Research progress on the main chemical components and pharmacological effects of Epimedium

1. Introduction

Epimedium, scientific name, belongs to the family Coptis chinensis. Its dried leaves are called Xianlingpi in traditional medicine. The Leigongpao Theory records that it is pungent in taste, sweet and warm in nature, and enters the liver and kidney meridians. It has the effects of warming kidney yang, strengthening tendons and bones, and removing rheumatism [1]. Modern research shows that the chemical composition of epimedium is complex and diverse, which not only increases the difficulty of research, but also provides a material basis for the multi-faceted pharmacological effects of epimedium. For example, studies on icariin in anti-osteoporosis and anti-tumor have shown its significant biological activity, while epimedium total flavonoids have excellent antioxidant and anti-inflammatory effects. This diversity of components may be the key to the widespread application of epimedium in traditional medicine [2]. These multi-component and multi-target characteristics make epimedium show significant efficacy in the treatment of multi-system diseases, and its clinical application field has been greatly expanded. There are certain differences in the efficacy of epimedium in different disease models, which may be related to the pathological mechanism of the disease itself and the target of epimedium components. For example, in the osteoporosis model, icariin works by regulating the balance of bone metabolism; while in the breast cancer model, it affects the proliferation and apoptosis of tumor cells. This difference suggests that we need to select appropriate epimedium components according to the characteristics of the disease in clinical application. This article reviews the pharmacological effects and mechanisms of epimedium in the treatment of various common diseases such as osteoporosis, breast cancer, Alzheimer's disease, heart failure and asthma, aiming to explore epimedium and its active ingredients, explore its wider clinical application, and discuss its potential for combined use with other treatments, in order to further improve its therapeutic benefits.

2. Research on the active ingredients of Epimedium

Currently, a large number of experimental studies have isolated more than 270 compounds from different species of Epimedium plants, including flavonoids, polysaccharides, organic acids, alkaloids, lignans, etc. Among them, flavonoids and their derivatives are the main active ingredients [3]. The total flavonoid content of Epimedium medicinal materials from different origins and seasons varies [4]. A study isolated and identified 36 main flavonoid components from more than two Epimedium plants, and identified five isopentenyl flavonoid compounds, including icariin, epimedin A, epimedin B, epimedin C and icariside II, as the main active ingredients of Epimedium and other species [5]. The total flavonoid content of the Epimedium sample measured by Fu Liang's team was 9.103% [6]. The total flavonoids content of leaves, stems and roots of wild Epimedium wushanense from Jincheng Mountain, Sichuan Province detected by QUANQ was 6.067%, 1.260% and 4.529%, respectively [7]. Wang C et al. detected the contents of epimedin A, epimedin B, epimedin C, icariin and total flavonoids in samples of Epimedium wushanense from seven representative populations in major distribution areas across China, and the content ranges were 0.40%-0.76%, 0.51%-0.83%, 1.70%-9.31%, 0.40%-1.23% and 3.05%-10.61%, respectively [8]. Wang Yueyun from Guizhou University of Traditional Chinese Medicine used high performance liquid chromatography to analyze 33 batches of epimedium samples from different origins. Among them, epimedin C was the main component, and epimedin A, epimedin B, and icariin can be used as index components for epimedium quality evaluation [9]. The above research results show that the flavonoid active ingredients of epimedium show certain variability under different growth environments (origins, seasons) and cultivation methods (wild and artificial cultivation). In general, the content of flavonoid compounds in the leaves of Wushan epimedium is higher than that in the roots and stems, and the content of flavonoid components in artificially cultivated epimedium is generally higher than that in wild species. In particular, the contents of total flavonoids and epimedin C in the leaves significantly exceeded the standards of the Chinese Pharmacopoeia, reaching more than 1.5 times the standards of the Pharmacopoeia. In addition, epimedin A, B, C, baohuoside I and icariin are the key flavonoid active ingredients in Wushan Epimedium, and their total content accounts for 1.61% to 2.78% of the Epimedium slices. Among them, epimedin C is particularly rich and is the main representative of flavonoid components in Wushan Epimedium.

3. Research on the main pharmacological effects and mechanisms of Epimedium

3.1. Osteoporosis

Osteoporosis is a bone metabolism-related disease, the main characteristics of which are decreased bone density and bone tissue microstructure deformation, as well as bone brittleness. At present, the treatment of osteoporosis has become a key application of Epimedium. Li Yongzhi et al. recently explored the effects of Qinling sagittal Epimedium on osteoporotic rats and found that Epimedium can reduce the inflammatory response of rats, regulate bone metabolism balance, and improve tibial bone microstructure. It is speculated that this may be related to the activation of the HIF-1α/VEGF/VEGFR-2 signaling pathway[9].

Icariin, an isopentenyl flavonoid glycoside compound extracted from the dried leaves of Epimedium, has been identified as the core active ingredient in Epimedium for the treatment of osteoporosis[3]. Studies have shown that estrogen significantly affects the generation and bone resorption of osteoclasts by binding to its receptor ERα and regulating the miRNA-503/RANK mechanism. Icariin has attracted widespread attention due to its biological effects similar to those of estrogen, and its significant effect in preventing and treating osteoporosis has been scientifically verified. Research by Li Weijuan's team showed that icariin can significantly upregulate the expression level of ERα, thereby reducing the expression of RANK in RA264.7 cells and osteoclasts through direct or indirect mechanisms[10]. This regulatory effect leads to a decrease in the activation of the RANKL/RANK signaling pathway, reducing the number of osteoclasts generated and inhibiting their bone resorption activity. This study deeply revealed the molecular mechanism of icariin enhancing ERα expression and inhibiting osteoclast differentiation and bone resorption at the gene transcription level, providing an important theoretical basis for the clinical application of icariin.

Kaempferol, a natural bioflavonoid compound widely found in fruits, vegetables and Chinese herbal medicines, as one of the active ingredients in epimedium, has been found to have the dual effects of promoting osteoblast differentiation and inhibiting osteoclast differentiation. This mechanism not only helps to maintain and improve bone density, but also has important significance for the prevention of osteoporosis[11]. The research of Dai Yi et al. further revealed the ability of kaempferol to activate the Wnt/β-catenin signaling pathway. The activation of this signaling pathway accelerates the differentiation and proliferation of osteoblasts and inhibits the activity of osteoclasts, thereby having a positive effect on the improvement of osteoporosis[12]. In addition, the high binding affinity and stability of kaempferol to RPN1 suggest that it may improve osteoporosis by regulating the expression of RPN1. The abnormally high expression of RPN1 was reversed in the castrated rat model, which provides a new biomarker and target for the diagnosis and treatment of osteoporosis[13]. These findings not only enrich the understanding of the biological function of kaempferol, but also provide new strategies for the prevention and treatment of osteoporosis.

3.2. Breast cancer

The incidence of breast cancer remains high worldwide, and its mortality rate is also among the highest among all cancers. Although targeted therapy has shown certain efficacy against specific molecular markers, many patients inevitably develop drug resistance, which seriously limits the sustainability of treatment effects[14]. In fact, about one-third of patients are still at risk of recurrence or metastasis after initial treatment[15]. Cisplatin, as an effective DNA replication inhibitor, significantly inhibits the proliferation of tumor cells through its alkylation and cross-linking with DNA, especially showing an important role in the treatment of triple-negative breast cancer[16]. However, the clinical application of cisplatin is limited by its development of drug resistance and relatively strong toxicity, which may not only lead to treatment failure, but also reduce the patient's quality of life and induce a variety of adverse reactions. Faced with the challenge of breast cancer cells developing resistance to cisplatin, clinical treatment strategies are increasingly inclined to adopt multi-drug combination therapy in order to improve the treatment effect [17]. Therefore, the development of sensitizers that can enhance the sensitivity of cisplatin chemotherapy and reduce its toxic side effects has become an urgent task in the scientific research and clinical fields. This requires us not only to conduct in-depth research on the pharmacological effects of existing chemotherapy drugs, but also to explore new treatment strategies to achieve more effective management and treatment of breast cancer.

The various active ingredients contained in Epimedium, such as icariin, icariin and icariin II, show significant inhibitory effects on breast cancer cells. These ingredients can not only effectively inhibit the proliferation of breast cancer cells and induce cell apoptosis, but also actively participate in regulating the immune microenvironment of the tumor, thereby effectively slowing down the development of drug resistance. In traditional Chinese medicine theory, epimedium is believed to have the effect of tonifying the kidney and strengthening the body. By strengthening the body's positive energy, it indirectly improves anti-tumor immune function, providing a powerful supplement to the comprehensive treatment strategy of breast cancer. Combining epimedium with Western medicine can give full play to the therapeutic advantages of each and achieve a more comprehensive anti-cancer effect. This combination of Chinese and Western medicine not only reflects the synergistic effect of the two medical systems, but also opens up a new path for breast cancer treatment [18]. Future research should further explore the molecular mechanism of epimedium's active ingredients and their potential for application in clinical treatment to provide more treatment options for breast cancer patients.

Qian Danping from Nanjing University of Chinese Medicine found that icariin can fight breast cancer by inhibiting proliferation, promoting apoptosis, inhibiting migration/invasion and other pathways. At the same time, in-depth research was conducted on icariin inducing breast cancer cell apoptosis by regulating MELK. Its mechanism may be to inhibit breast cancer growth by regulating the MELK-mediated Akt signaling pathway [19]. Liu Weiguo et al.'s study explored the synergistic effect of icariin combined with cisplatin in two different subtypes of breast cancer cell lines. Studies have found that compared with the use of cisplatin alone, the combined use of icariin can significantly enhance the inhibition of breast cancer cell invasiveness and the induction of cell apoptosis [20]. Specifically, the addition of icariin significantly enhanced the inhibitory effect of cisplatin on breast cancer cell proliferation and invasion, and played a more significant role in promoting cell apoptosis. This result suggests that icariin may enhance the anti-cancer activity of cisplatin by regulating signaling pathways related to cell cycle and apoptosis. In addition, this synergistic effect provides a scientific basis for the development of new combined treatment regimens for breast cancer, which is expected to improve patients' treatment response and prognosis in future clinical practice.

3.3. Alzheimer's disease

Alzheimer's disease (AD), as the most common form of dementia symptoms in the elderly, accounts for the majority of dementia cases worldwide, and approximately 50% to 70% of cases can be attributed to AD. According to the latest data from the World Health Organization, the patient population affected by AD is particularly large in Europe, Japan, and the United States, and the total number of patients worldwide has reached nearly 75 million [21]. This figure not only highlights the challenge of AD to public health, but also reflects the growing medical needs in an aging society. The high incidence and prevalence of AD have imposed a significant burden on the socioeconomic system and highlighted the urgency of developing effective prevention and treatment strategies. As the global population ages, in-depth research on risk factors, early diagnosis methods, and innovative treatment strategies for AD are of great significance for improving the quality of life of patients and reducing the pressure on the medical system.

In traditional Chinese medicine, AD is classified as "dementia" and "stupidity". Traditional Chinese medicine believes that the kidney stores essence, controls bones and produces marrow, and the brain is called the sea of ​​marrow. Therefore, kidney essence deficiency and marrow deficiency are considered to be the fundamental pathogenesis of AD. Therefore, epimedium, a traditional Chinese medicine that replenishes kidney yang, is believed to have a preventive and therapeutic effect on AD. Epimedium is well known for its warming and tonic properties and its effects of replenishing the kidney, strengthening yang, and strengthening muscles and bones[22]. The ancient medical work Huangdi Neijing states that “the kidney governs the bones, produces marrow, and is connected to the brain”, and Tang Rongchuan further elaborated in Neijing Jingyi: “the kidney produces essence, which is transformed into marrow and stored in the brain”. With age, the kidney’s essence and qi naturally decline, resulting in a weakened nourishing capacity, especially for the brain. This may lead to an empty brain marrow, impaired memory function, and worsening symptoms of dementia in the elderly [23]. When the essence of the five internal organs is abundant, the kidney’s essence and qi are filled and overflow appropriately, which in turn nourishes the sea of ​​marrow, enriches the brain marrow, and promotes mental alertness and mental vigor. The latest findings in the field of pharmacological research show that epimedium has significant potential value in neuroprotection, especially in the treatment of AD. Epimedium exerts its protective effect through a multi-level mechanism of action: it can effectively inhibit the excessive production of β-amyloid protein (Aβ) and abnormal phosphorylation of Tau protein in the patient’s brain cells, which plays a vital role in slowing down neurodegeneration. In addition, epimedium can regulate the balance of cholinergic neurotransmitters and maintain the normal function of the nervous system. Another important function of epimedium is its effect on the brain-derived neurotrophic factor (BDNF) signaling pathway, which plays a key role in promoting the growth, survival and functional recovery of neurons, thereby further enhancing the protective effect of epimedium on AD [24]. These findings not only provide a new perspective for our understanding of the role of epimedium in the treatment of AD, but also point out the direction for future clinical applications and drug development.

Icariin II (also known as baculoside I) contained in epimedium shows significant potential in the treatment of AD. Studies have shown that icarin II can inhibit the generation and deposition of β-amyloid protein (Aβ) and promote its degradation, thereby reducing neuroinflammation in the brain and stress response of the nervous system. In addition, icariin II can also activate brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase receptor B (TrkB), optimize neuronal connectivity and plasticity, and provide a new strategy for the prevention and delay of AD[25][26]. Studies by Shi Yijun et al. showed that icariin II promoted the regeneration of neurons in the brain of AD model mice and significantly improved the learning and memory abilities of mice. Zhen Jin et al. established an AD inflammation model and found that icariin can significantly improve the learning and memory abilities of model rats. Its mechanism of action may involve inhibiting the proliferation and activation of glial cells and the damage of neurons to neurons by inflammation[26]. Studies by Luan Jian et al. further confirmed that icariin can regulate the expression level of glycogen synthase kinase-3 (GSK-3β), inhibit its activity or expression, block the over-activation of Tau protein, and repair Aβ-induced neuronal damage by activating the PI3K/Akt signaling pathway[27]. These research results indicate that icariin II may be a promising candidate for the treatment of AD, including inhibiting the generation and deposition of pathological proteins, promoting their degradation, activating neurotrophic factors, promoting nerve regeneration, inhibiting inflammatory responses, and regulating key signaling pathways to repair neuronal damage.

3.4. Heart Failure

Heart failure (HF) is a complex disease involving multiple pathological processes, and its pathogenesis includes inflammatory response, remodeling of myocardial structure, myocardial cell hypertrophy, and ion balance disorders. Jia Liangliang's team used cutting-edge