Glycyrrhetinic acid is a major active ingredient in licorice, a famous traditional Chinese medicine. Many studies on its anti-tumor activities and low toxicity to normal cells have attracted a great deal of attention. Reports indicated that glycyrrhetinic acid inhibited the growth of tumor cells through inducing apoptosis, differentiation and the block of cell cycle, suppressing tumor metastasis, reversing the multidrug resistance. Glycyrrhetinic acid also presented synergistic effects combined with chemotherapeutics and could inhibit the carcinogenesis induced by carcinogen. With further studies on mechanism of anticancer actions, glycyrrhetinic acid is being expected to have a good prospect of development and application for cancer therapy.
Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Glycyrrhetinic Acid ; pharmacology ; Humans ; Neoplasm Invasiveness

The 3-succinate-30-stearyl glycyrrhetinic acid(18-GA-Suc) was inserted into glycyrrhetinic acid(GA)-tanshinone Ⅱ_A(TSN)-salvianolic acid B(Sal B) liposome(GTS-lip) to prepare liver targeting compound liposome(Suc-GTS-lip) mediated by GA receptors. Next, pharmacokinetics and tissue distribution of Suc-GTS-lip and GTS-lip were compared by UPLC, and in vivo imaging tracking of Suc-GTS-lip was conducted. The authors investigated the effect of Suc-GTS-lip on the proliferation inhibition of hepatic stellate cells(HSC) and explored their molecular mechanism of improving liver fibrosis. Pharmacokinetic results showed that the AUC_(Sal B) decreased from(636.06±27.73) μg·h·mL~(-1) to(550.39±12.34) μg·h·mL~(-1), and the AUC_(TSN) decreased from(1.08±0.72) μg·h·mL~(-1) to(0.65±0.04) μg·h·mL~(-1), but the AUC_(GA) increased from(43.64±3.10) μg·h·mL~(-1) to(96.21±3.75) μg·h·mL~(-1). The results of tissue distribution showed that the AUC_(Sal B) and C_(max) of Sal B in the liver of the Suc-GTS-lip group were 10.21 and 4.44 times those of the GTS-lip group, respectively. The liver targeting efficiency of Sal B, TSN, and GA in the Suc-GTS-lip group was 40.66%, 3.06%, and 22.08%, respectively. In vivo imaging studies showed that the modified liposomes tended to accumulate in the liver. MTT results showed that Suc-GTS-lip could significantly inhibit the proliferation of HSC, and RT-PCR results showed that the expression of MMP-1 was significantly increased in all groups, but that of TIMP-1 and TIMP-2 was significantly decreased. The mRNA expressions of collagen-I and collagen-Ⅲ were significantly decreased in all groups. The experimental results showed that Suc-GTS-lip had liver targeting, and it could inhibit the proliferation of HSC and induce their apoptosis, which provided the experimental basis for the targeted treatment of liver fibrosis by Suc-GTS-lip.
Humans ; Liposomes ; Hepatic Stellate Cells ; Glycyrrhetinic Acid/pharmacology* ; Liver ; Liver Cirrhosis/genetics* ; Collagen/pharmacology*

OBJECTIVETo determine glycyrrhetinic acid concentration in rat plasma and concentration of calcium (Ca), copper (Cu), iron (Fe), potassium (K), magnesium (Mg) and sodium (Na) in rat serum after oral administration by LC-MS/MS and the flame atomic absorption method, and analyze the effect of glycyrrhetinic acid on the six elements in serum.

RESULTA similar variation trend between the concentration of glycyrrhetinic acid in plasma and that of Na, Cu elements in serum after oral administration of glycyrrhetinic acid was observed. Glycyrrhetinic acid in plasma at 2 h after administration reached the peak. Meanwhile, the concentration of Na and Cu at 4 h after the administration of glycyrrhetinic acid exhibited a significant increase (P < 0.05). Moreover, an increasing glycyrrhetinic acid dosage could result in the accumulation of Cu and Na in rat serum. Compared with the control group, the concentration of Cu and Na in the the glycyrrhetinic acid administration group with doses of 200 and 400 mg x kg(-1) revealed a significant increase (P < 0.05). However, glycyrrhetinic acid did not exhibit the great impact on the concentration of other elements in serum.

CONCLUSIONThis study focuses on the effect of oral administration of glycyrrhetinic acid on six metal elements in rat serum and provides an experimental basis for the adverse effect of glycyrrhetinic acid in clinical-applications.

Administration, Oral ; Animals ; Female ; Glycyrrhetinic Acid ; administration & dosage ; pharmacology ; Male ; Metals ; blood ; Rats ; Rats, Sprague-Dawley

Cell Line, Tumor ; Cell Proliferation ; Colorectal Neoplasms ; Glycyrrhetinic Acid/pharmacology* ; Humans

Chemical modification was performed for improving the antioxidant activity of lead compound glycyrrhetinic acid (Ib). Two conjugated diene derivatives were prepared by reduction and dehydration reactions. Their in vitro antioxidant activities were studied using a cytochrome P450/NADPH reductase system from rat liver microsomes. The generation of microsomal free radicals was followed by oxidation of the DCFH-DA probe, while evaluating the capacity to inhibit reactive oxygen species (ROS) formation. The initial result showed that the two homo- and heterocyclic diene derivatives--18beta-olean-11,13(18)-diene-3beta, 30-diol (IV) and 18beta-olean-9 (11), 12-diene-3beta, 30-diol (V) exhibited strong antioxidant activities, at a concentration of 1.0 mg x mL(-1), they inhibited free radical (ROS) formation by 45% and 41%, respectively. In the same conditions, the lead compound (Ib) and the reference vitamin E inhibited ROS activity by 31% and 32%. Our results suggest that the elimination of the 11-keto group and the chemical reduction of 30-carboxylic group into hydroxyl function can increase the antioxidant activity of Ib significantly.
Animals ; Antioxidants ; chemical synthesis ; pharmacology ; Glycyrrhetinic Acid ; analogs & derivatives ; Male ; Microsomes, Liver ; metabolism ; Rats ; Reactive Oxygen Species ; metabolism ; Triterpenes ; chemical synthesis ; pharmacology

This study was aimed to explore the expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in 3 different lymphoblastic cell lines with relation to their glucocorticoid (GC) sensitivity. The 11β-HSD2 expressions in acute lymphoblastic leukemia Jurkat cells, lymphoma Daudi and Raji cells, and peripheral blood T cells of a healthy volunteer were analyzed by real time PCR and Western blot. Glucocorticoid (GC)-induced apoptosis in 3 different cell lines was detected by flow cytometry. Cell growth in Jurkat cells treated with cortisol was analyzed by trypan blue dye exclusion. Flow cytometry was performed to observe GC-induced apoptosis in Jurkat cells treated by combination of GC with 11β-HSD2 inhibition 18β-glycyrrhetinic acid (18β-GA). The results demonstrated that 11β-HSD2 highly expressed in Jurkat cells, but not in Daudi, Raji cells and normal blood T cells. Compared to Daudi and Raji cells, Jurkat cells were more resistant to GC-induced apoptosis. Furthermore, the inhibition of 11β-HSD2 by 18β-GA resulted in increased cellular sensitivity to GC as shown by elevated induction of apoptosis. it is concluded that 11β-HSD2 is at least partly responsible for GC resistance in Jurkat cells. 11β-HSD2 may be a potential target for reduction of GC-resistance in therapeutic applications.
11-beta-Hydroxysteroid Dehydrogenase Type 2 ; metabolism ; Cell Line, Tumor ; Glucocorticoids ; pharmacology ; Glycyrrhetinic Acid ; analogs & derivatives ; pharmacology ; Humans ; Jurkat Cells ; Lymphocytes ; drug effects ; metabolism

OBJECTIVE: To investigate 18β-sodium glycyrrhetinic acid impact on nasal mucosa epithelial cilia in rat models of allergic rhinitis (AR). METHOD: AR models were established by ovalbumin-induction. Wister rats were randomly divided into groups as normal group, model group, budesonide (0.2 mg/kg) group and sodium glycyrrhetinic acid (20 mg/kg and 40 mg/kg) group after the success of AR models. At 2 weeks and 4 weeks after treatment, the behavioral changes of rats were observed and recorded, and nasal septum mucosae were collected after 2 week and 4 week intervention, and the morphological changes of nasal mucosae were observed by electron microscope. RESULT: Model group developed typical AR symptoms, the total score in all animals was > 5. With budesonide and sodium glycyrrhetinic acid treatment, the AR symptoms were relieved, and the total scores were reduced significantly (P < 0.01). Compared with the model group: after 2 weeks' intervention, thick mucous secretions on the top of columnar epithelium cilia in rat nasal mucosa was significantly reduced, and cilia adhesion, lodging, shedding were relieved in budesonide group and sodium glycyrrhetinic acid group, the relieve in budesonide group was slightly better than that in sodium glycyrrhetinic acid group; after 4 week intervention, Cilia adhesion, lodging, shedding were completely vanished, and the cilia were ranged in regular direction in budesonide group and sodium glycyrrhetinic acid group. Cilia in sodium glycyrrhetinic acid (20 mg/kg) group was more orderly, smooth than that in budesonide group and sodium glycyrrhetinic acid group (40 mg/kg), and the condition of cilia in sodium glycyrrhetinic acid group (20 mg/kg) was similar to the normal group. CONCLUSION 18β-sodium glycyrrhetinic acid is effective to restrain the pathological changes of nasal mucosa cilia in rat models of AR.
Animals ; Budesonide ; pharmacology ; Cilia ; drug effects ; Disease Models, Animal ; Glycyrrhetinic Acid ; analogs & derivatives ; pharmacology ; Nasal Mucosa ; drug effects ; Ovalbumin ; Random Allocation ; Rats ; Rhinitis, Allergic ; drug therapy

The aim of the present study is to investigate the effect of 18β-glycyrrhetinic acid (18β-GA) on KCl- and PE-induced constriction of rat renal interlobar artery (RIA). Pressure myograph system was used to observe the constriction induced by KCl and PE (endothelial independent vasoconstrictor) in acutely separated RIA of Wistar rats with or without 18β-GA pretreatment. Whole-cell patch clamp recordings were used to observe the effect of 18β-GA on membrane input capacitance (C(input)), membrane input conductance (G(input)) or membrane input resistance (R(input)) of smooth muscle cells embedded in arteriole segment. The results showed that both KCl (30-100 mmol/L) and PE (0.1-30 μmol/L) induced contraction of RIA in a concentration-dependent way. After pretreatment with 18β-GA (100 μmol/L), KCl- or PE-induced constriction of RIA was significantly decreased. After application of 18β-GA (100 μmol/L), the C(input), G(input) and R(input) of the in situ smooth muscle cells were very close to those of dispersed single smooth muscle cells. These results suggest 18β-GA inhibits the contraction induced by KCl and PE, and the underlying mechanism may involve the inhibitory effect of 18β-GA on gap junction.
Animals ; Arteries ; drug effects ; physiopathology ; Constriction ; Gap Junctions ; Glycyrrhetinic Acid ; analogs & derivatives ; pharmacology ; In Vitro Techniques ; Myocytes, Smooth Muscle ; cytology ; Patch-Clamp Techniques ; Rats ; Rats, Wistar

OBJECTIVETo study the effect of glycyrrhetinic acid (GA) on the invasive capacity of leukemic cells and the activity of intracellular gelatinase.

METHODSThe effect of GA, in different concentrations, on the proliferation of cultured K562 and HL-60 leukemic cells in vitro was determined by MTT assay; that on cell invasive capacity was tested by Transwell cubicle matrigel invasion assay; and that on the activity of gelatinase in cells was detected by gelatin zymography.

RESULTSGA showed significant inhibitory effect on the proliferation of K562 and HL-60 leukemic cells; it inhibited the invasive capacity of cells in concentration-dependent manner; and significantly down-regulated the activity of gelatinase A and B in cells.

CONCLUSIONSGA can inhibit invasive capacity of K562 and HL-60 leukemia cells by way of suppressing the activity of gelatinase A and B. This study provides an experimental evidence for preventing extra-medullary infiltration of leukemic cells.

Cell Proliferation ; drug effects ; Down-Regulation ; Gelatinases ; metabolism ; Glycyrrhetinic Acid ; pharmacology ; HL-60 Cells ; Humans ; K562 Cells ; Leukemia ; drug therapy ; enzymology ; pathology ; physiopathology ; Neoplasm Invasiveness

OBJECTIVETo study the effects of glycyrrhetinic acid (GA) on the sodium ion channel currents (I(Na)) of rats' ventricular myocardial cells, and to explore its anti-arrhythmic mechanisms at the ion channel level.

METHODSSingle ventricular myocardial cells was isolated from SD rats. The whole cell patch clamp was used to record the effects of GA on I(Na) of rats' ventricular myocardial cells.

RESULTSGA could inhibit I(Na) of rats' ventricular myocardial cells dose-dependently. GA at 1, 5, and 10 micromol/L decreased I(Na) of rats' ventricular myocardial cells from (-4.26 +/- 0.15) nA to (-3.54 +/- 0.10) nA, (-2.19 +/- 0.09) nA, and (-1.25 +/- 0.08) nA, respectively. GA at 1, 5, and 10 micromol/L inhibited I(Na) by 16.08% +/- 2.3%, 50.82% +/- 3.56%, and 75.98% +/- 5.12%, showing statistical difference when compared with the control group (P < 0.05). GA at 10 micromol/L shifted I(Na) current-voltage curve more positively, but the activation potential and the peak potential were not changed.

CONCLUSIONGA inhibited the I(Na) of rats' ventricular myocardial cells dose-dependently, which was possibly associated with its antiarrhythmia effects.

Animals ; Glycyrrhetinic Acid ; pharmacology ; Heart Ventricles ; cytology ; metabolism ; Male ; Myocytes, Cardiac ; drug effects ; physiology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Sodium Channels ; drug effects ; physiology