Icariin What Is It?

Icariin(ICA) is derived from the above-ground parts of Epimedium koreanum and Epimedium berberidaceae maxim, both of the Berberidaceae family. Epimedium is a traditional Chinese tonic herb that is used to invigorate the kidney yang, strengthen the muscles and bones, and dispel rheumatism. It is used to treat impotence and spermatorrhea, infertility due to cold deficiency, frequent urination and incontinence, coughing due to kidney deficiency, weakness and soreness of the waist and knees, rheumatism and pain, and hemiplegia. Icaritin is the main component of Icaris flavonoid extract and the main antioxidant active ingredient in Icaris [1]. Its chemical structure belongs to the flavonoid class of compounds and has various biological activities in vivo and in vitro [2]. It enhances the body's immune system, has anti-tumor and antioxidant properties, promotes the synthesis of tissue proteins, promotes the growth of osteoblasts and inhibits the activity of osteoclasts, and has a two-way effect of regulating bone metabolism. The research progress of icariin is summarized as follows.

1. Properties of icariin

The molecular formula of icariin is C33 H42 O16 and the relative molecular mass is 694.65. It is easily soluble in pyridine, soluble in methanol, ethanol, and ethyl acetate, and slightly soluble in ether, benzene, acetone, and chloroform. It turns yellow in the presence of alkali, brown in the Molish reaction, dark green in the FeCl3 reaction, and pink in the HCl-Mg reaction.

2. The biological activity of icariin

2.1 Antitumor effect

Recent studies have shown that icariin has antitumor effects. Icariin may inhibit the proliferation of HepG2.2.15 cells by increasing G0/G1 phase cells and reducing S phase cells [3]. Icariin can also inhibit the secretion of the immunosuppressive factor TGF-β2 by tumors, reverse the immunosuppressive effect of TGF-β2, restore the killing activity of killer cells, inhibit the adhesion of tumor cells to the extracellular matrix and their ability to invade bags, inhibit the proliferation of human leukemia HL-60, K562, and U-937 cells, induce HL-60 cell differentiation and apoptosis, and inhibit their telomerase activity. Gu Xin et al. [4] found that icariin can reverse the malignant phenotype of the human thyroid cancer SW579 cell line by downregulating the ld-1 mRNA level to activate the expression of the p21 gene.

Epimedium and its main active ingredients can enhance the body's anti-tumor immune response at different levels and in different ways. The anti-tumor effect is achieved by enhancing the activity of immune organs, immune cells and immune factors and the antigenicity of tumor cells. At the same time, the drug and its main components reverse the biological behavior of tumor cells by inducing differentiation and apoptosis of cancer cells, inhibiting the growth, invasion and metastasis of cancer cells, and inhibiting the activity of immunosuppressive factors (TGF-β2), inflammatory cytokines, tumor telomerase and other activities, thereby reversing the biological behavior of tumor cells, and has a better therapeutic effect when used in combination with other drugs [5], and can enhance the anti-tumor activity of certain drugs [6]. Icariin can inhibit the two important determinants of tumor metastasis: tumor cell adhesion and movement, thereby exerting an effective anti-tumor metastasis effect. Zhang Jingwei [7] proved that icariin can inhibit the adhesion, movement and invasion of the gastric cancer cell line SGG-7901, and increase the activity of PKA in the cell, thereby reversing its malignant phenotype.

2. 2 Regulates the immune system and improves immunity

Modern immunopharmacological research has shown that icariin has a significant regulatory effect on the body's immune system, and can increase the immune levels of mice with experimentally induced immunodeficiencies. The mechanism may be that icariin can increase the absolute and relative numbers of splenocytes in the spleen, increase the number of immune cells in the body, and stimulate the proliferation of nucleated cells in the bone marrow, thereby exerting an immunomodulatory effect [8]. In addition to an increase in the number of immune cells, the enhancement of immune cell activity is also important for the enhancement of the body's immune function.

Liu Jing et al. [9] showed that the regulation of immune function by icariin in mice is not based on structural changes in immune tissues, but rather through the enhancement of immune cell activity. The allogeneic skin graft model is one of the classic models of graft rejection and is also a model for studying the effects of immunosuppressants on cellular immune responses. Teng Fei et al. [10] showed that the combined application of CSA and icariin can inhibit the immune rejection response caused by transplantation, possibly by inhibiting the activation and proliferation of reactive T cells in recipient mice to reduce the cellular immune response. In addition, studies have shown that icariin can promote the reconstruction and self-renewal of neural stem cells, thereby enhancing the learning and memory abilities of aging rats [11]. At the same time, icariin can improve the memory of rapidly aging mice [12].

2. 3 Promoting osteoblast growth and inhibiting osteoclast activity, etc., bidirectionally regulating bone

metabolism. During the development, formation and normal physiological processes of bone tissue, there is not only cell proliferation and differentiation, but also cell apoptosis. At the same time, apoptosis is also an important pathogenesis of tumors, deformities, autoimmune diseases and other diseases. Icariin can participate in anti-osteoporosis, osteogenesis regulation, anti-osteoclast, promote cartilage, angiogenesis and anti-inflammatory through multiple signal pathways [13]. Hypoxia can inhibit the proliferation of osteoblasts and promote osteoblast apoptosis, while icariin can promote the expression of osteoprotegerin [14], which has a protective effect on it. In addition, icariin has a protective effect on exercise-induced oxidative stress [16].

Icaritin has a unique effect in treating pain after prosthesis replacement and increasing bone density. Xiao Qiangbing et al. [17] showed that icariin can reduce the content of inflammatory cytokines around the prosthesis, thereby preventing the loosening of the prosthesis and relieving postoperative pain. The effect of icariin on promoting osteoblast maturation is prominent in two aspects: ① icariin can increase the activity of alkaline phosphatase and upregulate the expression of the osteoblast nuclear factor receptor; ② icariin can upregulate the expression of bone morphogenetic protein [18] and reduce the clinical symptoms of arthritis [19]. Icaritin can effectively increase peak bone density and bone mass in rats, prevent glucocorticoid-induced osteocyte apoptosis [20], and effectively prevent osteoporosis [21].

2. 4 Anti-atherosclerosis

Microscopic studies of the pharmacological mechanism of action have shown that icariin can protect the cardiovascular system by inhibiting apoptosis induced by endoplasmic reticulum stress, and can exert anti-atherosclerotic effects by promoting the apoptosis of proliferating vascular smooth muscle cells [22]. Zhao Junmei et al. [23] used icariin to induce apoptosis in cultured rabbit vascular smooth muscle cells, and observed the expression level of the apoptosis gene GRF78 in rabbit plaque tissue by in situ hybridization, indicating that icariin may promote smooth muscle cell apoptosis by upregulating the expression of the glucose-regulated protein 78 gene, thereby preventing atherosclerosis. Icaritin can also improve dementia after a stroke by enhancing CREB phosphorylation in the central cholinergic circuit [24].

2. 5 Other

Icariin not only promotes the maturation of osteoblasts, but also promotes embryonic development by inhibiting apoptosis through miRNA-21 [25], and is used to treat sexual dysfunction [26], improve complications such as erectile dysfunction caused by diabetes [27], and enhance the sensitivity of tumor cells to radiotherapy [28].

3 Preparation

The Chinese Pharmacopoeia (2010 Edition) stipulates that icariin is used as a control for the determination of total flavonoids and icariin content, and chaoexanthin C is used as a control for the determination of Wushan icariin content. Icariside and icariside A, B, and C are important active ingredients in Epimedium. Gao Mingzhe et al. [29] used industrially prepared high-performance liquid chromatography to isolate and prepare these four components from Epimedium extract. After the crude extract of Epimedium was separated by macroporous adsorption resin to obtain the corresponding components, industrial preparation of high performance liquid chromatography was used to complete the purification. This method can completely separate these four components in two steps. It is fast and efficient, with high product purity, and is suitable for the large-scale preparation of the Icariside, Icariin A, B, and C series of reference substances in Epimedium.

Wang Qiang et al. [30] extracted total flavonoids from Epimedium sagittatum using water, and determined the content of total flavonoids in Epimedium sagittatum using ultraviolet spectrophotometry at 270 nm with icariin as the control. The optimal extraction process for total flavonoids in Epimedium sagittatum was determined using an orthogonal test. The results showed that 2% Na2 CO3 aqueous solution 15 times the amount, extracted 3 times, each time 1.5 h, the total flavonoid extract yield of 97.92%, the process is simple, feasible, low production costs, and can be used for objective quality control of chromatographic analysis.

4 Prospects

Icariin has a variety of biological activities and pharmacological effects, especially in anti-tumor, regulating immune function, and promoting osteoblast growth, which have been studied extensively. As research continues, more and more pharmacological functions of icariside will be discovered. Using high-resolution mass spectrometry (HPLC-HRMS) and mass spectral similarity filtering (MTSF) technology, the metabolic pathway and metabolic map of Epimedium can be obtained [31]. However, most of the existing research focuses on the molecular level, and the efficacy is based on in vitro animal experiments. There are also few studies on the clinical application prospects, safety, and effectiveness. There are also not many studies on the pharmacological effects of icariin derivatives, which can be used as the main direction of future research. In addition, the industrial production of icariin by biotechnology can also be used as a research direction.

Reference:

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