Disease relevance of enoxolone

• Infection with the Cx37 adenovirus (but not control or other connexin adenoviruses) led to a dose-dependent death of the endothelial cells that was partially antagonized by the gap junction blocker alpha-glycyrrhetinic acid and altered the intercellular transfer of Lucifer yellow and neurobiotin [1].
• Glycyrrhetinic acid (GA), a free radical scavenger, protected gel entrapped hepatocytes from tacrine toxicity, but was ineffective in hepatocyte monolayers [2].

High impact information on enoxolone

• In the presence of GA, there was a shift of the ACTH concentration-response curves in the two culture conditions [3].
• Gap junction blockade with 18 alpha-glycyrrhetinic acid resulted in a loss of coordination between connected cells [4].
• Total inhibition of fluorescent dye transfer between normal and transformed cells by the 3 beta-O-hemisuccinate of 18 alpha-glycyrrhetinic acid (18 alpha-carbenoxolone), an inhibitor of gap-junctional communication in human fibroblasts, did not prevent growth inhibition of transformed cells in the cocultivation assay [5].
• A blockade of junctional communication by 18-beta-glycyrrhetinic acid (betaGA) reduced, in a concentration-dependent manner, the viability of undifferentiated neural progenitor cells [6].
• In parallel experiments, AGA decreased the immunodetection of phosphorylated Cx43 as analyzed by Western blot and inhibited fluorescent dye transfer [7].

Biological context of enoxolone

• The 9L cells exhibited a very good bystander effect, which was completely blocked by a long-term inhibitor of GJIC, 18 alpha-glycyrrhetinic acid [8].
• When the inhibitory activities were examined with intact transfected cells, 11 alpha OH-P was more potent than GA (IC50 = 5 and 150 nM, respectively) [9].
• These data implicate a gap junctional-mediated pathway insensitive to 18-beta-glycyrrhetinic acid in dilating the two arterioles upstream of the capillary module during "remote" muscle contraction [10].
• Last, our data indicate that the closure of gap junctions by the decoupling agent alpha-glycyrrhetinic acid increases cell apoptosis and inhibits hESC colony growth [11].
• An unexpected observation was the apparent lack of any effect of inhibiting GJIC by exposure to AGA on blastocyst formation and cell number allocation in the two principal stem cell lineages of the preimplantation mammalian embryo, trophectoderm and inner cell mass [12].

Anatomical context of enoxolone

• Our results show that alpha-glycyrrhetinic acid and endothelin-1 increase the uptake of glucose in highly, but not in poorly, coupled astrocytes [13].
• The exchange of dye between lymphocytes was inhibited by a connexin extracellular loop mimetic peptide and alpha-glycyrrhetinic acid, two reagents that restrict intercellular communication across gap junctions [14].
• Our work shows that apoptosis induction in granulosa cells is accompanied by an increased level of cell coupling and that decreasing cell coupling with the gap junction blocker alpha-glycyrrhetinic acid dose-dependently inhibits apoptosis [15].
• Using a Ca(2+)-sensitive electrode and Western blot, we showed that the gap junction inhibitors 18-beta-glycyrrhetinic acid (beta-GA), oleamide, and heptanol all induced concomitant release of Ca(2+) and cytochrome C in isolated mitochondria whereas the inactive analog 18-beta-glycyrrhizic acid failed to do so [16].
• In the present study we employed the gap junctional blocker 18-beta-glycyrrhetinic acid (BGA) to reduce electrical cell-to-cell coupling in confluent primary cultures of rat hepatocytes [17].

Associations of enoxolone with other chemical compounds

• 11 alpha-Hydroxyprogesterone (11 alpha OH-P) was an order of magnitude more potent a competitive inhibitor of the 11 beta HSD-2 than was glycyrrhetinic acid (GA) (approximate IC50 = 0.9 vs. 15 nM) [9].
• 11 beta OH-P, progesterone, and GA were almost equipotent (IC50 = 10 and 6 nM, respectively), and 5 alpha-pregnandione and 5 beta-pregnandione were less potent (IC50 = 100 and 500 nM, respectively) inhibitors of the enzyme [9].
• In both preparations, we observed that bath application of gap-junction blockers, including 18 alpha-glycyrrhetinic acid, 18 beta-glycyrrhetinic acid, and carbenoxolone, all caused a reduction in respiratory frequency [18].
• Results indicate that these connexon-mediated interliposomal channels are functional and are inhibited by the addition of alpha-glycyrrhetinic acid and by flufenamic acid, two gap junction communication inhibitors [19].
• 18 alpha-Glycyrrhetinic acid (10(-5) M), a putative gap junction uncoupler, significantly reduced acetylcholine-induced relaxations by 50% in both proximal and distal vessels [20].

Gene context of enoxolone

• Moreover, AGA-exposed cells showed a dose-dependent decrease in AP activity and a delay in the appearance of BN [21].
• Treatment with AGA, but not with an inactive analog, reversed the PTH-induced ECM mineralization [22].
• In contrast, 18-beta-glycyrrhetinic acid and competitive 5-lipoxygenase inhibitors (e.g., ZM-230,487 and L-739,010) did not affect labeling [23].
• Blockage of the RA + Tx-induced GJIC with 18-beta-glycyrrhetinic acid (beta-Gly) prevented in 34% the inhibition of MCF-7 proliferation and the E-cadherin increment in 30% at 96 h of culture [24].
• Since these substances mimic two known inhibitory activities of GA, they have been named 'Glycyrrhetic Acid-Like Factors', abbreviated as 'GALFs' or, more specifically 11 beta-GALF for substance(s) active against 11 beta-OHSD, and 5 beta-GALF for those inhibitory to 5 beta-SR [25].

Analytical, diagnostic and therapeutic context of enoxolone

• Determination of 18 beta-glycyrrhetic acid in human plasma by high-performance liquid chromatography [26].
• The method was applied to the determination of 18 beta-glycyrrhetic acid in plasma after oral administration of a herbal medicine containing 18 beta-glycyrrhitic acid in human volunteers [26].
• A feasible and reliable method which allows the simultaneous analysis of 1 and its aglycone, 18beta-glycyrrhetic acid (2), by means of an isocratic HPLC procedure is described [27].

References