Pharmacological Mechanisms Xiuying Zhao Medicinal Plant Research, 2024, Vol. 14, No. 4, 196-209 Chemical Constituents of Kiwifruit (Actinidia spp.) and Their Pharmacological Effects Jianmin Zheng, Guangman Xu Medicinal Plant Research, 2024, Vol. 14, No. 4, 210-222 Regulation of Secondary Metabolite Pathways in Ganoderma lucidumunder Environmental Stress Weidong Zhu Medicinal Plant Research, 2024, Vol. 14, No. 4, 223-233 Study on the Correlation Between the Physiological Characteristics of Dendrobium officinale and Optimal Cultivation Conditions Zhenyuan Zhang, Lingjuan Wang, Xiangqian Fan Medicinal Plant Research, 2024, Vol. 14, No. 4, 234-244
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 180 Systematic Review Open Access Ethnobotanical Uses and Phytochemistry of Eucommia ulmoides: A Comprehensive Review Honglin Wang1,2, BidaZhu1, Degang Zhao1,2 1 The Key Laboratory of Plant Resources Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), College of Life Sciences/Institute of Agro-Bioengineering, Guizhou University, Guiyang, 550025, Guizhou, China 2 Plant Conservation & Breeding Technology Center, Guizhou Key Laboratory of Agricultural Biotechnology/Guizhou Institute of Pomology Science, Guizhou Academy of Agricultural Sciences, Guiyang, 550006, Guizhou, China Corresponding author: dgzhao@gzu.edu.cn Medicinal Plant Research, 2024, Vol.14, No.4 doi: 10.5376/mpr.2024.14.0016 Received: 08 Jun., 2024 Accepted: 15 Jul., 2024 Published: 28 Jul., 2024 Copyright © 2024 Wang et al., This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Wang H.L., Zhu B.D., and Zhao D.G., 2024, Ethnobotanical uses and phytochemistry of Eucommia ulmoides: a comprehensive review, Medicinal Plant Research, 14(4): 180-195 (doi: 10.5376/mpr.2024.14.0016) Abstract Eucommia ulmoides, a widely used medicinal plant in traditional Chinese medicine, has a history of nearly two thousand years. This study systematically reviews the ethnobotanical uses and phytochemical properties of E. ulmoides, integrating historical knowledge with modern scientific research to explore its pharmacological activities and potential applications in modern medicine. The previous studies have demonstrated that E. ulmoides is rich in various bioactive compounds, including lignans, iridoids, flavonoids, and phenolic acids, which exhibit significant antioxidant, anti-inflammatory, antihypertensive and neuroprotective effects. Additionally, it reveals the potential applications of E. ulmoides extracts in treating cardiovascular diseases, neurodegenerative disorders and cancer. By thoroughly analyzing the traditional uses and phytochemical components of E. ulmoides, this study provides a scientific foundation for its application in modern medicine and identifies future research directions, particularly in the areas of bioactive compound isolation, pharmacological mechanisms, and clinical applications. This study is expected to promote the sustainable use and development of E. ulmoides in both traditional and modern medical systems. Keywords Eucommia ulmoides; Ethnobotany; Phytochemistry; Pharmacological activity; Modern medical applications 1 Introduction Eucommia ulmoides, commonly known as Dù-zhòng in traditional Chinese medicine (TCM), is the only species within the Eucommia genus, belonging to the family Eucommiaceae. It’s endemic to China and has been highly valued for its medicinal properties for nearly two thousand years (Wang et al., 2019a). Renowned for its various therapeutic properties, Eucommia ulmoides has been extensively used in traditional Chinese medicine for centuries. The bark, leaves, and seeds of Eucommia ulmoides are commonly used to treat a range of ailments, including hypertension, arthritis, lower back pain, and immune deficiencies (Feng et al., 2020; Xing et al., 2020). The importance of Eucommia ulmoides in Chinese culture is significant, holding a revered position in traditional Chinese medicine and deeply embedded in cultural practices and beliefs related to health and wellness. Its reputation as a potent medicinal plant has been passed down through generations, becoming a crucial symbol of traditional herbal medicine. Additionally, the leaves, bark, and fruits of Eucommia ulmoides produce latex when torn, a unique characteristic historically documented (Wang et al., 2019a). Various parts of Eucommia ulmoides are widely used in traditional therapies in China, Japan, and Korea, underscoring its broad cultural and medicinal relevance (He et al., 2014). The historical use of Eucommia ulmoidesin ethnobotany is well-documented, with records spanning different historical periods. The plant has been a cornerstone in TCM, used to treat a variety of ailments such as hypertension, hyperlipidemia, diabetes, obesity, sexual dysfunction, osteoporosis, Alzheimer's disease, aging, lupus-like syndrome, and for immunoregulation (He et al., 2014; Huang et al., 2021; Sun et al., 2022). Besides, Eucommia ulmoides exhibits various pharmacological activities, including antioxidant, anti-inflammatory, neuroprotective, anti-fatigue, anti-aging, anticancer, and immunomodulatory effects. The pharmacological properties of E. ulmoides have been extensively studied, revealing a wide range of bioactive compounds including
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 181 lignans, iridoids, flavonoids, phenols, steroids, and terpenes (Wang et al., 2019a). These compounds contribute to the plant's diverse therapeutic effects, making it a valuable resource in both traditional and modern medicine. This study provides a comprehensive review of the ethnobotanical uses and phytochemical properties of Eucommia ulmoides, combining historical knowledge with modern scientific research. It examines the traditional uses of Eucommia ulmoides and highlights the latest advances in phytochemistry, elucidating the therapeutic potential of the plant and its relevance in modern medicine. The study intends to identify gaps in current research and propose future research directions, particularly in areas such as the isolation of bioactive compounds, pharmacological mechanisms, and clinical applications. This study is expected to deepen the understanding of Eucommia ulmoides and its role in both traditional and modern medical systems, reinforcing its status as a medicinal plant of significant cultural and therapeutic value. 2 Traditional Ethnobotanical Uses of Eucommia ulmoides 2.1 Medicinal applications in traditional Chinese medicine Eucommia eucommia is a kind of woody plant with high economic and medicinal value, which was listed as top quality medicine in Shen Nong’s Herbal Classics. As a cornerstone of TCM, various parts of Eucommia eucommia, including the leaf, stem, bark and staminate flower, have been utilized to treat a wide array of ailments for nearly two thousand years. The earliest medical record about the bark of Eucommia ulmoides was found in the Zhi Bai Bing Fang in the Han Dynasty, which was about the treatment of internal injuries caused by consumptive diseases. The medicinal functions of Eucommia eucommia leaves, flowers, fruits and stems were similar to that of barks, which expounded in another pharmaceutical book named Ben Cao Tu Jing in the Song Dynasty (Wang et al., 2019b). Because of the Eucommia eucommia’s warm medicine nourishes the body, it can enter the liver meridian to tonify the kidneys and prevent miscarriage, was recorded in Ben Cao Gang Mu (Bao et al., 2024). China is a multi-ethnic country, in which people of all ethnic groups have accumulated a wealth of medical theories and drug experiences. Regarding the medicinal use of Eucommia eucommia by some ethnic minority groups in China, Jia and Li (2005) have summarized in the Zhong Guo Min Zu Yao Zhi Yao (Table 1). Table 1 The traditional medicine application of E. ulmoides recorded by ethnic minority groups in China Ethnic minorities Ethnic medicine names Medicinal part Medicinal value Medicinal record Yi / Stem/bark Kidney vacuity, lumbar pain, inability of the extremities, rheumatism bone pain, ache all over, fetal irritability, sexual dysfunction Ai Lao Shui Bimei Duzhong Stem/bark Hypotension, nephritis edema Shui Yi Yao Lisu Sigongzi Bark Low back pain, rheumatism, dizziness, hypotension, restless fetus, falls Nu Jiang Yao Maonan Meiduzhong Bark Kidney vacuity, lumbar pain Gui Yao Bian Miao Ndui zhoux sod, Det dent, Det uab udfab Stem/bark Lumbar pain, fetal irritability MiaoYi Yao Bark Kidney vacuity, lumbar pain, waist-leg weakness, fetal irritability, threatened abortion, hypertension Xiang Lan Kao Det dent Stem/bark Lumbar pain, fetal irritability MiaoYao Ji Keliu Bark External treatment of knife wounds Gui Yao Biao Hani Qida Stem/bark, leaves Fracture DianYaoLu Bark The Formula is used for the wound cure Dian Sheng Zhi De'ang / Bark Knife wound, waist and knee pain, fetal irritability, hypertension Dian Sheng Zhi Jingpo Sikjicq / Hypertension, giddy and dazzled, kidney deficiency and frequent micturition, fetal irritability De Hong Yao Lu Dai Yaregao, Dedai Bark The formula is used for the wound cure Dian Sheng Zhi Dong Meix sabt enl, Sangp meix sabt enl Bark Spermatorrhea DongYi Xue Tibetan Dabusang Bark Stomach heat, eye disease, bone fracture, catagma, sore and ulcer Zang Ben Cao Va Luokaoyangyi Bark Chronic kidney disease, hypertension Wa Zu Shi Liao ( Ⅲ) Note: /: No related information
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 182 Relevant statistics shown that, as of 2019, among the 9,985 varieties of proprietary Chinese medicines that have been already on the market, 220 of them contained Eucommia eucommia, which were mainly used in the fields of internal medicine, orthopedics, gynecology, ophthalmology and surgery (Li et al., 2021). Historical records highlight its use in managing conditions such as hypertension, hyperlipidemia, diabetes, obesity, sexual dysfunction, osteoporosis, Alzheimer's disease, aging, lupus-like syndrome, and immunoregulation (He et al., 2014; Wang et al., 2019a). For example, studies have found that Eucommia ulmoides extracts can alleviate the damage caused by hypertension by regulating blood pressure, improving kidney function, and reducing the levels of inflammatory factors. Specifically, by modulating the gut microbiota, Eucommia ulmoides extracts can enrich bacterial strains with antihypertensive effects, such as Parabacteroides, suggesting that Eucommia ulmoides exerts its antihypertensive effects through the regulation of gut microbiota (Yan et al., 2022). Eucommia ulmoides cortex extract inhibited palmitateinduced endoplasmic reticulum stress, reducing hepatic lipid accumulation through secretion of apolipoprotein B and associated triglycerides and cholesterol in hepatocytes (Lee et al., 2013). Eucommia ulmoides leaves extract may partly ameliorate hyperglycemia and hyperlipidemia with type 2 diabetes through increasing glycolysis, suppressing gluconeogenesis and the biosynthesis of fatty acid and cholesterol in the liver (Park et al., 2006). In addition, another research has revealed that the extracts of Eucommia ulmoides male flower ameliorated AD-like pathology in zebrafish possibly by inhibiting excessive autophagy and the abnormal expressions of ache and slc6a3genes (Sun et al., 2023). Additionally, Eucommia ulmoides has been employed to alleviate lumbar pain, knee pain, osteoporosis, hepatoprotection, paralysis, intestinal hemorrhages, vaginal bleeding, abortion, spermatorrhea, and foot fungus (Huang et al., 2021). For instance, E. ulmoides leaf extract may have curative properties for bone mineral density and body mass index in ovariectomy rats, and could provide an alternative therapy for the prevention of both postmenopausal osteoporosis and obesity (Zhang et al., 2012). Moreover, 5-(hydroxymethyl)-2-furaldehyde, isolated fromEucommia ulmoides Oliver Bark, not only inhibited the formation of adipose cells obviously, but also enhanced the osteoblastogenesis (Tan et al., 2014). The plant's extracts and active components have shown significant therapeutic effects, including antioxidant, anti-inflammatory, neuroprotective, anti-fatigue, anti-aging, anti-cancer, and immunoregulatory activities. 2.2 Non-medicinal uses in various cultures Beyond its medicinal applications, Eucommia ulmoides has found various non-medicinal uses across different cultures. In traditional Chinese practices, the plant's latex, obtained by tearing its leaves, bark, and fruit, has been used for its unique properties (Huang et al., 2021). Compared with natural rubber, the chemical structure of Eucommia ulmoides rubber is trans-1, 4-polyisoprene, the structure is more regular to crystallize easyly, and has the double characteristics of plastic and rubber (Wei et al., 2021). Therefore, it has been developed for a variety of innovative applications, such as a thermoplastic material, thermoelastic shape memory material (Kang et al., 2022), vibrationand sound-absorbing materials (Su et al., 2022). It not only has enriched the research field of materials science, but also promoted the application and development of gutta-percha in textile, aerospace, transportation, sports and construction (Wang et al., 2019a; Yan et al., 2024). Furthermore, the bioactive chemicals extracted from different parts of the plant, such as leaves, seeds, bark, and staminate flowers, are widely used as raw materials for food, powdery extracts and tinctures (Zhu and Sun, 2018; Ding et al., 2020). For instance, Eucommia ulmoides leaf superfine powder was used as an additive in the fermentation of glutinous rice (Semen Oryzae Glutinosae), could increase the contents of flavonoids, free amino acids, polyphenols and polysaccharides of sweet rice wine, and enhance its antioxidant activity (Ren et al., 2022). As a feed additive, it could increase the n-3 fatty acids content and decrease the n-6: n-3 PUFA ratio in egg yolk without affecting laying performance or egg quality (Feng et al., 2023). In flower preservation, pretreated with aqueous solution of Ag-NPs, synthesized with the leaf extract of Eucommia ulmoides, could effectively reduced bacteria-induced xylem blockage of cut tree peony, resulting in improved water uptake, extended vase life, and enhanced postharvest quality (Ma et al., 2023).
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 183 2.3 Conservation of traditional knowledge Protecting traditional knowledge related to Eucommia ulmoides is of great significance in promoting its sustainable use and further research. As a traditional medicinal herb, Eucommia ulmoides has been extensively documented in historical literature, with its applications spanning multiple historical periods. Preserving and passing on this valuable ethnobotanical knowledge not only helps to understand how Eucommia ulmoides has been used in different cultural contexts but also provides valuable references for modern scientific research (Wang et al., 2019a). By documenting and deeply studying the traditional applications of Eucommia ulmoides, we can uncover its phytochemical components and pharmacological properties, laying the foundation for its applications in medicine and health care. The protection of traditional knowledge related to Eucommia ulmoides involves not only the documentation of historical records but also the support of modern scientific research. Ongoing research can reveal potential new applications of Eucommia ulmoides, promoting its commercial development as a traditional medicine and health food (He et al., 2014; Wang et al., 2019a; Sayed et al., 2021). This study not only contributes to the inheritance and development of ethnobotanical knowledge but also brings new opportunities to the modern medical and health industries. Protecting and promoting the traditional knowledge of Eucommia ulmoides is not only a respect for history but also a drive for future innovation. 3 Phytochemistry of Eucommia ulmoides 3.1 Major chemical constituents Eucommia ulmoides is rich in lignans and iridoids, which are among the primary bioactive compounds isolated from this plant, and contribute significantly to its pharmacological properties. Lignans such as pinoresinol diglucoside and syringaresinol have been identified, along with iridoids like geniposidic acid and aucubin (He et al., 2014; Wang et al., 2019a). Eucommiapinoresinol diglucoside is a natural blood pressure lowering compound. As a candidate drug for the treatment of cardiovascular diseases, it could prevent the dysfunction of venous endothelial cells induced by oxidized low density lipoprotein (Yao et al., 2016). It also could mitigate dexamethasone-induced osteoporosis and chondrodysplasia by promoting bone formation and activating Wnt signaling (Zuo et al., 2024). Study has shown that the glucoside structure of lignans was extremely important, it would lose the ability to regulate blood pressure without the glucoside structure (Sih et al., 1976). Geniposide is a bioactive iridoid glucoside, which has significant therapeutic effect on digestive, cardiovascular and central nervous system diseases. Through activating AMPK-αand Sirt1 pathways, it’s able to reduce the heart damage caused by obesity symptoms (Ma et al., 2018), ameliorate DEX-induced osteoblast apoptosis by activating autophagy through GLP-1R/PI3K/AKT/mTOR pathway (Huang et al., 2022b), also could produce antiinflammatory effects by reducing the release of inflammatory cytokines (Li et al., 2019), alleviate osteoarthritis through inhibiting inflammation and chondrocytes ferroptosis via Nrf2 signalling pathway (Sun et al., 2024). Flavonoids and phenolic acids are also abundant in E. ulmoides. It contains 25 different flavonoids with different substituents, which have significant effects on treating cardiovascular diseases such as coronary heart disease and hypertension (Liu et al., 2020). Key flavonoids include quercetin and kaempferol, which have been shown to possess strong antioxidant and anti-inflammatory activities (Bai et al., 2015). The total flavonoids from E. ulmoides leaves can significantly alleviate neurological damage caused by ischemic stroke by inhibiting oxidative stress, including decrease the levels of reactive oxygen species, lactate dehydrogenase, and malondialdehyde, while increase catalase and glutathione (Qin et al., 2024). Quercetin glycoside, which fromE. ulmoides leaves, could bind to insulin receptors, and improve insulin resistance as demonstrated by the increased uptake of glucose and glycogen production through a signaling pathway called IRS-1/PI3K/Akt/GSK-3 (Tang et al., 2023). 3.2 Bioactive compounds with therapeutic potential The antioxidant properties of E. ulmoides are primarily attributed to its high content of flavonoids and phenolic acids. Compounds like quercetin and chlorogenic acid have demonstrated significant free radical scavenging activities, which help in mitigating oxidative stress-related damage (Bai et al., 2015; Gong et al., 2022). These antioxidants play a crucial role in the plant's ability to protect against various diseases, including
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 184 neurodegenerative disorders and cardiovascular diseases (Tang et al., 2021; Gong et al., 2022). Chlorogenic acid could cross the blood-cerebrospinal fluid barrier to exhibit its neuron protection and promotion of serotonin release through enhancing synapsin I expression, so that it may be developed as the natural drugs for the treatment of depression (Wu et al., 2016). E. ulmoides contains several compounds with potent anti-inflammatory effects. Iridoids such as aucubin and geniposidic acid have been shown to inhibit the production of pro-inflammatory cytokines like TNF-α and IL-1β (Wang et al., 2016; Tang et al., 2021). Additionally, flavonoids like quercetin and kaempferol inhibit the NF-κB pathway, further contributing to their anti-inflammatory properties (Bai et al., 2015). These bioactive compounds are effective in treating conditions such as rheumatoid arthritis and gastric ulcers (Wang et al., 2016; Gong et al., 2022). 3.3 Methods of phytochemical analysis Chromatography techniques are widely used for the analysis of phytochemicals in E. ulmoides. High-performance liquid chromatography (HPLC) is commonly employed to separate and quantify various bioactive compounds, including iridoids, flavonoids, and phenolic acids (Kim et al., 2009; Gong et al., 2022). Gas chromatography-mass spectrometry (GC-MS) has also been used to analyze the sterol profiles in E. ulmoides seed oil, identifying compounds such as β-sitosterol (Tang et al., 2021). Spectroscopy methods, including nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESIMS), are essential for the structural elucidation of bioactive compounds in E. ulmoides. These techniques have been used to identify and confirm the structures of various lignans, iridoids, and flavonoids isolated from the plant (Bai et al., 2015). Additionally, ultra-performance liquid chromatography (UPLC) coupled with mass spectrometry provides a rapid and accurate method for analyzing the main components in E. ulmoides extracts (Gong et al., 2022). By employing these advanced analytical techniques, researchers can better understand the complex phytochemical composition of E. ulmoides and its potential therapeutic applications. 4 Pharmacological Activities of Eucommia ulmoides 4.1 Anti-inflammatory and antioxidant properties Eucommia ulmoides exhibits significant anti-inflammatory properties through various mechanisms. The polysaccharides derived from E. ulmoides (EUP) have been shown to reduce inflammation by modulating the TLR-4-NF-κB pathway, which is crucial in the inflammatory response. Specifically, these polysaccharides decrease the levels of pro-inflammatory cytokines such as TNF-α and IL-1β, thereby mitigating inflammation in hepatic ischemia-reperfusion injury (Figure 1) (Gao et al., 2020). Additionally, the iridoid glycosides present in E. ulmoides seeds, such as aucubin, have demonstrated inhibitory effects on nitric oxide (NO) production in LPS-stimulated microglial cells, further contributing to their anti-inflammatory potential (Tang et al., 2021). The antioxidant properties of E. ulmoides are primarily attributed to its ability to enhance the activity of antioxidant enzymes and reduce oxidative stress markers. Studies have shown that E. ulmoides leaf extracts (ELE) increase the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) while decreasing malondialdehyde (MDA) levels in various tissues, indicating a reduction in oxidative stress (Ding et al., 2020; Liao et al., 2021). These antioxidant effects are crucial in preventing diseases associated with oxidative stress, such as cardiovascular diseases and neurodegenerative disorders (Huang et al., 2021; Huang et al., 2022a). 4.2 Cardiovascular and metabolic health benefits E. ulmoides has been traditionally used to manage hypertension, and modern research supports its efficacy in lowering blood pressure. The bark extract of E. ulmoides has been shown to reduce blood pressure in high-salt diet and L-NAME-induced hypertensive mice by modulating the gut microbiota and reducing inflammatory cytokines (Yan et al., 2022). Additionally, the leaf extract enhances NO production in endothelial cells, which plays a critical role in vasodilation and blood pressure regulation (Lee et al., 2018).
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 185 E. ulmoides also contributes to metabolic health by regulating lipid metabolism. The extracts fromE. ulmoides have been found to improve lipid profiles by reducing serum cholesterol and triglyceride levels. This effect is partly due to the enhancement of lipid metabolism enzymes and the modulation of gut microbiota, which collectively help in maintaining healthy lipid levels (Wang et al., 2019a; Zhao et al., 2022). Figure 1 The role of EUP in hepatic ischemia-reperfusion injury (Adopted from Gao et al., 2020) Image caption: The figure indicates that EUP reduces ROS production, inhibits HMGB1 release and the activation of its downstream TLR-4-NF-κB signaling pathway, thereby alleviating inflammation and oxidative stress caused by ischemia-reperfusion, ultimately reducing hepatocyte damage and liver necrosis. This result confirms the significant anti-inflammatory and antioxidant effects of EUP, supporting its potential application in preventing and treating hepatic ischemia-reperfusion injury (Adapted from Gao et al., 2020) 4.3 Neuroprotective and anticancer activities E. ulmoides exhibits neuroprotective properties that are beneficial in the context of neurodegenerative diseases. The iridoid glycosides, particularly aucubin, have been shown to protect neuronal cells by inhibiting oxidative stress and inflammation. These compounds reduce NO production and enhance the expression of antioxidant genes, thereby protecting against neurodegenerative conditions such as Parkinson's and Alzheimer's diseases (Huang et al., 2021; Tang et al., 2021). The anticancer potential of E. ulmoides is attributed to its ability to modulate various cellular pathways involved in cancer progression. The extracts from E. ulmoides have been shown to inhibit cancer cell proliferation and induce apoptosis through mechanisms involving the regulation of the NEI network and inflammatory pathways (Zhao et al., 2022). Additionally, the phytosterols and iridoids present in E. ulmoides seeds have demonstrated significant anti-inflammatory and anticancer activities, suggesting their potential use in cancer prevention and therapy (Tang et al., 2021). By understanding these pharmacological activities, researchers can further explore the therapeutic potential of E. ulmoides in various diseases, providing reference for new clinical applications and drug development.
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 186 5 Mechanisms of Action of Eucommia ulmoides 5.1 Cellular pathways Eucommia ulmoides exerts its pharmacological effects through various cellular pathways, prominently involving the PI3K/Akt signaling pathway. For instance, the flavonoids fromEucommia ulmoides leaves (TFEL) have been shown to regulate the PI3K/Akt pathway, which plays a crucial role in improving insulin resistance and regulating glucose and lipid metabolism in polycystic ovary syndrome (PCOS) models (Peng et al., 2021). Additionally, Eucommia ulmoides flavones have demonstrated protective effects against enterocyte damage induced by lipopolysaccharide (LPS) by modulating the PI3K-NFκB signaling pathway, enhancing cell viability, and reducing apoptosis (Hussain et al., 2020). These pathways are critical in mediating the anti-inflammatory and cytoprotective effects of Eucommia ulmoides. 5.2 Molecular targets The active compounds in Eucommia ulmoides target several key molecular entities. For example, in the treatment of Parkinson's disease (PD), Eucommia ulmoides downregulates the expression of p38 and JNK, which are upstream genes of the Fosl2, thereby reducing neuroinflammation (Fan et al., 2020). In the context of nonalcoholic fatty liver disease (NAFLD), Eucommia ulmoides components, particularly flavonoids, interact with lipid metabolism-regulating core proteins such as PPARγ, enhancing lipid metabolism and autophagy (Gong et al., 2021). The study found that Eucommia ulmoides leaf extract 50 significantly reduced lipid accumulation in HepG2 cells by regulating PPARγ expression and activating autophagy (Figure 2). Figure 2 Network pharmacology analysis of Eucommia ulmoides leaves (Adopted from Gong et al., 2021) Image caption: Figure A shows the target analysis of Eucommia ulmoides leaves related to NAFLD, while Figure B presents the composition-target network, revealing the association between multiple active components and the core targets of NAFLD. Figure C displays the protein-protein interaction (PPI) network, highlighting key targets such as PPARγ, ESR1, and PPARA. Figure D shows the KEGG enrichment analysis, indicating that these targets are primarily involved in metabolic pathways related to NAFLD. These analyses suggest that the flavonoid and phenolic components in Eucommia ulmoides leaves may exert therapeutic effects by modulating these key targets (Adapted from Gong et al., 2021)
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 187 Additionally, in a study on diabetic nephropathy, Do et al. (2018) found that E. ulmoides effectively reduced the accumulation of advanced glycation end-products (AGEs) and mitigated renal damage in streptozotocin-induced diabetic mice. Notably, E. ulmoides treatment did not alter blood glucose levels but significantly upregulated the expression of glyoxalase 1 (Glo1) and nuclear factor erythroid 2-related factor 2 (Nrf2), both of which play crucial roles in detoxifying AGEs and reducing oxidative stress. Histological analysis revealed that E. ulmoides significantly reduced glycation and oxidative damage in kidney tissues. This suggests that E. ulmoides, through its antioxidative and anti-glycation properties, may be a potential therapeutic agent for preventing or treating diabetic complications, particularly in protecting kidney function. 5.3 Synergistic effects The therapeutic efficacy of Eucommia ulmoides is often attributed to the synergistic interactions between its various bioactive compounds. For instance, the combination of Eucommia ulmoides and Dipsaci Radix (EU-DR) has been shown to exert a multi-component, multi-target, and multi-pathway interaction mechanism in the treatment of osteoporosis. The flavonoids in EU-DR play a significant role in regulating osteoclast differentiation-related signaling pathways, demonstrating strong binding efficiency to target proteins involved in bone metabolism (Feng et al., 2022). Similarly, the multitarget mechanism of Eucommia ulmoides in treating ankylosing spondylitis involves the interaction of its bioactive molecules with multiple targets such as IL-1B, PTGS2, and IL-8, mediated through interleukin-17 and TNF-α signaling pathways (Zhang et al., 2022). These synergistic effects highlight the complex interplay of E.ulmoides's compounds in modulating various biological processes and enhancing therapeutic outcomes. 6 Case Studies 6.1 The antihypertensive effects of Eucommia ulmoides extract through gut microbiota modulation The lignans, flavonoids, and iridoids in E. ulmoides extracts are considered the primary active components responsible for its antihypertensive effects. However, the significant antihypertensive effects remain difficult to fully explain due to the low oral bioavailability of these compounds. In recent years, researchers have begun to focus on the relationship between E. ulmoides extracts and the gut microbiota, hypothesizing that gut microbiota may play a key role in the antihypertensive effects. Yan et al. (2022) explored the mechanism by which E. ulmoides extracts exert their antihypertensive effects by regulating the gut microbiota, particularly by enriching Parabacteroides strains. In a six-week treatment of hypertensive mouse models induced by a high-salt diet and N(omega)-Nitro-L-arginine methyl ester, E. ulmoides extracts were administered. The results showed that E. ulmoides extracts significantly lowered blood pressure, improved kidney function, and reduced inflammation. Moreover, the study found that E. ulmoides extracts significantly altered the diversity and composition of the gut microbiota, especially by enriching Parabacteroides strains. Further animal experiments confirmed the crucial role of the Parabacteroides strain XGB65 in reducing blood pressure and renal inflammation (Figure 3). The study provides the first evidence that E. ulmoides reduces blood pressure through the regulation of gut microbiota, revealing the important role of the Parabacteroides strain XGB65 in this process. This discovery offers significant theoretical and practical references for the development of novel antihypertensive probiotics and prebiotic therapies, with potential clinical application value. 6.2 Effects of Eucommia ulmoides male flower extracts on Alzheimer’s disease E. ulmoides, a traditional Chinese medicinal herb, has garnered significant attention for its various bioactive components, known for their antioxidant and anti-inflammatory effects. Research indicates that the male flowers of E. ulmoides also contain abundant active compounds, which hold therapeutic potential for Alzheimer’s disease (AD) (Huang et al., 2021; Sun et al., 2022).
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 188 Sun et al. (2022) investigated the therapeutic effects of E. ulmoides male flower extracts (EUMF) in a zebrafish model of Alzheimer’s disease, focusing particularly on its impact on β-amyloid (Aβ) deposition, the expression of autophagy-related genes, and acetylcholinesterase (AChE) activity. The study found that EUMF significantly alleviated AD-like symptoms induced by aluminum chloride (AlCl3) in zebrafish. This was evidenced by a reduction in Aβ plaques in the zebrafish brain, inhibition of AChE activity, and decreased brain cell apoptosis (Figure 4). Additionally, EUMF modulated the expression of autophagy-related genes (such as ambra1a, atg5, ulk1b, and lc3b) and neurotransmitter regulation-related genes (ache and slc6a3), which play critical roles in AD pathology. Figure 3 Parabacteroides strain XGB65 reduces blood pressure. Blood pressure (A) in the XGB65 + HSD, NS + HSD, and NS + ND groups in week 6 and (B) in the XGB65 + HSD and NS + HSD groups from the beginning of the experiment to the end of week 6 (2-week L-NAME treatment, 1-week washout period, XGB65 + HSD treatment from week 4 to week 6). (C) HE staining of kidney tissues in the XGB65 + HSD, NS + HSD, and NS + ND groups (10 ×, scale bars = 100 µm; 40 ×, scale bars = 20 µm) (Adopted from Yan et al., 2022) Image caption: The figure demonstrates the antihypertensive effects and the improvement of kidney inflammation in high-salt diet-induced hypertensive mice treated with Parabacteroides strain XGB65. The results show that compared to the control group, the blood pressure in the XGB65-treated group was significantly reduced, and the expression of IL-17A in the kidneys was also significantly decreased. Histological analysis of the kidneys revealed that pathological damage was improved in the XGB65-treated group. These findings confirm that Parabacteroides strain XGB65 has antihypertensive and anti-inflammatory effects, further supporting the crucial role of gut microbiota in the antihypertensive mechanism of E. ulmoides and highlighting the therapeutic potential of the XGB65 strain (Adapted from Yan et al., 2022)
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 189 Figure 4 Effect of EUMF on apoptosis in the brains of the AlCl3-modeled zebrafish (Adopted from Sun et al., 2022) Image caption: Figure A shows the location of apoptotic cells in the zebrafish brain through TUNEL staining, while Figure B quantifies the number of apoptotic cells in each treatment group. The results indicate that AlCl3 treatment significantly increased the number of apoptotic cells in the zebrafish brain, whereas EUMF treatment significantly reduced these numbers. This figure reveals the protective effect of EUMF against AlCl3-induced apoptosis, further validating its potential as an anti-Alzheimer's disease agent (Adapted from Sun et al., 2022) The study suggests that E. ulmoides male flower extracts have a significant ameliorating effect on Alzheimer’s disease-like pathology, with mechanisms potentially involving the inhibition of excessive autophagy and the regulation of acetylcholinesterase and dopamine transporter gene expression. The flavonoids in EUMF are likely the key compounds responsible for its therapeutic effects. E. ulmoides male flower extracts show promise as a potential therapeutic agent for Alzheimer’s disease, acting through multiple pathological pathways and offering new perspectives and directions for the comprehensive treatment of AD. 6.3 Clinical trials involving E. ulmoides extracts Clinical trials have further substantiated the therapeutic potential of E. ulmoides extracts. In one study, the administration of E. ulmoides leaf extract to ox-LDL-treated human endothelial cells resulted in a significant recovery of nitric oxide levels and a reduction in oxidative stress, suggesting its potential in preventing vascular endothelial dysfunction (Lee et al., 2018). Another clinical investigation demonstrated that E. ulmoides extract could lower blood pressure in hypertensive patients by improving renal hemodynamics and reducing oxidative stress (Ishimitsu et al., 2021). These findings are consistent with traditional uses and provide a scientific basis for the continued use of E. ulmoides in cardiovascular treatments. E. ulmoides has shown significant promise in cardiovascular treatments, particularly in reducing blood pressure and improving vascular health. Its traditional uses are supported by modern research, which has elucidated the mechanisms behind its antihypertensive effects and highlighted its potential in clinical applications (Ishimitsu et al., 2021; Yan et al., 2022).
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 190 7 Environmental and Ecological Impacts onEucommia ulmoides 7.1 Ecological requirements for E. ulmoide scultivation E. ulmoides, a dioecious and pharmaceutically significant tree species, is endemic to China and thrives in specific ecological conditions. The species is predominantly found in the Wuling Mountains and other regions with similar geoclimatic conditions. Studies have shown that the average annual temperature and rainfall are critical factors influencing the phenotypic traits of E. ulmoides (Xie et al., 2023). These climatic conditions significantly affect leaf, fruit, and seed sizes, which are essential for the plant's growth and medicinal properties (Wang et al., 2023). Additionally, the annual sunshine duration has been identified as a crucial factor, positively correlating with economic traits and leaf yield, while negatively correlating with growth traits (Deng et al., 2022). Therefore, selecting appropriate cultivation areas with optimal temperature, rainfall, and sunshine duration is vital for the successful cultivation of E. ulmoides. 7.2 Impact of environmental factors on phytochemical profiles Environmental factors play a significant role in determining the phytochemical profiles of E. ulmoides. Variations in genotype, site, and genotype × environment interactions have been shown to influence the phenotypic traits and, consequently, the phytochemical composition of the plant. For instance, the gutta-percha content, total number of leaves, and chlorogenic acid content exhibit significant differences based on these environmental interactions (Deng et al., 2022). The phenotypic differentiation among populations of E. ulmoides is significantly correlated with geographic and climatic distances, indicating that environmental factors such as temperature and rainfall are crucial in shaping the phytochemical profiles (Wang et al., 2023). These findings suggest that environmental conditions must be carefully managed to optimize the production of valuable phytochemicals in E. ulmoides. 7.3 Conservation strategies for wild populations Conserving wild populations of E. ulmoides is essential for maintaining genetic diversity and ensuring the species' long-term survival. The phenotypic variation within and among natural populations highlights the need for targeted conservation strategies (Wang et al., 2018; Kardos et al., 2021). The significant phenotypic differentiation driven by geographic and climatic factors suggests that conservation efforts should focus on preserving diverse habitats that support various phenotypic traits (Wang et al., 2023). Additionally, the identification of key environmental factors, such as average annual temperature and rainfall, can inform the development of conservation plans that prioritize areas with optimal conditions for E. ulmoides growth (Deng et al., 2022; Wang et al., 2023). Implementing genetic improvement programs and resource management strategies can further enhance the conservation of this valuable species, ensuring its continued availability for medicinal and economic uses. 8 Challenges and Future Research Directions 8.1 Challenges in sustainable cultivation Sustainable cultivation of E. ulmoides faces several significant challenges, primarily due to the plant’s specific environmental requirements and the increasing demand for its medicinal properties. The cultivation of E. ulmoides requires specific soil types, optimal temperature ranges, and careful management of water resources to ensure healthy growth and high yield of bioactive compounds (Su et al., 2021; Dong et al., 2022). Climate change, with its unpredictable weather patterns, poses a threat to these conditions, potentially leading to reduced productivity (Wang et al., 2023). Additionally, as demand for E. ulmoides continues to grow, over harvesting and unsustainable agricultural practices risk depleting natural resources and compromising the genetic diversity of the species. There is a pressing need for developing sustainable agricultural practices that balance the need for high yield with environmental conservation, including the promotion of agroforestry systems, organic farming, and the development of resistant varieties through advanced breeding techniques. 8.2 Opportunities for new pharmacological discoveries Despite the challenges in sustainable cultivation, E. ulmoides presents numerous opportunities for new pharmacological discoveries. The plant’s rich phytochemical profile, which includes iridoids, lignans, flavonoids, and phenolic acids, offers a promising foundation for the development of new therapeutic agents (Liu et al., 2020).
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 191 Recent research has identified the potential of E. ulmoides extracts in treating a range of conditions, including hypertension, osteoporosis, and neurodegenerative diseases (Han et al., 2021; Liu et al., 2022). With the advancement of modern analytical techniques, there is an opportunity to explore lesser-known compounds in E. ulmoides, elucidating their mechanisms of action and potential therapeutic benefits. Furthermore, the integration of traditional knowledge with modern scientific research can lead to the discovery of novel bioactive compounds, contributing to the development of new drugs and health supplements. 8.3 Future research directions in ethnobotany and phytochemistry Future research on E. ulmoides should focus on bridging the gap between ethnobotanical knowledge and modern phytochemistry to fully harness the plant’s medicinal potential. In ethnobotany, there is a need for comprehensive studies documenting traditional uses of E. ulmoides across different cultures, as well as the ecological knowledge associated with its cultivation and harvest. This information is crucial for informing sustainable use practices and for identifying new applications of the plant in modern medicine. In phytochemistry, future research should prioritize the identification and characterization of bioactive compounds, as well as their pharmacokinetics and pharmacodynamics. Additionally, exploring the synergistic effects of multiple compounds found in E. ulmoides could lead to the development of more effective multi-target therapies. Collaborative research between ethnobotanists, chemists, pharmacologists, and agricultural scientists will be essential in advancing our understanding of E. ulmoides and its applications in both traditional and modern medicine. 9 Concluding Remarks E. ulmoides, a valuable medicinal plant endemic to China, has been extensively studied for its ethnobotanical uses and phytochemical properties. The plant has a rich history in traditional Chinese medicine, with various parts such as the leaves, bark, and fruit being utilized for their medicinal properties. Research has identified over 200 natural compounds in E. ulmoides, including lignans, iridoids, flavonoids, phenols, steroids, and terpenes, which exhibit a wide range of pharmacological activities such as antihypertensive, antihyperglycemic, antihyperlipidemic, antioxidative, anti-osteoporotic, antitumor, immunomodulatory, and neuroprotective effects. Additionally, studies have shown that the leaves of E. ulmoides are particularly effective in regulating lipid metabolism and treating nonalcoholic fatty liver disease through mechanisms involving flavonoids and phenolics. The comprehensive utilization of different parts of the plant, including leaves and bark, has been explored to improve its economic value and conservation. The extensive pharmacological properties of E. ulmoides suggest several potential applications in modern medicine and industry. The antihypertensive, antihyperglycemic, and antihyperlipidemic properties make it a promising candidate for developing treatments for cardiovascular diseases and metabolic disorders. The antioxidative and neuroprotective activities indicate potential uses in preventing and treating neurodegenerative diseases. Furthermore, the plant's antitumor and immunomodulatory effects could be harnessed in cancer therapy and immune system support. The identification of bioactive compounds and their mechanisms of action also opens avenues for the development of new drugs and therapeutic agents. Additionally, the comprehensive utilization of E. ulmoides, including its leaves and bark, can enhance its economic value and promote sustainable use of this valuable resource. Future research on E. ulmoides should focus on several key areas to fully realize its potential. For example, More in-depth studies on the pharmacological mechanisms of its bioactive compounds are needed to develop targeted therapies for specific diseases. Efforts should be made to standardize the quality and composition of E. ulmoides products to ensure their efficacy and safety. This includes developing reliable methods for quality control and authentication of different varieties and parts of the plant. Exploring the comprehensive utilization of E. ulmoides, including its leaves, bark, and other parts, can lead to more sustainable and economically viable practices. Furthermore, Interdisciplinary research combining ethnobotany, phytochemistry, pharmacology, and modern biotechnology will be essential to unlock the full potential of E. ulmoides and translate traditional knowledge into modern medical applications.
Medicinal Plant Research 2024, Vol.14, No.4, 180-195 http://hortherbpublisher.com/index.php/mpr 192 Funding This work was supported by the Guizhou Academy of Agricultural Sciences Talent Special Project (No.2023-02, No.2024-02), National High Technology Research and Development Program of China (“863′′ Program) [Grant No.2013AA102605-05], National Major Project of Cultivating New Varieties of Genetically Modified Organisms [Grant No.2016ZX08010003-009], Talent Base for Germplasm Resources Utilization and Innovation of Characteristic Plant in Guizhou (RCJD2018-14). Acknowledgments We would like to express our sincerest gratitude to Ms. Li from the Research Group of Eucommia ulmoides. During the course of this study, she assisted in collecting and organizing a large amount of literature related to Eucommia ulmoides, providing solid support for our study. Additionally, we extend our heartfelt thanks to the three anonymous peer reviewers for their valuable contributions during the review process of this manuscript. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. 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