Han Quanbin (Professor)
Project 1:
Natural polysaccharides are of great attention in the biomedical and pharmaceutical fields due to their unique therapeutic properties. Although polysaccharides are poorly absorbed via oral dosing, they exhibit diverse and significant bioactivities. The underlying mechanism is unclear. In our preliminary study, we found that Radix Astragali Polysaccharide (RAP) quickly triggered the immune responses in the Peyer’s Patches of small intestine several hours after oral gavage, where RAP was efficiently transported by M cells into Peyer’s Patches to contact macrophages and dendritic cells, and even stem cells in bone marrow. Therefore, we hypothesize that the orally-dosed polysaccharide has another bioavailable possibility: M cells transportation into lymph system. The current project aims to further investigate this new mechanism:
- to determine the receptors mediating the M cell transcytosis;
- to validate the selectivity and specificity of this new mechanism by testing more other polysaccharides. The success of this project will provide new ideas for R&D of polysaccharide-based new medicine.
Project 2:
Radix Astragali (Huangqi), the mostly used Qi tonic in Chinese Medicine, is popularly used in combination with chemotherapy to reduce the side effects, especially bone marrow suppression. The orally dosed Radix Astragali polysaccharide (RAP) has been proved to be able to protect blood cells, bone marrow, as well as mice/human hematopoietic stem cells (HSC). While the effects have been verified, it is hard to understand the underlying mechanisms, because this macromolecule is non-absorbing and indigestible.
In our preliminary study, we discovered that RAP could quickly enter Peyer’s patches (PPs) in the small intestine via transcytosis through microfold cells (M-cells) in PPs. This delivery route was confirmed in human gut explants and shown to depend on the specific binding of RAP to the GP2 receptor on M-cells. Furthermore, RAP induced the MAPK/NFkB signaling pathways and production of cytokine IL-6 in Peyer’s patches. As we observed in vitro, both IL-6 production and the activation of MAPK/NFkB signaling pathways could be attributed to RAP’s inducing effects on dendritic cells and macrophages. RAP also increased the ratio of cytotoxic T cells and decreased the ratio of regulatory T cells in PPs. These findings suggest that RAP can activate some specific immune cells in PPs. However, how RAP affects the distant bone marrow and HSCs remains unknown.
We have detected RAP’s fluorescence signal in bone marrow under confocal micrograph in our preliminary study. It is suggested that RAP may directly contact HSCs after transported to bone marrow by some specific immune cells, which are activated by RAP in PPs, as the transporter. In addition, these activated immune cells themselves may also affect HSCs when migrated to bone marrow. Therefore, we hypothesize that these specific immune cells might be the key player in the bone-marrow protection of RAP after its entering PPs, where they are activated by RAP, and then carrying RAP or not, migrate to bone marrow and affect the HSCs.
To test this hypothesis, the current project aims to:
- identify the antigen-presentation immune cells activated by RAP in PPs, and determine the mechanism of activation;
- identify the activated immune cells which migrated to bone marrow with/without RAP;
- determine the protection mechanism of RAP and/or the migrated immune cells towards HSCs.
The success of this project will help resolving the long-standing mystery of how an orally dosed polysaccharide affects immune system, and then facilitate Research & Development of polysaccharide-based new drugs.
Project 3:
An oral vaccine could be key to fighting pandemics. In our fresh experience of fighting against COVID-19, the timely use of vaccines is limited by the huge logistical burden, concerns of needle-associated side effects, and complicated manufacturering procedure, which, in turn, affected the vaccination efficiency finally. An oral vaccine that can be mailed worldwide and taken anytime anywhere will be a preferable solution for the next pandemic wave.
The major difficulty in developing oral vaccines is their poor accessibility to immune cells, so the efforts to develop oral vaccines focus on delivering the antigen in a form that maximizes the chances of its uptake by M cells of Peyer’s patches (PPs, the major intestinal mucosal immune organ) for initiation of the immune response. Besides, the oral tolerance and low immunogenicity of vaccines are also difficulties to solve, where adjuvants are needed.
In our preliminary studies, we found Radix Astragali polysaccharide RAP a promising vaccine material. Orally-dosed RAP quickly entered PPs via M-cell uptake which was mediated by GP2 as verified on gen-deficient mice. Besides, RAP remained indigestive and intact in the gastric intestinal tract, showing sufficient stability and tolerance to the acidic and biodegradable environment. More importantly, M-cell targeted transport of RAP also applied to human subjects. It is suggested that RAP could be an efficient vaccine carrier. Further investigation indicated that after entering PPs, RAP directly and specifically targeted Dendric cells which triggered a series of immune responses in PPs in terms of inducing signaling pathways and cytokine production, DC/B cell activation, and IgM/IgA production. RAP’s additional potential as immunostimulant was therefore highlighted. So we hypothesize that RAP-nanocapsule could be a promising oral vaccine dual-function adjuvant of both carrier and immunostimulant.
To test this hypothesis, the current project aims 1) to systematically evaluate RAP-induced immunogenicity and determine the molecular mechanism; 2) to determine if RAP-nanocapsule can specifically deliver antigens (e.g. OVA) to intestinal lymphatic system and characterize the properties of RAP-based oral vaccine.
Whether RAP’s potential as vaccine carrier and immunostimulant is verified, financial investment will be sought to further test the efficacy on animal models and in clinic. RAP’s success may generate a new broad-spectrum platform for designing effective oral vaccines with clearly determined molecular mechanism, which will directly benefit the R&D of oral vaccines and therefore the fight against pandemics such as COVID-19, and Ebola. The medical use of Chinese medicine polysaccharides will be also extended, which may facilitate, to some extent, the modernization of Chinese medicines.
Chong Wai Po (Associate Professor)
Radix Astragali, plays a significant role in regulating the immune response. Renowned for its immunomodulatory properties, it enhances the body's resistance to infections and diseases by stimulating the production and activity of immune cells and balancing pro-inflammatory and anti-inflammatory cytokines. Additionally, Radix Astragali supports the body's natural defense mechanisms, making it valuable in both traditional and modern medicine for maintaining overall immune health.
Radix Astragali polysaccharide (RAP), isolated from Radix Astragali, has been shown to quickly enter Peyer's patches (PPs) to specifically activate dendritic cells (DCs) and trigger immune responses. Our aim is to identify the molecular mechanisms involved in RAP's activation of DCs and understand how these DCs shape our adaptive immune system.
KWAN Hiu Yee (Associate Professor)
Obesity and type 2 diabetes (T2D) are closely interconnected, with approximately 80-90% of T2D patients being overweight or obese. In recent years, there has been a notable increase in the prevalence of obesity and T2D, particularly among younger populations. Emerging pharmacological research indicates that the polysaccharides found in Chinese herbal medicine possess various pharmacological activities, many of which are effective in addressing obesity and T2D. However, the specific mechanisms through which these herbal polysaccharides exert their anti-obesity and T2D effects, such as modulating gut microbiota, influencing cellular signaling pathways, or regulating the immune microenvironment, remain poorly understood. This gap in knowledge significantly impedes their clinical application.
Modern studies suggest that obesity can alter immune function, revealing innate immune differences between diabetic and non-diabetic individuals. Current research has shown that specific Chinese herbal polysaccharides, including Lycium barbarum polysaccharides (LBP), Poria cocos polysaccharides (PCP), and Atractylodes macrocephala polysaccharides (AMP), can effectively treat obesity and T2D.
This project aims to identify Chinese herbal medicines with established properties based on traditional Chinese medicine (TCM) theory, extract their polysaccharide components, and investigate the relationship between these polysaccharides and the immune microenvironment in the context of treating obesity and T2D. This research will provide a modern pharmacological framework for understanding the targets of herbal polysaccharides in the management of obesity and T2D.
Xu Jun (Assistant Professor)
Natural polysaccharides possess complex structural properties and exhibit significant immunomodulatory effects. Following oral administration, most polysaccharides remain undigested in the stomach and small intestine, as mammals lack the necessary enzymes for their breakdown. Instead, these polysaccharides are fermented in the large intestine by gut microbiota, which are equipped with various carbohydrate-active enzymes. This fermentation process highlights the gut microbiota's crucial role as a target through which natural polysaccharides can modulate immune responses. Concurrently, emerging evidence from a growing number of cause-and-effect studies suggests that different gut bacterial species serve diverse physiological and pathological functions in disease prevention and treatment. Our research interests focus on exploring the relationship between the structures of natural polysaccharides and their effects on gut microbiota regulation, as well as how this structure-property relationship contributes to their immunomodulatory effects.
Li Lifeng (Research Assistant Professor)
Polysaccharides from Traditional Chinese medicines (TCM), as a kind of natural high polar macromolecules, are the main compounds in decoctions. Many modern studies have shown that the polysaccharide can exhibit rich pharmacological activities after oral intake.
However, the research on the pharmacological mechanism of TCM polysaccharides is seriously backward, and the research and development of polysaccharides related products is not as smooth as expected. One of the biggest obstacles is that traditional pharmacokinetic studies (whether into the blood or not) believe that polysaccharides are not absorbed or very poorly absorbed after oral administration.
Interestingly, our previous data indicated that although Radix Astragali polysaccharide cannot be absorbed into the blood after oral administration, they can be absorbed through intestinal lymph nodes and rapidly activate immune responses. Also, we found that polysaccharides may be transported to the mesenteric lymph nodes, bone marrow and tumor tissue. The discovery of this new pathway provides a new sight into polysaccharide bioavailability.
However, the pharmacokinetic characteristics of polysaccharides and whether it can be transported to other lymphoid tissues is still unclear. Therefore, in this study, we intend to evaluate the absorption kinetics of polysaccharides via intestinal lymphatic system after oral administration. The kinetic characteristics will be obtained using the cell model, small intestine loop experiment and in vivo model. To qualitatively and quantitatively determine the polysaccharides, a combination of chemical analysis and molecular biology analysis will be adopted. The strategy used will be contribute the method development of tracking of intact polysaccharides in vivo and in vitro.
Zhu Peili (Research Assistant Professor)
Polysaccharides are extensively studied for their use as carrier materials and some of the polysaccharides, like Dendrobium officinale polysaccharide (DOP), are reported to have anti-colitis effects. However, the applications of polysaccharides are hindered by technological difficulties, including poor structural characterization, poor quality control and lack of mechanistic understanding. Our preliminary studies showed that DOP cannot be absorbed and digested by the upper gastrointestinal tract and is degraded in the colon. We also confirmed that DOP has anti-colitis effects. More importantly, DOP’s structure has been proved to be beta-D-1,4-mannan and patented quantitative and quality control method for DOP have been established. Considering DOP’s significant potential as the colon targeted carrier and the anti-colitis agent, we propose to combine DOP with 5-aminosalicylic acid (5-ASA) via chemical bond to produce a new biomolecule for ulcerative colitis treatment. This biomolecule would exhibit anti-colitis effects from two aspects: 1) the structure of DOP can be broken down in the colon by colonic microbiota, leading to specific release of 5-ASA in the colon; 2) the degradation products of DOP have anti-colitis effects, which may enhance the anti-colitis effects of 5-ASA. Herein, we hypothesize that the new biomolecule may be a safer and stronger anti-colitis drug. Based on this information, we will 1) determine the colon targeting property of this new biomolecule in vitro and in vivo; 2) evaluate whether the new biomolecule is superior to 5-ASA in alleviating UC and investigate the mechanism underlying the anti-colitis effects of the new biomolecule.
