Discovery of a sugar-based nanoparticle universally existing in boiling herbal water extracts and their immunostimulant effect

Abstract

Herbal medicine is mainly prepared from boiling herbal water extracts. Many epoch-making immunosuppressant drugs, such as glycyrrhizic acid (old example) and FTY720 (current example), were developed from herbal secondary metabolites in the boiling water extract by partition with organic solvents. However, few immunostimulants have been discovered by this method. Instead of the usual method, we aimed to find a novel immunostimulant component by two unique methods in the research of herbal medicine: ultracentrifugation and electron microscopy. The immunostimulant was not a secondary metabolite, as expected, but the structure was a nanoparticle formed by a polysaccharide. In addition, we clarified the immune effect of the nanoparticle. Intake of the nanoparticle by phagocytosis resulted in immunostimulant effects by increasing the genes and proteins of inflammatory cytokines in macrophage cells. The immunostimulant effects were inhibited by a phagocytosis inhibitor, cytochalasin D. To the best of our knowledge, this study is the first to describe the discovery of a nanoparticle in boiling herbal water extracts and its immunostimulant properties. This study will provide additional understanding of the efficacy of herbal medicine, in that the immunostimulant nanoparticle universally exists in boiling herbal water extracts. Thus, traditional herbal medicine may be an oldest known nanomedicine. Furthermore, this study suggests that the immunostimulant nanoparticle simply can be obtained from herbal medicine only by ultracentrifugation. We hope that this simple strategy will substantially contribute to drug development, including vaccine adjuvant, in the future.

Immunostimulatory effects of cell wall‑based nanoparticles in boiled Glycyrrhizae radix water extracts involves TLR4

“…In our previous study, it was demonstrated that nanoparticles obtained from boiled Glycyrrhizae radix water extracts where composed of the cell wall components arabinogalactan and cellulose, suggesting that they are a semi-artificial assembled form of plant cell wall degradants (3). The typical TLR4 ligands of PAMPs are cell wall components of bacteria (lipopolysaccharide) and fungi (mannan), which may provide insight into the immunological function of nanoparticles as TLR4 ligands (18,19).…”

“…However, limited information is currently available regarding the immunostimulant components of these herbal medicines. In our previous, it was demonstrated using electron microscopy that cell wall-based nanoparticles were universally present in boiled water herbal extracts and these nanoparticles were isolated using ultracentrifugation (3). In the present study, the immune effects of cell wall-based nanoparticles isolated from boiled Glycyrrhizae radix, the root and stolon of Glycyrrhiza uralensis Fischer (4) water extracts were primarily investigated, as this is a commonly used herb in traditional herbal medicines (5).…”

“…In the present study, the immune effects of cell wall-based nanoparticles isolated from boiled Glycyrrhizae radix, the root and stolon of Glycyrrhiza uralensis Fischer (4) water extracts were primarily investigated, as this is a commonly used herb in traditional herbal medicines (5). The isolated nanoparticles are taken up by mouse macrophages (RAW-blue cells) via phagocytosis, triggering immunostimulatory effects and inducing the expression of the inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in RAW-blue cells (3). However, the molecular mechanisms underlying these immunostimulatory effects have not yet been elucidated as these nanoparticles have only recently been discovered.…”

Medicine in motion: Opportunities, challenges and data analytics-based solutions for traditional medicine integration into western medical practice

“…These different delivery modalities will fundamentally change the pharmacodynamic and pharmacokinetics of the compounds. Similarly, formulation with natural excipients or even nano-izing agents ( Iitsuka et al, 2018 ) that are components of the TM may not be replicated with the filling agents, preservatives and other components that are more usually found in nutraceutical formulations for Western markets. Dose amounts may also be significantly altered as they are transposed between cultures, through either lowering to homeopathic amounts or heightening daily doses, based on considerations of lability and stability rather than evidence-based efficacy.…”

“…The function of Glycyrrhiza in this Kampo is to be an adjustment, harmonizing force, or pivot between another seven herbal medicines based on epistemology. Mechanistically, it, in fact, may be an excipient or nano-izing agent ( Iitsuka et al, 2018 ; Zhou et al, 2019 ) and/or broad immunostimulant ( Iitsuka et al, 2018 ). Glycyrrhiza, or the root and stolon (runner) of licorice, is used in 72% of the 294 Kampo formulations.…”