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Photothermal therapy (PTT) is a highly effective anti-tumor method. However, when laser radiation was used to ablate tumors, it usually triggers a series of inflammatory reactions, promoting the further development of tumors and affecting the effect of anti-tumor therapy. Therefore, it is an effective method to improve the anti-tumor effect by suppressing the inflammatory response through the precise targeted delivery of anti-inflammatory drug while realizing the photothermal treatment of tumors. To this end, the redox-responsive linker 3,3'-dithiodipropionic acid was used to bond the classic hydrophobic anti-inflammatory drug 18β-glycyrrhetinic acid (18β-GA) and the hydrophilic fragment methoxy-polyethylene glycol (mPEG-NH2) to obtain redox-responsive amphiphilic polymer PEG-DA-GA in this study. Then, photothermal agent IR-780 was encapsulated to prepare redox-responsive polymer micelle PDG/IR-780 NPs. The PDG/IR-780 NPs exhibited uniform particle size of 80.2 ± 5.3 nm and the polydispersity index (PDI) was 0.215 ± 0.079. All animal experiments followed the ethical requirements formulated by the Ethics Committee of Sichuan University. The results showed that PDG/IR-780 NPs could respond to the abundant glutathione (GSH) in tumor cells to promote the disintegration of nanoparticle and the release of 18β-GA, thus significantly improved the killing efficiency on 4T1 cells, when compared with the non-redox-responsive control PSG/IR-780 NPs. When the concentration of 18β-GA was 50 μg·mL-1, the cell viability of 4T1 cells in the PDG/IR-780 NPs group was only (19.29 ± 1.80) %, which was significantly lower than the result of in PSG/IR-780 NPs group (29.30 ± 1.37) %. The results of frozen sections of tumor tissues showed that the designed PDG NPs can promote the tumor-targeted distribution of drugs compared with the free drug group. Eventually, PDG/IR-780 NPs achieved wonderful anti-tumor efficacy on 4T1 triple-negative breast cancer model, revealing the new possibility of the combined therapy strategy of photothermal and anti-inflammatory therapy.
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OBJECTIVES: The present study aimed at investigating the potential of using 18β-glycyrrhetinic acid against the cariogenic characteristics of Streptococcus mutans UA159. METHODS: The effects of 18β-glycyrrhetinic acid on biofilm formation and acid production were evaluated; the latter are indicators of cariogenicity of S. mutans. Biofilm architecture was also analyzed by scanning electron microscopy (SEM), and changes in gene expression related to biofilm formation were studied by quantitative RT-PCR. RESULTS: Treatment with 18β-glycyrrhetinic acid at a concentration of 20 µg/ml inhibited biofilm formation by 95% in the absence of sucrose and 60% in its presence, reduced acid production by 88.8%, and significantly suppressed the gene expression of comDE, gbpB, gtfC and vicR, which are thought to be involved in the virulence of S. mutans. CONCLUSIONS: These results suggest that 18β-glycyrrhetinic acid could be used as a complementary or alternative agent for preventing dental caries by interfering with the virulence properties of S. mutans without affecting the viability of the bacterial population.
Subject(s)
Biofilms , Dental Caries , Gene Expression , Microscopy, Electron, Scanning , Streptococcus mutans , Streptococcus , Sucrose , VirulenceABSTRACT
Objective: To explore the inhibitory effect of 18β-glycyrrhetinic acid (18β-GA) on the inflammationrelated gastric cancer, and to clarify its mechanism. Methods: A total of 72 K19-Wnt/C2mE transgenic mice with gastric cancer were randomly divided into 18β-GA treatment group (drinking water contain 0.1 % 18β-GA, n-36) and control group (drinking normal water, n-36). After 52 weeks, the incidence of gastric cancer and morphology of gastric mucosa of the mice in two groups were detected. Immunohistochemistry staining was used to detect the histochemistry scores (H-score) of Ki-67, F4/80, ATP4a, KCNE2, pepsinogen C (PGC), Wnt-1, β-catenin, and cyclooxygenase-2 (COX-2) in gastric mucosa epithelial cells of the mice in two groups. Results: The gastric mucosa of the mice in control group showed protruded lesions, atypical hyperplasia and chronic gastritis. Compared with control group, the incidence (P-0. 019) and the volume of gastric cancer of the mice in 18β-GA treatment group were significantly decreased (P<0. 01); the structural heterozygosities of gastric cells and tissue were decreased, and the inflammation reactions of the mice in 18β-GA treatment group were alleviated. Compared with control group, the H-scores of Ki-67, F4/80, Wnt-1, β-catenin, and COX-2 in gastric mucosa epithelial cells of the mice in 18β-GA treatment group were decreased (P<0.05), and the H-scores of ATP4a, KCNE2, and PGC were increased (P<0. 05). Conclusion: 18β-GA can significantly inhibit the occurrence of gastric cancer in the K19-Wnt/C2mE transgenic mice. The inhibitory effect may be related to alleviating the inflammation reaction and promoting the differentiation of gastric mucosa epithelial cells and inhibiting the occurrence of gastric cancer.
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OBJECTIVES: To assess the absorption of α-tocopherol acetate and 18β-glycyrrhetinic acid, which are used as active ingredients in toothpaste, into a reconstructed gingival tissue. METHODS: EpiGingival™ tissues were treated with a 25% slurry of toothpaste containing 2% α-tocopherol acetate and 0.3% 18β-glycyrrhetinic acid, for 2 minutes. The treatment was repeated up to 6 times, with 1 hour intervals. After completion of all treatments, the active ingredients in the tissue extracts and receiver solutions were measured by high performance liquid chromatography. RESULTS: Although α-tocopherol acetate was not detected, α-tocopherol was detected in the tissue extracts, indicating that α-tocopherol acetate was bioconverted to α-tocopherol after absorption. We could detect 18β-glycyrrhetinic acid both in the tissue extracts and in the receiver solutions, with a positive correlation to the number of treatments. CONCLUSIONS: We found that our toothpaste effectively delivered α-tocopherol acetate and 18β-glycyrrhetinic acid to a reconstructed gingival tissue in vitro.
Subject(s)
Absorption , Chromatography, Liquid , In Vitro Techniques , Periodontal Diseases , Tissue Extracts , ToothpastesABSTRACT
Objective To observe the ultrastructure changes of nasal mucosa cilia in rat models of allergic rhinitis (AR), and the effect of 18β-glycyrrhetinic acid on the pathological changes of nasal mucosa cilia. Methods Totally 96 Wistar rats were randomly divided into 4 groups: normal control group, AR model group, loratadine treatment group and glycyrrhetinic acid treatment group.AR models were established by ovalbumin-induction, and then each group was administered with corresponding treatments. At 2 weeks, 4 weeks, 6 weeks, and 10 weeks after treatment, the behavioral changes were compared between different groups and the ultrastructure changes of nasal mucosa cilia were observed under scanning electron microscope and transmission electron microscope in each group. Results Model group developed typical AR symptoms: the cilia in the top layer of the nasal mucosa were disordered, lodging, matted together and some were even lost; the cilia membrane was broken, and the microtubules of cilia were reduced or disappeared; furthermore, small and abnormal cilia were observed, while mucous blanket on the top of cilia was thickened and contained neutrophils, monocytes, eosinophils and other inflammatory cells; and with persistent allergen exposure, the morphological changes of the nasal mucosa cilia aggravated gradually. While in both glycyrrhetinic acid treatment group and loratadine treatment group, the AR symptoms were relieved gradually, and the morphological damages of nasal mucosa were gradually recovered: the cilia were well arranged with the density similar to that of normal group, and small cilia were reduced and the thickened mucous blanket on the top of cilia disappeared. Conclusion Persistent exposure to allergen can lead to progressive ultrastructure damages to nasal mucosa cilia in rat AR model, and 18β-glycyrrhetinic acid can, to some extent, relieve or even reverse the ultrastructure changes of nasal mucosa cilia.
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OBJECTIVE: To explore the regulation of 18β-glycyrrhetinic acid on apoptosis of human acute leukemia U937 cell through Wnt/β-catenin signal.
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OBJECTIVE: The aim of our work was to study the effects of C-18 epimers of glycyrrhetinic acid, 18α-glycyrrhetinic acid (α-GA) and 18β-glycyrrhetinic acid (β-GA) on the function and expression of P-gp in Caco-2 cell monolayers. METHODS: Caco-2 cells were cultured, the effects of P-gp function were analyzed by means of rhodamine accumulation test, real-time PCR was used to measure the expression of MDR1 mRNA and western blot was used to analysis P-gp expression in Caco-2 cell. RESULTS: In the rhodamine accumulation test, middle and high concentrations (1 and 10 μmol · L-1) α-GA and high concentration (10 μmol · L-1) β-GA decreased the cellular rhodamine concentration. At high concentrations (10 μmol · L-1), α-GA up-regulated the expression of MDR1 mRNA while β-GA has no effect on the expression of MDR1 mRNA at three test concentrations. α-GA up-regulated the expression of P-gp protein at high concentrations (10 μmol · L-1) while β-GA has no effect on the expression of P-gp protein at three test concentrations. CONCLUSION: Our findings provide experimental evidence that α-GA up-regulated both function and expression of P-gp while β-GA only up-regulate the function of P-gp.
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OBJECTIVE: To study the effects of C-18 epimers of glycyrrhetinic acid, 18α-glycyrrhetinic acid(α-GA) and 18β-glycyrrhetinic acid(β-GA), on membrane transport of P-gp substrate rhodamine 123 in Caco-2 cell monolayers. METHODS: MTT assay was applied to determine the maximum non-cytotoxic dose of α-GA, β-GA and verapamil to ensure the activity of the cells during the test and to consult the maximum test concentration of each drug; appropriate Caco-2 monolayers were established in Transwell™ plates. ELISA Reader was applied to detect the concentration of Rho-123 in transfer fluid. The bi-directional transport of Rho-123 after being treated by instantaneous action and incubation with α-GA and β-GA for 72 h was studied. RESULTS: High concentration (10 μmol · L-1) of α-GA induced the efflux of Rho-123 both in the instantaneous action test and the incubation test. High concentration (10 μmol · L-1) of β-GA induced the efflux of Rho-123 only in the incubation test. The transport from AP to BL was not affected by any test drugs. CONCLUSION: The results of the transport experiments of P-gp substrates in Caco-2 monolayers indicated that α-GA and β-GA can induce the efflux function of P-gp and accelerate the excretion of P-gp substrates. It may be one of the mechanisms of that glycyrrhizin preparation enhances liver detoxification. Copyright 2012 by the Chinese Pharmaceutical Association.