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Abstract Introduction Chronic rhinitis (CR) represents a widespread inflammation with a high incidence in the general population. Although it is generally considered a benign condition, CR has a relevant impact on quality of life and requires a specific treatment approach. Objective The aim of the present study was to investigate the efficacy of glycyrrhizin and mannitol intranasal treatment on chronic rhinitis using cytological analysis and subjective evaluation of symptoms. Methods A total of 55 patients suffering from chronic rhinitis were enrolled in the present study, 34 with allergic rhinitis (AR) and 21 with nonallergic rhinitis (NAR). The severity of four different nasal symptoms was determined by using a visual analogue scale (VAS). Specimens obtained by nasal scraping were collected for cytological analysis. Data were acquired before and after a 30-day treatment with glycyrrhizin and mannitol nasal spray. Statistical analyses were performed. Results The VAS scores for all four nasal symptoms considered in the present study, as well as for neutrophil cells, reduced significantly after therapy in both allergic and nonallergic patients. The number of eosinophils was not significantly lower in nonallergic patients. Conclusion A 30-day topical treatment with glycyrrhizin and mannitol may improve nasal symptoms and reduce inflammatory cells in the nasal mucosa in patients with chronic rhinitis without significant contraindications. Further studies could support our results and would better clarify all the aspects of this treatment.
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Glycyrrhizae Radix et Rhizoma,a traditional Chinese medicine also known as Gan Cao(GC),is frequently included in clinical prescriptions for the treatment of pneumonia.However,the pharmacological com-ponents of GC for pneumonia treatment are rarely explored.Gan An He Ji oral liquid(GAHJ)has a simple composition and contains GC liquid extracts and paregoric,and has been used clinically for many years.Therefore,GAHJ was selected as a compound preparation for the study of GC in the treatment of pneumonia.We conducted an in vivo study of patients with pneumonia undergoing GAHJ treatments for three days.Using the intelligent mass spectrometry data-processing technologies to analyze the meta-bolism of GC in vivo,we obtained 168 related components of GC in humans,consisting of 24 prototype components and 144 metabolites,with 135 compounds screened in plasma and 82 in urine.After analysis of the metabolic transformation relationship and relative exposure,six components(liquiritin,liquiritigenin,glycyrrhizin,glycyrrhetinic acid,daidzin,and formononetin)were selected as potential effective components.The experimental results based on two animal pneumonia models and the in-flammatory cell model showed that the mixture of these six components was effective in the treatment of pneumonia and lung injury and could effectively downregulate the level of inducible nitric oxide synthase(iNOS).Interestingly,glycyrrhetinic acid exhibited the strongest inhibition on iNOS and the highest exposure in vivo.The following molecular dynamic simulations indicated a strong bond between glycyrrhetinic acid and iNOS.Thus,the current study provides a pharmaceutical basis for GC and reveals the possible corresponding mechanisms in pneumonia treatment.
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Photothermal therapy (PTT) is a highly effective anti-tumor method. However, when laser radiation was used to ablate tumors, it usually triggers a series of inflammatory reactions, promoting the further development of tumors and affecting the effect of anti-tumor therapy. Therefore, it is an effective method to improve the anti-tumor effect by suppressing the inflammatory response through the precise targeted delivery of anti-inflammatory drug while realizing the photothermal treatment of tumors. To this end, the redox-responsive linker 3,3'-dithiodipropionic acid was used to bond the classic hydrophobic anti-inflammatory drug 18β-glycyrrhetinic acid (18β-GA) and the hydrophilic fragment methoxy-polyethylene glycol (mPEG-NH2) to obtain redox-responsive amphiphilic polymer PEG-DA-GA in this study. Then, photothermal agent IR-780 was encapsulated to prepare redox-responsive polymer micelle PDG/IR-780 NPs. The PDG/IR-780 NPs exhibited uniform particle size of 80.2 ± 5.3 nm and the polydispersity index (PDI) was 0.215 ± 0.079. All animal experiments followed the ethical requirements formulated by the Ethics Committee of Sichuan University. The results showed that PDG/IR-780 NPs could respond to the abundant glutathione (GSH) in tumor cells to promote the disintegration of nanoparticle and the release of 18β-GA, thus significantly improved the killing efficiency on 4T1 cells, when compared with the non-redox-responsive control PSG/IR-780 NPs. When the concentration of 18β-GA was 50 μg·mL-1, the cell viability of 4T1 cells in the PDG/IR-780 NPs group was only (19.29 ± 1.80) %, which was significantly lower than the result of in PSG/IR-780 NPs group (29.30 ± 1.37) %. The results of frozen sections of tumor tissues showed that the designed PDG NPs can promote the tumor-targeted distribution of drugs compared with the free drug group. Eventually, PDG/IR-780 NPs achieved wonderful anti-tumor efficacy on 4T1 triple-negative breast cancer model, revealing the new possibility of the combined therapy strategy of photothermal and anti-inflammatory therapy.
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Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18β-GA)is a natural com-pound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18β-GA inhibited the expression of α-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon reso-nance,we found that 18β-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18β-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis,highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis.
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Abstract The aim of the present study is to investigate the cardioprotective effects of 18ß-glycyrrhetinic acid (18ß -GA) against oxidative and histological damage caused by global cerebral ischemia/ reperfusion (I/R) in C57BL/J6 mice. All male mice (n:40) were randomly divided into four groups: (1) sham-operated (Sham), (2) I/R, (3) 18ß-GA, and (4) 18ß -GA+I/R. Ischemia was not applied to the sham and 18ß-GA groups. In the I/R group, the bilateral carotid arteries were clipped for 15 min to induce ischemia, and the mice were treated with the vehicle for 10 days. In the 18ß-GA group, the mice were given 18ß-GA (100 mg/kg) for 10 days following a median incision without carotid occlusion. In the 18ß-GA+I/R group, the ischemic procedure performed to the I/R model was applied to the animals and afterwards they were intraperitoneally (i.p.) treated with 18ß-GA (100 mg/kg) for 10 days. It was found that global cerebral I/R increased TBARS levels and decreased antioxidant parameters. The 18ß-GA treatment decreased the level of TBARS and increased GSH, GPx, CAT, SOD activities. Also, the control group cardiac tissue samples were observed to have a normal histological appearance with the Hematoxylin-Eosin staining method. Histopathological damage was observed in the heart tissue samples belonging to the I/R group. The 18ß-GA treatment ameliorates oxidative and histological injury in the heart tissue after global ischemia reperfusion, and may be a beneficial alternative treatment
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Animals , Male , Mice , Cardiotonic Agents/adverse effects , Reperfusion/adverse effects , Brain Ischemia/pathology , Staining and Labeling/instrumentation , Oxidative Stress , Antioxidants/pharmacologyABSTRACT
The optimal prescription of tanshinone Ⅱ_A(TSN)-glycyrrhetinic acid(GA) solid lipid nanoparticles(GT-SLNs) was explored and evaluated in vivo and in vitro, and its effect on acne after oral administration was investigated. The preparation processing and prescription were optimized and verified by single factor and response surface methodology. The in vitro release of GA and TSN in GT-SLNs was determined by ultra-performance liquid chromatography(UPLC). The effect of GT-SLNs on acne was investigated by the levels of sex hormones in mice, ear swelling model, and tissue changes in sebaceous glands, and the pharmacokinetics was evaluated. The 24-hour cumulative release rates of GA and TSN in SLNs were 65.87%±5.63% and 36.13%±2.31% respectively. After oral administration of GT-SLNs and the mixture of GA and TSN(GT-Mix), the AUC_(0-t) and AUC_(0-∞) of TSN in GT-SLNs were 1.98 times and 4.77 times those in the GT-Mix group, respectively, and the peak concentration of TSN in the GT-SLNs group was 17.2 times that in the GT-Mix group. After intragastric administration of GT-SLNs, the serum levels of testosterone(T) and the ratio of testosterone to estradiol(T/E2) in the GT-SLNs group significantly declined, and the sebaceous glands of mice were atrophied to a certain extent. The results demonstrated that obtained GT-SLNs with good encapsulation efficiency and uniform particle size could promote the release of GA and TSN. GT-SLNs displayed therapeutic efficacy on acne manifested by androgen increase, abnormal sebaceous gland secretion, and inflammatory damage.
Subject(s)
Animals , Mice , Abietanes , Acne Vulgaris/drug therapy , Drug Carriers , Glycyrrhetinic Acid , Liposomes , Nanoparticles , Particle Size , TestosteroneABSTRACT
Objective: Based on response surface methodology, HPLC was applied to quantitatively determine the optimal processing technology of Glycyrrhizae Radix et Rhizoma Praeparata cum Melle (GRRPM) from the perspective of multi-index and comprehensive evaluation. Methods: HPLC was used for quantitative analysis, and the content of liquiritin, liquiritigenin, licochalcone A and glycyrrhetinic acid was used as inspection indexes. Response surface methodology was used to investigate the effects of the adding amount of honey, steaming and soaking time, frying temperature and frying time on the processing technology of GRRPM, and to optimize the optimal processing technology of GRRPM. Results: The chromatographic column was Diamonsil C18 (2) (4.6 mm × 200 mm, 5 μm); mobile phase was acetonitrile-0.1% phosphate aqueous solution, gradient eluting: 0-20 min, 12%-32% acetonitrile; 20-45 min, 32%-70% acetonitrile; 45-75 min, 70%-97% acetonitrile, with detection wavelength of 260 nm, column temperature of 20 ℃, and flow rate of 1 mL/min; Using liquiritin as internal standard, the relative correction factors of glycyrrhizin, licochalcone A, glycyrrhizinic acid and their relative correction factors were determined and calculated to be 0.56, 0.64 and 1.42, respectively. The optimum processing process of GRRPM was as follows: the amount of honey was 1/4, the soaking time was 15 min, frying pan bottom temperature was 160 ℃, and frying time was 13 min. Conclusion: The results of systematic adaptability investigation of the experimental content determination method meet the requirements. The best processing scheme of GRRPM optimized by response surface methodology is feasible and provides scientific basis for formulating quality standards and modern research of GRRPM.
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Objective: To explore the active compounds and mechanism of Lianhua Qingwen Prescription for the treatment of coronavirus, and provide a reference for the treatment of COVID-19. Methods: With the help of TCMSP, Batman, Swiss Target Prediction and other databases, the chemical constituents and targets of Lianhua Qingwen Prescription were retrieved. Coronavirus disease targets were screened by GeneCards. Cytoscape software was used to construct a “drug-component-target-disease” interaction network map and potential target interactions, and the action mechanism was predicted through enrichment analysis. The main active ingredients of Lianhua Qingwen Prescription were verified by molecular docking with Mpro and ACE2. Results: A total of 100 active ingredients, 636 drug targets, and 347 disease targets were excavated, and 67 drug-disease common targets were obtained. The key targets involved PTGS2, IL6, CASP3, MAPK1, EGFR, ACE2, etc. A total of 1 946 entries were obtained by GO enrichment analysis, which mainly involved T cell activation, viral receptors, and inflammatory responses. KEGG pathway enrichment screened 166 signaling pathways, including renin-angiotensin system, Toll-like receptor signaling pathway, JAK-STAT signaling pathway, T cell receptor signaling pathway, TNF signaling pathway and so on. The molecular docking results showed that kaempferol, quercetin and luteolin had good binding ability with Mpro; And glycyrrhetinic acid, stigmasterol, indigo had good binding ability with ACE2. Conclusion: Lianhua Qingwen Prescription acts on coronavirus through multiple components, multiple targets, and multiple pathways. The main components have good binding ability with Mpro and ACE2, so as to have a therapeutic effect on COVID-19.
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Objective: To make a preliminary prediction of the Q-marker of Glycyrrhizae Radix et Rhizoma from the perspective of the effectiveness and measurability of chemical components based on the concept of Q-marker of Chinese materia medica. Methods: Based on literature integration and data analysis, the source range of Glycyrrhizae Radix et Rhizoma Q-marker was screened, and the effectiveness of the ingredients was analyzed through network pharmacology. Qualitative and quantitative analysis of 15 batches of Glycyrrhizae Radix et Rhizoma from four places of origin was performed by HPLC. The pattern recognition method was used to screen out the main marker components that caused the differences between groups, which were combined with network pharmacological results to further determine the Q-marker of Glycyrrhizae Radix et Rhizoma. Results: Literature studies had determined that flavonoids and triterpenoids were the main source of Glycyrrhizae Radix et Rhizoma Q-marker; Network pharmacology results showed that liquiritin, glycyrrhizic acid and other components had high connectivity in the "component-target-pathway" network and were the main active components; The fingerprints of 15 batches of Glycyrrhizae Radix et Rhizoma samples were established, and five components, including liquiritin and liquiritin apioside, were identified as the main marker components by PLS-DA analysis; The content determination results of liquiritin, liquiritin apioside, glycyrrhizic acid and glycyrrhetinic acid showed that there were significant differences in the content of ingredients among different production areas. The qualitative and quantitative research on pharmacology combined with network pharmacology revealed that liquiritin, liquiritin apioside, glycyrrhizic acid and glycyrrhetinic acid can be used as Glycyrrhizae Radix et Rhizoma Q-marker. Conclusion: Taking flavonoids and triterpenoids as the source of Q-marker for Glycyrrhizae Radix et Rhizoma, the qualitative and quantitative (measurability) study of Glycyrrhizae Radix et Rhizoma herbs from multiple producing areas combined with network pharmacology (effectiveness) revealed liquiritin, liquiritin apioside, glycyrrhizic acid and glycyrrhetinic acid as the potential Q-marker of Glycyrrhizae Radix et Rhizoma are scientific and reasonable, which provide reference for quality control of Glycyrrhizae Radix et Rhizoma.
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OBJECTIVE：To pre pare Glycyrrhetinic acid-modified docetaxel magnetic nanoparticles （GA-DTX-NGO/IONP- NPs），and to evaluate its physicochemical properties. METHODS ：Magnetic nano graphene oxide （NGO/IONP）was chosen as the anti-tumor drug carrier ，docetaxel（DTX）as the model drug and glycyrrhetinic acid （GA）as the target molecule. Firstly ，NGO/ IONP was synthesized by hydrothermal method and GA-CS was synthesized by amidation reaction. Fourier IR spectrometer ，DSC and vibration sample magnetic measuring instrument were used to characterize NGO/IONP and GA-CS. GA-DTX-NGO/IONP-NPs Huperzine A in the nicotinic acetylcholine receptor alleviates Aβ -induced 1-42 treatment of Alzheimer ’s disease and vascular dementia ：a neurotoxicity via downregulation of p 38 and JNK MAPK meta-analysis[J]. Evid Based Complement Alternat Med ， signaling pathways[J]. Neurochem Int ，2018. DOI ：10. 2014. DOI ：10.1155/2014/363985. 1016/j.neuint.2018.09.005. were prepared by the ion gelation method. TEM and particle size analyzer were used to observe and determine the morphology ， particle size and Zeta potential of GA-DTX-NGO/IONP-NPs ；the ultrafiltration-centrifugation method was used to determine encapsulation efficiency and drug loading amount ；the magnetic properties were investigated by investigating the state with or without external magnetic field ；the photothermal conversion test was carried out with laser irradiation of 808 nm. RESULTS ：NGO/ IONP and GA-CS were successfully synthesized ，and NGO/IONP exhibited superparamagnetism characteristics. GA-DTX-NGO/ IONP-NPs were spherical under TEM ，the particle size was （262.8±4.23）nm and the Zeta potential was （13.6±1.51）mV. The encapsulation rate and drug loading amount were （94.29±0.50）％ and（17.12±0.12）％，respectively. GA-DTX-NGO/IONP-NPs were black in appearance and evenly dispersed. Under the external magnetic field ，the magnetic nanoparticles could move directionally，showing good magnetic properties. GA-DTX-NGO/IONP-NPs showed a good concentration- and time-dependent photothermal conversion effect under 808 nm laser irradiation. CONCLUSIONS ：GA-DTX-NGO/IONP-NPs are successfully prepared. This study could provide some theoretical basis for the combined treatment of magnetic heating-chemotherapy for liver tumors.
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OBJECTIVE：To prepare and characterize glycyrrhetinic acid （GA）nanoparticles，and to evaluate its in vitro anti-tumor activity. METHODS ：Using PVP K 30 as carrier ，GA nanoparticles were prepared by anti-solvent precipitation and freeze-drying method. X-ray diffraction ，infrared spectrum ，differential scanning calorimetry and granularity analysis were used to characterize the nanoparticles ；HPLC method was used to measure the solubility and drug-loading amount of GA in the nanoparticles. MTT method was used to assay the in vitro inhibition activity of GA raw material and nanoparticles （GA doses were 12.5，25，50，100，200 μmol/L）on human liver cancer cell HepG 2 and calculate its IC 50. RESULTS ：The characteristic peaks of X-ray diffraction and infrared absorption of GA disappeared in the nanoparticles and the endothermic peak changed. The particle size of the nanoparticles was （194.88±23.52）nm，which was lower than （2 592.33±207.51）nm of raw material. The dispersion index was 0.24±0.04，which was higher than 0.15±0.03 of raw material. The average drug-loading amount of GA was 15.99％. Moreover，the solubility of nanoparticles increased from （1.05±0.01）μg/mL to（250.00±0.15）μg/mL. The results of antitumor test in vitro showed that the cell survival rates in the group of GA raw material 200 μmol/L and GA nanoparticles groups were significantly lower than that in blank control group ，and the cell survival rates of GA nanoparticles groups （except for 12.5 μmol/L group）were significantly lower than that of same dose group of raw material （P＜0.01）. IC 50 of GA nanoparticles was 86.3 μmol/L，which was lower than 364.4 μmol/L of raw material. CONCLUSIONS：GA nanoparticles are prepared successfully ；the prepared nanoparticles have small size and uniform distribution ，and the solubility are increased and antitumor activity in vitro are enhanced.
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Objective: To explore the improvement of glycyrrhetinic acid (G A) on the damage of synaptic ultrastructures of hippocampus induced by realgar in the mice, and to clarify the related mechanisms. Methods: Sixty ICR mice were randomly divided into three groups with twenty mice in each group: control group (intragastrically treated with 0. 5 % CMC-Na), realgar group (intragatrically treated with realgar 1. 35 g • kg- 1), and GA intervention group (intragastrically administered with GA 48 mg • kgx and realgar 1. 35 g • kg1). The mice were administrated once a day for eight consecutive weeks. The cognitive and memory abilities were tested using object recognition task (ORT). The levels of glutathione (GSH) in the hippocampus in the mice in various groups were detected. The changes of the ultrastructures of synapse in hippocampal CA1 region, the width of synaptic cleft, the length of synaptic active zone, the thickness of post synaptic density (PSD) and the curvature of synaptic interface were observed by transmission electron microscope. Results: Compared with control group, the preferential index (PI) for the novel object and the level of GSH in the hippocampus tissue of the mice in realgar group were significantly decreased (P 0 . 05), and the level of GSH in the hippocampus tissue of the mice in GA intervention group was significantly increased (P 0 . 05). Conclusion: Realgar can change the synaptic structural parameters and cause deficits in cognitive and memory abilities. GA can alleviate the abnormal ultrastructural changes in the hippocampal synapses of the mice.
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Objective@#To explore the effect of 18β-sodium glycyrrhetinic acid on thymic stromal lymphopoietin (TSLP) in nasal mucosa of allergic rhinitis (AR) rats.@*Methods@#One hundred Wistar rats,half male and half female,were randomly divided into 5 groups by random number table method: control group, AR model group,budesonide group,18β-sodium glycyrrhetinic acid at dose of 20 mg/kg and 40 mg/kg groups, with 20 rats in each group. AR animal models were established by ovalbumin (OVA) sensitization in the other four experimental groups. After successful modeling, budesonide and 18β-sodium glycyrrhetinic acid were given in each group,and the detection time points were 2 weeks and 4 weeks. The distribution of TSLP in rat nasal mucosa was detected by immunohistochemistry,and the expression of TSLP in rat nasal mucosa was determined by Western blot at the protein level. The expression of TSLP-mRNA in rat nasal mucosa was detected and compared by real-time fluorescence quantitative PCR (RT-PCR) at mRNA level. The concentrations of IL-4 and OVA-sIgE in rat serum were measured and compared by ELISA. One-way analysis of variance and the least significant difference method were used for the comparison among groups, LSD t test was used for the comparison between the two groups,and the difference was statistically significant (P<0.05).@*Results@#Immunohistochemistry confirmed existence of TSLP in rat nasal mucosa, especially in epithelial cells,endothelial cells and epithelial cilia. Western blot and RT-PCR suggested that the expression of TSLP and TSLP-mRNA in nasal mucosa of AR model group was significantly higher than that of control group (2 weeks TSLP: 1.795 9±0.131 4 vs 0.990 5±0.164 2, 4 weeks TSLP: 1.809 7±0.253 4 vs 0.870 3±0.124 4; 2 weeks TSLP-mRNA:4.582 9±0.697 7 vs 1.108 7±0.081 1, 4 weeks TSLP-mRNA:4.814 4±0.662 8 vs 1.001 0±0.155 3; all P<0.05). After 2 weeks and 4 weeks of drug intervention,the expression of TSLP and TSLP-mRNA was inhibited in nasal mucosa of budesonide group,18β-sodium sodium glycyrrhetinic acid at dose of 20 mg/kg and 40 mg/kg group,which was significantly different from that of AR model group (2 weeks TSLP: (0.897 8±0.081 8)/(1.072 1±0.113 6)/(1.396 6±0.133 9) vs 1.795 9±0.131 4; 4 weeks TSLP: (1.191 0±0.161 3)/(1.141 0±0.152 3)/(1.200 5±0.189 6) vs 1.809 7±0.253 4; 2 weeks TSLP-mRNA: (1.175 6±0.100 9)/(1.254 4±0.078 2)/(2.037 2±0.559 2) vs 4.582 9±0.697 7; 4 weeks TSLP-mRNA: (1.158 3±0.104 3)/(1.224 0±0.034 0)/(1.275 2±0.099 6) vs 4.814 4±0.662 8; all P<0.05), and not significantly different from control group. With the inhibition of TSLP, the concentrations of IL-4 and OVA-sIgE in rat serum were also decreased.@*Conclusion@#18β-sodium glycyrrhetinic acid has obvious inhibitory effect on TSLP in nasal mucosa of AR rats, which can control Th2 type immune inflammatory reaction.
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Glycyrrhizae Radix et Rhizoma is one of the commonly used Chinese materia medica in clinic. It has the effects of tonifying spleen and replenishing qi, clearing heat and removing toxin, dispelling phlegm, relieving cough, relieving pain, and reconciling various drugs. Its main active ingredients are saponins, flavonoids and polysaccharides. Among them, glycyrrhizic acid and glycyrrhetinic acid not only have inhibitory effects on liver cancer, lung cancer, breast cancer and other cancers, but also can be combined with chemotherapeutic drugs to increase drug efficacy as well. At the same time, they can be developed as drug carrier for drug delivery to solve the problems of low water solubility, low bioavailability, high toxicity and side effects of drugs. It was found that their solubilization may be closely related to their amphiphilic structure, which is expected to further explore the role of their carrier characteristics in drug transmembrane transport. Based on the anti-tumor mechanisms of Glycyrrhizae Radix et Rhizoma, the applications of glycyrrhizic acid and glycyrrhetinic acid in drug delivery systems were systematically summarized in this paper, which could provide reference for the further study of glycyrrhizic acid and glycyrrhetinic acid as excipients of drug delivery systems.
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Objective: To explore the inhibitory effect of 18β-glycyrrhetinic acid (18β-GA) on the inflammationrelated gastric cancer, and to clarify its mechanism. Methods: A total of 72 K19-Wnt/C2mE transgenic mice with gastric cancer were randomly divided into 18β-GA treatment group (drinking water contain 0.1 % 18β-GA, n-36) and control group (drinking normal water, n-36). After 52 weeks, the incidence of gastric cancer and morphology of gastric mucosa of the mice in two groups were detected. Immunohistochemistry staining was used to detect the histochemistry scores (H-score) of Ki-67, F4/80, ATP4a, KCNE2, pepsinogen C (PGC), Wnt-1, β-catenin, and cyclooxygenase-2 (COX-2) in gastric mucosa epithelial cells of the mice in two groups. Results: The gastric mucosa of the mice in control group showed protruded lesions, atypical hyperplasia and chronic gastritis. Compared with control group, the incidence (P-0. 019) and the volume of gastric cancer of the mice in 18β-GA treatment group were significantly decreased (P<0. 01); the structural heterozygosities of gastric cells and tissue were decreased, and the inflammation reactions of the mice in 18β-GA treatment group were alleviated. Compared with control group, the H-scores of Ki-67, F4/80, Wnt-1, β-catenin, and COX-2 in gastric mucosa epithelial cells of the mice in 18β-GA treatment group were decreased (P<0.05), and the H-scores of ATP4a, KCNE2, and PGC were increased (P<0. 05). Conclusion: 18β-GA can significantly inhibit the occurrence of gastric cancer in the K19-Wnt/C2mE transgenic mice. The inhibitory effect may be related to alleviating the inflammation reaction and promoting the differentiation of gastric mucosa epithelial cells and inhibiting the occurrence of gastric cancer.
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Objective To evaluate the effects of compatibility of Glycyrrhiza uralensis and Laminaria japonica on liver and kidney functions as well as serum indexes in rats. Methods A total of 24 male SD rats were randomly divided into four groups. Group 1 was served as control and only received vehicle. Group 2 and group 3 were orally dosed of G. uralensis extracts (2.8 g/kg) and L. japonica extracts (3.8 g/kg) once daily, respectively. Group 4 was orally dosed with 6.8 g/kg of G. uralensis-L. japonica extracts once daily. The experimental rats were treated corresponding extracts or vehicle for 17 weeks. During the experiment, the weight of rats, organ coefficient, biochemical indexes, and liver histopathological photograms in each group were measured. Meanwhile, plasma glycyrrhetinic acid concentration in G. uralensis extract group and G. uralensis-L. japonica extract group were observed. Results The water extraction components from G. uralensis and L. japonica groups could significantly reduce the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), cholinesterase (CHE), total bile acid (TBA), and total bilirubin (TBIL) comparing with control group (P < 0.05). While the G. uralensis-L. japonica extracts group could reverse these biochemistry indexes. G. uralensis-L. japonica extracts markedly increased the plasma concentration and exposure of glycyrrhetinic acid. Electrolyte metabolism balance was disordered after long-term treatment of G. uralensis, L. japonica and G. uralensis-L. japonica extracts, showing the level of sodium (Na+), potassium (K+), and chloride ion (Cl-) in these three groups were significantly higher than that in control group. Conclusion These results indicated that G. uralensis or L. japonica extracts might has hepatoprotective effects. However, G. uralensis-L. japonica extracts attenuated the hepatoprotective effects, which might result from the increased plasma concentration of glycyrrhetinic acid.
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Objective To prepare TOGA-X4 microparticles with uniform size and good rehydration property and to obtain the stable and reliable preparation process, and evaluate the in vitro release characteristics. Methods With the average particle size, polydispersity index and rehydration as indexes, optimizing the process of antitumor active substance TOGA-X4 microparticles by stainless steel rapid film emulsification method through single factor investigation to investigate the factors influencing the size and dispersion of the drug microparticles and observe the morphology of the particles by scanning electron microscopy. With the cumulative release degree of TOGA-X4 as index, direct drug release method was adopted to determine the cumulative release rate of TOGA-X4 and the size of TOGA-X4 microparticles. The curve of in vitro drug release was fitted with different release model to estimate the in vitro release characteristics of TOGA-X4 raw powders and TOGA-X4 microparticles. Results The optimized preparation technology contained TOGA-X4 mass concentration of 5 mg/mL in oil phase, PVA mass concentration of 30 mg/mL in for aqueous phase, the ratio of oil to water was 1:1, transmembrane pressure at 0.4 MPa, sucrose aqueous solution of 50 mg/mL as freeze-drying protective agent, curing temperature at 70 ℃; Compared with other in vitro release models, the logistic equation was the fittest model to TOGA-X4 microparticles, zero order equation was the fittest model to TOGA-X4. Conclusion The preparation of microparticles by stainless steel rapid film emulsification is simple, stable and reliable, which can improve the dissolution rate of insoluble drugs and has advantages in the preparation of microparticles of poorly water-soluble drugs.
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Objective To study the toxicological mechanisms of the compatibility application of Sargassum pallidum and Glycyrrhiza uralensis on kidney in rats. Methods Rats were divided into control, Sargassum pallidum (S), Glycyrrhiza uralensis (G), and Sargassum pallidum-Glycyrrhiza uralensis extract (S-G) groups, which were respectively exposed (gavages) for 4 weeks. Then, the levels of blood urea nitrogen (BUN), serum creatinine (Scr), aldosterone, cortisol, and electrolytes in rat serum and pathological sections of kidney were detected. Six active contents of Glycyrrhiza uralensis in kidney of rats were detected by UPLC-TQ/MS method. The expression of HSD11B2 in kidney was detected by Western blotting. Results Compared with the control group, all biochemical indicators of S group had no obvious change. It was found that the level of aldosterone from G group and S-G group was significantly lower than that from control group (P < 0.05, 0.01). In contrast to the control group, S. pallidum-G. uralensis extract led to significantly increased concentration of cortisol, BUN, and Scr in serum (P < 0.05, 0.01). The level of K+ and Cl- in S-G group was significantly lower than that in control group (P < 0.05, 0.01). Pathological examination showed that the G group had mild inflammation infiltration, and a serious inflammatory response accompanied by protein tube was absolved in S-G group. Compared with the G. uralensis extract group, the combination of S. pallidum and G. uralensis significantly raised the concentration of glycyrrhetinic acid (GA) in kidney (P < 0.05).When compared to that of control group, there was an inhibited expression of HSD11B2 in the kidney of L group and S-G group. Moreover, the expression of HSD11B2 in S-G group was markedly higher than that in G group (P < 0.05). Conclusion The toxicity of S-G group was mainly result that increased accumulation of GA, and inhibited the expression of HSD11B2, which resulted the aldosterone-cortisol system disorders.
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Aim To prepare hyaluronic acid nanoparti-cles(Ade/GA-HA) using glycyrrhetinic acid modified hyaluronic acid as the carrier and adenine as a model drug, and analyze their physicochemical property and proliferation effect on Bel-7402 cells. Methods Gly-cyrrhetinic acid and hyaluronic acid were combined by chemical cross-linking method, dialysis and freeze-dr-ying,based on which Ade/GA-HA was prepared using ultrasonic method, and the particle size and Zeta po-tential were determined by Malvern laser particle analy-zer,and the morphology was observed by transmission electron microscopy, and the absorbance was deter-mined by ultraviolet-visible spectrophotometer, high performance liquid chromatograph and microplate read-er to caculate drug load, encapsulation efficiency and in vitro release. MTT assays were utilized to determine the proliferation of nanoparticles treated Bel-7402 cells. Results GA-HA nanoparticles had spherical shape with a good dispersion, at diameters of 398.1 nm, of which Zeta potential was - 34.2 mV, and presented good short term stability. The drug load and encapsulation efficiency of Ade/GA-HA nanoparticles were (22.5 ± 5.8)% and (87.27 ± 0.33) %, re-spectively. Burst release was observed in Ade/GA-HA nanoparticles within 4 h, while controlled release 4 h later. Compared with free adenine,Ade/GA-HA nano-particles had a stronger inhibitory effect on cell prolif-eration with statistically significant difference. Conclu-sion GA-HA nanoparticles has excellent physico-chemical properties and meet the design requirement.
ABSTRACT
OBJECTIVE:To investigate the effects of non-ionic polyacrylamide(model:NPAM 1400)alone or combined with nanoscale silica gel (nSiO2) on the stability of Glycyrrhetinic acid lipo-emulsion. METHODS:UV-spectrophotometer was used to determine absorbance of diluent at 500 nm before and after lipo-emulsion centrifugation. Using the preparation without stable excipient as blank,stability coefficient (KE) and it ratio (KE/KE blank) were calculated. Effects of different concentrations (200-600 mg/L) of non-ionic polyacrylamide on the stability of Glycyrrhetinic acid lipo-emulsion were evaluated. The optimal concentration of non-ionic polyacrylamide alone was determined primarily,and then the effects of it combined with different concentrations of hydrophilic nSiO2 (0.2％, 0.3％, 0.4％) or hydrophobic (0.2％, 0.3％, 0.5％) on the stability of Glycyrrhetinic acid lipo-emulsion were investigated. RESULTS:When adding non-ionic polyacrylamide alone,KE of Glycyrrhetinic acid lipo-emulsion mixed with 300 mg/L non-ionic polyacrylamide was the lowest,KE/KE blank was 0.22;when combined,KE of Glycyrrhetinic acid lipo-emulsion mixed with 300 mg/L non-ionic polyacrylamide and 0.2％ hydrophobic nSiO2 was the lowest,KE/KE blank was 0.27. CONCLUSIONS:Non-ionic polyacrylamide alone or combined with nSiO2 all can promote the stability of Glycyrrhetinic acid lipo-emulsion,among which 300 mg/L non-ionic polyacrylamide alone is the best.