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Diammonium Glycyrrhizinate-Based Micelles for Improving the Hepatoprotective Effect of Baicalin: Characterization and Biopharmaceutical Study.

ABSTRACT: Saponins are an important class of surface-active substances. When formulated as an active ingredient or co-used with other drugs, the effect of their surface activity on efficacy or safety must be considered. In this paper, diammonium glycyrrhizinate (DG), a clinical hepatoprotective drug that has long been used as a biosurfactant, was taken as the research object to study its combined hepatoprotective effect with baicalin (BAI). Animal experiments proved that the preparation of DG and BAI integrated into micelles (BAI-DG Ms) had a better protective effect on acute liver injury caused by carbon tetrachloride than the direct combined use of the two. From the perspective of biopharmaceutics, the synergistic mechanism of BAI-DG Ms was further explored. The results showed that after forming BAI-DG Ms with DG, the solubility of BAI increased by 4.75 to 6.25 times, and the cumulative percentage release in the gastrointestinal tract also increased by 2.42 times. In addition, the negatively charged BAI-DG Ms were more likely to penetrate the mucus layer and be absorbed by endocytosis. These findings provide support for the rational application of glycyrrhizin, and other saponins.

SUBMITTER: Dai X

PROVIDER: S-EPMC9864020 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Diammonium Glycyrrhizinate-Based Micelles for Improving the Hepatoprotective Effect of Baicalin: Characterization and Biopharmaceutical Study.

Dai Xingxing X Liao Yuyao Y Yang Cuiting C Zhang Yingying Y Feng Minfang M Tian Yuting Y Qu Qingsong Q Sheng Mengke M Li Zhixun Z Peng Xinhui X Cen Shuai S Shi Xinyuan X

Pharmaceutics 20221230 1

Saponins are an important class of surface-active substances. When formulated as an active ingredient or co-used with other drugs, the effect of their surface activity on efficacy or safety must be considered. In this paper, diammonium glycyrrhizinate (DG), a clinical hepatoprotective drug that has long been used as a biosurfactant, was taken as the research object to study its combined hepatoprotective effect with baicalin (BAI). Animal experiments proved that the preparation of DG and BAI inte ...[more]

PMID: 36678754

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Project description:The enantiomers of chiral drugs often have different potencies, toxicities, and biochemical properties. Therefore, the FDA and other worldwide regulatory agencies require manufactures to test and prove the enantiomeric purity of chiral drugs. Amino acid based molecular micelles (AABMM) have been used in chiral CE separations since the 1990's because of their low environmental impact and because their properties can easily be tuned by changing the amino acids in the chiral surfactant headgroups. Using molecular dynamics simulations to investigate the structures and properties of AABMM is part of an ongoing study focusing on investigating and elucidating the factors responsible for chiral recognition with AABMM. The results will be useful for the proper design and selection of more efficient chiral selectors. The micelles investigated contained approximately twenty covalently linked surfactant monomers. Each monomer was in turn composed of an undecyl hydrocarbon chain bound to a dipeptide headgroup containing of all combinations of L-Alanine, L-Valine, and L-Leucine. These materials are of interest because they are effective chiral selectors in capillary electrophoresis separations. Molecular dynamics simulation analyses were used to investigate how the sizes and positions of the headgroup amino acid R-groups affected the solvent accessible surface areas of each AABMM chiral center. In addition, headgroup dihedral angle analyses were used to investigate how amino acid R-group size and position affected the overall headgroup conformations. Finally, distance measurements were used to study the structural and conformational flexibilities of each AABMM headgroup. All analyses were performed in the context of a broader study focused on developing structure-based predictive tools to identify the factors responsible for (a) self-assembly, (b) function, (c) higher ordered structure and (d) molecular recognition of these amino acid based molecular micelles.

Project description:Glycyrrhizic acid (GA), a natural compound isolated from licorice (Glycyrrhiza glabra), has exhibited anti-inflammatory and anti-tumor effects in vitro. Dipotassium glycyrrhizinate (DPG), a dipotassium salt of GA, also has shown an anti-tumor effect on glioblastoma cell lines, U87MG and T98G. The study investigated the DPG effects in the melanoma cell line (SK-MEL-28). MTT assay demonstrated that the viability of the cells was significantly decreased in a time- and dose-dependent manner after DPG (IC50 = 36 mM; 24 h). DNA fragmentation suggested that DPG (IC50) induced cellular apoptosis, which was confirmed by a significant number of TUNEL-positive cells (p-value = 0.048) and by PARP-1 [0.55 vs. 1.02 arbitrary units (AUs), p-value = 0.001], BAX (1.91 vs. 1.05 AUs, p-value = 0.09), and BCL-2 (0.51 vs. 1.07 AUs, p-value = 0.0018) mRNA compared to control cells. The proliferation and wound-healing assays showed an anti-proliferative effect on DPG-IC50-treated cells, also indicating an inhibitory effect on cell migration (p-values < 0.001). Moreover, it was observed that DPG promoted a 100% reduction in melanospheres formation (p-value = 0.008). Our previous microRNAs (miRs) global analysis has revealed that DPG might increase miR-4443 and miR-3620 expression levels. Thus, qPCR showed that after DPG treatment, SK-MEL-28 cells presented significantly high miR-4443 (1.77 vs. 1.04 AUs, p-value = 0.02) and miR-3620 (2.30 vs. 1.00 AUs, p-value = 0.01) expression compared to control cells, which are predicted to target the NF-kB, CD209 and TNC genes, respectively. Both genes are responsible for cell attachment and migration, and qPCR revealed significantly decreased CD209 (1.01 vs. 0.54 AUs, p-value = 0.018) and TNC (1.00 vs. 0.31 AUs, p-value = 2.38 × 10-6) mRNA expression levels after DPG compared to untreated cells. Furthermore, the migration of SK-MEL-28 cells stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) was attenuated by adding DPG by wound-healing assay (48 h: p-value = 0.004; 72 h: p-value = 7.0 × 10-4). In addition, the MMP-9 expression level was inhibited by DPG in melanoma cells stimulated by TPA and compared to TPA-treated cells (3.56 vs. 0.99 AUs, p-value = 0.0016) after 24 h of treatment. Our results suggested that DPG has an apoptotic, anti-proliferative, and anti-migratory effect on SK-MEL-28 cells. DPG was also able to inhibit cancer stem-like cells that may cause cerebral tumor formation.

Dataset Information

Diammonium Glycyrrhizinate-Based Micelles for Improving the Hepatoprotective Effect of Baicalin: Characterization and Biopharmaceutical Study.

Publications

Diammonium Glycyrrhizinate-Based Micelles for Improving the Hepatoprotective Effect of Baicalin: Characterization and Biopharmaceutical Study.

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