Copper Ion-Inspired Dual Controllable Drug Release Hydrogels for Wound Management: Driven by Hydrogen Bonds.

Bacterial infections and inflammation progression yield huge trouble for the management of serious skin wounds and burns. However, some hydrogel dressing exhibit poor wound-healing capabilities. Additionally, little information is given on the molecular theory of hydrogel gelation mechanisms and drug release performance from drug-polymer network in the water environment. Herein, cationic guar gum (CG) is first mixed with dipotassium glycyrrhizinate (DG), and then crosslinked Cu2+ to strengthen the mechanical strength followed by encapsulating mussel adhesive protein (MAP) as composite dressings. Intriguingly, CG-Cu2+ 0.5-DG10 possessed proper rheological properties and mechanical strength predominantly driven by strong CG-H2O-Cu2+ and Cu2+-CG hydrogen bonding interaction. Weak DG-CG hydrogen bonding only controlled DG release in the initial 4 h, while strong hydrogen bonding is the main force regulating the sustained release of Cu2+ within 48 h. The incorporation of MAP further loosened the tight crosslinking of CG-Cu2+ 0.5-DG10. The screened CG-Cu2+ 0.5-DG10/MAP possessed excellent self-healing, injectability, antibacterial, anti-inflammatory, cell proliferation-promotion activities with high biocompatibility. Therefore, CG-Cu2+ 0.5-DG10/MAP hydrogel expedited wound closure on S. aureus-infected full-thickness skin wound model and lowered necrosis progression to the unburned interspaces on a rat burn model. The results highlight the promising translational potential of Cu2+-inspired hydrogels for the management of burns and infected wounds.

Influence of the pKa value on the antioxidant activity of licorice flavonoids under solvent-mediated effects.

Licorice flavonoids (LCFs) have been widely used in food care and medical treatment due to their significant antioxidant activities. However, the molecular mechanism of their antioxidant activity remains unclear. Therefore, network pharmacology, ADMET, density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulation were employed to explore the molecular mechanism of the antioxidant effects of LCF. The network pharmacology and ADMET studies showed that the active molecules of kumatakenin (pKa = 6.18), licoflavonol (pKa = 6.86), and topazolin (pKa = 6.21) in LCF are key antioxidant components and have good biosafety. Molecular docking and MD simulation studies demonstrated that active molecules interacted with amino acid residues in target proteins to form stable protein-ligand complexes and exert their antioxidant effects. DFT studies showed that the antioxidant activity of LCF could be significantly modulated under the solvent-mediated effect. In addition, based on the derivation of the Henderson-Hasselbalch and van't Hoff formulas, the functional relationships between the reaction-free energy (ΔG) of LCF and the pH and pKa values were established. The results showed that active molecules with larger pKa values will be more conducive to the improvement of their antioxidant activity under solvent-mediated effects. In conclusion, this study found that increasing the pKa value of LCF would be an effective strategy to improve their antioxidant activity under the effect of solvent mediation. The pKa value of an LCF will be a direct standard to evaluate its solvent-mediated antioxidant activity. This study will provide theoretical guidance for the development of natural antioxidants.

Mechanisms of Penetration Enhancement and Transport Utilizing Skin Keratine Liposomes for the Topical Delivery of Licochalcone A.

Keratin liposomes have emerged as a useful topical drug delivery system given theirenhanced ability to penetrate the skin, making them ideal as topical drug vehicles. However, the mechanisms of the drug penetration enhancement of keratin liposomes have not been clearly elucidated. Therefore, licochalcone A(LA)-loaded skin keratin liposomes (LALs) were prepared to investigate their mechanisms of penetration enhancement on the skin and inB16F10 cells. Skin deposition studies, differential scanning calorimetry (DSC), attenuated total reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR), and skin distribution and intracellular distribution studies were carried out to demonstrate the drug enhancement mechanisms of LALs. We found that the optimal application of LALs enhanced drug permeation via alterations in the components, structure, and thermodynamic properties of the stratum corneum (SC), that is, by enhancing the lipid fluidization, altering the skin keratin, and changing the thermodynamic properties of the SC. Moreover, hair follicles were the main penetration pathways for the LA delivery, which occurred in a time-dependent manner. In the B16F10 cells, the skin keratin liposomes effectively delivered LA into the cytoplasm without cytotoxicity. Thus, LAL nanoparticles are promising topical drug delivery systems for pharmaceutical and cosmetic applications.

Formulation and Characterization of a 3D-Printed Cryptotanshinone-Loaded Niosomal Hydrogel for Topical Therapy of Acne.

Cryptotanshinone (CPT) is an efficacious acne treatment, while niosomal hydrogel is a known effective topical drug delivery system that produces a minimal amount of irritation. Three-dimensional (3D) printing technologies have the potential to improve the field of personalized acne treatment. Therefore, this study endeavored to develop a 3D-printed niosomal hydrogel (3DP-NH) containing CPT as a topical delivery system for acne therapy. Specifically, CPT-loaded niosomes were prepared using a reverse phase evaporation method, and the formulation was optimized using a response surface methodology. In vitro characterization showed that optimized CPT-loaded niosomes were below 150 nm in size with an entrapment efficiency of between 67 and 71%. The CPT-loaded niosomes were added in a dropwise manner into the hydrogel to formulate CPT-loaded niosomal hydrogel (CPT-NH), which was then printed as 3DP-CPT-NH with specific drug dose, shape, and size using an extrusion-based 3D printer. The in vitro release behavior of 3DP-CPT-NH was found to follow the Korsmeyer-Peppas model. Permeation and deposition experiments showed significantly higher rates of transdermal flux, Q24, and CPT deposition (p < 0.05) compared with 3D-printed CPT-loaded conventional hydrogel (3DP-CPT-CH), which did not contain niosomes. In vivo anti-acne activity evaluated through an acne rat model revealed that 3DP-CPT-NH exhibited a greater anti-acne effect with no skin irritation. Enhanced skin hydration, wide inter-corneocyte gaps in the stratum corneum and a disturbed lipid arrangement may contribute towards the enhanced penetration properties of CPT. Collectively, this study demonstrated that 3DP-CPT-NH is a promising topical drug delivery system for personalized acne treatments.

Fe-Catalyzed enaminone synthesis from ketones and amines.

We have developed an iron-catalyzed direct olefination for enaminone synthesis, with saturated ketones as a source of olefins. This direct ketone ß-functionalization reaction has readily available starting materials and a wide range of substrates and requires mild reaction conditions.

The molecular mechanisms underlying optical isomer arbutin permeating the skin: The molecular interaction between arbutin and skin components.

Arbutin, a typical optical isomer, has garnered widespread acclaim in the whitening cosmetics for its favorable efficacy and safety. However, the molecular mechanisms underlying α-arbutin and ß-arbutin permeating across the skin have not elucidated clearly yet. Herein we aimed to unveil how α-arbutin and ß-arbutin interacted with keratin or SC lipids, further demonstrating their relationship with their drug permeability. We found that α-arbutin displayed significantly higher drug accumulation into the porcine skin than ß-arbutin within 24 h through in vitro permeation test. Moreover, α-arbutin predominantly induced the alternations of secondary structure of amide II during the drug permeation, which was favorable for α-arbutin permeation. On the contrary, ß-arbutin exhibited an observable effect on the stretching vibration of SC lipids, possessing a significantly stronger mixing energy, binding energy and compatibility with ceramide (Cer) than that of α-arbutin, which ultimately restricted its permeation. Interestingly, free fatty acids and ceramides of the SC lipids specifically utilized its oxygen atom of carboxyl group to dock the arbutin molecules, enhancing their affinity with ß-arbutin, as confirmed by molecular simulation and 13Carbon Nuclear Magnetic Resonance. Nevertheless, a favorable compatibility between α-arbutin and keratin was observed. It was emphasized that the distinct spatial configuration and opposite optical rotation of arbutin was the leading factor impacting the intermolecular force between arbutin and the SC, and resulted in a diverse drug permeation. In cellular and in vivo skin pharmacokinetic studies, α-arbutin also possessed a higher cellular uptake and topical bioavailability than ß-arbutin. This study revealed the transdermal permeation mechanisms of optical isomer arbutin at the molecular levels, providing methodological reference for the investigations of permeation behaviors of other isomers with similar spatial configuration.

Carrier-free cryptotanshinone-peptide conjugates self-assembled nanoparticles: An efficient and low-risk strategy for acne vulgaris.

Acne vulgaris ranks as the second most prevalent dermatological condition worldwide, and there are still insufficient safe and reliable drugs to treat it. Cryptotanshinone (CTS), a bioactive compound derived from traditional Chinese medicine Salvia miltiorrhiza, has shown promise for treating acne vulgaris due to its broad-spectrum antimicrobial and significant anti-inflammatory properties. Nevertheless, its local application is hindered by its low solubility and poor skin permeability. To overcome these challenges, a carrier-free pure drug self-assembled nanosystem is employed, which can specifically modify drug molecules based on the disease type and microenvironment, offering a potential for more effective treatment. We designed and synthesized three distinct structures of cationic CTS-peptide conjugates, creating self-assembled nanoparticles. This study has explored their self-assembly behavior, skin permeation, cellular uptake, and both in vitro and in vivo anti-acne effects. Molecular dynamics simulations revealed these nanoparticles form through intermolecular hydrogen bonding and π-π stacking interactions. Notably, self-assembled nanoparticles demonstrated enhanced bioavailability with higher skin permeation and cellular uptake rates. Furthermore, the nanoparticles exhibited superior anti-acne effects compared to the parent drug, attributed to heightened antimicrobial activity and significant downregulation of the MAPK/NF-κB pathway, leading to reduced expression of pro-inflammatory factors including TNF-α, IL-1ß and IL-8. In summary, the carrier-free self-assembled nanoparticles based on CTS-peptide conjugate effectively address the issue of poor skin bioavailability, offering a promising new approach for acne treatment.

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 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.

Exploring the mechanism of solubilization and release of isoliquiritigenin in deep eutectic solvents.

Isoliquiritigenin (ISL) is a natural medicinal product with extensive pharmacological activities. However, its low solubility limits its application. Therefore, this study aimed to explore the solubilization and release mechanism of the ISL using deep eutectic solvents (DESs). The choline chloride (ChCl) and oxalic acid (OA)/malic acid (MA)/gallic acid (GA) were used to synthesize ChCl-OA/MA/GA DESs, and the solubility of ISL in these DESs was studied to explore the solubilization mechanism of ISL. The thermodynamic properties of DESs were characterized using differential scanning calorimetry (DSC). The molecular interactions in DESs were studied using spectroscopy and molecular dynamics (MD) simulations. The relative density of DESs was measured using a pycnometric method, its accuracy was validated by comparing it with the MD simulation. The release of ISL from ChCl-OA/MA/GA eutectogels was studied using Carbomer 940 as the thickener, and the release mechanism of ISL in the eutectogels was explored by the drug release kinetic model. The solubility study found that the solubility of ISL in ChCl-OA/MA/GA DESs is 30073, 5055, and 68,103 times higher than that in an aqueous solution. In addition, further studies using MD simulations revealed that enhancing the interactions between ISL and solvent molecules can improve the solubility of ISL in DESs. In vitro release studies showed that the release of ISL in ChCl-OA/MA/GA eutectogels followed a first-order release model, with correlation coefficients of 0.9812, 0.9916, and 0.9961, respectively. In conclusion, the study of the solubilization and release mechanism of ISL in DESs provides new ideas and methods for the study of poorly soluble drugs, which is expected to improve the efficacy and clinical application value of drugs.

Exploring the molecular mechanism of Licorice rose beverage anti-melasma based on network pharmacology, molecular docking technology and in vivo and in vitro experimental verification.

Melasma is a pigmentation disease with refractory and high recurrence risk. Therefore, finding effective treatment has become the focus of research. This study aimed to reveal the mechanism of Licorice rose beverage (LRB) in treating melasma from the perspective of network pharmacology and in vitro and in vivo experimental techniques. Network pharmacological studies have shown that Isolicoflavonol, quercetin, and kaempferol are the main active components of anti-melasma and tyrosinase is the main target. Molecular docking studies have shown that these compounds have a good affinity for these targets. In vitro tyrosinase inhibition experiments showed that LRB could significantly inhibit tyrosinase activity. In vivo studies showed that LRB could significantly improve skin damage and skin pigmentation, reduce the activities of serum and skin tyrosinase in model mice, increase the activity of SOD in serum, and reduce the content of MDA in mice, showing a good effect of anti-melasma. In conclusion, these findings reveal the molecular mechanism of LRB in treating melasma and provide the scientific basis for this product's development and clinical application.

4'-OH as the Action Site of Lipids and MRP1 for Enhanced Transdermal Delivery of Flavonoids.

To date, the transdermal delivery study mainly focused on the drug delivery systems' design and efficacy evaluation. Few studies reported the structure-affinity relationship of the drug with the skin, further revealing the action sites of the drugs for enhanced permeation. Flavonoids attained a considerable interest in transdermal administration. The aim is to develop a systematic approach to evaluate the substructures that were favorable for flavonoid delivery into the skin and understand how these action sites interacted with lipids and bound to multidrug resistance protein 1 (MRP1) for enhanced transdermal delivery. First, we investigated the permeation properties of various flavonoids on the porcine skin or rat skin. We found that 4'-OH (hydroxyl group on the carbon 4' position) rather than 7-OH on the flavonoids was the key group for flavonoid permeation and retention, while 4'-OCH3 and -CH2═CH2-CH-(CH3)2 were unfavorable for drug delivery. 4'-OH could decrease flavonoids' lipophilicity to an appropriate log P and polarizability for better transdermal drug delivery. In the stratum corneum, flavonoids used 4'-OH as a hand to specifically grab the C═O group of the ceramide NS (Cer), which increased the miscibility of flavonoids and Cer and then disturbed the lipid arrangement of Cer, thereby facilitating their penetration. Subsequently, we constructed overexpressed MRP1 HaCaT/MRP1 cells by permanent transfection of human MRP1 cDNA in wild HaCaT cells. In the dermis, we observed that 4'-OH, 7-OH, and 6-OCH3 substructures were involved in H-bond formation within MRP1, which increased the flavonoid affinity with MRP1 and flavonoid efflux transport. Moreover, the expression of MRP1 was significantly enhanced after the treatment of flavonoids on the rat skin. Collectively, 4'-OH served as the action site for increased lipid disruption and enhanced affinity for MRP1, which facilitate the transdermal delivery of flavonoids, providing valuable guidelines for molecular modification and drug design of flavonoids.

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.

Preparation, characterisation and comparison of glabridin-loaded hydrogel-forming microneedles by chemical and physical cross-linking.

Poly(vinyl alcohol) (PVA) and carbomer were used as the hydrogel system to fabricate glabridin-loaded hydrogel-forming microneedles (HFMNs) by chemical cross-linking (CCMNs) and physical cross-linking (PCMNs). The properties and drug permeation effects of glabridin-loaded HFMNs with different methods were compared. They both owned excellent shapes, mechanical and insertion properties. PCMNs showed collapsed shapes during swelling due to the low cross-linking rate and high porosity, which probably results in resealing of skin pores during transdermal drug delivery. However, CCMNs could rapidly swell within 2 h with slightly bending. The infrared spectra indicate that CCMNs and PCMNs might form the hydrogel network by generating hydrogen and covalent bonds, respectively. The in vitro release studies showed that cumulative permeation amount within 24 h (1654 µg/cm2) of CCMNs significantly higher than that (372 µg/cm2) achieved by PCMNs and that (118 µg/cm2) achieved by glabridin-loaded gel. The skin barrier recovery test suggests the desirable security of both microneedles (MNs), notwithstanding the presence of mild erythema in the mouse skin applied CCMNs. These results indicate that CCMNs were more desirable for glabridin delivery using PVA and carbomer as a skeleton of the hydrogel network.

Pharmacological Effects and Underlying Mechanisms of Licorice-Derived Flavonoids.

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.

Mechanism insight on licorice flavonoids release from Carbopol hydrogels: Role of "release steric hindrance" and drug solubility in the release medium.

The present study was to systematically evaluate different licorice flavonoids (LFs) compounds release behaviors from the single payload hydrogel and LFs extracts hydrogels based on the drug solubility in the release medium (DSRM), intermolecular strength of the hydrogel and the "release steric hindrance" (RSH). Two kinds of LFs (LFs 1: LFs 2 = 5:1, W/W) hydrogels were prepared with Carbopol 940 (CBP) as the thickener, and ten LFs single payload hydrogels were prepared according to the actual content in the LFs 1 extracts. The drug release mechanisms were confirmed by in vitro release experiments and molecular dynamic simulation analysis, and evaluated using novel indicators of ERLFs 1/Sin (the enhancement ratio (ER) of drug release percent of LFs 1-CBP hydrogel to the single payload hydrogel), ERLFs 2/ LFs 1 (ER of drug release percent of LFs 2-CBP hydrogel to LFs 1-CBP hydrogel) and ERrelease medium (ER of drug release percent in different release medium). We found that LFs 1-CBP possessed a significantly higher intermolecular strength and RSH than LFs 2-CBP, resulting in a higher viscosity, which had a positive correlation with the payload content and a negative correlation with the drug release percent. Therefore, the ERLFs 2/ LFs 1 values of ten LFs compounds were all higher than 1. For liquiritigenin and retrochalcone with higher DSRM, they displayed similar ERLFs 1/ Sin, ERLFs 2/ LFs 1 and ERrelease medium values (≈1). For formononetin, licoflavone A and licochalcone A with low DSRM, they exhibited ERLFs 1/Sin values >1. The low DSRM was the decisive factor to restrict their release from the single payload hydrogel. The presence of glycyrrhizin acid (GA) in the LFs could facilitate their release from the LFs extracts hydrogel. For isoliquiritin, isoliquiritigenin and glabridin with a lower content in the LFs extracts, they exhibited ERLFs 1/Sin values <1. The RSH predominantly restricted its release. The study provided guidelines for the reasonable design of LFs extracts hydrogel in pharmaceutical topical formulations.

Log P Determines Licorice Flavonoids Release Behaviors and Classification from CARBOMER Cross-Linked Hydrogel.

The dynamic drug release mechanisms from Carbomer 940 (CP) hydrogels have not been systematically explored elsewhere. This study aimed to investigate the quantitative structure-activity relationship of licorice flavonoids (LFs) compounds on their drug release from CP hydrogels based on LFs-CP interactions and drug solubility in the release medium. Ten LFs-CP hydrogels were formulated, and their in vitro release study was conducted. The intermolecular forces of LFs-CP systems were characterized by FTIR, molecular docking and molecular dynamic simulation. Ten LFs compounds were classified into I (high-release capability) LFs and II (low-release capability) LFs according to the different negative correlations between drug release percent at 48 h and intermolecular forces of drugs-CP, respectively. Moreover, high-release LFs possessed significantly lower log P and higher drug solubility in the release medium than low-release LFs. All I LFs release behaviors best followed the first-order equation, while II LFs release characteristics best fitted the zero-order equation except for isoliquiritigenin. Log P mainly affect the hydrogel relaxation process for I drugs release and the drug diffusion process for II drugs release. Higher log P values for LFs resulted in higher intermolecular strength for I drugs-CP systems and lower drug solubility in the release medium for II drugs, which hindered drug release. Hydrophobic association forces in drug-CP hydrogel played a more and more dominant role in hindering I LFs release with increasing release time. On the other hand, lower drug solubility in the release medium restricted II LFs release, and the dominant role of drug solubility in the release medium increased in 24 h followed by a significant decline after 36 h. Collectively, log P of LFs served as a bridge to determine LFs compound release behaviors and classification from CP hydrogels, which provided guidelines for reasonable design of LFs hydrogels in pharmaceutical topical formulations.

Network pharmacology, molecular docking and in vivo and in vitro experiments to explore the molecular mechanism of licorice green tea beverage to scavenge oxygen free radicals.

Excessive oxygen free radicals can lead to aging, cancer, and other diseases. Therefore, searching for effective antioxidants to scavenge oxygen free radicals has become the focus of modern medicine. In this study, the molecular mechanism of Licorice Green Tea Beverage (LGTB) in scavenging oxygen free radicals was investigated by means of network pharmacology, molecular docking and experimental verification. Network pharmacology studies have shown that paeonol, eugenol, cinnamaldehyde, swertisin, rutin, glycyrrhetinic acid, oleic, pelargonidin-3-O-glucoside and quercetin, kaferempol were the main active components of LGTB, and SOD and CAT are important targets for LGTB in scavenging oxygen free radicals. The results of molecular docking showed that these representative compounds had good affinity to SOD and CAT target proteins. In vitro free radical scavenging experiments showed that LTGB had significant scavenging effects on both DPPH and ABTS radicals, and had strong total reducing power. In vitro cell experiments showed that LGTB could protect HaCaT cells from oxidative stress induced by H2 O2 . The mechanism of LGTB was related to the increase of SOD and CAT activity. Western blotting showed that LGTB could inhibit PI3K/AKT/HIF-1 signaling pathway and improve the antioxidant capacity of HaCaT cells. In vivo experiments showed that LGTB could significantly increase mouse visceral index, increase serum SOD and GSH-Px activity, decrease the content of MDA, and improve liver and kidney pathological state. This study reported the molecular mechanism of LTGB scavenging oxygen free radicals, which provided scientific basis for the treatment and clinical research of aging and other diseases caused by excessive free radicals. PRACTICAL APPLICATIONS: Free radicals are produced by the normal response of cells during aerobic respiration and perform various functions, such as signaling and providing protection against infection. However, excessive free radicals can lead to aging, cancer, and other diseases. The antioxidant can overcome the harm caused by excessive free radicals. In this study, we investigated the molecular mechanism of scavenging oxygen free radicals of Licorice Green Tea Beverage (LGTB) through network pharmacology and molecular docking, and its efficacy was verified by free radical scavenging experiment in vitro, HaCaT cell oxidative stress injury induced by H2 O2 , D-galactose to establish an aging model in mice and Western blotting experiment. It not only elucidates its mechanism at the system level, but also proves its validity at the biological level. It provides the theoretical basis and experimental evidence for the follow-up research and promotion of the product.

Skin microbiome reconstruction and lipid metabolism profile alteration reveal the treatment mechanism of Cryptotanshinone in the acne rat.

BACKGROUND: Acne has become one of the most prevalent skin disorders, affecting mostly young people's physical and mental health globally. Cryptotanshinone (CPT) is a potential drug for acne, but its mechanism of acne treatment has not been thoroughly studied on the microbiota. Till date, only a few studies are directed to the impact of acne therapy on skin microbiota and lipid metabolites. PURPOSE: The action mechanism of CPT treatment of acne was investigated by the strategy of microbiome integration with lipidomics. METHODS: The 16Sr DNA sequencing was used to detect skin microbiota composition, and absolute quantitative lipidomics was utilized to identify lipid metabolites profiles levels. Four key proteins of the glycolysis pathway were detected with the immunochemistry method. Antibacterial analysis was used to evaluate CPT treatment of acne. RESULTS: CPT significantly inhibited Staphylococcus epidermidis and Staphylococcus aureus. Combination of the skin microbiome and lipidomics analysis, 29 types of differentially expressed flora (DEFs) and 782 differentially expressed lipid metabolites (DELMs) were significantly altered, especially Staphylococcus, Corynebacterium, Ralstonia, Enhydrobacter, Burkholderia, and Streptococcus. Cer was mainly regulated by Staphylococcus and Corynebacterium, whereas TG and DG were mainly regulated by Ralstonia, Enhydrobacter, Burkholderia, and Streptococcus. The glycolysis pathway was significantly regulated by Staphylococcus on CPT treatment of acne. The energy metabolism, lipid metabolism, immune system, glycan biosynthesis, and metabolism could be reversed by CPT. CONCLUSION: CPT might help acne rats rebuild their skin microbiota and alter lipid metabolism signatures. Furthermore, since skin microbes and skin lipid metabolites have a close correlation and are both regulated by CPT, the findings potentially provide a research foundation for the discovery of biomarkers of skin microbiome imbalance and targeted treatment of acne development mechanisms.