Glycyrrhizin (GL) is known to have various immunomodulating activities and has long been used clinically as an anti-allergic and anti-hepatitis agent. While the potency of GL against lung inflammatory diseases has been expected, the effect of GL on the lung has been poorly understood. Lung fibroblasts are known as a potent producer of inflammatory chemokines, IL-8 and eotaxin 1, by which neutrophils and eosinophils are strongly attracted during inflammation. Therefore, we studied the effects of GL on the production of these chemokines using a human fetal lung fibroblast cell line, HFL-1, stimulated with TNF-alpha and IL-4. Moreover, we examined the structure-activity relationships of GL to explore more beneficial compounds. 18alpha,beta-GL inhibited IL-8 dose-dependently and inhibited eotaxin 1 slightly. 18alpha,beta-Glycyrrhetic acid (GA) did not inhibit IL-8 but inhibited eotaxin 1. The effect of 18alpha,beta-glycyrrhetic acid monoglucuronide (MGA) resembled that of 18alpha,beta-GL but was weaker. Both 3beta-[(2-O-beta-D-glucopyranuronosyl-beta-D-glucopyranuronosyl)oxy]-18beta-11-deoxo-olean-12-en-30-oic acid (11-deoxo-GL) and 3beta-[(2-O-beta-D-glucopyranuronosyl-beta-D-glucopyranuronosyl)oxy]-olean-11,13,(18)-dien-30-oic acid (hetero-GL) exhibited inhibitory activity with significant cytotoxicity. 3beta-[(2-O-beta-D-Glucopyranuronosyl-beta-D-glucopyranuronosyl)oxy]-18beta-olean-9,12-dien-30-oic acid (homo-GL) did not have cytotoxicity but its activity was mild like that of 18alpha,beta-GL. 3beta-[(2-O-beta-d-Glucopyranuronosyl-beta-D-glucopyranuronosyl)oxy]-olean-11,13(18)-dien-30-ol (hetero-30-OH-GL) and 3beta-[(2-O-beta-D-glucopyranuronosyl-beta-D-glucopyranuronosyl)oxy]-18beta-olean-9,12-dien-30-ol (homo-30-OH-GL) showed potent inhibitory effects, at concentrations lower than 18alpha,beta-GL with no significant cytotoxicity. These results suggest that GL-related compounds are effective in reducing chemokine production and that GL-modified compounds including hetero-30-OH-GL and homo-30-OH-GL appear most beneficial in view of their inhibitory capacity with less cytotoxicity.
Chemically modified compounds of glycyrrhizin have been synthesized and evaluated for their inhibitory effect on the replication of human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1). Among them, the 11-deoxo compound having a heteroannular diene structure at the C and D rings proved as active against HIV-1 as glycyrrhizin in MT-4 and MOLT-4 cells. It completely inhibited HIV-1-induced cytopathogenicity in both cell lines at a concentration of 0.16 mM. The compound was also effective against HSV-1 with a 50% inhibitory concentration of 0.5 mM [corrected].
Where ongoing gallbladder drainage is required, conversion from PTGBD to EUS-GBD is a feasible, effective, and safe technique for patients who cannot undergo cholecystectomy.
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