Xin-Yi Wang
Rong-Can Wang
Zheng-Yi Qu1
Ya-Li Li- 1Institute of Special Animal and Plant Sciences of Chinese Academy of Agricultural Sciences, Changchun, China
- 2Jilin Provincial Key Laboratory of Traditional Chinese Medicinal Materials Cultivation and Propagation, Changchun, China
Astragalus membranaceus (AM) is a traditional chinese medicine (TCM) with active substances such as saponins and polysaccharides, The most abundant active ingredient is astragalus polysaccharides (APS). It is a natural extract with multiple activities such as anti-viral, anti-tumor and the immune-enhancing effects. In recent years, studies on the role of APS in immunomodulatory direction have been increasing, and numerous studies have shown that APS has a better immune enhancing effect. This paper outlines the immunomodulatory effects of APS in terms of immune cells, nonspecific immunity, anti-viral immunity, anti-tumor effects, and applications in animal production, which would provide a base for the further applications of APS. Herein, this current review intends to describe the immunomodulatory effects of APS with underlying mechanisms of therapeutic effects.
Introduction
In China, A. membranaceus (AM) which also known as Huangqi, is derived from the dried root of the perennial legume A. membranaceus Bge. var. mongholicus (Bge.) Hsiao and A. membranaceus (Fisch.) Bge. It is a perennial traditional chinese medicine (TCM) that belongs to the legume family, mainly distributed in Shanxi province, Liaoning province, Neimenggu province, and other province (Ma et al., 2019) which have a cold temperate zone. Astragalus is a TCM with diuretic, anti-aging, and anti-hypertensive effects (Wang et al., 2022). Moreover, AM has been included in the list of national drug and food homology in 2018 (Tian et al., 2020). Astragalus contains a variety of active ingredients, including polysaccharides, saponins, flavonoids, amino acids, and a variety of trace elements (Li et al., 2009; T et al., 2009; Zhang et al., 2012).
In recent years, pharmacological studies on AM, especially the immunomodulatory effects of APS, have become a hot topic. Numerous studies have demonstrated that APS has significant immunomodulatory effects both in vivo and vitro in immunosuppression animal models (Li et al., 2020), and it also enhances the immune effects of normal animals (Angela et al., 2020). The fundamental mechanisms of the APS include organ immunity, regulation of the immune-related genes, immune cells, and synergistic effects of Astragalus with other TCM. This review will overview the immunomodulatory effects of APS.
Effects of APS on non-specific immune cells
The effects of APS on macrophages
Macrophages are important cells in the body’s non-specific immunity, providing an effective defense system for tumor cells, parasites, and fungi against the host body cells (Wang et al., 2015). Its phagocytic ability can reflect the immune capacity of the body (Jin et al., 2014), APS improves macrophage function and enhances phagocytosis of macrophages. APS can increase the secretion of TNF-α and nitric oxide, promote the increase of macrophages, and protect macrophages’ integrity (Shi et al., 2019). Chai et al. (2019) found that intraperitoneal injection of 2 mg/ml APS in mice for 7 days could significantly increase the polarization of M1-type peritoneal macrophages in mice. Yang et al. (2013) found that 100 and 400 mg/kg APS could significantly enhance the phagocytic function of peritoneal macrophages in H22 liver cancer mice and inhibit the growth of solid hepatoma tumors. These results suggested that APS can enhance immunomodulatory effects by stimulating macrophage activity.
Effects of APS on dendritic cells and erythrocytes
Dendritic cells (DCs) help to regulate autoimmune and other immune responses (Iberg and Hawiger, 2020). Red Blood Cells (RBC) are emerging as important modulators of the innate immune response (Anderson et al., 2018). APS can promote the maturation and differentiation of DCs by upregulating CD36 and IL-27 and downregulating IFI16, thus positively influencing the development and progression of atherosclerosis (Chen et al., 2015). Shao et al. (2006) investigated the regulatory effects of ASP on the maturation and the function of cultured mouse bone marrow-derived DCs, showing that ASP could increase the co-expression of CD-11c and primary histocompatibility complex class II molecules on DC surface, the 100 μg/ml is the optimal dose, After using the APS treatment, the DCs showed a more mature morphology with longer projections. APS may enhance the immune adhesion of chicken erythrocytes by affecting the activity or number of complement receptors on the erythrocyte membrane (Li et al., 2007a).
Effects of APS on specific immune cells
The effects of APS on specific immune cells are mainly reflected in the increase of proliferation and differentiation of B and T lymphocytes, and the increase of serum antibody concentration, the proliferation of lymphocytes can reflect the state of cellular immunity (Lin et al., 2015). Studies have shown that Astragalus polysaccharide inhibits the increase of Tregs in immunosuppression models and melanoma models (Sun et al., 2013). Nie et al. (2004) reported that APS significantly promoted Con A-induced proliferative responses in mouse splenic T lymphocytes and thymic T lymphocytes. The highest value of T lymphocytes was observed at 50 μg/ml for APS. Li et al. (2007b) found a downregulation of the Th1/Th2 cytokine ratio in mice injected with APS. By grouping 100 patients with diabetic nephropathy (DN), Zhang et al. (2022) added APS injection therapy to the observation group. 14 days later found that astragalus polysaccharide reduced BUN, Cr, Th1, Th2 levels, and NLR, Th1/Th2 values in DN patients and was more effective than conventional Western medicine alone. Wang et al. (2007) reported that APS could induce the proliferation of B and T lymphocytes through synergistic Lipopolysaccharides (LPS) and ConA at the appropriate doses.
Effects of APS in anti-viral immunity
Antiviral immunity is an important immunity of the organism against viruses and is one of the main bases of adaptation to the natural environment, and its immune pattern includes both cellular and humoral immunity (Huang et al., 2015). It has been demonstrated that antiviral immunity is closely related to CTL cells (cytotoxic T lymphocytes), CD3+ CD4+ (helper/inducer T lymphocytes) and cytokines such as IL, IFN-γ, nuclear transcription factor (NF)-κB.
APS has a wide range of anti-viral applications; not only can prevent viral infections in humans and prevent many animal viruses. Studies have shown that APS can prevent hepatitis B virus (HBV) and effectively inhibit the proliferation of HepG2 2 2 15 cells (Zou et al., 2003). APS has an inhibitory effect on HBV replication in vivo and can be used as a supplementary modality in treating of hepatitis B infection (Dang et al., 2009). In addition, APS can also be used as a potent adjuvant for the hepatitis B DNA vaccine (Du et al., 2012). APS, as a vaccine adjuvant, has advantages of low toxicity and hypoallergenic (Wei et al., 2002). APS also has significant resistance to Herpesvirus, which can cause a variety of diseases such as herpes, rashes, tumors, and other diseases (Gable et al., 2014). APS can block the replication of Epstein-Barr virus (EBV) and exert anti-EBV effects (Guo et al., 2014).
In addition, APS plays an important role in the treatment of coronavirus disease 2019 (COVID-19). Since the outbreak of COVID-19, it has rapidly swept the world. In China, TCM has played an essential role in preventing and treating this new coronavirus pneumonia outbreak. A comprehensive review of the available literature revealed that AM could be used to treat COVID-19 in all periods (He et al., 2020). Zhao et al. (2020) collected 64 drugs to prevent COVID-19 in various provinces and found that AM was used most frequently. Clinical data disclosed by government departments and regions indicate that the combined treatment of COVID-19 with Chinese and Western medicine is effective. There may be a positive correlation between the cure rate of patients and the participation rate of Chinese medicine treatment.
Immunomodulatory effects of APS anti-tumor
At present, tumor has become one of the diseases with the highest mortality rate, and the incidence and death rate of tumor in China are on the rise, which seriously endangers people’s health. Tumors are formed by excessive and abnormal proliferation of local tissue cells under the prolonged stimulation of various intrinsic or extrinsic factors (Kankuri et al., 2005). It is widely used APS in the clinical treatment of diseases, especially the research related to anti-tumor effects, which is gaining attention. In recent years, numerous academic studies on the tumor immune mechanism of APS have found that the enhancing effects of APS are mainly related to T-lymphocyte (T cells), DCs, interferon (IFN), TNF-α, interleukin cells (IL), and so forth.
APS enhances the anti-tumor immune function of the body
The immune function of the body is closely related to tumorigenesis (Zhang and Zhao, 2012). In tumor tissues, the number of Th1 cells decreases, and T cells’ immune function is reduced. APS can promote T cells proliferation and induce Th1/Th2 to Th1 transition. Moreover, APS can induce DCs maturation and enhance the body’s anti-tumor immune function (Bo et al., 2015; Jing et al., 2021). Regulatory cells (Treg) can suppress T cell activation and value-added, and APS can inhibit tumor production by reducing Treg numbers in the spleen (Sun et al., 2013). Lai et al. (2017) administered APS at different doses to hepatocellular carcinoma H22-bearing mice to investigate their anti-tumor effects, and results showed that APS could inhibit the growth of H22 cells and the concentration of IL-2, IL-6, and TNF-α cytokines increased significantly, indicating that APS could affect immune regulation and suppress tumors. CD4+/CD8+ in a stable state can maintain the body’s immune function (Saber et al., 2016), however, the immune function of cancer patients is suppressed, and the T cells ratio is imbalanced. Hence, it is crucial to maintain the CD4+/CD8+ balance (Song et al., 2015). Getachew et al. (2014) also demonstrated that APS significantly increased lung cancer patients’ CD3+, CD8+, CD4+, and CD4+/CD8+.
Anti-tumor clinical applications
Cancer has always been a disease with a high clinical mortality rate, and the treatment for cancer patients is still mainly surgical, but the risk of surgery is high. Clinical research on TCM against cancer has been conducted for many years, and studies have found that Astragalus has an intervention effect on many types of tumors. The use of APS injection combined with chemotherapy, radiotherapy, and other clinical use of tumor achieved better efficacy. Li and Yu (2019) have found that Patients who used APS injection were found to have significantly increased disease control and treatment efficiency. APS injection increased CD4+/CD8+ and completely reversed tumor progression.
On the clinical effects of APS injection used together with chemotherapy, Lin et al. (2009) observed the efficacy of 40 patients with malignant tumors treated with APS injection combined with chemotherapy for one course (21 days). The cure rate was 70%, higher than the chemotherapy group (50%). Combining APS injections with chemotherapy is more effective than chemotherapy alone in cure rates and improved body function. Radiation therapy is also an essential tool in the treatment of tumors. Yu (2013) found that the use of APS injection could weaken bone marrow hematopoiesis in patients with non-small cell lung cancer caused by radiotherapy, maintain the hematopoietic microenvironment, and enhance the immune level of patients. Radioactive particle implantation combined with APS injections can improve the physical status, lower serological tumor markers, and improve immunity (Sun et al., 2014). APS combined with infrared (IR) treatment increased the sensitivity of human nasopharyngeal carcinoma to IR and indirectly increased the number of apoptotic cancer cells (Zhang et al., 2020).
Effects on expression of related genes
The immunomodulatory effect of APS is attribute to its ability to promote the synthesis of DNA, RNA, and proteins in cells and regulate the expression of relevant genetic material. As an immunomodulator related to Foot and mouth disease (FMD) vaccine, Li et al. (2011), found that APS can increase the titer of specific antibody and up-regulated mRNA expression of IFN-γ and IL-6. Liu et al. (2015) found that APS could reduce lipopolysaccharide-induced immune stress in chickens by decreasing gene transcription of Toll-like receptor 4 (TLR4) and NF-κB. Yuan et al. (2008) also found that APS can regulate immune gene expression in the head and kidney of carp. APS can enhance the protective immunity of the body against toxoplasmosis by regulating the relevant immune genes and also provides a new idea for the control of Toxoplasma gondii (Yang et al., 2010).
The effects of Astragalus complex
Astragalus can be used in combination with various TCM to enhance the immune function. AM can be used with other TCM, for example, Echinacea, Astragalus, and Glycyrrhiza herbal tinctures stimulated immune cells, can be quantified by CD69 expression of CD4 and CD8 T cells (Brush et al., 2006). Feeding carp with Astragalus and Ganoderma together can stimulate their respiratory activity and immune response (Yin et al., 2009). Feeding tilapia with Astragalus and Lonicera japonica can significantly increase blood phagocytosis, reduce mortality after hydrophilic infection, and improve immune response and disease resistance in cultured fish (Ardó et al., 2008). For specific roles, APS can be used directly with other TCM ingredients (Table 1).
TABLE 1. APS in combination with other ingredients and applications.
Summary and observations
The immunomodulatory effect of APS is one of the core issues of Astragalus-related research. As a TCM feed additive, APS can replace antibiotics, but more research is needed to promote the use of APS in animal production. APS can play an immunomodulatory role by regulating immune organs, immune cells, immune factors, and certain messenger substances, which have a regulatory effect on both specific and non-specific immunity, and have immunomodulatory functions on both normal and abnormal organisms (Fang, 1994). In terms of tumor immunity APS can be used clinically with traditional therapies for tumors, such as chemotherapy, improving cure rates and reducing the damage caused by the drugs. In addition, APS as a compound adjuvant also shows a good immune synergistic effect, which provides a valuable supplement for developing new, safe, and efficient immune adjuvants in the future, and has a broad application prospect (Figure 1). With the widespread of COVID-19 worldwide, anti-viral research is even more urgent. TCM plays a massive role in the fight against COVID-19. However, there is less research on the mechanism of TCM for COVID-19, and research should be strengthened in this area to better utilize the role of herbal ingredients in fighting the epidemic.
FIGURE 1. Immune function of APS in humans.
Author contributions
By sorting out APS-related literature, the research overview and future trend of APS in immunology were obtained, and the role and mechanism of APS on human immunity were clarified. YL provided research directions and ideas. XW reviewed the literature and wrote the manuscript. RW, ZQ, and YZ participated in the verification and revision of literature. All authors contributed to the article.
Acknowledgments
Authors sincerely thank the project of the Key R&D projects of Jilin Provincial Department of science and technology (No. 20210204178YY).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: astragalus polysaccharides, immunomodulation, anti-viral immunization, anti-tumor, overview
Citation: Wang X-Y, Wang R-C, Qu Z-Y, Zhu Y-Z and Li Y-L (2022) Advances on immunoregulation effect of astragalus polysaccharides. Front. Nat. Prod. 1:971679. doi: 10.3389/fntpr.2022.971679
Received: 17 June 2022; Accepted: 11 August 2022;
Published: 07 September 2022.
Edited by:
Christopher S. Jeffrey, University of Nevada, Reno, United StatesReviewed by:
Caixiang Liu, University of Chinese Academy of Sciences, ChinaCopyright © 2022 Wang, Wang, Qu, Zhu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ya-Li Li, yalilee@126.com