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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 201-210

Chemistry Behind the Immunomodulatory Activity of Astragalus membranaceus


1 Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hawaii 96720, USA
2 Hubei Provincial Key Laboratory of Quality and Safety of Traditional Chinese Medicine Health Food, Jing Brand Research Institute, Jing Brand Co., Ltd., Daye 435100, Hubei, China

Date of Submission30-Aug-2021
Date of Acceptance09-Nov-2021
Date of Web Publication28-Dec-2021

Correspondence Address:
Prof. Shugeng Cao
Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hawai'i 96720
USA
Dr. Yuancai Liu
Hubei Provincial Key Laboratory of Quality and Safety of Traditional Chinese Medicine Health Food, Jing Brand Research Institute, Jing Brand Co., Ltd., Daye 435100, Hubei
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CMAC.CMAC_40_21

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  Abstract 


Huang Qi (黄芪 Astragalus membranaceus) is a well-known and widely used herb in traditional Chinese medicine (TCM) tonic preparations. It has been used for many ailments over the last 2000 years. Flavonoids, saponins, and polysaccharides have been shown to be the main compounds responsible for the biological and pharmacological activities, especially the immunomodulatory properties, of such tonic preparations. This review summarizes the published data on Astragalus extracts and fractions and the natural compounds responsible for the immunomodulatory activity with special reference to the modulation of nuclear factor-kappa B and related pathways (e.g., Nrf2). In addition, this review highlights the importance of Astragalus membranaceus in TCM for treating patients with diseases related to immunocompromised conditions, such as cancer and diabetes.

Keywords: Huang Qi (黄芪 Astragalus membranaceus), immunomodulatory, nuclear factor-kappa B, phytochemicals


How to cite this article:
Qader M, Xu J, Yang Y, Wu X, Liu Y, Cao S. Chemistry Behind the Immunomodulatory Activity of Astragalus membranaceus. Chin Med Cult 2021;4:201-10

How to cite this URL:
Qader M, Xu J, Yang Y, Wu X, Liu Y, Cao S. Chemistry Behind the Immunomodulatory Activity of Astragalus membranaceus. Chin Med Cult [serial online] 2021 [cited 2022 Jun 26];4:201-10. Available from: https://www.cmaconweb.org/text.asp?2021/4/4/201/334089




  Introduction to the Traditional Uses of Huang Qi (黄芪 Astragalus membranaceus) Top


Astragalus is one of the largest genera in the family Leguminosae and is widely distributed in temperate and arid regions as annual and perennial shrubs and subshrubs. It is estimated that the genus Astragalus contains more than 3000 species.[1],[2],[3] In traditional Chinese medicine (TCM), the roots of Astragalus are one of the major constituents of many herbal formulations. The Astragali Radix or “Huang Qi” is the dried roots of Astragalus membranaceus (A. membranaceus), which is a major component in tonic formulations used in TCM and is also popular worldwide.[1],[2],[3],[4] The medicinal use of Astragalus boasts a history of over 2000 years and was first recorded in the Shen Nong Ben Cao Jing (《神农本草经》Shennong's Classic of Materia Medica) in 200 A.D. This book was the first recorded document concerning herbal medicine in TCM.[5] In TCM, Huang Qi is commonly used to treat anemia, wounds, fever, allergies, fatigue, loss of appetite, and abnormal menstrual bleeding.[6],[7],[8] Nowadays, Astragalus is used to treat a broad spectrum of diseases, such as diabetes, hypertension, cirrhosis, leukemia, nephritis, viral infections, and cancer. Most importantly, it does not show any toxicity.[1],[2],[3],[4],[5] In addition, Astragalus enhances immunity, protects the liver, and possesses anti-aging, anti-stress, diuretic, anti-hypertensive, and antibacterial activity.[1],[2],[3],[4],[5],[6] Owing to its medicinal importance and applications, Astragalus is included in the Grade-III National Protected Plant List in China.[7]

There have been many review articles published over the past few years and they highlight the importance of Astragalus species.[3],[5],[6] The current review focuses on two major Astragalus species, namely A. membranaceus (Fisch.) Bge. and A. membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao. which are categorized under the same species.[6]


  Major Classes of Compounds Found in Astragalus membranaceus Top


More than 200 compounds have been isolated and identified from Astragalus species.[3] These compounds can be mainly grouped into three major classes of compounds, namely flavonoids, polysaccharides, and saponins [Figure 1]. These major compounds are responsible for the diverse pharmacological activities of Astragalus species.[3],[5],[6]
Figure 1: The three major classes of compounds present in Astragalus membranaceus

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Astragalus polysaccharides are the most abundant substances[9] and they consist of dextran and heteropolysaccharides, i.e., polysaccharides with multiple monosaccharide units such as glucose, rhamnose, arabinose, galactose, mannose, fructose, fucose, ribose, xylose, glucuronic acid, and galacturonic acid.[6],[7],[10] Astragalus polysaccharides are complicated macromolecules with molecular weights ranging from 8.7 to 4800 kDa and up to nine different monosaccharide units with different ratios.[10] Due to their complexity, to date, there have only been 24 polysaccharides isolated and identified from A. membranaceus.[10] Cycloartane- and oleanane-type saponins are important pharmacologically active substances in Astragalus species.[3],[10] Astragalosides (AS) I (1), II (2), and IV (3) and isoastragalosides I (4) and II (5) [Figure 2] are the major saponin constituents (more than 80%) found in A. membranaceus.[11] Similar to other plants, Astragalus species are also rich in flavonoids, including abundant isoflavones and other flavanols, flavones, flavonones, isoflavans and pterocarpans.[12] More than 60 flavonoids have been identified from A. membranaceus.[3],[11] Among them, calycosin-7-O-β-D-glycoside (6) [Figure 2] is a biomarker compound in the flavonoid fraction of A. membranaceus.[11]
Figure 2: Biomarker compounds in Astragalus membranaceus

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  Immunomodulatory Activity of Astragalus membranaceus Top


A. membranaceus has been extensively used in herbal formulations, especially in tonics, in order to strengthen the immune system. A. membranaceus is used for adults with weak immune system, for the patients suffering from chronic diseases (e.g., diabetes and cancer) with low-grade inflammation, and for those people under physiological stress.[13] Herbal formulations of A. membranaceus have been shown to regulate immunity by (i) exerting an effect on organs (e. g., thymus and spleen), lymphatic tissues, bursa of Fabricius (birds), and dendritic cells in bone marrow;[14],[15] (ii) increasing the development of primary stem cells in lymph nodes (B and T lymphocytes) and regulating natural killer cells and macrophages;[16] (iii) influencing immunomodulatory compounds, which protect cells from increased levels of cytokines during an inflammatory response; (iv) affecting the secretion of immunoglobulins; and (v) influencing the immune signal transduction in immune signaling pathways [Figure 3].[17] To regulate immune signaling transduction, there is the nuclear factor-kappa B (NF-κB) transcription factors, which play an important role in the activation of the immune system are modulated.[18],[19] NF- κB is a family of transcription factors that regulates gene expression as a result of immune and inflammatory responses in the body. This review will focus on the immunomodulatory activity of A. membranaceus with special reference to NF-κB and the chemical constituents and natural products responsible for the activity.
Figure 3: Immune enhancing effects of Astragalus membranaceus in biological systems

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Innate or natural immunity and acquired or adaptive immunity are the two major immune responses in biological systems. Innate immunity provides the first line of immunity and is developed when an organism is born. When immunity is low, innate immunity is not always sufficient to protect the organism. In this situation, adaptive immunity plays a major role in protecting the organisms.[20] Cells in the adaptive immunity are capable of destroying foreign pathogens and dead cells, producing antigens, acting as messengers between the innate and adaptive immune systems, controlling and limiting the spread of microbial infections, damaging the cell walls of microorganisms, promoting immune activation, and controlling overactivation.[21],[22],[23] Macrophages, natural killer cells, dendritic cells, and erythrocytes are part of the innate immune response, and T and B lymphocytes are part of the adaptive immune response. A. membranaceus extracts and fractions have been shown to have an ability to modulate the immune systems of biological organisms.[5],[16]

Astragalus total extract

Administration of different parts (e.g., aerial parts and roots) of A. membranaceus in different forms (e.g., fine powder, decoction, or polysaccharide, saponin, or flavonoid fractions) in animal models has shown a significant development of immune system, especially in poultry.[24] Several studies have reported that administration of the total extract of A. membranaceus to 7-d-old chickens, in addition to a basic diet and water, significantly increased the development of immune organs before the chickens were 35 days old.[24],[25]

Long-term administration of an A. membranaceus total extract has been shown to strengthen the immune organs of mice.[14],[26] Several studies have concluded that the immunoregulation of A. membranaceus extracts or fractions was entirely dose dependent, and 300 mg/kg in mice was the optimum dose to enhance the immune function by improving cell proliferation in immune organs and balancing cytokine levels.[12],[18],[27] Demethylhomopterocarpin (7), formononetin (8), and formononetin-7-O-β-D-glucopyranoside (9) [Figure 4] in A. membranaceus extracts were found to be responsible for this immunoregulatory activity.[28] The ability of the total extract of A. membranaceus to cause neuroregeneration has been studied using a mouse model. The mice were dosed with 1.5 or 3.0 g/kg of extract daily for 4 weeks. The results showed that the neuronal function was significantly improved in the high-dose extract group. The levels of fibroblast growth factor, nerve growth factor, interleukin-1 (IL-1), and interferon (IFN) were decreased in the high-dose group but were increased in the low-dose group. Therefore, a low dose of the total extract of A. membranaceus could be helpful for the regeneration of nerves, especially in the case of nerve injuries.[28] Similarly, the total extract was administered to mice infected with chronic bronchitis. During the dosing, the inflammation in pulmonary tissues and the bronchus of infected mice was significantly reduced, and the proliferation of lymphocytes in the alveolar macrophages was increased.[29] These results indicated that an A. membranaceus crude extract could improve the immune system in the treatment of chronic bronchitis. During an infection, the migration of macrophages is an innate immune response. Heparanase (HPA) is a key regulator of migration and immune response mediators in macrophages. Qin et al. have shown that the total extract of A. membranaceus increased HPA activity, cell migration, and mRNA gene expression through the secretion of interleukin-1β (IL-1β and tumor necrosis factor [TNF])- α in macrophages. Therefore, the A. membranaceus crude extract can activate an immune response through HPA cell migration.[30] The effect of the total extract on the viability and apoptosis of different carcinoma cell lines has been studied. In one study, the human nasopharyngeal carcinoma CNE2 cell line was treated with the total extract of A. membranaceus. The results showed that the total extract was effective in inducing apoptosis in cancer cells. After treatment with the total extract, the apoptosis-related protein BCL-2 became underexpressed and caspase-3 and-8 and BAX proteins were overexpressed. The percentage of T-lymphocytes was also increased. This study suggested that Astragalus could alleviate the immunological effects of cancer.[31] The water and whole ingredient extracts of A. membranaceus have been investigated through the application different extraction methods. The in vivo immunomodulatory effect of the extracts was studied in cyclophosphamide-immunosuppressed mice. The results showed that polysaccharides, flavonoids, and saponins were abundant in the water extract. Oral administration of the water extract for 18 days significantly increased the immune responses in the tested mice, including effects on body weight, peripheral white blood cells, thymus and spleen indexes, splenocyte proliferation, natural killer cells activity, splenic lymphocytes, and serum levels of Immunoglobulin G and M (IgG and IgM).[4] The total extract of Astragalus was administrated both orally and intracolonically to Dawley rats with 2, 4, 6-trinitrobenzene sulfonic acid TNBS-induced colitis. In both cases, the extract protected the rats from the induced colitis. The extract decreased the colonic lesions and damage scores and ameliorated colonic myeloperoxidase activity. Moreover, oral administration of the extract was able to reduce the overexpression of TNF-a, IL-1b, and IL-10 genes. Therefore, this study showed the applicability of Astragalus as a food supplement for immunocompromised patients.[32]
Figure 4: Bioactive flavonoids in Astragalus membranaceus

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Astragalus polysaccharide fraction

Many research results have indicated that the polysaccharide fraction of A. membranaceus contains major bioactive constituents that are responsible for the diverse biological and pharmacological activities of A. membranaceus, including immunomodulatory, anticancer, antitumor, anti-inflammatory, neuroprotective, and antidiabetes effects.[10] Administration of a polysaccharide-rich fraction of A. membranaceus to ducklings infected with Muscovy duck reovirus (MDRV) showed thickened intestinal wall, inhibited reduction in lymphocytes and goblet cells because of the infection, and increased the levels of secretory immunoglobulin A (sIgA), cytokines (IL)-4, IL-6, and IL-15, and TNF-α[33] MDRV infections are a major problem among ducklings and are an economic trouble for the poultry industry.[33] Polysaccharide fractions have been administrated to mice inoculated with hepatitis B virus (HBV) to investigate the effect of immunomodulation on mice. Administration of the polysaccharide fraction increased the levels of HBV antibodies and T cells, which induced the production of IL-2 and IL-4, enhanced the activity of cytotoxic lymphocytes, and stimulated dendritic cells as an immune response.[34] Similarly, the polysaccharide fraction has been administered to chickens inoculated with avian infectious bronchitis virus (IBV) at different doses over different time frames post inoculation. IBV-specific antibodies, lymphocyte proliferation, and expression of IL-1 β, IL-2, IL-8, TNF-α, and mRNA were found to be increased in the polysaccharide-administrated group.[35] Gao et al. have studied the immunological characteristics of Astragalus polysaccharides in the trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (colitis) in the mouse model. The rats were treated with the polysaccharide fraction at a dose of 0.5 g/kg daily for 14 days. Both macroscopic lesions and histological colonic damage induced by TNBS were found to be reduced, and the expression of T-beta and GATA-3 binding protein was enhanced. In addition, T helper cell-1 (Th-1)- and T helper cell-2 (Th-2)-specific transcription factors were overexpressed. These observations suggested that the polysaccharide fraction of A. membranaceus has therapeutic potential in colitis.[36] Li et al. have investigated the immunotherapeutic activity of Astragalus in diabetes using a mouse model. Diabetic mice treated with an Astragalus polysaccharide fraction showed decreased level of blood glucose, increased level of serum insulin, increased β-cell mass, and decreased level of apoptotic β-cells in the pancreas. The following were also observed:[37] downregulation of Th-1- and Th-2-specific transcription factors, a decrease in Th-1/Th-2 cytokine ratio, and upregulation of peroxisome proliferator activated receptor-γ gene expression in the spleen as immunomodulatory actions against diabetes (by increasing the insulin sensitivity).

Astragalus flavonoid fraction

Immunomodulatory actions associated with flavonoid fraction of Astragalus have been investigated using in vivo mice model and in vitro cell models. Histopathological studies on mice treated with the Astragalus flavonoid fraction showed that there was an increase in the macrophage index and decreased hypersensitivity. This suggests an enhanced nonspecific immunity by increasing the phagocytosis of macrophages, thus initiating immune reaction.[38] In addition, reduced ear and paw edema and vascular permeability as an example of the anti-inflammatory and immunomodulatory actions was observed.[38] In an in vitro cell model, the flavonoid fraction of Astragalus stimulated the expression of NO, IL-1β, IL-6, and TNF-α in RAW267.4 cells.[38] In a mouse model, the amount of food for the mice was restricted and the mice were forced to swim for 6 weeks to induce fatigue. The flavonoid fraction was given orally at different doses for 6 weeks. Immunohistopathological studies showed that mice administered with the flavonoid fraction showed increased cytokine production (high IL-2 and low IL-4 levels) and a high endurance capacity for swimming. The high capacity of the mice to endure these stressful conditions may be because of the immunomodulatory balance caused by the dominance of Th-1 over Th-2 cells and the secretion of specific cytokines.[27] Furthermore, flavonoid compounds, particularly formononetin (8), calycosin (10), and the saponin glycosides calycosin-7-O-β-D-glucopyranoside (6), and formononetin-7-O-β-D-glucopyranoside (9), which are present in A. membranaceus extracts enhanced the upregulation of phagocytic activity in macrophages.[27] Li et al. isolated 12 flavonoids from A. membranaceus, namely isoliquiritigenin (11), liquiritigenin (12), calycosin (10), calycosin 7-O-β-D-glucoside (6), formononetin (8), formononetin 7-O-β-D-glucoside (9), daidzein (13), daidzein 7-O-β-D-glucoside (14), methylnissolin (15), methylnissolin 3-O-β-D-glucoside (16), isomucronulatol (17), and isomucronulatol 7-O-β-D-glucoside (18) [Figure 5] and they investigated the effect of the compounds on cytokine production in bone marrow-derived dendritic cells. Isoliquiritigenin (11) demonstrated significant inhibition of the pro-inflammatory cytokines IL-6 and IL-12, as well as TNF-α.[39]
Figure 5: Bioactive flavonoids in Astragalus membranaceus

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Astragalus saponin fraction

The mucosal immune system is made up of mucosa-bound lymphoid tissues that are widely distributed in the intestine, respiratory, and genitourinary tracts. This system regulates immunity by producing sIgA proteins and cytokines in the mucosa. Wu et al. have investigated the immune response in mucosal immunocompromised mice after administration of A. membranaceus saponin fractions for 14 days. IgA was found to be expressed in the intestinal and respiratory mucosal lymphoid tissues.[40] Administration of A. membranaceus saponin fractions significantly upregulated NO and TNF-α synthesis in macrophages and increased the phagocytic activity and the capacity in macrophages.[41],[42],[43] The antitumorigenic activity of Astragalus saponins has been investigated in vitro and in vivo. The proliferation, progression of cell cycle, and apoptosis of BGC-823 gastric cancer cells were inhibited by the saponin fraction acting as a tumor suppressor. In an in vivo study, BCG-823 cell xenografted tumors were induced, and the tumor volume was significantly reduced after injecting saponin fractions.[44] The saponin biomarker compound astragaloside IV (AS-IV) (3) has been investigated in human non-small cell lung cancer cell carcinoma (NSCLC). High doses of AS-IV (3) inhibited NSCLC cell growth, whereas low doses did not show any toxicity affecting the cell viability. In combination with the chemotherapy drug cisplatin, AS-IV (3) increased the chemosensitivity of cisplatin and inhibited the expression of mRNA and B7-H3 genes. The inhibition of the B7-H3 gene has an immunomodulatory action against NSCLC.[45] In addition, topical application of AS-IV (3) promoted the healing of wounds induced in diabetic mice by promoting re-epithelialization and collagen deposition. The expression of fibronectin and collagen IIIα genes was induced by AS-IV (3), which promoted the wound healing. In addition, AS-IV (3) promoted the formation of new blood vessels and endothelial cells through the expression of the responsible genes.[46] In addition, Du et al. have reported that oral administration of AS-IV (3) significantly reduced eosinophilic airway inflammation induced in mice. AS-IV (3) also downregulated the IL-4 and IL-13 levels in the bronchoalveolar lavage fluid and immunoglobulin E (IgE) levels in the serum.[47] A. membranaceus extracts and fractions upregulated microphage stimulating and releasing factors and increased the Ca2+ ion concentrations in macrophages, and AS-IV (3) was determined to be responsible for these biological actions.[5] Astragaloside IV (3) is a biomarker in accessing the quality of Astragali Radix and showed widespread pharmacological activities, including anti-inflammatory, anticancer, antidiabetic, cardioprotective, and immunoregulatory effects.[5] A review of the properties of astragaloside IV (3) has been done by Zhang et al.[5]


  Actions of the Nuclear Factor-Kappa B Pathway in Immune Regulation by Astragalus membranaceus Top


When an organism recognizes the presence of foreign pathogens, the organism tends to respond immediately to clear the pathogen. This process starts at the cellular level as a function of the immune system. NF-κB is inactive and available in the cytoplasm under normal circumstances. NF-κB is a family of inducible transcription factors that regulates a large array of genes involved in different processes of the immune and inflammatory responses. When stimulated by cytokines, inactive NF-κB is activated and translocated to the nucleus to induce the expression of the relevant genes.[48],[49] The activation of NF-κB in an immune response mainly refers to a combination of two processes. The major pathway is classical (canonical) and is involved in the regulation of the immune response and the expression of cytokines, TNF receptors, and T cell and B cell receptors. The second pathway is alternative (noncanonical) and assists the classical pathway in the regulation of immune functions in the adaptive immune system.[50],[51]

Innate immune cells, such as macrophages, dendritic cells, natural killer cells, and neutrophils are found in different tissues at different locations. These cells can be activated in an immune response against infections of microbes and changes in the microenvironment. As part of an immune response, these cells release cytokines.[52] Cytokines can be differentiated into pro-inflammatory cytokines, such as IL-1, IL-6, IL-12, and TNF-α that are necessary for the inflammatory process, T cells (Th-1 and Th-17) that mediate the inflammation, and anti-inflammatory cytokines (IL-10 and IL-13) that are important for the final healing stage.[53] Therefore, NF-κB is a key transcriptor that is important for inducing pro-inflammatory and anti-inflammatory genes to regulate the immune system.

In recent years, many studies have been carried out on A. membranaceus to investigate the mechanism of action of phytochemicals in A. membranaceus to understand how these phytochemicals regulate the immune systems of organisms via modulation of the NF-κB pathway. Qin et al. have studied the involvement of the NF-κB pathway in the pro-inflammatory response in Ana-1 macrophages treated with advanced glycation end products (AGE). The total extract of A. membranaceus inhibited the AGE-induced inflammatory cytokines, IL-1β and TNF-α, and mRNA expression, and these effects might have been mediated through the NF-κB signaling pathway.[54] Yang et al. have proven that Astragalus extract inhibited the translocation of NF-κB from cytoplasm to nucleus, abolished the expression of NF-κB in asthmatic mice, and consequently suppressed the pro-allergic cytokines IL-4 and IL-5.[55] Microglial cells treated with an Astragalus polysaccharide fraction showed downregulation of nitric oxide (NO), inhaled NO (iNO), and prostaglandin E genes. The downregulation of the pro-inflammatory cytokines IL-1β and TNF-α was observed in lipopolysaccharide-stimulated cells. Thus, Astragalus polysaccharides could inhibit the translocation of NF-κB induced by the inflammatory response in microglial cells.[56] Similarly, the Astragalus polysaccharide fraction has been shown to downregulate the pro-inflammatory cytokines IL-1 β, IL-6, IL-16, and TNF-α in dextran sulfate sodium-induced colitis mice model. This reduction in the levels of NF-κB and cytokines improved colitis in the Astragalus-treated group.[57] Lee and Jeon have demonstrated that Astragalus polysaccharides significantly stimulated macrophage expression of the NO synthase (iNOS) gene in mice. In addition, the polysaccharide fraction also induced iNOS and mRNA transcription in RAW 264.7 cells. Further, in vivo and in vitro investigations have indicated that nuclear translocation, activation of NF-κB, and DNA binding were strongly inhibited by the Astragalus polysaccharide fraction.[58]

In RAW264.7 cells, an Astragalus polysaccharide-rich fraction mixed with plant flavonoid quercetin (19) decreased NO production and iNOS gene expression, although quercetin alone had no effect. The combination of the polysaccharide fraction and quercetin inhibited cytokine production, cellular phosphorylation, and ultimately macrophage activation in the RAW264.7 cells,[59] and the polysaccharide fraction alone upregulated the production of NO, TNF-α, IL-6, and iNOS genes. More importantly, these findings indicated that the immunomodulatory effect of the polysaccharide fraction was mediated via the activation of the NF-κB p65/mitogen-activated protein kinase (MAPK) signaling pathway.[60] In a previous study, a combination of quercetin (19) and the polysaccharide fraction showed no effect on the NF-κB pathway to exert immunomodulatory activity.[59] Li et al. concluded that quercetin (19) might interfere with the immunomodulatory activity of the polysaccharide fraction of A. membranaceus.[59]

Several studies have investigated the involvement of active compounds in Astragalus extracts in immune-enhancing activity through the NF-κB pathway. The immune response activity of the saponin metabolites AS-VII (20) and macrophyllosaponin B (21) [Figure 6] has been studied by Nalbantsoy et al. in an albino mouse model. Both compounds strongly upregulated the inflammatory cytokines IL-2 and IFN-γ and downregulated Th-2 cytokine production (IL-4). Interestingly, the observed immune response did not affect the NF-κB pathway.[61] In streptozotocin-induced diabetic rats, the NF-κB activity and mRNA protein expression increased in the kidneys. These abnormalities were restored partially when the rats were treated with the saponin biomarker astragaloside IV (AS-IV) (3). Administration of AS-IV resulted in decreased levels of TNF-α and cytokine proteins MCP-1 and ICAM-1. AS-IV (3) inhibited the activation, translocation, and overexpression of NF-κB in diabetic nephropathy.[62] Thus, Astragalus total extracts, fractions, and phytochemicals can activate cell proliferation, increase cytokine production, and stimulate macrophages to express the iNOS gene through inhibiting the translocation and expression of NF-κB genes, thus deactivating the NF-κB pathway.
Figure 6 Saponins in Astragalus membranaceus responsible for the upregulation of pro-inflammatory cytokines

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In a recent study, the active natural compound methylnissolin-3-O-β-D-glucopyranoside (16) was isolated from Jing liquor of which A. membranaceus is a major component. Wu et al. have studied the cytoprotective activity of methylnissolin-3-O-β-D-glucopyranoside (16). Methylnissolin-3-O-β-D-glucopyranoside (16) activated Nrf2 and antioxidant genes, such as HO-1 and NQO-1.[63],[64] Adesso et al. have proven that the Astragalus polysaccharide fraction reduced the levels of pro-inflammatory cytokines IFN- g, TNF- α, and iNOS in nontumorigenic intestinal epithelial cells and suppressed inflammation induced by lipopolysaccharides. The polysaccharide fraction induced the production of reactive oxygen species, thus activating Nrf2 genes.[65]


  Conclusions and Future Perspectives Top


A. membranaceus has been used as a herbal medicine for more than 2000 years and has a broad spectrum of pharmacological and biological activities ranging from anti-inflammatory, anticancer, antidiarrhea, antiviral, and neuroprotective functions. In addition, A. membranaceus is also a common dietary supplement. There are many reports regarding the mechanism of action of Astragalus in enhancing immunity in biological systems. However, there are few reports that summarize the immunomodulatory activity of Astragalus extracts and/or fractions and/or the responsible phytochemicals. This review focuses on the use of Astragalus for immune enhancement in diabetes, cancer, infections, colitis, chronic bronchitis, asthma, wound healing, viral infections, neuron regeneration, and fatigue, and summarizes the in vitro and in vivo investigations of the immunomodulatory activity of the total extract and the polysaccharide, flavonoid, and saponin fractions of A. membranaceus. Few studies have investigated the structure–activity relationship of the active compounds in Astragalus, which is worthy of further investigation. Supplementation of the daily diet with Astragalus may be beneficial for enhancing immunity. Astragalus is easily accessible from online shopping sites and is available in such forms as powders, capsules, drinks, injections, and granules.[7]

Funding

None.

Ethical approval

This article does not contain any studies with human or animal subjects performed by either of the authors.

Author contributions

Mallique Qader drafted and corrected the manuscript; Shugeng Cao conceived, guided, and revised this article. All the authors, Mallique Qader, Jian Xu, Yuejun Yang, Xiaohua Wu, Yuancai Liu, and Shugeng Cao, have read and agreed to the published version of the manuscript.

Conflict of interest

None.



 
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