Ginseng Extract Ginsenoside and Immune Regulation

Ginseng is widely used as a natural tonic in Asian countries. It was first used mainly as a source of food and energy, but researchers have gradually discovered its important effects on immune function, the cardiovascular system, the nervous system, and cancer treatment [1–2]. Ginsenosides are the main active ingredients in ginseng. Many studies have reported that ginsenosides have the effect of regulating immune function, and have observed that ginsenosides improve insulin resistance, inhibit viruses in vitro, improve limb ischemia in mice, and promote angiogenesis. This article mainly reviews and analyzes the regulatory effects of ginsenosides on immune organs, immune cells and immune molecules, as well as their possible mechanisms of action.

1 Overview of ginsenosides

Ginseng saponins are a group of triterpene saponins extracted mainly from the roots, stems, leaves, flowers and fruits of ginseng. They are a kind of polysaccharide derivative, mainly composed of the hydroxyl group of the sugar and non-saccharide compound [6]. More than 100 types of ginseng saponins have been isolated and identified. Due to the difference in aglycones, they are mainly divided into two types: damarane and oleanane types, of which the damarane type has the highest content of ginsenosides. The damarane type ginsenosides are divided into Rb1, Rb2, Rb3, Rc, Rg3) and protopanaxatriol type ginsenosides (such as Re, Rf, Rg, Rg2, Rh1) [7]. Ginsenosides have a wide range of biological functions, such as antioxidant, anti-cancer, anti-obesity, immune regulation, liver protection, blood lipid lowering, as well as regulating metabolism and improving cardiovascular disease. They can even be used as adjuvant drugs for targeted tumor therapy and diabetes treatment [3, 8-11].

2. The regulatory effect of ginsenosides on immune organs

Immune organs are fundamental to immune regulation and mainly include central immune organs and peripheral immune organs. The former are mainly composed of bone marrow and thymus, while the latter are mainly composed of spleen and lymphoid structures. Ginseng saponins can delay the progression of various diseases by regulating immune organs. Ginseng saponin Rg3 enhances mitochondrial antioxidant capacity through a Ca2+-dependent pathway, improves the proliferation and differentiation potential of human bone marrow mesenchymal stem cells, prevented the aging of bone marrow mesenchymal stem cells [12]. Liu et al. [13] found that cyclophosphamide induced immunosuppression in mice, resulting in weight loss, decreased thymus and spleen indices, and severe pathological damage. However, when treated with Rg3, the cyclophosphamide-induced immunosuppressive effect was reversed, and the morphology of the thymus and spleen was significantly improved, and the organ index was increased, indicating that Rg3 can improve the immunity of immunosuppressed mice [13].

Rg3 can reverse the immunosuppressive effect induced by cyclophosphamide. The morphology of the thymus and spleen is significantly improved, and the organ index is increased, indicating that Rg3 can improve the immunity of immunosuppressed mice.

Rg1 can delay the aging of the body by improving the proliferation ability of thymus cells and the thymus index. In anti-tumor studies, the positive regulatory effect of ginsenosides on immune organs has also been observed. In a mouse model of aplastic anemia, protopanaxadiol-type ginsenosides significantly increased the number of hematopoietic cells in the bone marrow, and the colony numbers of myeloid, erythroid, and megakaryocyte progenitor cells were significantly increased [15]. Cao et al. [16] found that ginsenoside Rg1 improved the hematopoietic stem cells of aplastic anemia by inhibiting Bax translocation-induced mitochondrial apoptosis, thereby restoring hematopoietic function.

Chemotherapy is one of the main treatments for tumors, and bone marrow suppression is one of its main adverse reactions. Animal experiments have shown that Rb1, Rc, Rb2, and Rd in the protopanaxadiol type and Re, Rg1, and Rf in the protopanaxatriol type can effectively improve cyclophosphamide-induced bone marrow suppression. After treatment with ginsenosides, the body weight, blood cell count, hematopoietic-related cytokines, and spleen and thymus indices increased, and apoptosis of bone marrow cells was inhibited [17]. In addition, after continuous administration of Rg3 to a mouse model of liver cancer, the activity of superoxide dismutase in the immune organs of mice was enhanced, while the activity of xanthine oxidase and malondialdehyde levels were reduced, indicating that Rg3 has good anti-tumor and antioxidant activity, and can improve the immune status of tumor-bearing organisms, indicating that ginsenosides can regulate the body's antitumor immune function by promoting the growth of immune organs [18]. More and more studies have found that ginsenosides and their metabolites may exert their antioxidant effects by participating in the regulation of various oxidative signaling pathways [8], such as the Keap1/Nrf2/ARE, PI3K/Akt, and NF-κB signaling pathways.

3. The regulatory effect of ginsenosides on immune cells

Immune cells are participants in the body's immune response and also the executors of immune function, including lymphocytes, dendritic cells, macrophages, NK cells, mast cells, etc. Modern pharmacological studies have shown that ginsenosides have a regulatory effect on immune cells.

3. 1 Regulation of T cells

T cells play an important role in the immune response process and have a variety of biological functions, such as directly killing target cells, assisting and inhibiting B cells from producing antibodies, responding to specific antigens and mitogens, and producing cytokines. Several studies have reported the immunomodulatory effects of ginsenosides on T cells. Wang et al. [19] found that ginsenoside Rh2 inhibited tumor growth and prolonged the survival of mice after treatment with a mouse melanoma model. T lymphocyte infiltration of the tumor was significantly increased, indicating that Rh2 can enhance the anti-tumor immune response of mice. However, under certain conditions, ginsenosides can also inhibit T cell proliferation. Wang et al. [20] observed through a rat skin graft model that Rd can significantly reduce the number of CD4+ T cells and CD8+ T cells in rat peripheral blood, inhibit the expression level of Th1 cytokines, prolong the survival time of skin grafts, improve the pathological damage of grafts, effectively antagonizes allograft rejection, which makes ginsenoside Rd potentially useful in the treatment of Th1-induced diseases, including graft rejection. In addition, excessive Th17 cell autoimmune responses and Treg cell dysfunction may be important causes of autoimmune diseases such as multiple sclerosis and autoimmune encephalomyelitis [21]. Park et al. [22] found that Rg3 can negatively regulate the expression of RORγt in CD4+ T cells, thereby inhibiting Th17 cell differentiation and Th17-mediated neuroinflammation.

3. 2 Regulation of B cells

B cells mainly produce antibodies after being stimulated by antigens and exert an immunomodulatory effect through humoral immunity. It has been found that the main form of ginsenoside absorbed by the human body is the ginsenoside metabolite compound K (CK). Zhang et al. [23] found through research that For collagen-induced arthritis, CK treatment can reduce the levels of the mouse multiple arthritis index, the number of swollen joints, the spleen pathology score, B cell proliferation, and serum antibodies IgG1 and IgG2a, and improve the deterioration of collagen-induced arthritis in part by inhibiting B cell activation. Chen et al. [24] also found that CK can alleviate the severity of non-specific arthritis by inhibiting memory B cells in a rat model of non-specific arthritis. In the complex pathogenesis of systemic lupus erythematosus, immune function regulation disorders are one of the main causes of the disease, which is characterized by the hyperactivation of B cells and the production of a large number of autoantibodies. Yu Xin [25] found in a study on the regulation of systemic lupus erythematosus humoral immunity by ginsenosides that Rb1, Rh1, Rg1 and Rg3 can all inhibit B cell proliferation, promote B cell apoptosis, and inhibit IgG and IgM secretion, indicating that ginsenosides have the function of inhibiting humoral immunity.

3. 3 Regulation of macrophages

Macrophages are the main effector cells of the inflammatory response, and under different conditions, they have obvious morphological and functional abnormalities. According to the activation state, function and secreted factors, they are mainly divided into classically activated M1 macrophages and selectively activated M2 macrophages. M1 macrophages are generally stimulated by lipopolysaccharide, IFN-γ, TNF-α or granulocyte-macrophage colony-stimulating factor (GM-CSF). M1 macrophages express CD68, CD80 and CD86 and secrete pro-inflammatory factors such as IL-1β, IL-6 and IL-12. They play an important role in the early stages of inflammation and in the anti-tumour process.

M2 macrophages are activated by Th2 cytokines such as IL-4, IL-10, and IL-13 and immune complexes. They express CD163, CD204, and CD206 and suppress inflammatory factors, playing a role in inhibiting inflammatory responses and tissue repair. secreting cytokines such as IL-10, TNF, and CCL17 in tumors to promote tumor progression [26]. Ginseng saponins have different regulatory effects on different macrophage subtypes under different conditions.

Ginsenoside Rg3 was found to inhibit the expression of M1 macrophage marker genes and the production of iNOS and NO when it acts on lipopolysaccharide-induced mouse peritoneal macrophages. It also induces the polarization of M2 macrophages and promotes the elimination of inflammation in a mouse peritonitis model, providing a new idea for the pharmacological design of anti-inflammatory drugs [27]. Ginsenoside Rh2 can significantly induce M2 macrophages to differentiate into the M1 phenotype, thereby inhibiting the proliferation and migration of lung cancer cells and reducing the expression of various factors such as vascular endothelial growth factor-related proteins, MMP2, and MMP9. suggesting that ginsenoside Rh2 can improve the tumor microenvironment by regulating the phenotype of tumor-associated macrophages in lung cancer [28]. In addition, CK, an active metabolite of ginsenoside, can also regulate macrophages. Liu et al. [29] found that CK can significantly inhibit the phagocytic function of macrophages and promote the transformation of macrophages from M1 to M2 during the treatment of collagen-induced arthritis in mice. It can inhibit the secretion of inflammatory factors in the plasma and peritoneal macrophage culture supernatant of mice, and increase the level of IL-10, indicating that CK can treat collagen-induced arthritis by increasing the polarization of anti-inflammatory macrophages [30].

culture supernatant, and increase the level of IL-10, indicating that CK can treat collagen-induced arthritis by increasing the polarization of anti-inflammatory macrophages [30].

3. 4 Regulation of NK cells

NK cells are a type of cytotoxic innate lymphoid cell that is the first line of immune defense when the body is attacked by foreign pathogens. NK cells can produce a variety of chemokines and cytokines (such as IFN-γ), recruit and activate various immune cells (such as T cells and macrophages), and coordinate an immune response against target cells. NK cells are involved in the occurrence, development, or treatment of various diseases, and ginsenosides can delay disease progression by regulating NK cells.

Studies have found that the deglucosylated metabolite ginsenoside F1 can reduce the inflammatory response of eosinophils in chronic sinusitis by promoting NK cell function, and reduce the expression of IL-4 and IL-13 and the hematopoietic prostaglandin D synthase required for the production of prostaglandin D2. However, when NK cells are absent, ginsenoside F1 treatment is ineffective, suggesting that ginsenoside F1 enhances NK cell activity and may be a potential strategy for the treatment of eosinophil inflammation in chronic sinusitis [31]. Kwon et al. [32] also found that ginsenoside F1 can promote the cytotoxicity of NK cells and the production of IFN-γ. The above results all indicate that ginsenoside F1 can enhance the function of NK cells, providing a theoretical basis for NK cell-based immunotherapy. In terms of tumor research, the regulatory effect of ginsenosides on NK cells also plays a key role. Lee et al. [33] found that Rg3 promotes NK cell activity by activating the MAPK/ERK pathway, suggesting that Rg3 can be used as a cytotoxic activator of NK cells for the treatment of various cancers. In summary, ginsenosides can enhance the activity of NK cells and improve the body's immune function.

3. 5 Regulation of dendritic cells

Dendritic cells are the body's most powerful professional antigen-presenting cells. They can efficiently ingest, process and present antigens, and effectively activate initial T cells, which are at the center of initiating, regulating and maintaining the immune response. At present, there have been many reports in the literature on the immunomodulatory effects of ginsenosides on dendritic cells.

Wang Yi et al. [34] found that Rg1 and Rh1 can increase the expression of HLA-DR and ICAM-1, important molecules in the first and second signal systems on the cell surface, and increase the expression of CD25, CD11c, and CD44, molecules that mediate intercellular adhesion, which is conducive to the formation of T cell clusters and antigen presentation by dendritic cells. which in turn enhances the immune function of dendritic cells, indicating that ginsenosides Rg1 and Rh1 can enhance the antigen-presenting ability of dendritic cells. A large number of literatures have reported that ginsenosides have a two-way immunomodulatory effect, which not only enhances the antigen-presenting ability of dendritic cells, but also inhibits the function of dendritic cells under certain conditions.

Chen et al. [35] found that the ginsenoside metabolite CK can down-regulate T cell activation initiated by dendritic cells in arthritis, inhibit CCL21/CCR7-mediated dendritic cell migration, and signal transduction between T cells and dendritic cells, thereby reducing inflammation. Luo Hong et al. [36] found that ginsenosides can inhibit inflammation by regulating the proportion of dendritic cells in spleen cells of collagen-induced rheumatoid arthritis (RA) model mice, thereby alleviating the pathological changes of arthritis in RA model mice, indicating that ginsenoside may inhibit the inflammation of peripheral blood in RA model mice by regulating the types of traditional dendritic cell subsets in the spleen. Son et al. [37] co-cultured splenic dendritic cells (CD11c+) with calreticulin-labeled tumor cells and found that the proportion of CD11c+ cells was significantly increased after treatment with Rg3, indicating that Rg3 can enhance the uptake of tumor cells by dendritic cells.

4 Regulation of immune molecules

Immune molecules are mainly produced by T lymphocytes, B lymphocytes, macrophages, and other cells after stimulation by antigens. They mainly include lymphokines, complement, antibodies, etc. Ginseng saponins play an important role in the regulation of immune molecules in various diseases and are currently considered to be the first choice of traditional Chinese medicine for regulating the body's immunity.

4.1 Regulation of cytokines

Cytokines include various types, such as interleukins, interferons, and tumor necrosis factors. Studies have found that ginsenosides interfere with the occurrence and development of various diseases by participating in the regulation of cytokines. Long et al. [38] used ginsenoside Rg1 to intervene in sodium dextran sulfate-induced ulcerative colitis in BALB/c mice and found that after 14 days of continuous administration, the body weight, colon weight, colon length, colon weight index and pathological damage score of colitis mice were effectively improved, with less ulcer formation and inflammatory cell infiltration, and reduced levels of IL-6, IL-33, CCL-2, and TNF-α, as well as elevated levels of IL-4 and IL-10, suggesting that ginsenoside Rg1 can effectively regulate the expression of inflammatory cytokines in colonic tissue. After ginsenoside Rg1 acts on CD14+ monocytes, the levels of IL-6, TNF-α and IL-10 in the cell supernatant increased significantly, but the level of IL-1b did not increase significantly, suggesting that ginsenosides can regulate the function of monocytes [39]. In the H22 tumor-bearing mouse model, it was also observed that Rh2 octyl ester derivatives can enhance the proliferation and cytotoxicity of splenic lymphocytes, and is associated with TLR4; the secretion levels of cytokines such as IFN-γ, IL-2, and IL-4 in the spleen lymphocytes of TLR4-/- mice are significantly increased [11]. The above studies all indicate that ginsenosides exert anti-inflammatory and anti-tumor effects by regulating the levels of cytokines.

4. 2 Regulation of complement

Complement is widely present in serum, tissue fluid and on the surface of cell membranes. It is a protein response system with a sophisticated regulatory mechanism that is widely involved in the body's anti-infection defense response, immune response and the occurrence and development of certain immune pathologies. At present, the regulatory effect of ginsenosides on complement in immune response is attracting more and more attention from researchers. You Yanli et al. [40] found that ginsenosides can improve the clinical efficacy of prednisone treatment, reduce ESR, and promote the production of complement C3, indicating that ginsenosides can enhance the body's immune defense function through their role in complement.

4. 3 Regulation of antibodies

Antibodies are immunoglobulins produced by plasma cells differentiated from B cells or memory B cells under the stimulation of antigens by the immune system. They can specifically bind to corresponding antigens. Antibodies can be divided into five categories according to their physicochemical properties and biological functions: IgM, IgG, IgA, IgE, and IgD. Park et al. [41] found that ginsenosides Rg1 and 20(S)ⅣRg3 can directly stimulate B cells to produce IgA, indicating that ginsenosides can enhance the body's immune function. In a systemic lupus erythematosus model study, Yu et al. [42] found that ginsenosides Rb1, Rh1, Rg1, and Rg3 can inhibit the secretion of IgG and IgM by B cells in a dose-dependent manner.

5 Prospects

The immune system is composed of immune organs, immune cells and immune molecules. It is an important system for the body to carry out immune responses and immune functions. It has the function of recognizing and eliminating antigenic foreign substances, coordinating with other systems of the body to maintain the stability of the internal environment and physiological balance of the body. When the body's immune system is disrupted, it can lead to the occurrence of various diseases, such as inflammation, tumors, diabetes, liver and kidney diseases. Therefore, it is crucial to choose the right medicine to maintain the balance of the body's immune system. Ginsenosides, as a type of traditional Chinese medicine, have attracted much attention from researchers. In recent years, a number of studies have reported that ginsenosides play a regulatory role on immune organs, immune cells or immune molecules (Table 1), indicating that ginsenosides have medicinal value in the treatment of tumors, inflammation or diabetes.

At present, the research on the mechanism of ginsenosides in the immune system is not yet in-depth, and the potential mechanism of anti-oxidative stress is not yet clear. Although there are many studies on ginsenosides in animal models, there are fewer reports of clinical trials. In the future, further research is needed on the mechanism of ginsenosides in the immune system, and more research on clinical applications is needed to provide more reliable evidence to promote the clinical application of ginsenosides.

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