What Is the Use of Epimedium Extract Icariin?

Epimedium is the dried above-ground part of Epimedium sagittatum, Epimedium brevicornum, Epimedium sagittatum var. japonicum, Epimedium pubescens and Epimedium wushanense. It is a traditional Chinese tonic herb that has been recorded in ancient herbal medicine books. Li Shizhen described it in Compendium of Materia Medica as “pungent and warm, non-toxic, strengthens the muscles and bones, nourishes the essence and vital energy, strengthens the waist and knees, and strengthens the heart and mind”. It is mainly used to treat “husband with no children due to complete Yang deficiency, senile dementia, forgetfulness in middle age, limb numbness, and hemiplegia”. However, its clinical application currently far exceeds the scope discussed by the ancients, and it is used to treat coronary heart disease, hypertension, aplastic anemia, bronchitis, neurasthenia, chronic hepatitis, etc., all of which have a certain effect. The author hereby summarizes the current research status as follows.

1 Chemical composition of Epimedium plants

There are currently 74 reported chemical components in Epimedium plants, mainly flavonoids, followed by polysaccharides, lignans, phenyl glycosides, iridoids, sesquiterpenes, phenylethanoids, and alkaloids [1]. In addition, carotenoids, hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, iso-licoricidin, glycyrrhizin, astragaloside, kaempferol, 2-hydroxy-3,4,6,7-tetramethoxy-9,10-dihydrophenanthrene, luteolin, emodin, 3-hydroxy-2-methyl-pyronone[2], as well as volatile oil, tridecyl alcohol, phytosterol, palmitic acid, stearic acid, linolenic acid, ginkgolide, glucose and fructose, etc.[3].

2 Pharmacological effects of flavonoids in Epimedium

2. 1    Effects on the cardiovascular system

Icaris flavonoids (TFE) can selectively block β1-receptors in isolated and intact animal heart muscle, and have no blocking effect on β2-receptors in the trachea and α-receptors in vascular smooth muscle. Clinically, it can be used to treat coronary heart disease, angina pectoris and other diseases [4]. Icaris has a slow but long-lasting cardiotonic effect, and does not cause arrhythmia in the heart muscle. Intravenous administration of 60 and 120 mg/kg of Korean TFE can antagonize barium chloride- and aconitine-induced arrhythmias in rats and epinephrine-induced arrhythmias in guinea pigs [5]. Icariin (ICA) can significantly inhibit myocardial contractility (especially the rate of increase in ventricular pressure), reduces myocardial oxygen consumption, while significantly shortening the pre-ejection period of the ventricle. Under conditions of decreased intraventricular pressure, the left ventricular ejection period remains unchanged, while the isovolumic contraction period is shortened, reflecting a decrease in total peripheral resistance. This causes a decrease in arterial blood pressure, while also causing a significant increase in pulse pressure and the difference between systolic and diastolic pressures, reflecting a decrease in peripheral resistance and a reduction in cardiac afterload, which is particularly beneficial for coronary heart disease patients with hypertension [6].

The excessive proliferation of vascular smooth muscle cells (VSMC) can easily lead to atherosclerosis and hypertension. Puerarin and ICA have a significant synergistic effect on the pro-apoptotic effect of interleukin-1 (L-1) on VSMC stimulated proliferation, which is not greatly affected by concentration and is positively correlated with time [7]. Both TFE and ICA intravenous infusion can significantly increase cerebral blood flow and and reduce cerebral vascular resistance [8]. ICA can directly dilate vascular smooth muscle and cerebral blood vessels, increase cerebral blood flow, and reduce cerebral vascular resistance. Its effect is weaker than papaverine, but its effect lasts longer than papaverine [9]. Wang Min et al. [10] found that the mechanism is to inhibit the inward flow of CA2+ in vascular smooth muscle. It has also been reported that serum containing icariin extract can promote the release of NO from human umbilical vein endothelial cells [11].

2. 2 Effects on the blood system

Systemic administration of TFE can significantly inhibit in vitro thrombosis in rabbits, reduce red blood cell aggregation and blood viscosity, and has no effect on platelet aggregation, platelet adhesion, bleeding or clotting time. Explanation: TFE has no significant effect on platelet function in terms of changing blood rheology. Its efficacy in treating cardiovascular disease is mainly achieved by reducing blood viscosity, inhibiting in vitro thrombosis, facilitating the elimination of blood stasis and preventing its formation [12]. Further research has shown that icariin can promote the fibrinolytic effect of mouse macrophages and increase plasminogen activator activity [13]. therefore, it not only prevents stroke, but also has a certain blood pressure lowering effect [13]. ICA can promote the production of colony stimulating factor C (SF) like activity in mouse spleen lymphocytes in vitro. CSF is a class of glycoproteins that promote the proliferation, differentiation, maturation and survival of human or animal bone marrow cells. It can promote hematopoiesis in the body and stimulate the function of mature cells, which is important for the body's hematopoietic function [14]. Zhao Yong et al. [15] also found that ICA can synergistically induce IL-2, 3, and 6, and IL-6 can synergistically support the proliferation of pluripotent stem cells with IL-3, thereby promoting hematopoietic function.

2.3 Effect on the immune system

TFE has a significant enhancing effect on both human T cell immunity and B cell immunity [16], and can antagonize the inhibition of IL-2 and natural killer (NK) cell activity in a mouse model by hydroxyurea [17]. TFE 400 mg/kg can significantly enhance the phagocytic function of normal monocytes and macrophages, increase the antibody production level of serum hemolysin, and has no significant effect on delayed hypersensitivity. Further studies have shown that the immunomodulatory effect of TFE is related to its regulation of the TH/TS ratio, suggesting a bidirectional regulatory effect [18]. Li Shutong et al. [14] found that ICA significantly promoted the proliferation of mouse splenocytes induced by Con A and produced CSF-like activity in a dose-dependent manner in the range of 0.001 to 10 μg/mL. suggesting that ICA may have an immunostimulatory effect by enhancing T cell function through the production of CSF-like activity. ICA and its intestinal bacterial metabolites icariin and icariside I promote the production of IL-8 and have a significant inhibitory effect on the production of IL-1α. and procyanidins inhibit the production of tumor necrosis factor T (NF-α) [19].

2. 4 Antitumor effect

Lin Xin et al. [20] found that icariin “inhibits human nasopharyngeal carcinoma and oral epithelial carcinoma K(B) cells to the greatest extent, with an inhibition rate of 89.7%, followed by human red leukemia K562 cells, with an inhibition rate of 78.2%, and 59.6% for promyelocytic leukemia (HL)-60 cells.

ICA can induce the proliferation of various tumor cell lines in vitro and induce the differentiation of human acute promyelocytic leukemia cells along the granulocytic line. It has typical morphological and biochemical characteristics of apoptosis and is time- and dose-dependent [21].

Studies have also found that

(1) ICA can down-regulate the mRNA and protein expression levels of the apoptosis-related genes bcl-2 and c-myc, which may be one of the mechanisms by which it induces apoptosis in tumor cells [21].

2) Inhibits telomerase activity in tumor cells, and has a synergistic effect when used in combination with all-trans retinoic acid. It has been reported that 90% of malignant tumor cells and tissues have high telomerase activity, while normal tissues and benign tumors do not express telomerase activity. Therefore, inhibiting telomerase activity may become a new direction in tumor treatment. Studies have found that ICA may inhibit telomerase activity in tumor cells through a cascade of gene-protein-cell effects [22].

(3) Reversing the immunosuppressive effect of transforming growth factor β2 (TGF-β2). TGF-β is the most potent immunosuppressive factor commonly found in the tumor microenvironment. It strongly inhibits the proliferation of T cells and the cytotoxic lymphocytes C (TL), NK, lymphokine-activated killer cells L (AK), CD3AK, tumor-infiltrating lymphocytes T (IL), and Mφ cells. It is directly related to the poor efficacy of adoptive immunotherapy. The mechanism by which ICA reverses the immunosuppressive effect of TGF-β2: on the one hand, it can inhibit the protein and mRNA expression of TGF-β2 in human lung adenocarcinoma cells; on the other hand, can reverse the killing activity of LAK and CD3AK cells inhibited by TGF-β2, and can partially restore the expression of IL-2Rα on the surface of LAK cells and the mRNA level of perforin in CD3AK cells, as well as the proliferative activity of CD3AK cells, which are inhibited by TGF-β2 [23].

(4) Inhibits tumor cell metastasis. ICA can reduce the adhesion of highly metastatic human lung giant cell adenocarcinoma cells (PG) to the extracellular matrix and their invasive motility, and reduce the expression of the PG cell surface adhesion molecule CD44V6, laminin receptor (LN-R) and intracellular CK18. ICA can downregulate the T-lymphoma invasion protein (TIam-1), c-myc gene mRNA levels, affect the organization of the cell skeleton, and reduce the expression of CK18 in the cytoplasm. At the same time, it upregulates the mRNA level of the metastasis suppressor gene Nm23, promotes the polymerization of microtubules and the formation of spindles, and suppresses the cell's ability to move [24].

(5) Increase the antigenicity of tumor cells. ICA can increase the fluidity of the cell membrane of human lung giant cell adenocarcinoma cells, increase the expression of MHC-1 class antigens on the membrane surface, and increase the antigenicity of tumor cells, thereby inducing the body's anti-tumor immune response [25].

(6) Enhances the activity of immune cells. ICA can enhance the killing activity of NK cells and LAK cells, and has the effect of inducing IL-2, 3, and 6 [15, 26].

2. 5    Effects on the skeletal system

Wang Junqin et al. [27] reported that ICA has a proliferative effect on osteoblasts, with the strongest effect at a mass concentration of 10 ng/mL. ICA can significantly inhibit the activity of FGH in early osteoblast differentiation and significantly promote the activity of FGH in late osteoblast differentiation. ICA promotes osteoblast proliferation while also increasing osteoblast activity. TFE at 1 to 10 μg/mL has a significant effect of promoting osteoblast proliferation, i.e., increasing the number of mineralized nodules formed [28]. Ma Huiping [29] used the model of rat osteoporosis caused by retinoic acid gavage to investigate the changes in biochemical indicators of bone metabolism during the prevention and treatment of experimental osteoporosis in rats by TFE. It was found that after rats were given TFE orally, the levels of testosterone, estradiol and osteocalcin increased significantly; the levels of Ca, P, urinary deoxypyridinol and serum parathyroid hormone in the urine were lower than those in the model group; the calcium, phosphorus and bone density of the femur increased, approaching the normal control group, and the difference with the model group was significant.

2. 6 Effects on the reproductive and endocrine systems

ICA can increase the weight of the mouse epididymis and seminal vesicles. In vitro experiments have shown that ICA can significantly promote the basal secretion of testosterone by rat testicular interstitial cells [30]. ICA 3 (0–1000 μg/L) has a direct stimulating effect on follicular granulosa cells secreting estradiol, and also promotes the secretion of corticosterone by adrenal cortical hormones at very high doses [31].

2. 7 Anti-inflammatory effect

TFE has a significant inhibitory effect on ear swelling caused by croton oil in mice, increased capillary permeability in the abdominal cavity of mice caused by acetic acid, foot swelling caused by carrageenan in mice, and granulation tissue hyperplasia caused by croton oil. Preliminary studies have shown that TFE can significantly reduce the content of prostaglandin E and propylene glycol in inflammatory exudates, and it also has an inhibitory effect on ear swelling in adrenalectomized mice. It has no significant effect on the weight of the adrenal glands or the vitamin C content in the adrenal glands of rats [32].

2. 8 Antiviral effect

Ren Yuhao et al. [33] studied the effects of astragalus polysaccharide (APS), epimedium polysaccharide E (EPS) and TFE on cells infected with Newcastle disease virus N (DV). They found that APS and EPS had an inhibitory effect on NDV when added before the virus, while TFE had an inhibitory effect on the virus regardless of the method of administration. This suggests that they have a certain antiviral effect, which is related to their concentration.

3. Pharmacological effects of epimedium polysaccharide

3. 1. Effects on immune cells

EPS can promote the release of mature thymocytes into the periphery in a dose-dependent manner, and has a mitogenic effect on mouse lymphocytes, promoting the proliferation of T cells and B cells [34]. EPS can significantly increase the activity of NK cells in old rats, improve the phagocytic function of peritoneal macrophages in mice, and restore the phagocytic function of peritoneal macrophages damaged by cyclophosphamide in mice to normal [35].

3. 2 Effect on cytokines

EPS 100 mg/kg has the effect of inducing interferon (INF), which can significantly increase the ability of mouse thymus and spleen cells to produce IL-2 [36].

3. 3 Effect on the hematopoietic system

EPS can reverse the side effects of the anti-AIDS drug azidothymidine, such as a decrease in the number of peripheral blood leukocytes, bone marrow hematopoietic stem cells and granulocyte-monocytic progenitor cells, and a decrease in the proliferation of splenic lymphocytes and their ability to produce IL-2. EPS can also increase the proliferation of bone marrow cells and the rate of DNA synthesis in mice with “yang deficiency” caused by hydroxyurea [37].

3. 4    Effects on the endocrine system

EPS can increase the physique of old rats, significantly increase the hypothalamus and cortical β-endorphin content and the activity of IL-2 and NK cells in old rats, and weakly increase the content of testosterone, luteinizing hormone and estradiol E(2), resulting in a decrease in the E2/T ratio [38].

4 Conclusion

Current research on Epimedium has focused on discovering new compounds, studying the pharmacological aspects of EPS, TFE and ICA, while the activity determination of newly discovered compounds has not been done enough, and structural modification of effective monomers in Epimedium has not been reported.

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