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.

The Anti-Inflammatory Properties of Licorice (Glycyrrhiza glabra)-Derived Compounds in Intestinal Disorders.

Intestinal diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancer (CRC), are a significant source of morbidity and mortality worldwide. Epidemiological data have shown that IBD patients are at an increased risk for the development of CRC. IBD-associated cancer develops against a background of chronic inflammation and oxidative stress, and their products contribute to cancer development and progression. Therefore, the discovery of novel drugs for the treatment of intestinal diseases is urgently needed. Licorice (Glycyrrhiza glabra) has been largely used for thousands of years in traditional Chinese medicine. Licorice and its derived compounds possess antiallergic, antibacterial, antiviral, anti-inflammatory, and antitumor effects. These pharmacological properties aid in the treatment of inflammatory diseases. In this review, we discuss the pharmacological potential of bioactive compounds derived from Licorice and addresses their anti-inflammatory and antioxidant properties. We also discuss how the mechanisms of action in these compounds can influence their effectiveness and lead to therapeutic effects on intestinal disorders.

Dipotassium Glycyrrhizinate on Melanoma Cell Line: Inhibition of Cerebral Metastases Formation by Targeting NF-kB Genes-Mediating MicroRNA-4443 and MicroRNA-3620-Dipotassium Glycyrrhizinate Effect on Melanoma.

Glycyrrhizic acid (GA), a natural compound isolated from licorice (Glycyrrhiza glabra), has exhibited anti-inflammatory and anti-tumor effects in vitro. Dipotassium glycyrrhizinate (DPG), a dipotassium salt of GA, also has shown an anti-tumor effect on glioblastoma cell lines, U87MG and T98G. The study investigated the DPG effects in the melanoma cell line (SK-MEL-28). MTT assay demonstrated that the viability of the cells was significantly decreased in a time- and dose-dependent manner after DPG (IC50 = 36 mM; 24 h). DNA fragmentation suggested that DPG (IC50) induced cellular apoptosis, which was confirmed by a significant number of TUNEL-positive cells (p-value = 0.048) and by PARP-1 [0.55 vs. 1.02 arbitrary units (AUs), p-value = 0.001], BAX (1.91 vs. 1.05 AUs, p-value = 0.09), and BCL-2 (0.51 vs. 1.07 AUs, p-value = 0.0018) mRNA compared to control cells. The proliferation and wound-healing assays showed an anti-proliferative effect on DPG-IC50-treated cells, also indicating an inhibitory effect on cell migration (p-values < 0.001). Moreover, it was observed that DPG promoted a 100% reduction in melanospheres formation (p-value = 0.008). Our previous microRNAs (miRs) global analysis has revealed that DPG might increase miR-4443 and miR-3620 expression levels. Thus, qPCR showed that after DPG treatment, SK-MEL-28 cells presented significantly high miR-4443 (1.77 vs. 1.04 AUs, p-value = 0.02) and miR-3620 (2.30 vs. 1.00 AUs, p-value = 0.01) expression compared to control cells, which are predicted to target the NF-kB, CD209 and TNC genes, respectively. Both genes are responsible for cell attachment and migration, and qPCR revealed significantly decreased CD209 (1.01 vs. 0.54 AUs, p-value = 0.018) and TNC (1.00 vs. 0.31 AUs, p-value = 2.38 × 10−6) mRNA expression levels after DPG compared to untreated cells. Furthermore, the migration of SK-MEL-28 cells stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) was attenuated by adding DPG by wound-healing assay (48 h: p-value = 0.004; 72 h: p-value = 7.0 × 10−4). In addition, the MMP-9 expression level was inhibited by DPG in melanoma cells stimulated by TPA and compared to TPA-treated cells (3.56 vs. 0.99 AUs, p-value = 0.0016) after 24 h of treatment. Our results suggested that DPG has an apoptotic, anti-proliferative, and anti-migratory effect on SK-MEL-28 cells. DPG was also able to inhibit cancer stem-like cells that may cause cerebral tumor formation.

Dipotassium glycyrrhizinate relieves leptospira-induced nephritis in vitro and in vivo.

Chronic leptospirosis usually occurs during sublethal doses infection of susceptible animal and reservoir host, which typical symptom is interstitial nephritis, and leptospira urine, contaminating the environment and threatening other susceptible animals and humans. Dipotassium glycyrrhizinate (DG) is a replacement for glycyrrhizic acid, which exhibits anti-inflammation, immunomodulation effects. This study is to investigate whether DG relieves leptospira-induced nephritis. In vitro, DG inhibited the leptospira-induced transcription levels of IL-1ß, IL-6, TNF-α, RANTES, MCP-1 and iNOS, and protein levels of IL-1ß and TNF-α, and downregulated NF-κB and MAPK pathway in TCMK-1 cells. In vivo, DG attenuated the kidney histopathological change and downregulated the expression of IL-1ß and TNF-α, as well as reduced kidney leptospiral burden. In summary, DG alleviated leptospira-induced inflammation through inhibitory NF-κB and MAPK pathway, and DG decreased the renal colonization of leptospires in mice.

Preparation and in vitro/in vivo evaluations of novel ocular micelle formulations of hesperetin with glycyrrhizin as a nanocarrier.

The purpose of this study was to explore the potential of formulating hesperetin into an ophthalmic solution with dipotassium glycyrrhizinate (DG) as a micelle nanocarrier. A DG-based micelle ophthalmic solution encapsulating hesperetin (DG-Hes) was developed and its in vitro/in vivo characterizations were evaluated. The optimal formulation featured a DG/hesperetin (Hes) weight ratio of 12:1 and an encapsulation efficiency of 90.4 ± 1.7%; The optimized DG-Hes was characterized as small uniform spheres with an average micelle size of 70.93 ± 3.41 nm, a polydispersity index of 0.11 ± 0.02, and an electrically negative surface (-36.12 ± 2.79 mV). The DG-Hes ophthalmic solution had good tolerance in rabbit eyes. DG-Hes significantly improved the in vitro passive permeation, ex vivo corneal permeation, and in vivo ocular bioavailability of Hes. DG-Hes showed markedly increases in in vitro antioxidant activity. In vitro antibacterial activity tests revealed a lower minimum inhibitory concentration and lower minimum bactericidal concentration for DG-Hes ophthalmic solution were lower than for free Hes. DG-Hes ophthalmic solution also significantly reduced symptoms of eye infection in the rabbit bacterial keratitis model when compared to a Hes suspension. These results suggest that DG-Hes eye drops may be useful as a new ophthalmic preparation for the treatment of ocular diseases, especially bacterial ophthalmopathy.

Glycyrrhizin micelle as a genistein nanocarrier: Synergistically promoting corneal epithelial wound healing through blockage of the HMGB1 signaling pathway in diabetic mice.

The purpose of this study was to explore the feasibility of targeting the HMGB1 signaling pathway to treat diabetic keratopathy with a dipotassium glycyrrhizinate-based micelle ophthalmic solution encapsulating genistein (DG-Gen), and to evaluate whether these dipotassium glycyrrhizinate (DG) micelles could synergistically enhance the therapeutic effect of encapsulated genistein (Gen). An optimized DG-Gen ophthalmic solution was fabricated with a Gen/DG weight of ratio 1:15, and this formulation featured an encapsulation efficiency of 98.96 ± 0.82%, and an average particle size of 29.50 ± 2.05 nm. The DG-Gen ophthalmic solution was observed to have good in vivo ocular tolerance and excellent in vivo corneal permeation, and to remarkably improve in vitro antioxidant activity. Ocular topical application of the DG-Gen ophthalmic solution significantly prompted corneal re-epithelialization and nerve regeneration in diabetic mice, and this efficacy might be due to the inhibition of HMGB1 signaling through down-regulation of HMGB1 and its receptors RAGE and TLR4, as well as inflammatory factor interleukin (IL)-6 and IL-1ß. In conclusion, these data showed that HMGB1 signaling is a potential regulation target for the treatment of diabetic keratopathy, and novel DG-micelle formulation encapsulating active agents such as Gen could synergistically cause blockage of HMGB1 signaling to prompt diabetic corneal and nerve wound healing.

Quantitative 1H Nuclear Magnetic Resonance Method for Assessing the Purity of Dipotassium Glycyrrhizinate.

A simple, rapid, accurate, and selective quantitative method based on 1H nuclear magnetic resonance (qNMR) was successfully established and developed for assessing the purity of dipotassium glycyrrhizinate (KG). In this study, using potassium hydrogen phthalate and fumaric acid as internal standard (IS), several important experimental parameters, such as relaxation delay and pulse angle, were explored. Reliability, specificity, linearity, limit of quantification, precision, stability, and accuracy were also validated. Calibration results obtained from qNMR were consistent with those obtained from HPLC coupled with ultraviolet detection. The proposed method, independent of the reference standard substance, is a useful, reliable, and practical protocol for the determination of KG and glycyrrhizin analogs.

Screening compounds of Chinese medicinal herbs anti-Marek's disease virus.

CONTEXT: Marek's disease (MD) seriously threatens the world poultry industry and has resulted in great economic losses. Chinese medicinal herbs are a rich source for lead compounds and drug candidates for antiviral treatments. OBJECTIVE: To investigate the anti-MDV activity and mechanism of 20 compounds extracted from Chinese medicinal herbs. MATERIALS AND METHODS: Antiviral assay, time of addition experiments, and virucidal assay were performed on chicken embryo fibroblast cells. The 50% cytotoxic concentration and 50% effective concentration were determined and, accordingly, selectivity index and inhibition ratio were calculated. RESULTS: Antiviral assay showed dipotassium glycyrrhizinate (DG) and sodium tanshinone IIA sulfonate (STS) exhibited significantly inhibitory activity against MDV in a dose-dependent manner. EC50 of DG and STS were 893.5 ± 36.99 µg/mL and 54.82 ± 2.99 µg/mL, and selective index (SI) were >3.36 and >9.12, respectively. Time of addition experiment and virucidal assay demonstrated DG inhibited viral replication in the full replication cycle and inactivated MDV particles in non-time-dependent manner, but STS interfered with the early stage of MDV replication and inactivated MDV particles in a time-dependent manner. Moreover, both DG and STS promoted apoptosis of cells infected by MDV. DISCUSSION AND CONCLUSION: DG and STS have great potential for developing new anti-MDV drugs for clinic application.

Effectiveness of perioperative oral hygiene management using a cetylpyridinium chloride-, dipotassium glycyrrhizinate, and tranexamic acid-based mouthwash as an adjunct to mechanical oral hygiene in patients with maxillomandibular fixation: A randomized controlled clinical trial.

OBJECTIVES: Maxillomandibular fixation requires the jawbones to remain static. Mechanical cleaning is also carried out by brushing or with a water flosser to maintain the oral cavity in a hygienic state, but this cannot be considered sufficient. Mouthwashes are used as a substitute for mechanical cleaning or in a supplementary role after such cleaning. The aim is to evaluate the effectiveness of HABITPRO mouthwash, which contains cetylpyridinium chloride, dipotassium glycyrrhizinate, and tranexamic acid in the specific environment created by maxillomandibular fixation used as an adjunct to mechanical cleaning. MATERIAL AND METHODS: A total of 55 patients who had undergone maxillomandibular fixation were randomly allocated to either a HABITPRO group (n = 29) or a placebo group (n = 26). To investigate their oral hygiene status, their plaque control record (PCR) was reviewed, and the caries-related bacterial counts, pH, acid buffering capacity, white blood cell count, and ammonia in saliva were measured immediately before maxillomandibular fixation, on Day 10 of fixation, and immediately after fixation was released. RESULTS: After approximately 2-3 weeks of mouthwash use, the PCR index also increased significantly in the placebo group compared with baseline, whereas it remained almost steady in the HABITPRO group. Additionally, salivary ammonia levels decreased significantly in the HABITPRO group compared to that of the placebo group. CONCLUSIONS: Even with maxillomandibular fixation, continued gargling with HABITPRO mouthwash in the perioperative period as an adjunct to mechanical cleaning can help maintain better oral hygiene and reduce bacterial counts.

Anti-histamine effects of dipotassium glycyrrhizinate on lung fibroblasts, implicating its therapeutic mechanism for pulmonary fibrosis.

OBJECTIVES: To examine the possible anti-histamine effects of dipotassium glycyrrhizinate (DG), a dipotassium salt of glycyrrhizic acid, on histamine-mediated lung fibroblast activation, differentiation and proliferation; to investigate the potential and underlying mechanisms for pulmonary fibrosis (PF) treatment. METHODS: Rat primary lung fibroblasts were extracted to establish cell models; histamine, DG and loratadine (LTD, a histamine receptor antagonist) were applied. Cell proliferation, migration and cell cycle were explored; intracellular signal proteins were detected; mitochondrial membrane potential was examined. KEY FINDINGS: The anti-histamine effects of DG were found in a similar pattern of LTD on lung fibroblasts. DG inhibited histamine-induced cell activation, proliferation and migration; DG altered histamine-mediated mitochondrial membrane potentials. DG reduced the histamine-induced PAR-2 (a tryptase receptor) expression to impair mast cell tryptase co-working. Histamine-induced expressions of MMP-2, FAK, TNF-α, P38, iNOS were decreased by DG, while Bax and caspase-3, P53 were increased by DG against histamine effects. Histamine drove cells from G0/G1 to S phases, whereas DG rested cells by inhibiting G0/G1 and G2/M phases. CONCLUSIONS: This study provided the evidences that DG can inhibit histamine-induced effects on lung fibroblasts and promote apoptosis of abnormally activated lung fibroblasts, implicating its potential therapeutic mechanisms against PF development, also for those histamine-related diseases.

Novel carvedilol-loaded pro-phytomicelles: formulation, characterization and enhanced protective efficacy against acetaminophen-inducedliverinjury in mice.

The work describes a novel, small-molecule phytochemicals as nanomaterials based pro-micelles (pro-phytomicelles) drug delivery system, for oral delivery of carvedilol (CAR). This novel nanoformulation of CAR, named CAR pro-phytomicelles, was prepared with rebaudioside A (RA) and dipotassium glycyrrhizinate (DG) as mixed nanomaterials. The formulation was optimized, leading to a 502-fold increase in solubility of CAR in water as a result of encapsulation within mixed phytomicelles based on DG and RA. CAR pro-phytomicelles samples could be instantly dissolved into aqueous media to formulate clear phytomicelle solutions with CAR encapsulation efficiency of 99.67 ± 0.02 %, and small micelle size of 15.62 ± 0.27 nm. CAR pro-phytomicelles exhibited good storage stability, rapid in vitro release in simulated intestinal fluid, and improved in vitro antioxidant activity. CAR pro-phytomicelles had good biocompatibility. Protective efficacy evaluation revealed that acetaminophen overdose could induce high mortality and severe liver injury in mice, while CAR pro-phytomicelle treatment exhibited significant protective effect against acetaminophen overdose. This protective efficacy was due to a mechanism that involved the regulation of high-mobility group box 1 and its signaling-related proinflammatory cytokines. These results show that pro-phytomicelles could provide a new concept and promising therapeutics as nanomedicines for improving the activities of CAR against acetaminophen-induced liver injury.

Anti-Migratory Effect of Dipotassium Glycyrrhizinate on Glioblastoma Cell Lines: Microarray Data for the Identification of Key MicroRNA Signatures.

The nuclear factor kappa B (NF-κB) pathway has been reported to be responsible for the aggressive disease phenomenon observed in glioblastoma (GBM). Dipotassium glycyrrhizinate (DPG), a dipotassium salt of glycyrrhizic acid isolated from licorice, has recently demonstrated an anti-tumoral effect on GBM cell lines U87MG and T98G through NF-κB suppression by IRAK2- and TRAF6-mediating microRNA (miR)-16 and miR-146a, respectively. Thus, the present study aimed to evaluate the expression profiles of miRNAs related to NF-κB suppression in T98G GBM cell line after DPG exposure using miRNA microarray (Affymetrix Human miRNA 4.0A), considering only predicted miRNAs as NF-κB regulator genes. Additional assays using U251 and U138MG cells were performed to validate the array results. DPG cytotoxicity was determined by (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and cellular apoptosis was quantified by DNA fragmentation and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The anti-proliferative effect was observed by cell proliferation and wound-healing assays, and the sphere formation assay examined whether DPG reduced stem cell subpopulation formation. The most over-expressed miRNAs were miR-4443 and miR-3620. The cytotoxic effect of DPG in U251 and U138MG was observed with an IC50 of 32 and 20 mM for 48 h, respectively. The IC50 of each cell line was used in all further assays. DPG treatment-induced apoptosis is observed by DNA fragmentation and increased TUNEL-positive cells. Cell proliferation and wound-healing assays showed an anti-proliferative and anti-migratory effect by DPG on the evaluated cell lines. In addition, DPG treatment led to a 100% reduction in sphere formation. The qPCR results in U251 and U138MG cells showed that DPG increased miR-4443 (2.44 vs. 1.11, p-value = 0.11; 8.27 vs. 1.25, p-value = 0.04) and miR-3620 expression (1.66 vs. 1.00, p-value = 0.03; 8.47 vs. 1.01, p-value = 0.03) and decreased CD209 (0.44 vs. 1.10, p-value = 0.03; 0.49 vs. 1.07, p-value = 0.04) and TNC (0.20 vs. 1.03, p-value = 0.001; 0.39 vs. 1.06, p-value = 0.01) mRNA levels compared to controls. Our results suggest that DPG inhibits cell viability by activating apoptosis and inhibiting cell proliferation and stem cell subpopulation formation through miR-4443 and miR-3620 upregulation. Both miRNAs are responsible for the post-transcriptional inhibition of NF-κB by CD209 and TNC modulation.

Preparation and characterization of a naringenin solubilizing glycyrrhizin nanomicelle ophthalmic solution for experimental dry eye disease.

An ophthalmic solution of naringenin (NAR) based on dipotassium glycyrrhizinate (DG) micelle solubilization, called DG-NAR, was prepared, and its effect on dry eye disease (DED) was evaluated. DG-NAR was a clear, colorless aqueous solution with small micelle size (24.75±0.52 nm), narrow size distribution of polydispersity index 0.273±0.160, and a high entrapment efficiency (99.67±0.51%). The solution also revealed good storage stability in a 12-week short-term storage evaluation; it also displayed good vivo ocular tolerance in rabbit eyes investigated via a slit lamp observation and histopathological examination. When observed under fluorescence microscopy, the solution further exhibited improved in vivo corneal permeation profiles in mice eyes. As expected, in a BAC-induced DED mouse model, ocular topical administration of DG-NAR achieved a remarkable efficacy against dry eye symptoms when compared to the DG&NAR physical mixture solution or free NAR solution; this included decreased rose bengal and fluorescein staining, increased tear volume and corneal sensitivities, alleviated histopathological symptoms, and reversed corneal epithelium and endothelium damages. Additionally, performance in some efficacy evaluation parameters were better than in the commercialized 0.1% hyaluronic acid sodium salt eye drops. This therapeutic effect can be attributed to the mechanisms regulating HMGB1 signaling and its related proinflammatory cytokines. Together, these in vitro/in vivo results suggested that this novel phytochemical-based nanoformulation of DG-NAR may be a promising candidate in the efficacious treatment of DED.

Natural Plant Compounds: Does Caffeine, Dipotassium Glycyrrhizinate, Curcumin, and Euphol Play Roles as Antitumoral Compounds in Glioblastoma Cell Lines?

Many plant-derived compounds are shown to be promising antitumor therapeutic agents by enhancing apoptosis-related pathways and cell cycle impairment in tumor cells, including glioblastoma (GBM) cell lines. We aimed to review four natural plant compounds effective in GBM cell lines as caffeine, dipotassium glycyrrhizinate (DPG), curcumin, and euphol. Furthermore, antitumoral effect of these plant compounds on GBM cell lines through microRNAs (miRs) modulation was investigated. However, only DPG and curcumin were found as effective on miR modulation. Caffeine arrests GBM cell cycle in G0/G1 phase by cyclin-dependent kinases (CDK) complex inhibition and by decreasing BCL-2 and increasing FOXO1 expression levels causing greater apoptotic activity. Caffeine can also directly inhibit IP3R3, p38 phosphorylation, and rho-associated protein kinase (ROCK), decreasing cell invasion and migration capacity or indirectly by inhibiting the tissue inhibitor metalloproteinase-1 (TIMP-1) and integrins ß1 and ß3, leading to lower matrix metalloproteinases, MMP-2 and MMP-9. DPG presents antitumoral effect in GBM cells related to nuclear factor kappa B (NF-κB) pathway suppression by IRAK2 and TRAF6-mediating miR-16 and miR-146a, respectively. More recently, it was observed that DPG upregulated miR-4443 and miR-3620, responsible for post-transcriptional inhibition of the NF-κB pathway by CD209 and TNC modulation, respectively leading to lower MMP-9 and migration capacity. Curcumin is able to increase miR-223-3p, miR-133a-3p, miR-181a-5p, miR-34a-5p, miR-30c-5p, and miR-1290 expression leading to serine or threonine kinase (AKT) pathway impairment and also it decreases miR-27a-5p, miR-221-3p, miR-21-5p, miR-125b-5p, and miR-151-3p expression causing p53-BCL2 pathway inhibition and consequently, cellular apoptosis. Interestingly, lower expression of miR-27a by curcumin action enhanced the C/EBP homologous protein(CHOP) expression, leading to paraptosis. Curcumin can inhibit miR-21 expression and consequently activate apoptosis through caspase 3 and death receptor (DR) 4 and 5 activation. Autophagy is controlled by the LC-3 protein that interacts with Atg family for the LC3-II formation and autophagy activation. Euphol can enhance LC3-II levels directly in GBM cells or inhibits tumor invasion and migration through PDK1 modulation.

Preparation and in vitro-in vivo evaluation of novel ocular nanomicelle formulation of thymol based on glycyrrhizin.

The development of an efficient ocular drug delivery system is helpful in improving the ocular diffusion of topically delivered drugs as well as enhancing drugs therapeutic efficacy. The objective of this study was to explore the potential of self-assembled nanomicelles based on glycyrrhizin in ocular topical applications. In brief, a dipotassium glycyrrhizinate (DG)-based nanomicelle ophthalmic solution encapsulating thymol (DG-THY) was developed using a simple thin-film dispersion method. The optimal formulation featured a DG/thymol (THY) weight ratio of 9:1 and an encapsulation efficiency of 98.25 ±â€¯1.16%; the nanomicelles were ultra-small spheres with an average particle size of 3.30 ±â€¯0.39 nm, a polydispersity index of 0.22 ±â€¯0.02, and an electrically negative surface (-[10.03 ±â€¯1.31] mV) for the optimized DG-THY. This DG-THY ophthalmic solution was observed to be stable upon good storage at both 4 °C and 25 °C for 12 weeks. The DG-THY was observed to remarkably improve in vitro antioxidant activity, in vitro release, and the membrane permeation of THY. The DG-THY ophthalmic solution proved to be very well-tolerated in a rabbit model. The DG-THY ophthalmic solution also demonstrated distinct improvements in the ex vivo and in vivo intraocular permeations of THY. The DG-THY ophthalmic solution also exhibited decreased minimal inhibitory concentrations and minimum bactericidal concentrations of THY. Treatment with the DG-THY ophthalmic solution significantly relieved ocular infection symptoms in rabbit eyes by lowering the number of colony-forming units recovered from the corneas. Therefore, these results demonstrate that DG-THY may be a promising new ophthalmic formulation for the treatment of ocular diseases, especially in terms of oxidative stress-, bacteria-, and inflammation-related eye diseases.

Ameliorating effect of dipotassium glycyrrhizinate on an IL-4- and IL-13-induced atopic dermatitis-like skin-equivalent model.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is not fully understood. Defects in skin barrier function and dysregulation of the Th2 immune response are thought to be pivotal in AD pathogenesis. In this study, we used keratinocytes and AD-like skin equivalent models using Th2 cytokines IL-4 and IL-13. The keratinocytes and AD-like skin model were used to investigate the effect of dipotassium glycyrrhizinate (KG), which is widely used as an anti-inflammatory agent for AD treatment. KG decreased AD-related gene expression in keratinocytes stimulated with Th2 cytokines. KG alleviated AD-like phenotypes and gene expression patterns and inhibited release of AD-related cytokines in the AD-like skin equivalent models. These findings indicate KG has potential effectiveness in AD treatment and AD-like skin equivalent models may be useful for understanding AD pathogenesis.

Growth Inhibitory Effects of Dipotassium Glycyrrhizinate in Glioblastoma Cell Lines by Targeting MicroRNAs Through the NF-κB Signaling Pathway.

It has been shown that nuclear factor kappa-B (NF-κB) is constitutively activated in glioblastoma (GBM), suggesting that the pathway could be a therapeutic target. Glycyrrhetic acid (GA), a compound isolated from licorice (Glycyrrhiza glabra), has been shown to decrease cell viability and increases apoptosis in human cancer cell lines by NF-κB signaling pathway suppression. Dipotassium glycyrrhizinate (DPG), a dipotassium salt of GA, has anti-inflammatory properties without toxicity. The current study examined the effectiveness of DPG as an anti-tumor in U87MG and T98G GBM cell lines. Additionally, we assessed DPG as a candidate for combinational therapy in GBM with temozolomide (TMZ). Our results demonstrated that the viability of U87MG and T98G cells significantly decreased in a time- and dose-dependent manner after DPG treatment, and the apoptotic ratio of DPG-treated groups was significantly higher than that of control groups. In addition, DPG in combination with TMZ revealed synergistic effects. Furthermore, the expression of NF-κB-luciferase-reporter in transfected GBM cell lines was remarkably reduced after DPG exposure by up-regulating miR16 and miR146a, which down-regulate its target genes, IRAK2 and TRAF6. A reduced neuro-sphere formation was also observed after DPG in both GBM cells. In conclusion, DPG presented anti-tumoral effect on GBM cell lines through a decrease on proliferation and an increase on apoptosis. In addition, our data also suggest that DPG anti-tumoral effect is related to NF-κB suppression, where IRAK2- and TRAF6-mediating miR16 and miR146a, respectively, might be a potential therapeutic target of DPG.

Calcium alginate microspheres containing metformin hydrochloride niosomes and chitosomes aimed for oral therapy of type 2 diabetes mellitus.

Metformin is an oral hypoglycemic agent used in the type 2 diabetes, whose poor bioavailability and short half-life make the development of effective extended-release formulations highly desirable. Different metformin-loaded chitosomal and niosomal formulations were developed and suitably characterized, but were unable to provide the desired sustained release. The entrapment of both kinds of colloidal dispersions in calcium alginate beads enabled to strongly reduce the amount of drug released at gastric level (from 18 up to a maximum of 30%), and to obtain a sustained release in simulated intestinal fluid, which was properly tuned by varying the percentage of calcium alginate in the beads. In vivo studies on rats revealed a significant improvement of metformin hypoglycemic effect when orally administered as chitosomal and even more as niosomal dispersion entrapped in alginate beads, not only with respect to the drug as such, but also to the alginate beads loaded with the plain drug. The more intense and sustained therapeutic effect with time provided by the drug-in niosomes-in alginate bead formulation could be very profitable for maintaining tight blood glucose levels over prolonged period of time after oral administration, allowing a reduction of its dose and related collateral effects, and improving patient compliance.