Licorice flavonoid ameliorates ethanol-induced gastric ulcer in rats by suppressing apoptosis via PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is the dry roots and rhizomes of Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L. and Glycyrrhiza inflata Bat., which was first recorded in Shengnong's herbal classic. Licorice flavonoid (LF) is the main compound isolated from licorice with an indispensable action in treating gastric ulcer (GU). However, the underlying mechanisms need to be further explored. AIM OF THE STUDY: This study aimed to investigate and further elucidate the mechanisms of LF against ethanol-induced GU using an integrated approach. MATERIALS AND METHODS: The anti-GU effects of LF were evaluated in an ethanol-induced gastric injury rat model. Then, the metabolomics approach was applied to explore the specific metabolites and metabolic pathways. Next, the network pharmacology combined with metabolomics strategy was employed to predict the targets and pathways of LF for GU. Finally, these predictions were validated by molecular docking, RT-qPCR, and western blotting. RESULTS: LF had a positive impact on gastric injury and regulated the expression of GU-related factors. Upon serum metabolomics analysis, 25 metabolic biomarkers of LF in GU treatment were identified, which were primarily involved in amino acid metabolism, carbohydrate metabolism, and other related processes. Subsequently, a "components-targets-metabolites" network was constructed, revealing six key targets (HSP90AA1, AKT1, MAPK1, EGFR, ESR1, PIK3CA) that may be associated with GU treatment. More importantly, KEGG analysis highlighted the importance of the PI3K/AKT pathway including key targets, as a critical route through which LF exerted its anti-GU effects. Molecular docking analyses confirmed that the core components of LF exhibited a strong affinity for key targets. Furthermore, RT-qPCR and western blotting results indicated that LF could reverse the expression of these targets, activate the PI3K/AKT pathway, and ultimately reduce apoptosis. CONCLUSION: LF exerted a gastroprotective effect against gastric ulcer induced by ethanol, and the therapeutic mechanism may involve improving metabolism and suppressing apoptosis through the PI3K-AKT pathway.

Exploration of formation and in vitro release mechanism of supramolecular self-assembled Licochalcone A eutectogel for food application.

Licochalcone A (LCA) is extracted from licorice plants and used as a food additive. Citric acid (CA) and alanine (Ala) are food additives with good regulatory functions. This study aims to investigate the formation and in vitro release mechanism of the LCA eutectogel using supramolecular self-assembly technology. The mechanism of self-assembly indicates that the resulting eutectogel has strong intermolecular interactions. The formation mechanism of LCA eutectogel suggests that LCA is dispersed in nano form in the DES solution before self-assembly and dispersed in molecular form in the eutectogel after self-assembly. Mesoscopic MD simulation studies indicate that the interaction energy between LCA Ala-CA(5:5) eutectogel and the solvent interface is relatively low, suggesting it may have a better drug release rate, consistent with the in vitro release results. In conclusion, the study successfully prepares LCA eutectogel and provides theoretical guidance for the development and application of novel eutectogel for food application.

Licorice flavonoid alleviates gastric ulcers by producing changes in gut microbiota and promoting mucus cell regeneration.

Licorice flavonoid (LF) is the main component of Glycyrrhizae Radix et Rhizoma, a "medicine food homology" herbal medicine, which has anti-digestive ulcer activity, but the mechanism in anti-gastric ulcer (GU) remains to be elucidated. In this study, we manifested that LF increased the viability of human gastric mucosal epithelial (GES-1) cells, attenuated ethanol (EtOH)-induced manifestations, reduced histological injury, suppressed inflammation, and restored gastric mucosal barrier in GU rats. After LF therapy, the EtOH-induced gut dysbiosis was partly modulated, and short-chain fatty acids (SCFAs) like butyric acid, propionic acid, and valeric acid were found in higher concentrations. We discovered that the majority of genera that increased in the GU group had a negative correlation with SCFAs in the intestinal tract. In addition, LF-upregulated SCFAs boosted mucus secretion in the gastric epithelium and the expression of mucoprotein (MUC) 5AC and MUC6, particularly the MUC5AC in the gastric foveola. Moreover, LF triggered the EGFR/ERK signal pathway which promoted gastric mucus cell regeneration. Therefore, the findings indicated that LF could inhibit inflammation, promote mucosal barrier repair and angiogenesis, regulate gut microbiota and SCFA metabolism; more importantly, promote epithelial proliferation via activation of the EGFR/ERK pathway, exerting a protective and regenerative effect on the gastric mucosa.

The implications of lipid mobility, drug-enhancers (surfactants)-skin interaction, and TRPV1 activation on licorice flavonoid permeability.

Licorice flavonoids (LFs) are derived from perennial herb licorice and have been attaining a considerable interest in cosmetic and skin ailment treatments. However, some LFs compounds exhibited poor permeation and retention capability, which restricted their application. In this paper, we systematically investigated and compared the enhancement efficacy and mechanisms of different penetration enhancers (surfactants) with distinct lipophilicity or "heat and cool" characteristics on ten LFs compounds. Herein, the aim was to unveil how seven different enhancers modified the stratum corneum (SC) surface and influence the drug-enhancers-skin interaction, and to relate these effects to permeation enhancing effects of ten LFs compounds. The enhancing efficacy was evaluated by enhancement ratio (ER)permeation, ERretention, and ERcom, which was conducted on the porcine skin. It was summarized that heat capsaicin (CaP) and lipophilic Plurol® Oleique CC 497 (POCC) caused the most significance of SC lipid fluidity, SC water loss, and surface structure alterations, thereby resulting in a higher permeation enhancing effects than other enhancers. CaP could completely occupied drug-skin interaction sites in the SC, while POCC only occupied most drug-skin interactions. Moreover, the enhancing efficacy of both POCC and CaP was dependent on the log P values of LFs. For impervious LFs with low drug solubility, enhancing their drug solubility could help them permeate into the SC. For high-permeation LFs, their permeation was inhibited ascribed to the strong drug-enhancer-skin strength in the SC. More importantly, drug-surfactant-skin energy possessed a good negative correlation with the LFs permeation amount for most LFs molecules. Additionally, the activation of transient receptor potential vanilloid 1 (TRPV1) could enhance LFs permeation by CaP. The study provided novel insights for drug permeation enhancement from the viewpoint of molecular pharmaceutics, as well as the scientific utilization of different enhancers in topical or transdermal formulations.

Glycyrrhizin micellar nanocarriers for topical delivery of baicalin to the hair follicles: A targeted approach tailored for alopecia treatment.

Alopecia affected approximately 16.6% of all people in China, however, treatment options remain limited due to the side effects. Plant bioactive compound baicalin (BC) possesses hair growth-promotion activity, but poor water solubility and unsuitable log P value restrict its topical application, and natural Glycyrrhizin (GL) can exactly overcome these drawbacks. Here, BC was encapsulated in GL to form GL-BC micelles for alopecia treatment. Simultaneously, tween 80 (TW) as carriers was incorporated in the GL-BC to form GL-TW-BC micelles. The topical penetration, penetration pathways, cellular uptake and the underlying mechanisms behind the hair loss reconstruction of the GL micelles were investigated. We found the optimal GL-BC and GL-TW-BC formulations significantly improved the penetration and accumulation of BC in the porcine skin predominantly through the hair follicles pathways without causing skin irritation, which resulted in a targeted treatment. The proliferation of human dermal papilla cells (hDPCs) and effective cellular uptake was also enhanced. Moreover, the activation of the Wnt/ß-catenin pathway, up-expression of vascular endothelial growth factor (VEGF), α-melanocyte-stimulating hormone (α-MSH) and interleukin-10 (IL-10) were the mechanisms of micelles for the hair recovery. Interestingly, GL and BC exhibited a synergistic treatment of alopecia. Collectively, GL-BC and GL-TW-BC can be used as promising approaches for the treatment of alopecia.