This study aimed to systematically compare licochalcone A (LicA) and glabridin (Gla) (whitening agents) release and permeation from Carbomer 940 (CP) hydrogels with different enhancers, and evaluate the relationship between the quantitative enhancement efficacy and structures of the enhancers. An in vitro release study and an in vitro permeation experiment in solution and hydrogels using porcine skin were performed. We found that the Gla–CP hydrogel showed a higher drug release and skin retention amount than LicA–CP due to the higher solubility in medium and better miscibility with the skin of Gla than that of LicA. Enhancers with a higher molecular weight (MW) and lower polarizability showed a higher release enhancement effect (ERrelease) for both LicA and Gla. The Van der Waals forces in the drug–enhancers–CP system were negatively correlated with the drug release percent. Moreover, enhancers with a higher log P and polarizability displayed a higher retention enhancement effect in solution (ERsolution retention) for LicA and Gla. Enhancers decreased the whole intermolecular forces indrug–enhancers-skin system, which had a linear inhibitory effect on the drug retention. Moreover, C=O of ceramide acted asthe enhancement site for drug permeation. Consequently, Transcutol® P (TP) and propylene glycol (PG), seven enhancers showed a higher retention enhancement effect in hydrogel (ERhydrogel retention) for LicA and Gla. Taken together, the conclusions provide a strategy for reasonable utilization of enhancers and formulation optimization in topical hydrogel whitening.

Pseudomonas aeruginosa, Escherichia coli, Pseudomonas cepacia and Moraxella catarrhalis were selected for their markedly different resistance patterns to sulphonamides and trimethoprim. In addition, strains of E. coli and P. cepacia were selected having different resistance profiles to the inhibition of dihydropteroate synthetase and dihydrofolate reductase. All inhibitors of dihydropteroate synthetase combined in any combination with inhibitors of dihydrofolate reductase resulted in mutual enhancement of bacterial uptakes of the inhibitors and corresponding increased antibacterial activity of the combinations. High concentrations of sulphonamides or p-aminobenzoic acid plus trimethoprim caused a decrease in overall activity of the combination and indicated that both sulphonamides and p-aminobenzoic acid at high concentrations can interact with dihydrofolate reductase. The antibacterial activity of p-aminobenzoic acid at high concentrations is considered to be a blocking effect on dihydrofolate reductase even though p-aminobenzoic acid at low concentrations is an essential part of the synthesis of dihydrofolic acid. These findings support an alternative hypothesis for the mechanism of antibacterial action of individual antifolates and their mechanism of synergism in combination.

Glycyrrhizae Radix et Rhizoma is the most frequently prescribed natural medicine in China and has been used for more than 2,000 years. The flavonoids of licorice have garnered considerable attention in recent decades due to their structural diversity and myriad pharmacological effects, especially as novel therapeutic agents against inflammation and cancer. Although many articles have been published to summarize different pharmacological activities of licorice in recent years, the systematic summary for flavonoid components is not comprehensive. Therefore, in this review, we summarized the pharmacological and mechanistic data from recent researches on licorice flavonoids and their bioactive components.

A functional pharmacokinetic/pharmacodynamic (PK/PD) index that could simultaneously describe three controlling PD variables, i.e., bactericidal activity, postantibiotic effect (PAE), and susceptibility, in relation to pharmacokinetics, was designed using an in vitro kinetic model. Tobramycin was tested against one standard and five clinical strains of Pseudomonas aeruginosa. The organisms showed minimum inhibitory concentrations (MICs) ranging between 1 and >1000 microg/ml. The model allowed antibiotic concentrations to be reduced exponentially from initial concentrations at fixed multiples of MIC. Antibiotic removal was performed when the decreasing concentrations hit the MIC of individual strain to provide a wide range of AUC(>MIC) within an identical frame of AUC(>MIC)/MIC (AUIC) values. Viable counts were measured at antibiotic addition and before/after its removal for bactericidal activity and PAE assessments. A linear relationship was observed between PAE and bactericidal rate constants, though the pattern varied among different strains. Characterization of the exposure (AUC(>MIC))-effect relationships using the Emax model revealed that the less susceptible strains displayed lower Emax and higher EC50 for both antimicrobial effects. By employing the AUIC as a common frame of reference, regression analysis showed a significant linear correlation (p < 0.05) between the mean PAE and bactericidal rate data and, thereby simultaneously defining the four contributing factors of the PK/PD system. It appears that the AUIC, by conveying the pharmacokinetic and susceptibility information, could serve as a PK/PD index in bridging the interdependency of PAE and bactericidal activity. More importantly, the collective assessment of these four factors would allow more optimal evaluation of dosage regimens.

The label-free methods of proteomic combined with metabolomics were applied to explore the mechanisms of Cryptotanshinone (CPT) intervention in rats with acne. The model group consisted of rats given oleic acid (MC), then treated with CPT, while control groups did not receive treatment. The skin samples were significantly different between control, model and CPT-treated groups in hierarchical clustering dendrogram. Obvious separations of the skin metabolic profiles from the three groups were found through PCA scoring. In total, 231 and 189 differentially expressed proteins (DEPs) were identified in MC and CPT groups, respectively. By the KEGG analysis, five protein and metabolite pathways were found to be significantly altered. These played important roles in response to oleic acid-induced acne and drug treatment. CPT could negatively regulate glycolysis/gluconeogenesis and histidine metabolisms to decrease keratinocyte differentiation and improve excessive keratinization and cellular barrier function. CPT could down-regulate the IL-17 signaling pathway and regulate the acne-driven immune response of sebum cells. The biosynthesis of unsaturated fatty acids metabolism, glycerophospholipid metabolism and linoleic acid pathways could significantly alter sebum production and control sebaceous gland secretion after CPT treatment. The gap junction was up-regulated after CPT treatment and the skin barrier turned back to normal. Krt 14, Krt 16 and Krt 17 were significantly down-regulated, decreasing keratinization, while inflammatory cell infiltration was improved by down-regulation of Msn, up-regulation of linoleic acid and estrogen pathways after CPT treatment. These results propose action mechanisms for the use of CPT in acne, as a safe and potential new drug.

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Licorice flavonoids (LCFs) are natural flavonoids isolated from Glycyrrhiza which are known to have anti-melanoma activities in vitro. However, the molecular mechanism of LCF anti-melanoma has not been fully understood. In this study, network pharmacology, 3D/2D-QSAR, molecular docking, and molecular dynamics (MD) simulation were used to explore the molecular mechanism of LCF anti-melanoma. First of all, we screened the key active components and targets of LCF anti-melanoma by network pharmacology. Then, the logIC50 values of the top 20 compounds were predicted by the 2D-QSAR pharmacophore model, and seven highly active compounds were screened successfully. An optimal 3D-QSAR pharmacophore model for predicting the activity of LCF compounds was established by the HipHop method. The effectiveness of the 3D-QSAR pharmacophore was verified by a training set of compounds with known activity, and the possible decisive therapeutic effect of the potency group was inferred. Finally, molecular docking and MD simulation were used to verify the effective pharmacophore. In conclusion, this study established the structure–activity relationship of LCF and provided theoretical guidance for the research of LCF anti-melanoma.

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