Glycyrrhetinic acid loaded in milk-derived extracellular vesicles for inhalation therapy of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors ß1 (TGF-ß1), Smad3 and inflammatory cytokines IL-6, IL-1ß and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF.

Protection function of 18ß-glycyrrhetinic acid on rats with high-altitude pulmonary hypertension based on 1H NMR metabonomics technology.

18ß-Glycyrrhetinic acid (GA) is the triterpenoid aglycone component of glycyrrhizic acid, a natural product of traditional Chinese medicine, and has been proven to possess a variety of pharmacological effects. The protection function and the mechanism of GA on rats with high-altitude pulmonary hypertension (HAPH) are studied using proton nuclear magnetic resonance (1H NMR) metabonomics technology and biochemical analysis. An HAPH model is established, and 60 male rats are randomly divided into the following groups: Control(normal saline, 0.4 mL/100 g), model (normal saline, 0.4 mL/100 g), Nifedipine (nifedipine, 2.7 mg/kg), and high-, medium-, and low-dose GA groups (100, 50, and 25 mg/kg GA designated as GA.H, GA.M, and GA.L, respectively). Serum biochemical indicators of rats in each group are measured, and pathological changes in the pulmonary artery are observed. 1H NMR metabonomics technology is used for serum analysis. Results show that GA can significantly reduce pulmonary arterial pressure and malondialdehyde levels and increase the glutathione peroxidase and superoxide dismutase activities in HAPH rats. Pathological results show that GA can alleviate pulmonary artery injuries of HAPH rats. Metabolomics analytical findings show that GA can alleviate the metabolic disorder of HAPH rats through anti-oxidation and anti-inflammatory effects, improve their bodies' ability to resist hypoxia, and restore various metabolic pathways (energy metabolism, amino acid metabolism, and lipid metabolism). GA has potential therapeutic effects on HAPH rats, but its target needs to be further studied.

18ß-Glycyrrhetinic acid inhibits the apoptosis of cells infected with rotavirus SA11 via the Fas/FasL pathway.

CONTEXT: 18ß-Glycyrrhetinic acid (18ß-GA), a pentacyclic triterpenoid saponin metabolite of glycyrrhizin, exhibits several biological activities. OBJECTIVE: We investigated the effects of 18ß-GA on MA104 cells infected with rotavirus (RV) and its potential mechanism of action. MATERIALS AND METHODS: Cell Counting Kit-8 was used to assess tissue culture infective dose 50 (TCID50) and 50% cellular cytotoxicity (CC50) concentration. MA104 cells infected with RV SA11 were treated with 18ß-GA (1, 2, 4, and 8 µg/mL, respectively). Cytopathic effects were observed. The virus inhibition rate, concentration for 50% of maximal effect (EC50), and selection index (SI) were calculated. Cell cycle, cell apoptosis, and mRNA and protein expression related to the Fas/FasL pathway were detected. RESULTS: TCID50 of RV SA11 was 10-4.47/100 µL; the CC50 of 18ß-GA on MA104 cells was 86.92 µg/mL. 18ß-GA showed significant antiviral activity; EC50 was 3.14 µg/mL, and SI was 27.68. The ratio of MA104 cells infected with RV SA11 in the G0/G1 phase and the G2/M phase decreased and increased, respectively, after 18ß-GA treatment. 18ß-GA significantly induced apoptosis in the infected cells. Furthermore, after 18ß-GA treatment, the mRNA and protein expression levels of Fas, FasL, caspase 3, and Bcl-2 decreased, whereas the expression levels of Bax increased. DISCUSSION AND CONCLUSIONS: The study demonstrates that 18ß-GA may be a promising candidate for the treatment of RV SA11 infection and provides theoretical support for the clinical development of glycyrrhizic acid compounds for the treatment of RV infection.

Potential therapeutic approaches for the early entry of SARS-CoV-2 by interrupting the interaction between the spike protein on SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2).

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread around the globe. At present, there is no precise and effective treatment for the patients with COVID-19, so rapid development of drugs is urgently needed in order to contain the highly infectious disease. The virus spike protein (S protein) can recognize the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane and undergo a series of conformational changes, protease cleavage and membrane fusion to complete the virus entry, so S protein is an important target for vaccine and drug development. Here we provide a brief overview of molecular mechanisms of virus entry, as well as some potential antiviral agents that act on S/ACE2 protein-protein interaction. Specifically, we focused on experimentally validated and/or computational prediction identified inhibitors that target SARS-CoV-2 S protein, ACE2 and enzymes associated with viral infection. This review offers valuable information for the discovery and development of potential antiviral agents in combating SARS-CoV-2. In addition, with the deepening understanding of the mechanism of SARS-CoV-2 infection, more targeted prevention and treatment drugs will be explored with the aid of the advanced technology in the future.

Glycyrrhetinic acid remodels the tumor microenvironment and synergizes with doxorubicin for breast cancer treatment in a murine model.

We aimed to combine glycyrrhetinic acid with doxorubicin to prepare, characterize and evaluate a drug delivery nano-system with REDOX sensitivity for the treatment of breast cancer. M-DOX-GA NPs prepared by nano sedimentation were spherical, with a particle size of 181 nm. And the maximum encapsulation efficiency and drug loading in M-DOX-GA NPs were 89.28% and 18.22%, respectively. Cytotoxicity and cellular uptake experiments of nanoparticles to KC cells, Cal-27 cells and 4T1 cells were studied by the CCK-8 method. The result indicated that M-DOX-GA NPs could accurately release the drug into the tumor cells, thus achieving the targeted release of the drug. Comparing the survival rate of the above three cells, it was found that M-DOX-GA NPs had a good tumor selectivity and had a more significant therapeutic effect on breast cancer. A 4T1-bearing mouse model was established, and the tumor inhibition rate was 77.37% after injection of nanoparticle solution for 14 d. Normal tissue H&E stained sections and TUNEL assay were verified M-DOX-GA NPs have excellent tumor suppressive effect, and can efficiently reduce the toxic side effects on normal organisms, and effectively avoided 4T1 cells metastasis. Immunofluorescence detection and Western-blot analysis figured a decline in both CUGBP1 and α-SMA, which verifying the TME remodeling induced by glycyrrhetinic acid. Collectively, the combination of doxorubicin and glycyrrhetinic acid is an effective and safe strategy for remodeling fibrotic TME by improving the therapeutic outcome for breast cancer.

Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor.

BACKGROUND: Therapeutic regimens of breast cancer treatment are increasingly inclined to adopt combination strategy based on the broad spectrum antitumor effect of doxorubicin (Dox). Currently, combination therapy comprises of conventional anti-cancer drugs and angiogenesis inhibitors have been corroborated as an effective approach in cancer treatment. PURPOSE: We explored the ability of a natural anti-angiogenic compound glycyrrhetinic acid (GA), derived from an edible-medicinal herb licorice, to enhance the breast cancer suppression effect of Dox. STUDY DESIGN: The drug ratio of GA and Dox with synergistic anticancer effect against MCF-7 cells was optimized by combination index (CI) value in vitro, followed by evaluation of the improved anticancer effects and reduced side-effects of this combination in vitro and in vivo. METHODS: Cell viability was measured by MTT assay. Analyses of mitochondrial membrane potential and cell apoptosis on MCF-7 cells were performed by JC-1 dye and Annexin V-FITC/PI assays. The cellular accumulation of Dox when combined with GA was evaluated. Levels of apoptosis-related proteins in MCF-7 cells were measured by Western blot analysis. Synergistic anti-angiogenic effects on HUVECs were evaluated. A breast cancer mouse model was established to investigate the anti-tumor effects in vivo. RESULTS: Based on the optimization by CI value, Dox and GA at 1:20 molar ratio was chosen as the optimal combination drug ratio that exhibited synergistic effect against MCF-7 breast cancer cells. In addition, the combination of GA and Dox exhibited significantly enhanced cytotoxicity, apoptosis, and loss of mitochondrial membrane potential via the upregulation of a mitochondrial-dependent apoptosis pathway against MCF-7 cells. Interestingly, the addition of GA increased the intracellular accumulation of Dox in MCF-7 cells. Moreover, VEGF-induced HUVECs proliferation, migration, and tube formation were strongly inhibited by Dox when used with GA via the significant down-regulation of VEGFR2-mediated pathway, indicating that the combination of Dox and GA could exhibit ideal synergistic anti-angiogenesis effect. Expectedly, the enhanced anti-tumor efficacy of Dox and reduced Dox-induced cardiotoxicity when used in combination with GA were evident in a mouse breast tumor model. CONCLUSIONS: These findings support that the combination of Dox with GA is a novel and promising therapeutic strategy for the treatment of breast cancer.

Functional recovery in human partial thickness skin wounds after application of multicomponent hydrolipidic film (MAS063DP): A prospective, open-label, comparative clinical trial.

Acute and minor skin wounds are common in daily life. However, in clinical practice, after initial management in the acute phase, the wounds are managed mainly through observation, and the patients are usually lost to follow-up. Considering a multicomponent hydrolipidic dressing (MAS063DP) long-known for its safe application in eczema and recently in laser-induced wounds, we aimed to evaluate its ability in functional recovery of impaired skin integrity during wound healing. Sixteen patients (N = 16) were enrolled and completed (n = 8 vs n = 8) this prospective, open-label, vehicle-controlled clinical trial with 12-week follow-up. Transepidermal water, skin viscoelasticity and bioimpedance analysis were measured initially, at the 1st, 4th, 8th, and 12th weeks. Improvements in these parameters were greater in the MAS063DP group (from 31.4 ± 9.0 to 16.4 ± 4.3 g/m2 h, P < .001; from 77 ± 16% to 88 ± 9%, P < .05; from 4182 ± 3823 to 2644 ± 1772 Ω) than in the white petrolatum group. No significant adverse events occurred, and all participants were more satisfied with the intervention. In this study, MAS063DP can restore skin integrity and reinstitute physiologic function as a feasible and safe intervention more markedly than management through observation during the healing process by providing protective hydrolipidic layer on the skin with simultaneous anti-inflammatory and antioxidant activities from its key ingredients such as glycyrrhetinic acid, Vitis vinifera, telmesteine, and vitamins C and E.

Evaluation of the Percutaneous Absorption of Drug Molecules in Zebrafish.

In recent decades, zebrafish (Danio rerio) has become a widely used vertebrate animal model for studying development and human diseases. However, studies on skin medication using zebrafish are rare. Here, we developed a novel protocol for percutaneous absorption of molecules via the zebrafish tail skin, by applying a liquid solution directly, or using a filter paper imbibed with a chemical solution (coating). Human skin is capable of absorbing felbinac and loxoprofen sodium hydrate (LSH), but not glycyrrhetinic acid (GA) and terbinafine hydrochloride (TH). To evaluate the possibility and the quality of transdermal absorption in zebrafish, we transdermally administered these four drugs to zebrafish. Pharmacokinetics showed that felbinac was present in the blood of zebrafish subjected to all administration methods. Felbinac blood concentrations peaked at 2 h and disappeared 7 h after administration. GA was not detected following transdermal administrations, but was following exposure. LSH was not found in the circulatory system after transdermal administration, but TH was. A dose-response correlation was observed for felbinac blood concentration. These findings suggest that zebrafish are capable of absorbing drug molecules through their skin. However, the present data cannot demonstrate that zebrafish is a practical model to predict human skin absorption. Further systemic studies are needed to observe the correlations in percutaneous absorption between humans and zebrafish.

Enhanced targeted delivery of adenine to hepatocellular carcinoma using glycyrrhetinic acid-functionalized nanoparticles in vivo and in vitro.

Hepatocellular carcinoma (HCC), a common malignancy in China and globally, is primarily treated through surgical resection and liver transplantation, with chemotherapy as a significant synergistic option. Adenine (Ade), a nucleobase, exhibits antitumor effects by blocking human hepatic carcinoma cells in S phase and inhibiting tumor cell proliferation. However, its use is limited owing to its low solubility, poor targeting ability, and nephrotoxicity. Therefore, liver-targeting drug delivery systems have attracted considerable attention for the treatment of HCC. In this study, we explored the liver-targeting efficacy and antitumor effect of adenine-loaded glycyrrhetinic acid-modified hyaluronic acid (Ade/GA-HA) nanoparticles in vitro and in vivo. The GA-HA nanoparticles possessed obvious targeting specificity toward liver cancer cells, which was mainly achieved by the specific binding of the GA ligand to the GA receptor that was highly expressed on the liver cell membrane. In vitro and in vivo results showed that Ade/GA-HA nanoparticles could inhibit liver cancer cell proliferation and migration, promote apoptosis, and significantly inhibit the growth of tumor tissues. Altogether, this study is the first to successfully demonstrate that the targeting activity and antitumor effect of Ade against HCC are enhanced by using GA-HA nanoparticles in vitro and in vivo.

Administration of glycyrrhetinic acid reinforces therapeutic effects of mesenchymal stem cell-derived exosome against acute liver ischemia-reperfusion injury.

Recent studies have shown that mesenchymal stem cell-derived exosome could attenuate ischaemia-reperfusion (I/R) injury by suppressing inflammatory response in the liver. Glycyrrhetinic acid was also shown to be capable of repressing the TLR4 signalling pathway. However, it remains to be explored as whether the combined administration of mesenchyma stem cell (MSC)-derived exosome and glycyrrhetinic acid (GA) could increase their therapeutic effects on I/R injury. Western blot was performed to evaluate the expression of proteins associated with inflammatory response in THP-1 cells and I/R rat models treated under different conditions. Flow cytometry was carried out to analyse the proportions of different subtypes of peripheral blood cells in I/R rats. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to assess the liver injury in I/R rats. Combined treatment with MSC-derived exosome and GA effectively maintained the expression of key proteins involved in inflammatory response in LPS stimulated THP-1 cells and THP-1 cells treated under hypoxia conditions. In the established of I/R rat models, GA administration reinforced the therapeutic efficiency of MSC-derived exosomes by maintaining the proportion of different subgroups of peripheral blood cells, decreasing the concentration of ALT and AST, and restoring the expression of dysregulated proteins associated with inflammation. Our results demonstrated that treatment with exosomes derived from mesenchymal stem cells (MSCs) attenuated liver I/R injury, while the pre-treatment with GA may further promote the therapeutic effect of mesenchymal stem cell-derived exosome against acute liver ischaemia-reperfusion injury.

18ß-Glycyrrhetinic Acid Improves Cardiac Diastolic Function by Attenuating Intracellular Calcium Overload.

Ranolazine, a late sodium current inhibitor, has been demonstrated to be effective on heart failure. 18ß-glycyrrhetinic acid (18ß-GA) has the similar inhibitory effect on late sodium currents. However, its effect on diastolic function is still unknown. This study aimed to determine whether 18ß-GA can improve the diastolic function and to explore the underlying mechanisms. Eighty male Sprague Dawley (SD) rats of Langendorff model were randomly divided into the following groups: group A, normal cardiac perfusion group; group B, ischemia-reperfusion group; group C, ischemia-reperfusion with anemoniasulcata toxin II (ATX-II); group D, ranolazine group; and group E, 18ß-GA group with four different concentrations. Furthermore, a pressure-overloaded rat model induced by trans-aortic constriction (TAC) was established. Echocardiography and hemodynamics were used to evaluate diastolic function at 14th day after TAC. Changes of free intracellular calcium (Ca2+) concentration was indirectly detected by laser scanning confocal microscope to confirm the inhibition of late sodium currents. With the intervention of ATX-II on ischemia reperfusion injury group, 5 µmol/L ranolazine, and 5, 10, 20, 40 µmol/L 18ß-GA could improve ATX-II-induced cardiac diastolic dysfunction. 630 mg/kg glycyrrhizin tablets could improve cardiac diastolic function in the pressure-overloaded rats. 18ß-GA and ranolazine had similar effects on reducing the free calcium in cardiomyocytes. The study demonstrates that 18ß-GA and glycyrrhizin could improve diastolic dysfunction induced by ischemia-reperfusion injury in Langendorff-perfused rat hearts and pressure-overloaded rats. The mechanism may be attributed to the inhibition of enhanced late sodium currents.

3D-printed microfluidic chip for the preparation of glycyrrhetinic acid-loaded ethanolic liposomes.

18-α-Glycyrrhetinic acid (GA) is a bioactive compound extracted from licorice that exhibits many biological and pharmacological effects such as anti-inflammatory and antioxidant activities on the skin. However, its lipophilic nature results in poor bioavailability that limits clinical applications. Liposomes, presenting the ability to carry both hydrophobic and hydrophilic payloads and a good cytocompatibility, are effective to overcome this barrier. Furthermore, the addition of permeation enhancers such as ethanol into liposomal formulations helps the diffusion of these systems through the skin barrier. Here, we aimed to formulate GA-loaded ethanolic liposomes, using a natural soybean lecithin via a microfluidic approach. Using a fused deposition modeling (FDM) 3D printer we customized a microfluidic chip, and manufactured vesicles that presented spherical shape with a size of 202 ± 5.2 nm, a narrow size distribution and a good stability over a period of 30 days. After reaching a drug encapsulation efficiency of 63.15 ± 2.2%, liposomes were evaluated for their cytocompatibility and skin permeation potentiality after hydrogelation using xanthan gum. The in vitro release and permeation studies were performed using Franz diffusion cells comparing two different media and three synthetic membranes including a polymeric skin-mimicking membrane. The selected formulation presented no cytotoxicity and an increased permeation compared to GA saturated hydrogel. It could perform therapeutically better effects than conventional formulations containing free GA, as prolonged and controlled release topical dosage forms, which may lead to improved efficiency and better patient compliance.

A comparison between mometasone furoate nasal spray and intranasal glycyrrhetic acid in patients with allergic rhinitis: a preliminary study in clinical practice.

Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction consequent to the exposure to the causal allergen. Glycyrrhetic acid (GlyAc) is a natural compound extracted from the liquorice that exerts anti-inflammatory activity. This real-life study compared intranasal GlyAc, present in a medical device containing also glycerol and mannitol, with mometasone furoate nasal spray (MFNS) in 50 adult outpatients with AR. Both treatments lasted 2 months. Endoscopic signs, perception of symptom severity, assessed by VAS, and nasal function measured by rhinomanometry were evaluated at baseline (T0), after one (T1) and two (T2) months. The intergroup analysis showed that at T1 there was no significant difference between groups about the use of decongestants and antihistamines, turbinate hypertrophy and pale mucosa, perception of olfaction and snoring. At T2 there was no significant difference between groups about use of relievers, all endoscopic signs, and perception of nasal discomfort, nasal obstruction, olfaction, and snoring. The intragroup analysis showed that in MFNS group there was a significant change during the entire period of treatment for all parameters except watery rhinorrhea (sign) and ocular discomfort; in GlyAc group there was a significant change during the entire period of treatment for all parameters. In conclusion, this preliminary study, conducted in clinical practice, evidenced that intranasal CysAC plus mannitol was able to significantly improve nasal endoscopic signs, perception of symptoms, and nasal function in patients with AR. Therefore, GlyAc could be a reasonable therapeutic option to control allergic inflammation.

A Previously Unknown Drug-Drug Interaction Is Suspected in Delayed Elimination of Plasma Methotrexate in High-Dose Methotrexate Therapy.

Background: High-dose methotrexate (HD-MTX) therapy is widely implemented for leukemia, osteosarcoma, and lymphoma. Although various measures have been taken to avoid toxicity from high serum MTX concentrations, there are many cases of delayed elimination of MTX. Objective: We suspected that delayed elimination of serum MTX was caused by unknown interactions between MTX and concomitant drugs. Methods: Concerning concomitant drugs in the case of delayed elimination of MTX, we performed screening tests in 35 patients who had undergone HD-MTX therapy. We then investigated the risk factors for delayed MTX elimination in 94 patients with leukemia, lymphoma, or osteosarcoma retrospectively. Results: The percentages of concomitant use of Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, and vincristine were higher in the delayed group. The percentage of delayed MTX elimination in patients receiving HD-MTX therapy was 41%. Multiple logistic regression analysis revealed that the concomitant use of SNMC solely was a significant risk factor for delayed MTX (odds ratio = 12.20; 95% CI = 1.06-139.84). Conclusion and Relevance: Concomitant use of SNMC was shown to be related to delayed elimination of serum MTX, and our results suggested a previously unknown drug-drug interaction between MTX and SNMC.

New Technological Approach for Glycyrrethic Acid Oral and Topical Administration.

BACKGROUND: 18ß- glycyrrhetinic acid (Gly) is the major bioactive component of licorice roots and rhizomes of the Glycyrrhiza glabra species. It shows many activities such as antiviral, anti-inflammatory, antioxidant, antimicrobial, and antifungal, however, its use in the health field is very limited due to the low water solubility. METHODS: This paper deals with the development of a new technological approach for Gly dissolution rate enhancement. It consists of Gly intercalation (guest) in the interlamellar spaces between the inorganic spaces (host) of the anionic clays "hydrotalcites" (HTlc) to obtain hybrids MgAl-HTlc-Gly and ZnAl-HTlc-Gly. Gly can find applications in both systemic and local therapies, thus advantages of the use of the hybrids in these two fields were investigated. RESULTS: Gly dissolution rate from hybrids in the intestinal environment, site in which it is preferentially absorbed, resulted enhanced (ZnAl-HTlc-Gly > MgAl-HTlc-Gly) compared to the crystalline form, thereby, making them suitable for oral administration as dry powder in hard capsules. For a local therapy, bioadhesive, vaginal emulgels loaded with the hybrids were developed. These showed suitable mucoadhesive property to the vaginal mucosa, necessary to prolong the residence time in the application site. The emulgel containing ZnAl-HTlc-Gly showed a faster and higher release profile than that containing MgAl- HTlc-Gly. CONCLUSION: The obtained results suggest that Gly intercalation into HTlc, especially in ZnAl-HTlc, allows to enhance Gly dissolution when the hybrids are formulated both as oral or topical products.

Glycyrrhetinic acid-modified graphene oxide mediated siRNA delivery for enhanced liver-cancer targeting therapy.

Graphene oxide (GO) has attracted huge attention in biomedical field in recent years. However, limited attempts have been invested in utilizing GO on active targeted delivery for gene therapy in liver cancer treatments. Glycyrrhetinic acid (GA) has been reported to be widely used as a targeting ligand to functionalize nanomaterials to treat hepatocellular carcinoma. In this article, GA is employed as a liver targeting ligand to construct GA, polyethylene glycol (PEG), polyamidoamine dendrimer (Dendrimer) and nano-graphene oxide (NGO) conjugate (GA-PEG-NGO-Dendrimer, GPND) for siRNA delivery for the first time. As we expected, GPND exhibited excellent stability, low toxicity, negligible hemolytic activity and remarkably high transfection efficiency in vitro. We also found effective VEGFa gene silencing in both mRNA and protein level in HepG2 cells. Notably, siRNA efficiently gathered in liver tumor tissues by the delivery of GPND, and eventually the growth of tumor tissues were inhibited with enhanced targeting capability and no obvious pathological changes. Moreover, histopathological results preliminarily support the high in vivo safety of GPND/anti-VEGFa siRNA nanocomplex. Collectively, GPND/siRNA nanocomplex, with high safety, targeting and transfection as well as prolonged half-life, is a promising nanomedicine and may provide a new direction for highly-specific targeted gene therapy.

18ß-Glycyrrhetinic acid: its core biological properties and dermatological applications.

Recently, attention has been focused on identifying natural herbal compounds with high biological activity, especially antioxidative, anti-inflammatory and antimicrobial properties, for preventing and controlling various skin conditions, including inflammation-related diseases such as atopic dermatitis and UV-induced skin photoaging. One key active plant ingredient is 18ß-glycyrrhetinic acid (GA), the main metabolite of glycyrrhizin (GL), obtained from licorice root. The review examines the valuable biological properties of GA, particularly those playing key roles in the treatment of various dermatological disorders in humans. The review highlights the key anti-inflammatory, antioxidant and antimicrobial properties of GA and its toxicity towards normal cells lines. It also examines the physicochemical properties of GA and presents methods of increasing its penetration through the stratum corneum and bioaccumulation with the use of modern delivery systems such as liposomes and nanoemulsions.

Récemment, l'attention s'est concentrée sur l'identification de composés naturels à base de plantes ayant une activité biologique élevée, en particulier des propriétés antioxydantes, anti-inflammatoires et antimicrobiennes, pour prévenir et contrôler diverses affections cutanées, y compris les maladies liées à l'inflammation telles que la dermatite atopique et le photovieillissement induit par les UV. Un ingrédient actif végétal clé est l'acide 18ß-glycyrrhétinique (GA), le principal métabolite de la glycyrrhizine (GL), obtenu à partir de la racine de réglisse. La revue examine les propriétés biologiques précieuses de l'AG, en particulier celles qui jouent un rôle clé dans le traitement de divers troubles dermatologiques chez l'homme. La revue met en évidence les propriétés anti-inflammatoires, anti-oxydantes et antimicrobiennes essentielles de l'AG et sa toxicité vis-à-vis des lignées cellulaires normales. Il examine également les propriétés physicochimiques de l'AG et présente des méthodes pour augmenter sa pénétration dans la couche cornée et sa bioaccumulation grâce à l'utilisation de systèmes d'administration modernes tels que les liposomes et les nanoémulsions.

Inhibiting hepatic gluconeogenesis by chitosan lactate nanoparticles containing CRTC2 siRNA targeted by poly(ethylene glycol)-glycyrrhetinic acid.

Diabetes mellitus is a chronic metabolic disorder characterized by insulin deficiency and impaired glucose metabolism. Overexpression of cAMP response element binding protein (CREB)-regulated transcriptional coactivator 2 (CRTC2) plays an important role in high gluconeogenesis in patients with diabetes type II. Using RNA interference technology for silencing CRTC2 gene expression could be helpful in controlling the level of blood glucose and gluconeogenesis. In this study, we designed a siRNA delivery platform comprising blended chitosan lactate (CT) and polyethylene glycol (PEG) conjugated with glycyrrhetinic acid (GA) for controlling gluconeogenesis. The nanoparticles showed spherical and smooth surface with ~ 189-nm size and + 5.1 zeta potential. Targeted nanoparticles were efficiently stable in serum and different levels of heparin media over 48 h. The gene knockdown efficiency of nanoparticles was comparable to Lipofectamine®, while they had no significant in vitro and in vivo toxicity. The in vivo therapeutic efficacy of targeted nanoparticles was also confirmed by reduced amount of fasting blood sugar in diabetic rat models. Furthermore, the nanoparticles were mostly accumulated in the liver after 2 h indicating the significant targeting ability of the prepared nanoparticles. Therefore, CT/PEG-GA nanoparticles can be considered as a potential candidate for targeted delivery of siRNA into hepatocytes in order to regulate gluconeogenesis in diabetes.

What's new in atopic eczema? An analysis of systematic reviews published in 2016. Part 1: treatment and prevention.

This review is part of a series of annual updates summarizing the evidence base for atopic eczema (AE). It provides a summary of key findings from 28 systematic reviews that were published or indexed during 2016 with a focus on treatment and prevention of AE. There is reasonable evidence of benefit for topical corticosteroids, calcineurin inhibitors, a glycyrrhetinic acid-containing preparation (Atopiclair® ), oral ciclosporin, oral azathioprine, narrowband ultraviolet B radiation and education programmes. Overall, there is evidence that topical corticosteroids and calcineurin inhibitors have similar efficacy and that both can prevent AE flares when used twice weekly as maintenance therapy. However, topical calcineurin inhibitors are costlier and have more adverse reactions, thus topical corticosteroids should remain the standard of care for patients with AE. There is no evidence that multiple applications are better than once-daily application of topical corticosteroid. There is inconsistent evidence to support omalizumab and specific allergen immunotherapy use in AE. There is some evidence that vitamin D supplementation and synbiotics reduce AE severity, although the margin of improvement may not be clinically meaningful. There is little evidence to support the use of wet wraps or of complementary/alternative medicine (including Chinese herbal medicine). There is some evidence to suggest that a diet high in fish in infancy may be preventative for AE, but other dietary interventions for the prevention of AE show little promise. This review provides a succinct guide for clinicians and patients wishing to remain up to date with the latest evidence for the treatment and prevention of AE.

Effect of glucocorticoids on androgen biosynthesis in the testes of the toad Rhinella arenarum (Amphibia, Anura).

In rat Leydig cells, glucocorticoids (GCs) inhibit testosterone production through the interaction with the glucocorticoid receptor (GR). However, the sensitivity of those cells to GCs is regulated by the enzyme 11ß-hydroxysteroid dehydrogenase Type 1 (11ß-HSD1). In the testes of the toad Rhinella arenarum, the presence of an 11ß-HSD similar to type 2 and a cytosolic GR has also been described. However, there is a lack of information regarding the effects of GCs on amphibian testicular steroidogenesis. In this study, the effects of corticosterone on androgen production, and the activity of two steroidogenic enzymes in toad testes were reported. Corticosterone inhibits androgen production via the GR because the GR antagonist RU486 prevents corticosterone-induced inhibition of testosterone. Corticosterone also reduced the activity of the cytochrome P450 17-hydroxylase, C17,20-lyase (Cyp450 c17 ) without affecting the 3ß-hydroxysteroid dehydrogenase/isomerase activity. This effect on Cyp450 c17 was likewise inhibited by RU486. On the other hand, corticosterone had no effect on the amount of steroidogenic acute regulator protein. These results suggest that GCs inhibit steroidogenesis in toad testes by reducing of Cyp450 c17 activity via a GR-mediated mechanism.