18β-glycyrrhetinic Acid Research Articles

Synthesis and Anti-HCV Activities of 18β-Glycyrrhetinic Acid Derivatives and Their In-Silico ADMET Analysis

Synthesis and Anti-HCV Activities of 18β-Glycyrrhetinic Acid Derivatives and Their In-Silico ADMET Analysis

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

18β-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.

β-Glycyrrhetinic acid inhibits the bacterial growth and biofilm formation by supragingival plaque commensals.

β-Glycyrrhetinic acid (BGA) is a natural antibacterial agent. Previous studies reported that BGA has antibacterial effects against several bacteria. This study evaluated the effects of BGA on the regulation of supragingival plaque bacteria. First, the minimum inhibitory concentrations (MICs) of BGA against oral bacteria were measured. Next, the minimum concentrations for inhibition of biofilm formation were evaluated against Streptococcus mutans and Streptococcus sobrinus, possessing insoluble glucan synthesis abilities. The MICs of biofilm formation by these bacteria ranged from 1/8 to 2× MIC. Furthermore, the inhibition effects of BGA against the coaggregation of Porphyromonas gingivalis and Streptococcus gordonii were evaluated. BGA at 32 or 64 μg/mL inhibited the coaggregation of these bacteria after a 30 min incubation. Lastly, the inhibition effects of BGA against human supragingival plaque bacteria were evaluated. Human supragingival plaque samples were obtained from 12 healthy donors. The inhibition effects of BGA against biofilm formation by these plaque bacteria were evaluated. Of 12 samples, the biofilm formation by 11 was significantly attenuated by 128-256 μg/mL of BGA. The number of colony forming units in these biofilms was also significantly attenuated. In conclusion, it was revealed that BGA inhibits the growth and biofilm formation of bacteria, furthermore, the same effect was confirmed with supragingival plaque bacteria. BGA is a good candidate for a natural agent that prevents the outbreak and progression of periodontal disease because it suppresses not only the growth and biofilm formation of bacteria, but also the coaggregation of P. gingivalis with plaque bacteria.

A novel 18β-glycyrrhetinic acid derivative supramolecular self-assembly hydrogel with antibacterial activity

A novel 18β-glycyrrhetinic acid derivative supramolecular self-assembly hydrogel with antibacterial activity

Anti-inflammatory and Pro-apoptotic Effects of 18beta-Glycyrrhetinic Acid In Vitro and In Vivo Models of Rheumatoid Arthritis.

18β-Glycyrrhetinic acid (18β-GA), an active component from Glycyrrhiza glabra L. root (licorice), has been demonstrated to be able to protect against inflammatory response and reduce methotrexate (MTX)-derived toxicity. This study was therefore designed to test the therapeutic possibility of 18β-GA on rheumatoid arthritis (RA) and to explore the underlying mechanism. LPS or TNF-α-induced inflammatory cell models and collagen-induced arthritis (CIA) animal models were applied in this study. Real-time quantitative PCR (RT-qPCR) was used to measure the mRNA levels of various cytokines and FOXO family members. The protein levels of molecules in the MAPK/NF-κB signaling pathway were analyzed using western blot. The cell proliferation assay and colony-forming assay were used to test the influence of 18β-GA on cell viability. The cell apoptosis assay and cell cycle assay were performed to detect the effect of 18β-GA on cell proliferative capacity by using flow cytometry. Hematoxylin and eosin (H&E) staining was performed to evaluate pathological changes after drug administration. The enzyme-linked immunosorbent assay (ELISA) was carried out for the detection of cytokines in serum. In vitro, we found that 18β-GA decreased the mRNA levels of IL-1β, IL-6, and COX-2 by inhibiting the MAPK/NF-κB signaling pathway in MH7A and RAW264.7 cell lines. Moreover, 18β-GA was able to suppress cell viability, trigger cell apoptosis, and G1 phase cell cycle arrest in our in vitro studies. 18β-GA dramatically enhanced the mRNA level of FOXO3 in both TNF-α- and LPS-induced inflammation models in vitro. Interestingly, after analyzing GEO datasets, we found that the FOXO3 gene was significantly decreased in the RA synovial tissue as compared to healthy donors in multiple microarray studies. In vivo, 18β-GA exhibited a promising therapeutic effect in a collagen-induced arthritis mouse model by alleviating joint pathological changes and declining serum levels of TNF-α, IL-1β, and IL-6. Finally, we observed that 18β-GA administration could mitigate liver damage caused by collagen or MTX. Collectively, the current study demonstrates for the first time that 18β-GA can inhibit inflammation and proliferation of synovial cells, and the underlying mechanism may be associated with its inhibition of MAPK/NF-κB signaling and promotion of FOXO3 signaling. Therefore, 18β-GA is expected to be a new drug candidate for RA therapy.

Controlled Release of 18-β-Glycyrrhetinic Acid from Core-Shell Nanoparticles: Effects on Cytotoxicity and Intracellular Concentration in HepG2 Cell Line.

18β-glycyrrhetinic acid (GA) is a pentacyclic triterpene with promising hepatoprotective and anti-Hepatocellular carcinoma effects. GA low water solubility however reduces its biodistribution and bioavailability, limiting its applications in biomedicine. In this work we used core-shell NPs made of PolyD-L-lactide-co-glycolide (PLGA) coated with chitosan (CS), prepared through an osmosis-based methodology, to efficiently entrap GA. NPs morphology was investigated with SEM and TEM and their GA payload was evaluated with a spectrophotometric method. GA-loaded NPs were administered to HepG2 cells and their efficiency in reducing cell viability was compared with that induced by the free drug in in vitro tests. Cell viability was evaluated by the MTT assay, as well as with Electric Cells-Substrate Impedance Sensing (ECIS), that provided a real-time continuous monitoring. It was possible to correlate the toxic effect of the different forms of GA with the bioavailability of the drug, evidencing the importance of real-time tests for studying the effects of bioactive substances on cell cultures.

Liquiritin enhancing intestinal absorption of paeoniflorin in in situ single-pass intestinal perfusion and in vitro Caco-2 cell monolayer absorption models

Background: Paeoniflorin and liquiritin are the primary active components of Shaoyao-Gancao-tang (SGT), a classical prescription for reducing pains. However, the interaction of paeoniflorin and liquiritin during intestinal absorption needs to be further studied. Objectives: In this study, we aimed to determine the interaction of paeoniflorin and liquiritin during intestinal absorption. Materials and Methods: The interaction between paeoniflorin and liquiritin (100 μM) was studied using in situ single-pass intestinal perfusion (SPIP) model use the whole small intestine and in vitro Caco-2 cell monolayer bidirectional transport model. Results: In situ SPIP research demonstrated that liquiritin significantly increased the Ka, Papp, absorption rate, and cumulative amount of paeoniflorin up to 7.97, 8.98, 7.07, and 10.71 folds, respectively, even higher than that of verapamil, a specific P-gp inhibitor, and control. Furthermore, 18 β-glycyrrhetinic acid (18 β-GA) markedly increased the Ka, Papp, absorption rate, and cumulative amount of paeoniflorin up to 3.30, 3.27, 3.42, and 4.04 folds, respectively. Bidirectional transport studies indicated that liquiritin and paeoniflorin could prompt the absorption of each other by increasing the Papp (AP-BL) of paeoniflorin and liquiritin from (3.83 ± 0.51) ×10−7 to (5.60 ± 0.51) ×10−7 cm/s and (3.86 ± 0.34) ×10−7 to (8.26 ± 0.51) ×10−7 cm/s, respectively. The 18 β-GA significantly prompted the Papp (AP-BL) of paeoniflorin to (5.54 ± 0.92) ×10−7 cm/s. Conclusion: Liquiritin and paeoniflorin increased the absorption of each other. This could provide essential reference to predict the oral bioavailability, the pharmacokinetics, and the clinical application of coadministration of liquiritin-and paeoniflorin-containing SGT and other herbal formulas.

The protective effects of 18β-glycyrrhetinic acid against acrylamide-induced cellular damage in diabetic rats.

This study was aimed at elucidating the protective effects of 18β-glycyrrhetinic acid (18βGA) against acrylamide (Acr)-induced cellular damage in diabetic rats. Rats were randomly assigned into eight groups (n = 8) following 12 h of fasting: control group, a single dose of 50 mg/kg streptozotocin (STZ) intraperitoneally (diabetic group), 50 mg/kg 18βGA orally after 2 weeks from STZ injection (18βGA group), 20 mg/kg Acr after 1month from STZ injection (Acr group), STZ plus Acr (STZ-Acr group), STZ plus 18βGA (STZ-18βGA group), Acr plus 18βGA (Acr-18βGA group), or STZ plus Acr plus 18βGA (STZ-Acr-18βGA group). Administration of 18βGA alone increased GSH, GSH-PX, SOD, and CAT in both liver and kidneys. While STZ injection was associated with diabetic and oxidative stress changes as indicated by the higher serum glucose, cholesterol, creatinine, IL-1β, IL-6, TNF-α, and antioxidant enzyme activities, together with increased lipid peroxides and decreased antioxidant biomarkers in the liver and kidneys. Similarly, the co-administration of STZ and Acr was associated with similar, more augmented effects, compared to STZ alone. The administration of 18βGA normalized STZ and Acr-induced elevations in oxidative defense variables in the liver and kidney tissues and blood biomarkers. Thus, our study demonstrated that the damaging effects of Acr were more exaggerated in diabetic rats. Furthermore, it showed the ability of 18βGA to inhibit reactive oxygen species generation and restore the antioxidant defenses in diabetic rats with Acr-induced liver and kidney cytotoxicity.

Formulation of pH-responsive lipid-polymer hybrid nanoparticles for co-delivery and enhancement of the antibacterial activity of vancomycin and 18β-glycyrrhetinic acid

Despite advancement in the control and therapeutics of infectious diseases, antimicrobial resistance remains a global burden. Hence there is a need for novel strategies that improve and potentiate available antibiotics to prevent a regress to a pre-antibiotic era. This study aimed to co-deliver vancomycin (VCM) and 18β-glycyrrhetinic acid (GA) via pH-responsive lipid-polymer hybrid nanoparticles (VCM-GAPAH-LPHNPs) to explore its potential for enhanced activity and targeted delivery of VCM. The stability of VCM-GAPAH-LPHNPs were supported by in silico studies. Biosafe VCM-GAPAH-LPHNPs were prepared using the microemulsion technique. VCM-GAPAH-LPHNPs demonstrated size, polydispersity index, zeta potential and encapsulation efficiency of 198.4 ± 0.302 nm, 0.255 ± 0.003, −3.8 ± 0.335 mV and 69.46 ± 2.52%, respectively. In vitro drug release studies revealed that VCM-GAPAH-LPHNPs had sustained and faster release at acidic conditions compared to bare VCM. VCM-GAPAH-LPHNPs also demonstrated greater in vitro antibacterial potential against methicillin-resistant Staphylococcus aureus by 16-fold, when compared to the bare drug. Additionally, the time-killing assay indicated the ability of VCM-GAPAH-LPHNPs to eliminate 75% of MRSA in less than 12 h. Furthermore, crystal violet assay confirmed VCM-GAPAH-LPHNPs potential to eliminate biofilms. Therefore, these novel LPHNPs may serve as promising nanocarriers for enhancing antibiotic drug delivery and antibacterial activity.

WITHDRAWN: Formulation & evaluation of β-glycyrrhetinic acid patches with natural bioenhancer

Abstract The main of the present investigation is to prepare and evaluate the patches of 18β-glycyrrhitic acid with synthetic polymers. For reservoir type patch drug and polymer selected were 18 β-glycyrrhetinic acid and carbopol 934. Infrared spectra were recorded using FTIR equipment by the potassium bromide disc method at wavelength range between 4000 and 400 cm−1. 23 factorial design was employed to study the effect of independent variables (gel base, penetration enhancer, rate controlling membrane) on dependent variable (% drug release). The patches were evaluated on the basis of percentage drug content, permeation, skin irritancy test and stability studies. White colour powder, tasteless, odourless. It is freely soluble in ethanol, chloroform. Melting point: 294°C. Infrared absorption spectroscopy (IR) of 18 β- glycyrrhetinic acid showed sharp band at 603, 1380, 1612, 1715 and 1760 cm−1 due to stretching vibration bands of aromatic ring, –CH3, C = C (Cyclic), C = O and –COOH respectively. API (18 β-glycyrrhetinic acid) exhibited peak at 293.9°C accordance with its melting point (292–297°C). CONCLUSION- Reservoir type F4 patch formulated using 5% menthol, 42% ethanol, 50 g carbopol934 gel base with 0.5% piperine as bioenhancer. The present study was one of the few attempts to incorporate phytconstituents in transdermal system and it needs to be further optimized and characterised. These types of herbal formulations possess tremendous potential for the treatment of some of the disease.

A Novel N-Tert-Butyl Derivatives of Pseudothiohydantoin as Potential Target in Anti-Cancer Therapy.

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of glucocorticosteroids, may contribute to the development and implementation of new therapeutic options in the treatment process. Our research focuses on understanding the role of 11β-HSD1 and 11β-HSD2 as factors involved in the differentiation and proliferation of neoplastic cells. In this work, we obtained the 9 novel N-tert-butyl substituted 2-aminothiazol-4(5H)-one (pseudothiohydantoin) derivatives, differing in the substituents at C-5 of the thiazole ring. The inhibitory activity and selectivity of the obtained derivatives in relation to two isoforms of 11β-HSD were evaluated. The highest inhibitory activity for 11β-HSD1 showed compound 3h, containing the cyclohexane substituent at the 5-position of the thiazole ring in the spiro system (82.5% at a conc. 10 µM). On the other hand, the derivative 3f with the phenyl substituent at C-5 showed the highest inhibition of 11β-HSD2 (53.57% at a conc. of 10 µM). A low selectivity in the inhibition of 11β-HSD2 was observed but, unlike 18β-glycyrrhetinic acid, these compounds were found to inhibit the activity of 11β-HSD2 to a greater extent than 11β-HSD1, which makes them attractive for further research on their anti-cancer activity.

Network Pharmacology-Based Strategy for Elucidating the Molecular Basis Forthe Pharmacologic Effects of Licorice (Glycyrrhiza spp.)

Licorice (Glycyrrhiza spp.) is used widely in traditional Chinese medicine (TCM) due to its numerous pharmacologic effects. However, the mechanisms of action of the chemical constituents of licorice and their structure–function relationships are not fully understood. To address these points, we analyzed the chemical compounds in licorice listed in the TCM Systems Pharmacology database and TCM Integrated database. Target proteins of the compounds were predicted using Integrative Pharmacology-based Research Platform of TCM v2.0. Information on the pharmacologic effects of licorice was obtained from the 2020 Chinese Pharmacopoeia, and disease-related genes that have been linked to these effects were identified from the Encyclopedia of TCM database. Pathway analyses using the Kyoto Encyclopedia of Genes and Genomes database were carried out for target proteins, and pharmacologic networks were constructed based on drug target–disease-related gene and protein–protein interactions. A total of 451 compounds were analyzed, of which 211 were from the medicinal parts of the licorice plant. The 241 putative targets of 106 bioactive compounds in licorice comprised 52 flavonoids, 47 triterpenoids, and seven coumarins. Four distinct pharmacologic effects of licorice were defined: 61 major hubs were the putative targets of 23 compounds in heat-clearing and detoxifying effects; 68 were targets of six compounds in spleen-invigorating and qi-replenishing effects; 28 were targets of six compounds in phlegm-expulsion and cough-suppressant effects; 25 compounds were targets of six compounds in spasm-relieving and analgesic effects. The major bioactive compounds of licorice were identified by ultra-high-performance liquid chromatography–quadrupole time-of-flight–tandem mass spectrometry. The anti-inflammatory properties of liquiritin apioside, liquiritigenin, glycyrrhizic acid and isoliquiritin apioside were demonstrated by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Liquiritin apioside, liquiritigenin, isoliquiritin, isoliquiritin apioside, kaempferol, and kumatakenin were the main active flavonoids, and 18α- and 18β-glycyrrhetinic acid were the main active triterpenoids of licorice. The former were associated with heat-clearing and detoxifying effects, whereas the latter were implicated in the other three pharmacologic effects. Thus, the compounds in licorice have distinct pharmacologic effects according to their chemical structure. These results provide a reference for investigating the potential of licorice in treatment of various diseases.

Use of 18β-glycyrrhetinic acid nanocrystals to enhance anti-inflammatory activity by improving topical delivery

18β-Glycyrrhetinic acid (GA) is often topically applied in clinical treatment of inflammatory skin diseases. However, GA has poor solubility in water, which results in poor skin permeability and low bioavailability. Nanocrystallization of drugs can enhance their permeability and improve bioavailability. We prepared GA nanocrystals (Nano GA) by high-pressure homogenization. These nanocrystals were characterized by photon correlation spectroscopy, scanning electron microscopy, thermogravimetric analysis, and X-ray diffractometry. The ability of Nano GA to improve dermal permeability was investigated ex vivo using Franz diffusion vertical cells and mouse skin. The topical anti-inflammatory activity of Nano GA was assessed in vivo by a 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced model in mouse ears. The average particle size of a GA nanocrystalline suspension was 288.6 ± 7.3 nm, with a narrow particle-size distribution (polydispersity index ∼0.13 ± 0.10), and the particle size of the lyophilized powder increased (552.0 ± 9.8 nm). After nanocrystallization, the thermal stability and crystallinity decreased but solubility increased significantly. Nano GA showed higher dermal permeability than Coarse GA. Macroscopic and staining-based observations of mouse ears and the levels of proinflammatory factors and myeloperoxidase revealed that the Nano GA hydrogel exhibited better anti-edema ability and more strongly inhibited inflammation development than the Coarse GA hydrogel and indomethacin hydrogel (positive drug). These results suggest that Nano GA could be an efficacious topical therapeutic agent for skin inflammation.

Development of sodium carboxymethyl cellulose based polymeric microparticles for in situ hydrogel wound dressing formation

18β-glycyrrhetinic acid (Gly), a natural compound obtained from licorice, is known both for the anti-inflammatory and antioxidant activities and for this reason useful for wound treatment. Due to its poor solubility, Gly is not suitable for formulations used in conventional topical products such as gels, foams and creams. Polymeric bioadhesive microparticles (MP), loaded with Gly, were developed to be introduced in the wound bed and swell, once in contact with the exudate, to form a hydrogel in situ able to close the wound. The MP were prepared by spray drying method from the polymeric solution of polysaccharide sodium carboxymethyl cellulose (CMC) and copolymer Soluplus® (SL). Soluplus® introduction in MP composition, using a 3:1 ratio (CMC/SL wt./wt.), allowed to stabilize Gly in non-crystalline form, favoring the improvement of water solubility, and to obtain a spherical with rugged surface MP morphology. Ex vivo studies showed these MP maintain high swelling capability and are able to form in situ a hydrogel for wound repair. The controlled release of Gly from the hydrogel stimulates keratinocyte growth, potentially supporting the physiological healing processes.

18β-Glycyrrhetinic acid alleviates demyelination by modulating the microglial M1/M2 phenotype in a mouse model of cuprizone-induced demyelination

This research aimed to examine the nutritious supplementary function of 18β-Glycyrrhetinic acid (18β-GA) in moderating the myelin sheath destruction and behavioral impairments observed in the cuprizone model of demyelination. Mice were fed daily on food containing cuprizone (0.3 %) and given doses of 18β-GA (5 or 1 mg/kg) for a period of five weeks. The groups treated with 18β-GA exhibited improvements in exploratory behavior, locomotive activity, and weight. As assessed using luxol-fast blue and myelin basic protein (MBP) staining, which were used to detect demyelination in the brain, 18β-GA both reduced and prevented instances of cuprizone-induced demyelinating lesions; treatment with 18β-GA also caused the MBP level in the corpus callosum to increase. Furthermore, alongside these positive results following 18β-GA treatment, microglial polarisation was also observed to shift towards the beneficial M2 phenotype. The results of this research thus indicate the potential clinical application of 18β-GA for the prevention of myelin damage and behavioral dysfunction.

Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents

A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus spp. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative 33 showed good potency against all four Staphylococcus spp. (MIC = 1.25–5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase to rationalize the observed antibacterial activity. This series of GA derivatives has strong potential for the development of a new type of triterpenoid antibacterial agent.

Ultrasound-assisted extraction for simultaneous quantitation of potential sweetening compounds from Derris reticulata aqueous extracts: a response surface methodology approach

Derris reticulata or “Oi Sam Saun” is an extremely sweet Thai plant, rich in bioactive compounds, and widely used for its medicinal properties. In this study, sweet aqueous extracts from the stems of “Oi Sam Saun” were prepared using ultrasound-assisted extraction (UAE). Phenolic, flavonoid, and sugar compound extraction was optimised using response surface methodology based on the Box–Behnken design (BBD). Three independent variables—extraction temperature (40–80 °C), sonication time (20–60 min), and extraction ratio (1:10–1:30 g/mL)—were investigated, and the values of 80 °C, 60 min, and a ratio 1:10 g/mL, respectively, were optimal. Under these conditions, experimental values were well correlated with predicted values, and phenolic, flavonoid, and sugar contents were 0.483 ± 0.032 mg GAE/g DW, 0.149 ± 0.033 mg CE/g DW, and 4.802 ± 0.651 mg/g DW, respectively. High performance liquid chromatography-diode array detector (HPLC–DAD) analysis showed that the “Oi Sam Saun” UAE extract contained gallic acid, p-coumaric acid, quercetin, and kaempferol. Moreover, the extract contained 18β-glycyrrhetinic acid (0.529 ± 0.002 mg/100 mg) and was 166 times sweeter than sucrose. Therefore, this Thai medicinal plant, which has several pharmacological benefits, is highly potent and can be utilised as a sweetening agent or sugar substitute in foods.

Carbenoxolone and 18β-glycyrrhetinic acid inhibit inositol 1,4,5-trisphosphate-mediated endothelial cell calcium signalling and depolarise mitochondria.

Background and PurposeCoordinated endothelial control of cardiovascular function is proposed to occur by endothelial cell communication via gap junctions and connexins. To study intercellular communication, the pharmacological agents carbenoxolone (CBX) and 18β‐glycyrrhetinic acid (18βGA) are used widely as connexin inhibitors and gap junction blockers.Experimental ApproachWe investigated the effects of CBX and 18βGA on intercellular Ca2+ waves, evoked by inositol 1,4,5‐trisphosphate (IP3) in the endothelium of intact mesenteric resistance arteries.Key ResultsAcetycholine‐evoked IP3‐mediated Ca2+ release and propagated waves were inhibited by CBX (100 μM) and 18βGA (40 μM). Unexpectedly, the Ca2+ signals were inhibited uniformly in all cells, suggesting that CBX and 18βGA reduced Ca2+ release. Localised photolysis of caged IP3 (cIP3) was used to provide precise spatiotemporal control of site of cell activation. Local cIP3 photolysis generated reproducible Ca2+ increases and Ca2+ waves that propagated across cells distant to the photolysis site. CBX and 18βGA each blocked Ca2+ waves in a time‐dependent manner by inhibiting the initiating IP3‐evoked Ca2+ release event rather than block of gap junctions. This effect was reversed on drug washout and was unaffected by small or intermediate K+‐channel blockers. Furthermore, CBX and 18βGA each rapidly and reversibly collapsed the mitochondrial membrane potential.Conclusion and ImplicationsCBX and 18βGA inhibit IP3‐mediated Ca2+ release and depolarise the mitochondrial membrane potential. These results suggest that CBX and 18βGA may block cell–cell communication by acting at sites that are unrelated to gap junctions.

Grafting of 18β-Glycyrrhetinic Acid and Sialic Acid onto Chitosan to Produce a New Amphipathic Chitosan Derivative: Synthesis, Characterization, and Cytotoxicity.

Chitosan is the only cationic polysaccharide found in nature. It has broad application prospects in biomaterials, but its application is limited due to its poor solubility in water. A novel chitosan derivative was synthesized by amidation of chitosan with 18β-glycyrrhetinic acid and sialic acid. The chitosan derivatives were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, and measurement of the zeta potential. We also investigated the solubility, cytotoxicity, and blood compatibility of chitosan derivatives. 18β-glycyrrhetinic acid and sialic acid could be grafted onto chitosan molecular chains. The thermal stability of the synthesized chitosan derivatives was decreased and the surface was positively charged in water and phosphate-buffered saline. After chitosan had been modified by 18 β-glycyrrhetinic acid and sialic acid, the solubility of chitosan was improved greatly in water and phosphate-buffered saline, and percent hemolysis was <5%. Novel amphiphilic chitosan derivatives could be suitable polymers for biomedical purposes.

Antibacterial Activity of Novel 18β-Glycyrrhetinic Hydrazide or Amide Derivatives

Through a facile structural modification on the natural bioactive ingredient 18β-glycyrrhetinic acid(GA), a series of novel GA hydrazide or amide derivatives was obtained, and their final molecular frameworks were characterized by NMR and HRMS analysis. Antibacterial bioassays revealed that some of the GA hydrazide or amide derivatives were able to suppress the growth of three tested plant pathogens. Particularly, compound 3c exhibited excellent in vitro activity against Xanthomonas oryzae pv. Oryzae (Xoo), Pseudomonas syringae pv. actinidiae(Psa), and Xanthomonas axonopodis pv. citri(Xac), providing the EC50 values of 5.89, 16.1, and 3.64 µg/mL, respectively. The data were better than those of the positive controls thiodiazole copper(92.7, 77.8, and 89.9 µg/mL, respectively) and bismerthiazol(31.1, 125.6, and 77.4 µg/mL, respectively). In addition, in vivo experiments suggested that, compared with thiodiazole copper(41.93% and 39.73%, respectively), compound 3c exerted prominently curative and protective activities against rice bacterial leaf blight at 200 µg/mL with the control effects of 52.36% and 51.40%, respectively. Given these obtained results, GA hydrazide or amide derivatives could serve as the feasible leads for exploring highly bioactive substrates.