Exercise Changes Gut Microbiota: A New Idea to Explain that Exercise Improves Autism.

The effect of exercise interventions on autism spectrum disorder (ASD) has been demonstrated in many studies, and the discovery of a bidirectional relationship between the gut microbiome (GM) and the central nervous system (CNS) has led to the concept of the microbial gut-brain axis (MGBA) and has linked the abnormal GM to a variety of neuropsychiatric disorders, autism being one of them. Research on improving the GM through exercise is also starting to come into focus. However, there are currently few studies on exercise intervention in the GM of autism. The purpose of this review was to find evidence to explore the possible potential effects of exercise to improve the behavior of individuals with autism in the MGBA in this treatment, as well as the potential of GM as an exercise treatment for autism. We will explore (1) changes in GM components of ASD and their relationship to the pathophysiology of ASD; (2) the relationship between exercise and changes in GM components, and (3) the effect of exercise on GM in CNS disorders. Ultimately, we concluded that Streptococcus, Bifidobacterium, Clostridium, Bacteroides, and Blautia may be potential effectors through the MGBA network during exercise to ameliorate ASD targeting microbiotas. They deserve high attention in the follow-up studies.

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.

Reversible Structural Transformation of CuI-TbIII Heterometallic MOFs with Highly Efficient Detection Capability toward Penicillin.

A CuI-TbIII heterometallic MOF, namely 1·DMF, was obtained via a coordination assembly process of isonicotinic acid with CuI and TbIII. 1·DMF can be switched to 1·MeOH in methanol with a luminescent emission response. Meanwhile, 1·MeOH exhibits a reversible single-crystal transformation to 1·DMF after immersion in DMF. Both MOFs have superior physicochemical stability. The 1·DMF-based biosensor has a remarkable sensing performance toward penicillin.

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.

A Double-Walled Bimetal-Organic Framework for Antibiotics Sensing and Size-Selective Catalysis.

The first double-walled bimetal-organic framework [Cd4K4(TADA)4(H2O)12]·6DMF (1, TADA = 3,3'-((6-hydroxy-1,3,5-triazine-2,4-diyl)bis(azanediyl)) dibenzoate) has been successfully constructed. In virtue of its high porosity and abundant basic sites, MOF 1 can be served as a high-efficiently size-selective heterogeneous catalyst for Knovenagel condensation reaction. Remarkably, 1 also exhibits excellent luminescent detectability for metronidazole (MDZ) with the highest quenching constant ( Ksv) of 1.16 × 105 M-1. The results demonstrate that 1 can be served as a unique bifunctional platform for antibiotics sensing and size-selective catalysis.

Myoepithelial Carcinoma: The Role of Radiation Therapy. A Case Report and Analysis of Data From the Surveillance, Epidemiology, and End Results (SEER) Registry.

PURPOSE/OBJECTIVE: The role of radiation therapy in the treatment of myoepithelial carcinoma (MC) is unknown. We present a case of a high-grade soft-tissue MC in a pediatric patient and retrospectively examine the effect of postoperative radiation on survival in patients with MC. MATERIALS AND METHODS: Our patient was treated with 4 cycles of ifosfamide, cisplatin, and etoposide followed by 3 cycles of ifosfamide vincristine and etoposide. Radiation was delivered to a total dose of 5580 cGy in 180 cGy/fraction to the surgical bed with a 2 cm margin starting after the third cycle of chemotherapy. The Surveillance, Epidemiology, and End Results (SEER) registry database was queried for cases of surgically resected MC. Retrospective analysis was performed with the endpoint of overall survival (OS). RESULTS: Two hundred thirty-four cases of MC were identified; for 62 of these cases, the grade of the tumor wasidentified. Of these 62 patients, 27 received postoperative radiation. OS was improved with adjuvant radiation therapy in patients with grade III or IV MC (P<0.01) as determined by the log-rank test. CONCLUSIONS: This analysis of SEER data showed an OS benefit with adjuvant radiation therapy in the treatment of high-grade MC. Physicians should report all cases of MC to improve clinical decision making in the treatment of this rare disease.

Heparin Oligosaccharides as Vasoactive Intestinal Peptide Inhibitors via their Binding Process Characterization.

BACKGROUND: It has been proven that vasoactive intestinal peptide (VIP) was involved in the pathogenesis of prostate cancer. Cardin et al. found that by an alanine scan, the heparin- binding site on VIP was exactly the same sequence in VIP and its receptor. Therefore, heparin could competitively block the binding of VIP and its receptor. However, the structure-activity relationship between heparin and VIP has not been reported, especially in terms of the sequence and sulfation patterns of heparin oligosaccharides upon binding to VIP. OBJECTIVE: A variety of experiments were designed to study the binding process and structure-activity relationship between heparin oligosaccharides and VIP. METHODS: Heparin was enzymatically digested and purified to produce heparin oligosaccharides, and the structures were characterized by NMR. The binding capacity between heparin oligosaccharides and VIP was analyzed by GMSA and ITC experiments. The binding between heparin oligosaccharides and VIP was simulated using a molecular docking program to show the complex. ELISA assay was used to investigate the effect of non-anticoagulant heparin oligosaccharides on the VIP-mediated cAMP/PKA signaling pathway in vitro. RESULTS: The results indicated that both the length and the sulfation pattern of heparin oligosaccharides affected its binding to VIP. VIP could induce the expression of cAMP at a higher level in PC3 cells, which could be regulated by the interaction of heparin oligosaccharides and VIP. CONCLUSION: The binding between heparin oligosaccharides and VIP could block the binding between VIP and its receptor on tumor cells. Downloading the regulation of the expression level of cAMP could possibly further affect the subsequent activation of PKA. These non-anticoagulant heparin oligosaccharides may block the VIP-mediated cAMP/PKA signaling pathway and thus exert their antitumor activity.

Aerobic exercise protects MI heart through miR-133a-3p downregulation of connective tissue growth factor.

OBJECTIVE: To investigate the effect of aerobic exercise intervention to inhibit cardiomyocyte apoptosis and thus improve cardiac function in myocardial infarction (MI) mice by regulating CTGF expression through miR-133a-3p. METHODS: Male C57/BL6 mice, 7-8 weeks old, were randomly divided into sham-operated group (S group), sham-operated +aerobic exercise group (SE group), myocardial infarction group (MI group) and MI + aerobic exercise group (ME group). The mice were anesthetized the day after training and cardiac function was assessed by cardiac echocardiography. Myocardial collagen volume fraction (CVF%) was analyzed by Masson staining. Myocardial CTGF, Bax and Bcl-2 were detected by Western blotting, and myocardial miR-133a-3p was measured by RT-qPCR. RESULTS: Compared with the S group, miR-133a-3p, Bcl-2 and EF were significantly decreased and CTGF, Bax, Bax/ Bcl-2, Caspase 3, Cleaved Caspase-3, LVIDd, LVIDs and CVF were significantly increased in the MI group. Compared with the MI group, miR-133a-3p, Bcl-2 and EF were significantly increased, cardiac function was significantly improved, and CTGF, Bax, Bax/ Bcl-2, Caspase 3, Cleaved Caspase-3, LVIDd, LVIDs and CVF were significantly decreased in ME group. The miR-133a-3p was significantly lower and CTGF was significantly higher in the H2O2 intervention group compared with the control group of H9C2 rat cardiomyocytes. miR-133a-3p was significantly higher and CTGF was significantly lower in the AICAR intervention group compared to the H2O2 intervention group. Compared with the control group of H9C2 rat cardiomyocytes, CTGF, Bax and Bax/Bcl-2 were significantly increased and Bcl-2 was significantly decreased in the miR-133a-3p inhibitor intervention group; CTGF, Bax and Bax/Bcl-2 were significantly decreased and Bcl-2 was significantly upregulated in the miR-133a-3p mimics intervention group. CONCLUSION: Aerobic exercise down-regulated CTGF expression in MI mouse myocardium through miR-133a-3p, thereby inhibiting cardiomyocyte apoptosis and improving cardiac function.

Emerging roles of long noncoding RNAs in enzymes related intracellular metabolic pathways in cancer biology.

Metabolic reprogramming plays critical roles in the development and progression of tumor by providing cancer cells with a sufficient supply of nutrients and other factors needed for fast-proliferating. Emerging evidence indicates that long noncoding RNAs (lncRNAs) are involved in the initiation of metastasis via regulating the metabolic reprogramming in various cancers. In this paper, we aim to summarize that lncRNAs could participate in intracellular nutrient metabolism including glucose, amino acid, lipid, and nucleotide, regardless of whether lncRNAs have tumor-promoting or tumor-suppressor function. Meanwhile, modulation of lncRNAs in glucose metabolic enzymes in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle (TCA) in cancer is reviewed. We also discuss therapeutic strategies targeted at interfering with enzyme activity to decrease the utilization of glucoses, amino acid, nucleotide acid and lipid in tumor cells. This review focuses on our current understanding of lncRNAs participating in cancer cell metabolic reprogramming, paving the way for further investigation into the combination of such approaches with existing anti-cancer therapies.

Effect of different exercise modalities on nonalcoholic fatty liver disease: a systematic review and network meta-analysis.

Physical exercise intervention can significantly improve the liver of patients with Non-alcoholic fatty liver disease (NAFLD), but it is unknown which exercise mode has the best effect on liver improvement in NAFLD patients. Therefore, we systematically evaluated the effect of exercise therapy on liver and blood index function of NAFLD patients through network meta-analysis (NMA). Through systematic retrieval of PubMed, Cochrane Library, Web of Science, EBSCO, and CNKI (National Knowledge Infrastructure), two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies by means of databases from inception to January 2023. The NMA was performed using the inconsistency model. A total of 43 studies, 2070 NAFLD patients were included: aerobic training (n = 779), resistance training (n = 159), high-intensity interval training (n = 160), aerobic training + resistance training (n = 96). The results indicate that aerobic training + resistance training could significantly improve serum total cholesterol (TC) (Surface under the cumulative ranking curve (SUCRA) = 71.7), triglyceride (TG) (SUCRA = 96.8), low-density lipoprotein cholesterol (LDL-C) (SUCRA = 86.1) in patients with NAFLD including triglycerides. Aerobic training is the best mode to improve ALT (SUCRA = 83.9) and high-density lipoprotein cholesterol (HDL-C) (SUCRA = 72.3). Resistance training is the best mode to improve aspartate transaminase (AST) (SUCRA = 81.7). Taking various benefits into account, we believe that the best modality of exercise for NAFLD patients is aerobic training + resistance training. In our current network meta-analysis, these exercise methods have different effects on the six indicators of NAFLD, which provides some reference for further formulating exercise prescription for NAFLD patients.

The binding affinity of human pediatric respiratory syncytial virus Phosphoprotein's C-terminal tail to nucleocapsid can be improved by a rationally designed halogen-bonded system.

Human respiratory syncytial virus (hRSV) is a common contagious virus that causes infections of pediatric pneumonia and specifically impacts infants and small children. The hRSV phosphoprotein is a key component of the viral RNA polymerase, which can interact with nucleocapsid and other partners through its C-terminal tail (CTT) to promote the formation of viral transcriptase complex, where the Phe241 is a key anchor residue. Based on the crystal template-modeled complex structure of hRSV nucleocapsid with a peptidic segment derived from the phosphoprotein's CTT, we successfully introduced a rationally designed halogen-bonded system to the complex interface by substituting para (p)-position of the side-chain phenyl moiety of CTT Phe241 residue with a halogen atom X (X = F, Cl, Br or I). The halogen-bonded system consists of a halogen bond (X-bond) between nucleocapsid Ser131 residue and CTT Phe241 residue as well as a hydrogen bond (H-bond) between nucleocapsid Ser131 residue and nucleocapsid Glu128 residue; the X-bond and H-bond share a common hydroxyl group of nucleocapsid Ser131 residue. High-level theoretical calculations suggested that bromine Br is the best choice that can render strong potency for the X-bond and can confer high affinity to the nucleocapsid-CTT binding. Affinity analysis revealed that the p-brominated CTT ([p]bCTT) exhibited 6.3-fold affinity improvement relative to its nonhalogenated counterpart. In contrast, the Br-substitutions at ortho (o)- and meta (m)-positions, which resulted in two negative controls of o-brominated [o]bCTT and m-brominated [m]bCTT, respectively, were unable to form effective X-bond with nucleocapsid according to theoretical investigation and did not improve the binding affinity essentially relative to native CTT.

Water-responsive 4D printing based on self-assembly of hydrophobic protein "Zein" for the control of degradation rate and drug release.

Four-dimensional (4D) printing is a promising technology that provides solutions for compelling needs in various fields. Most of the reported 4D printed systems are based on the temporal shape transformation of printed subjects. Induction of temporal heterogenicity in functions in addition to shape may extend the scope of 4D printing. Herein, we report a 4D printing approach using plant protein (zein) gel inspired by the amyloid fibrils formation mechanism. The printing of zein gel in a specialized layered-Carbopol supporting bath with different water concentrations in an ethanol-water mixture modulates hydrophobic and hydrogen bonding that causes temporal changes in functions. The part of the construct printed in a supporting bath with higher water content exhibits higher drug loading, faster drug release and degradation than those printed in the supporting bath with lower water content. Tri-segment conduit and butterfly-shaped construct with two asymmetrical wings are printed using this system to evaluate biomedical function as nerve conduit and drug delivery system. 4D printed conduits are also effective as a drug-eluting urethral stent in the porcine model. Overall, this study extends the concept of 4D printing beyond shape transformation and presents an approach of fabricating specialized baths for 4D printing that can also be extended to other materials to obtain 4D printed medical devices with translational potential.

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.

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.

Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

INTRODUCTION: SHANK3 is an important excitatory postsynaptic scaffold protein, and its mutations lead to genetic cause of neurodevelopmental diseases including autism spectrum disorders (ASD), Philan McDermid syndrome (PMS), and intellectual disability (ID). Early prevention and treatment are important for Shank3 gene mutation disease. Swimming has been proven to have a positive effect on neurodegenerative diseases. METHODS: Shank3 gene exon 11-21 knockout rats were intervened by a 40 min/day, 5 day/week for 8-week protocol. After the intervention, the rats were tested to behavioral measures such as learning and memory, and the volume and H-spectrum of the brain were measured using MRI; hippocampal dendritic spines were measured using Golgi staining and laser confocal. RESULTS: The results showed that Shank3-deficient rats had significant deficits in social memory, object recognition, and water maze learning decreased hippocampal volume and number of neurons, and lower levels of related scaffold proteins and receptor proteins were found in Shank3-deficient rats. CONCLUSION: It is suggested that early swimming exercise has a positive effect on Shank3 gene-deficient rats, which provides a new therapeutic strategy for the prevention and recovery of neurodevelopmental disorders.

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.