ArticleLiterature Review

Liquorice, a unique "guide drug" of traditional Chinese medicine: A review of its role in drug interactions

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Liquorice is the root of Glycyrrhiza uraleusis Fisch. or G. glabra L., Leguminosae. It is a widely used herbal medicine native to southern Europe and parts of Asia and has beneficial applications in both the medicinal and the confectionery sectors. Unlike its usage in Europe, liquorice in traditional Chinese medicine is commonly combined with other herbs in a single prescription, as a unique ''guide drug'' to enhance the effectiveness of other ingredients, to reduce toxicity, and to improve flavor in almost half of Chinese herbal formulas. A review on phytochemical and pharmacological research to explain this unique ''guide" effect is suggested for future investigations. The information was collected from scientific journals, books, and pharmacopeia. The studies about the traditional uses, randomized controlled trials, chemical, pharmacological and pharmacokinetic data related to liquorice-herb/drug interaction or combination were included in the review. According to recent reports, the "guide" effect of liquorice is partially through components transformed in liquorice-drug interaction; altering enzyme activity of P450 isoforms, as evidenced by induction of model probe substrates; and modulation of drug transporter proteins such as intestinal P-glycoprotein. The overview and comparison of traditional uses of liquorice with recent pharmacological studies and randomized controlled trials provide new insights into this ancient drug for future investigations and clinical use, especially in drug combination.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... We recorded the feed intake at 13-17 days and 18-24 days. Then, the average feed intake (AFI [13][14][15][16][17] and AFI [18][19][20][21][22][23][24][25] ) and average body weight gain (AWG [13][14][15][16][17] and AWG [18][19][20][21][22][23][24][25] were calculated. The feed conversion ratio (FCR) is the net feed consumption of broiler unit weight gain. ...
... We recorded the feed intake at 13-17 days and 18-24 days. Then, the average feed intake (AFI [13][14][15][16][17] and AFI [18][19][20][21][22][23][24][25] ) and average body weight gain (AWG [13][14][15][16][17] and AWG [18][19][20][21][22][23][24][25] were calculated. The feed conversion ratio (FCR) is the net feed consumption of broiler unit weight gain. ...
... The FCR was calculated as follows: FCR = AFI/AWG. Where, FCR 13-17 = AFI 13-17 /AWG [13][14][15][16][17] , FCR 18-25 = AFI 18-25 /AWG 18-25 . ...
Article
Full-text available
This study was conducted to evaluate the therapeutic effects and safety of GA in MG-infected broilers. Our results showed that the minimum inhibitory concentration of GA was 31.25 μg/mL. Moreover, GA inhibited the expression of MG adhesion protein (pMGA1.2) in the broilers’ lungs. GA treatment clearly decreased the morbidity of CRD and mortality in the MG-infected broilers. Compared with the model group, GA treatment significantly decreased gross air sac lesion scores and increased average weight gain and feed conversion rate in the MG-infected broilers. Histopathological examination showed GA treatment attenuated MG-induced trachea, immune organ and liver damage in the broilers. Moreover, GA treatment alone did not induce abnormal morphological changes in these organs in the healthy broilers. Compared with the model group, serum biochemical results showed GA treatment significantly decreased the content of total protein, albumin, globulin, alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine, uric acid, total cholesterol, and increased the content of albumin/globulin, alkaline phosphatase, apolipoprotein B and apolipoprotein A-I. In conclusion, GA displayed a significant therapeutic efficacy regarding MG infection and had no adverse effects on the broilers (100 mg/kg/d).
... 88 The constituents of liquorice have complex effects on CYP enzymes, and further research is required to elucidate these effects. 89 For example, liquorice extract has been shown to be a potent inhibitor of CYP3A4 activity. This effect appears to be due not to the major active component GLA 1 but to other constituents of the extract, such as flavanone-class liquiritigenin 11 ( Figure 2). ...
... This effect appears to be due not to the major active component GLA 1 but to other constituents of the extract, such as flavanone-class liquiritigenin 11 ( Figure 2). 89 Both GLA 1 and GRA 3 appear to increase CYP3A4 activity, whereas GRA 3 and isoflavane-class glabridin 5 inhibit CYP2C9. Liquorice may therefore potentiate the effects of warfarin therapy. ...
... Liquorice may therefore potentiate the effects of warfarin therapy. 89 GLA 1 has been shown to have effects on the pharmacokinetics of prednisolone. A pharmacokinetic study in six healthy men treated with intravenous prednisolone (prednisolone hemisuccinate, PSL-HS) found that pretreatment with oral administration of GLA 1 significantly increased the concentrations of total prednisolone (PSL) at 6, 8 h, and of free PSL at 4, 6 and 8 h after PSL-HS infusion. ...
Article
Full-text available
Liquorice has a long history of use in traditional Chinese, Ayurvedic and herbal medicine. The liquorice plant contains numerous bioactive compounds, including triterpenes, flavonoids and secondary metabolites, with glycyrrhizin being the main active compound. Liquorice constituents have been found to have anti-inflammatory, antioxidant, antiviral, anticancer, hepatoprotective and neuroprotective properties. In addition, they appear to have antidepressant actions and effects on morphine tolerance. Glycyrrhizin, its metabolite glycyrrhetic (glycyrrhetinic) acid and other liquorice-derived compounds such as isoflavonoids and trans-chalcones, exert potent anti-inflammatory effects via a wide range of mechanisms including high mobility group box 1 protein (HMGB1) inhibition, gap junction blockade and α 2A -adrenoceptor antagonism. These properties, together with an increasing body of preclinical studies and a long history of use in herbal medicine, suggest that liquorice constituents may be useful for pain management. Glycyrrhizin is used widely in the confectionary, food and tobacco industries, but has documented adverse effects that may limit clinical use. Whether liquorice plant-derived compounds represent a novel class of analgesics is yet to be established. Having a host of bioactive compounds with a broad range of mechanisms of effect, liquorice is a plant that, in the future, may give rise to new therapies for pain.
... The biologically active ingredients of GU include glycyrrhizin, liquiritin, liquiritigenin, and flavones [16]. It can modulate and complement the properties of other herbal medicines, serving as a guide for several herbal medicines [17]. It also contains species-specific flavonoids that demonstrate excellent therapeutic effects on liver injury [15,18]. ...
... It also contains species-specific flavonoids that demonstrate excellent therapeutic effects on liver injury [15,18]. It has numerous pharmacological effects, such as anti-obesity, antitumor, antioxidant, anti-inflammatory, and antihypertensive effects [16,17,19,20]. ...
Article
Full-text available
Metformin, an antidiabetic drug, and Glycyrrhiza uralensis Fischer (GU), an oriental medicinal herb, have been reported to exert anti-obesity effects. This study investigated the synergistic action of metformin and GU in improving diet-induced obesity. Mice were fed a normal diet, a high-fat diet (HFD), or HFD + 0.015% GU water extract for 8 weeks. The HFD and GU groups were then randomly divided into two groups and fed the following diets for the next 8 weeks: HFD with 50 mg/kg metformin (HFDM) and GU with 50 mg/kg metformin (GUM). GUM prevented hepatic steatosis and adiposity by suppressing expression of mRNAs and enzyme activities related to lipogenesis in the liver and upregulating the expression of adipocyte mRNAs associated with fatty acid oxidation and lipolysis, and as a result, improved dyslipidemia. Moreover, GUM improved glucose homeostasis by inducing glucose uptake in tissues and upregulating mRNA expressions associated with glycolysis in the liver and muscle through AMP-activated protein kinase activation. GUM also improved inflammation by increasing antioxidant activity in the liver and erythrocytes and decreasing inflammatory cytokine productions. Here, we demonstrate that GU and metformin exert synergistic action in the prevention of obesity and its complications.
... Glycyrrhizin, a triterpene saponin, is one of the main components isolated from Glycyrrhiza glabra, Fabaceae, a plant with a long history of use [85]. On the market, it can often be found in the form of dietary supplements. ...
... On the market, it can often be found in the form of dietary supplements. Glycyrrhiza glabra and its derivatives are generally recognized as safe by the FDA (GRAS) [85,86]. Glycyrrhizin has a wide range of antiviral activity (HIV, porcine reproductive and respiratory syndrome virus, human respiratory syncytial virus, influenza viruses, herpes viruses, hepatitis B and C) [77,87]. ...
Article
Full-text available
The first case of SARS-CoV-2 infection was reported in December 2019. Due to the rapid spread of the disease and the lack of adequate therapy, the use of plants that have a long history in the treatment of viral infections has often been considered. The aim of this paper is to provide a brief review of the literature on the use of phytochemicals during the new pandemic. An extensive search of published works was performed through platforms Google Scholar, PubMed, Science Direct, Web of Science and Clinicaltrials.gov. Numerous preclinical studies on the use of phytochemicals (quercetin, curcumin, baicalin, kaempferol, resveratrol, glycyrrhizin, lycorine, colchicine) against SARS-CoV-2 have shown that these components can be effective in the prevention and treatment of this infection. Clinical research has proven that the use of black cumin and green propolis as well as quercetin has positive effects. As for other phytochemicals, in addition to preclinical testing which has already been carried out, it would be necessary to conduct clinical tests in order to assert their effectiveness. For those phytochemicals whose clinical efficacy has been proven, it would be necessary to conduct research on a larger number of patients, so that the conclusions are more representative.
... Liquorice (Glycyrrhizae radix et rhizome), the roots of Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L. or Glycyrrhiza inflate Bat., has long been used as a tonic herbal medicine in traditional Chinese medicine (TCM) due to its ability to harmonize unpleasant characteristics of other herbs or reduce the toxicities of certain herbs when used together in the herbal formulas (Wang et al., 2013;Wahab et al., 2021). In China, although there are no reports on the scientific rationale, liquorice is presented with PA-containing herbs in TCM compound formulas, yet no PA-poisoning cases have been reported with this combinational use. ...
... In the normal practice of TCM, these PA-containing herbs are commonly combined with other herbs in a single prescription in TCM. Liquorice, as a widely used herbal medicine applied in both medicinal and confectionery sectors, is regarded as a unique 'guide drug' to enhance the effectiveness of other ingredients, to reduce toxicity, or improve flavor in almost half of Chinese herbal formulas/prescriptions (Wang et al., 2013). Based on our study, we found that liquorice is present in almost half of the formulas which contain PA-containing herbs (Table 1), and no PApoisoning cases have been reported under such combinational use, which may suggest the effect of liquorice against potential PA poisoning, and is warranted for future in-depth investigations. ...
Article
Full-text available
Misuse of pyrrolizidine alkaloid (PA)-containing plants or consumption of PA-contaminated foodstuffs causes numerous poisoning cases in humans yearly, while effective therapeutic strategies are still limited. PA-induced liver injury was initiated by cytochrome P450 (CYP)-mediated metabolic activation and subsequent formation of adducts with cellular proteins. Liquorice, a hepato-protective herbal medicine, is commonly used concurrently with PA-containing herbs in many compound traditional Chinese medicine formulas, and no PA-poisoning cases have been reported with this combination. The present study aimed to investigate hepato-protective effects of liquorice aqueous extract (EX) and 18β-glycyrrhetinic acid (GA, the primary bioactive constituent of liquorice) against PA-induced hepatotoxicity and the underlying mechanism. Histopathological and biochemical analysis demonstrated that both single- and multiple-treatment of EX (500 mg/kg) or GA (50 mg/kg) significantly attenuated liver damage caused by retrorsine (RTS, a representative hepatotoxic PA). The formation of pyrrole-protein adducts was significantly reduced by single- (30.3% reduction in liver; 50.8% reduction in plasma) and multiple- (32.5% reduction in liver; 56.5% reduction in plasma) treatment of GA in rats. Single- and multiple-treatment of EX also decreased the formation of pyrrole-protein adducts, with 30.2 and 31.1% reduction in rat liver and 51.8 and 53.1% reduction in rat plasma, respectively. In addition, in vitro metabolism assay with rat liver microsomes demonstrated that GA reduced the formation of metabolic activation-derived pyrrole-glutathione conjugate in a dose-dependent manner with the estimated IC 50 value of 5.07 µM. Further mechanism study showed that GA inhibited activities of CYPs, especially CYP3A1, the major CYP isoform responsible for the metabolic activation of RTS in rats. Enzymatic kinetic study revealed a competitive inhibition of rat CYP3A1 by GA. In conclusion, our findings demonstrated that both EX and GA exhibited significant hepato-protective effects against RTS-induced hepatotoxicity, mainly through the competitive inhibition of CYP-mediated metabolic activation of RTS.
... Correlation coefficients >0.98 were determined for all calibration curves. Due to rhaoglycyrrhizin (5) was used; licorice saponin 18 used a calibration of 24-hydroxy-(20α)-glycyrrhizin (21) with the 20α structure moiety; for 17, a calibration of the structure isomer (20α)-glycyrrhizin (16) was used; and 13, 14, and 15 used a calibration of 11-deoxo-glycyrrhizin (12) with the 11-deoxo structure moiety. ...
... Calculation of the corresponding DoT factors revealed values above 1 for compounds 1−3, 5, 9, 11, and 14 for sweet taste; 1−3, 5,9,11,12,14,15,17,20, and 21 for licorice taste, and 16 and 22 for bitter taste ( Figure 3B). In contrast to A, saponins 1−3, 5,9,11,12,14,15,17,20,21, and 22 elicited a sweet, licorice, and bitter taste sensation in C−G. Due to the lower saponin contents in C−G, contrary to A, lower DoT factors were calculated. ...
Article
Application of a sensitive UHPLC-MS/MSMRM method enabled the simultaneous quantitation of 23 sweet-, licorice-, and bitter-tasting saponins in Glycyrrhiza glabra L., Glycyrrhiza uralensis Fisch., different licorice plants and root compartments, processed licorice, as well as different Glycyrrhiza spp. The combination of quantitative data with sweet, licorice, and bitter taste thresholds led to the determination of dose-over-threshold factors to elucidate the sweet, licorice, and bitter impact of the individual saponins with and without mycorrhiza symbiosis to evaluate the licorice root quality. Aside from glycyrrhizin (1), which is the predominant sweet- and licorice-tasting saponin in all licorice samples, 20 out of 22 quantitated saponins contributed to the taste profile of licorice roots. Next to sweet-/licorice-tasting glycyrrhizin (1), 24-hydroxy-glycyrrhizin (9), 30-hydroxy-glycyrrhizin (11), and 11-deoxo-24-hydroxy-glycyrrhizin (14) as well as licorice tasting saponins 20α-galacturonic acid glycyrrhizin (17), 24-hydroxy-20α-glycyrrhizin (21), and 11-deoxo-glycyrrhizin (12) were determined as key contributors to licorice root's unique taste profile. A quantitative comparison of 23 saponins as well as 28 polyphenols between licorice roots inoculated with arbuscular mycorrhiza fungi and controls showed that important taste-mediating saponins were increased in mycorrhizal roots, and these alterations depended on the growth substrate and the level of phosphate fertilization.
... Licorice (Glycyrrhiza glabra) is widely used in the production of candies due to its sweet taste and commonly used in Chinese medicine due to its anti-allergic and anti-inflammatory activities. Such effects are attributed to the high concentration of the triterpenoid saponin phytochemicals (glycyrrhizic and glycyrrhizic acid) (WANG et al., 2013). ...
Chapter
Full-text available
Cancer is characterized by the uncontrolled growth of cells that can invade tissues causing metastasis. Cancer cells have specific characteristics such as uncontrolled proliferation, differentiation, loss of function and resistance to cellular homeostasis mechanisms, making them highly capable of invading other tissues. The nematode Caenorhabditis elegans provides advances in the understanding of cancer progression, as its homology with human genes and the possibility of obtaining mutant strains allow the application of the model to understand a range of diseases, including tumorigenesis. Among the pathways known to be involved in the formation of tumors in humans are Ras, Wnt and Notch, in addition to the ESPL1, FOS and p53/BRCA-1 genes. In C. elegans, mutations such as inhibition or overexpression of these signaling pathways or genes can cause different physiological changes in the worm recognized as different phenotypes. In this chapter, we will discuss the main pathways and genes involved in the formation of tumors in mammals and C. elegans, in addition to the use of the alternative experimental model for the screening of new molecules with anticancer potential.
... The root of licorice, Glycyrrhiza glabra Linne, is a widely used herbal medicine worldwide; it is used to treat gastritis, bronchial and urological diseases, and food poisoning in Western and Asian countries [5]. In almost 50% of traditional Chinese herbal formulas, licorice is used (as a guide drug) with other herbs in a single prescription to enhance the efficacy of the other herbs, reduce toxicity, and improve flavor [6]. Licorice contains several bioactive components, including glycyrrhizic acid, glycyrrhetinic acid, isoliquiritigenin, licochalcone, and glabridin [7]. ...
Article
Platelets are crucial for hemostasis and arterial thrombosis, which may lead to severe cardiovascular diseases (CVDs). Thus, therapeutic agents must be developed to prevent pathological platelet activation. Glabridin, a major bioalkaloid extracted from licorice root, improves metabolic abnormalities (i.e., obesity and diabetes) and protects against CVDs and neuronal disorders. To the best of our knowledge, no studies have focused on glabridin's effects on platelet activation. Therefore, we investigated these effects in humans and mice. Glabridin exhibited the highest inhibitory effects on collagen-stimulated platelet aggregation and moderate effects on arachidonic-acid-stimulated activation; however, no effects were observed for any other agonists (e.g., thrombin or U46619). Glabridin evidently reduced P-selectin expression, ATP release, and intracellular Ca2+ ([Ca2+]i) mobilization and thromboxane A2 formation; it further reduced the activation of phospholipase C (PLC)γ2/protein kinase C (PKC), phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β), mitogen-activated protein kinase (MAPK), and NF-κB. In mice, glabridin reduced the mortality rate caused by acute pulmonary thromboembolism without altering bleeding time. Thus, glabridin effectively inhibits the PLCγ2/PKC cascade and prevents the activation of the PI3K/Akt/GSK3β and MAPK pathways; this leads to a reduction in [Ca2+]i mobilization, which eventually inhibits platelet aggregation. Therefore, glabridin may be a promising therapeutic agent for thromboembolic disorders.
... To invigorate the qi of the heart and spleen, and harmonize the characteristics of other herbs [37]. ...
Article
Full-text available
Qi-invigorating herbs (QIHs) are a group of herbs that invigorate Qi, the most vital force for maintaining the physiological functions of the human body in traditional medicine. However, the mechanism underlying the Qi-invigorating effects remains unclear. This study aimed to elucidate the unique mechanisms of QIHs based on unique compounds, using a network pharmacology approach. QIHs and their compounds were identified using existing literature and the TCMSP database, respectively. Subsequently, a method was proposed to screen for unique compounds that are common in QIHs but rare in other traditional herbs. Unique compounds’ targets were predicted using the TCMSP, BATMAN-TCM, and SwissTargetPrediction databases. Finally, enriched GO and KEGG pathways were obtained using DAVID to uncover the biomolecular functions and mechanisms. Thirteen unique compounds, mainly including amino acids and vitamins that participate in energy metabolism and improve Qi deficiency syndrome, were identified among the eight QIHs. GO and KEGG pathway analyses revealed that these compounds commonly participate in neuroactive ligand–receptor interaction and the metabolism of amino acids, and are related to the components of mitochondria and neuronal cells. Our results appropriately reflect the characteristics of traditional Qi-invigorating effects; therefore, this study facilitates the scientific interpretation of Qi functions and provides evidence regarding the treatment effectiveness of QIHs.
... Licorice, the dried root and rhizome of Glycyrrhiza uralensis, Glycyrrhiza inflata or Glycyrrhiza glabra in the Fabaceae family, is a traditional herbal medicine which is extensively used in Europe and Asia [12,13]. Glycyrrhizic acid (GL), also known as glycyrrhizin, is the principal bioactive constituent in licorice and exists as two isomers, 18α-GL and 18β-GL, which make up 5-9% of licorice. ...
Article
Full-text available
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which is characterized by hyperglycemia, chronic insulin resistance, progressive decline in β-cell function, and defect in insulin secretion. It has become one of the leading causes of death worldwide. At present, there is no cure for T2DM, but it can be treated, and blood glucose levels can be controlled. It has been reported that diabetic patients may suffer from the adverse effects of conventional medicine. Therefore, alternative therapy, such as traditional Chinese medicine (TCM), can be used to manage and treat diabetes. In this review, glycyrrhizic acid (GL) and its derivatives are suggested to be promising candidates for the treatment of T2DM and its complications. It is the principal bioactive constituent in licorice, one type of TCM. This review comprehensively summarized the therapeutic effects and related mechanisms of GL and its derivatives in managing blood glucose levels and treating T2DM and its complications. In addition, it also discusses existing clinical trials and highlights the research gap in clinical research. In summary, this review can provide a further understanding of GL and its derivatives in T2DM as well as its complications and recent progress in the development of potential drugs targeting T2DM.
... Polysaccharides are a type of sugar moiety with complex molecular structures, created by the condensation and dehydration of several monosaccharide molecules. Glycyrrhiza polysaccharides (GPS) are the main active macromolecules in Glycyrrhiza uralensis (18,19), and have previously shown promising results as an antibacterial (20), antiviral and antitumor agent (21,22), a liver protectant (23), and immune regulator (14). In one study that highlighted this immune-regulation potential, Glycyrrhiza polysaccharide was fed to CT-26 tumor-bearing mice and significantly inhibited tumor growth, increased the immune organ index, activated CD4+ and CD8+ immune cells, and increased levels of IL-2, IL-6, and IL-7 cytokines (24). ...
Article
Full-text available
Glycyrrhiza polysaccharide extract 1 (GPS-1) is a bioactive component isolated from Glycyrrhiza uralensis, also known as Chinese licorice. It appears to be pharmacologically active as an antibacterial, antiviral, and anti-tumor agent. GPS-1 has also been shown to buffer liver health and regulate the immune system. Moreover, GPS-1 is low cost and easy to extract. More study was needed to elucidate the biochemical pathways underlying the immunomodulatory and antioxidant benefits observed in Glycyrrhiza polysaccharide extract 1 (GPS-1). in vitro experiments on chicken lymphocytes and dendritic cells (DCs) show that GPS-1 significantly promotes the proliferation of immune cells and is linked to lymphocytes' secretion of IL-12, IFN-γ, and TNF-α by. DC secretion of NO, IL-2, IL-1β, IFN-γ, TNF-α, and IL-12p70 was also increased significantly. Additionally, GPS-1 also displayed a significant antioxidant effect in vitro , able to scavenge DPPH, hydrogen peroxide, ABTS, and other free radicals like superoxide anions. Separately, GPS-1 was tested in vivo in combination with the Newcastle disease virus (NDV) – attenuated vaccine. 120 Lohmann Brown chickens were vaccinated, while another 30 became the unvaccinated blank control (BC) group. For three consecutive days 1 mL of GPS-1 was administered at doses of 19.53 μg/mL, 9.77 μg/mL, or 4.88 μg/mL to the ND-vaccinated birds, except for the vaccine control (VC), where n = 30 per group. In vivo results show that GPS-1 combined with Newcastle disease (ND) vaccine had the best efficacy at significantly increasing chickens' body weight and ND serum antibody titer, enhancing their secretion of IL-2 and IFN- γ, and promoting the development of immune organs. The results also indicate that GPS-1 was able increase the proliferation of in vitro immune cells and elevate their cytokine secretion, which enhances the body's immune response. GPS-1 also clearly has the potential to be used as an immune adjuvant alongside ND vaccination.
... Crude licorice is good at relieving cough, dissipating phlegm, and detoxication and is usually used to cure bronchitis, sore throat, and intoxication caused by drugs and food, while honey-processed licorice is known for invigorating vital energy, and is usually used to treat immune deficit, dyspepsia, and arrhythmia. [2][3][4] However, in the Chinese Pharmacopeia, the quality standards of raw licorice and honey-processed licorice stipulate the same index components. [5] Nonetheless, honey-processed licorice lacks specific index components, which may influence its therapeutic effects. ...
... Licorice is a small shrub with oval leaflets, white or purplish flower clusters, flat pods, a main taproot, and several runners, and it is mostly growing in arid and semi-arid desert grassland, desert edge, and loess hilly areas. Ethnopharmacological studies have demonstrated that licorice can stimulate energy, clear heat, detoxify the body, lubricate the lungs and relieve congestion, ease spasm, and discomfort, and minimize drug adverse effects [4][5][6][7][8]. Over 300 distinct chemicals are found in licorice, some of which have antibacterial, antiviral activities, antitumor, anti-inflammatory, anti-diabetic, and hepatoprotective, such as non-toxicity and non-specific immune system stimulants [22][23][24]. ...
Article
Full-text available
Licorice is known as “Gan-Cao” in traditional Chinese Medicine (TCM), belonging to the genus Glycyrrhiza (Family: Fabaceae/Leguminosae). It has a long medicinal history and wide applications in China. Polysaccharides of licorice (LPs) are one of the key bioactive components. As herbal polysaccharides attracted increasing interest in the past several decades, their extraction, isolation, structural characterization, pharmacological activities, and medicinal application have been explored extensively. It is worth heeding that the method of extraction and purification effects LPs, apart from specie and origin specificity. This review evaluates the method of extraction and purification and demonstrates its performance in gaining specific composition and its structure-activity relationship, which might lead the readers to a fresh horizon for developing advanced treatment strategies. It is recently reported that the conformation of LPs plays a vital role as biopolymers, such as selenized modification, microencapsulation, nanocomposite, liposome formulation, drug/hydrogel combinations, biosensor device, and synergistic effect with a vaccine. In addition, LPs showed a good thermodynamics profile, as these properties enable them to interact with additional supramolecular interaction by chemical modifications or copolymerization. Functional polymers that are responsive to various external stimuli, such as physical, chemical, and biological signals, are a promising study topic. Thus, LPs are emerging as a new biomaterial that can enhance intended formulation along exerting its inherent medicinal effects. It is hoped that this review will provide a basis for the utilization and further developments of licorice polysaccharides in the vast medium.
... Taking into consideration the wide range of phytochemicals that have been used for combination therapies in herbal medicine, it is crucial to elucidate the mechanisms of herb-herb interactions and herb-drug interactions [1,2]. Licorice is a popular guide drug used to harmonize different ingredients in traditional herbal medicines [3]. Glycyrrhizic acid (GA), in particular, is a major component of licorice [4]. ...
Article
In this study, nanocomplexes composed of glycyrrhizic acid (GA) derived from the root of the licorice plant (Glycyrrhiza glabra) were formulated for the delivery of curcumin (CUR). Sonication of amphiphilic GA solution with hydrophobic CUR resulted in the production of nanosized complexes with a size of 164.8 ± 51.7 nm, which greatly enhanced the solubility of CUR in aqueous solution. A majority of the CURs were released from these GA/ CUR nanocomplexes within 12 h. GA/CUR nanocomplexes exhibited excellent intracellular uptake in human breast cancer cells (Michigan cancer foundation-7/multi-drug resistant cells), indicating enhanced anti-cancer effects compared to that of free CUR. In addition, GA/CUR nanocomplexes demonstrated high intracellular uptake into macrophages (RAW264.7 cells), consequently reducing the release of the pro-inflammatory cytokine tumor necrosis factor-α. Furthermore, GA/CUR nanocomplexes successfully reduced the levels of serum pro-inflammatory cytokines and splenomegaly in a rheumatoid arthritis model.
... In addition, one of the active ingredients of Glycyrrhiza uralensis, saponin, has a surfactant property and is used to promote absorption of poorly absorbed drugs, such as anthraquinone glycosides, including emonin and optusin [27,28]. As such, Glycyrrhiza uralensis has the effect of regulating and supplementing the properties of other drugs and reducing toxic intermediates, so it is widely used in oriental medicine prescriptions to increase the activity of herbal medicines [29]. While it is composed of 14 compounds, it has been reported that mainly, six of the following components are contained: glycyrrhizin, liquiritin, liquiritin apioside, isoliquiritin, isoliquiritin apioside, and liquiritingenin [30]. ...
Article
Full-text available
This study sought to confirm the effect of using a mouthwash containing Glycyrrhiza uralensis extract for oral health management by investigating changes in the pH of dental plaque and bacteria that cause dental caries. A randomized, double-blind, placebo-controlled study was conducted on 60 subjects categorized in either the Glycyrrhiza uralensis extract gargle group (n = 30) or the saline gargle group (n = 30). Scaling was conducted in order to ensure the homogeneity of the oral environment, while gargling was performed once daily before the subjects went to bed for 5 days based on the group. Caries activity was assessed using the Cariview test, while detection of the bacteria that cause dental caries was confirmed using microbiological analysis. All clinical measurements and evaluations were conducted by two trained dental hygienists under the supervision of a dentist. Based on the analysis of dental caries activity and dental caries-causing bacteria, the Glycyrrhiza uralensis extract gargle group showed a clear decrease in bacteria compared to the saline gargle group. Glycyrrhiza uralensis extract demonstrated no risk of tooth demineralization. It also showed excellent antibacterial activity through inhibition and effective reduction of bacteria that cause dental caries. Therefore, the mouthwash containing Glycyrrhiza uralensis extract is an effective oral care product suitable for use as an effective dental caries prevention agent.
... Licorice, the root of Glycyrrhiza glabra, has been widely used as a traditional herbal medicine to harmonize the characteristics of other ingredients in herbal prescriptions in Asian countries, and as a sweetener and flavoring agent in candies and drinks in Western countries. [40][41][42] Numerous previous studies have highlighted the evidence of the pharmacological effects of licorice, such as the anti-inflammatory, antiviral, hepatoprotective and anti-ulcer effects. [43,44] The therapeutic effects of licorice on gastrointestinal disorders have been reported to increase the eradication rate of Helicobacter pylori [45] and promote ulcer healing to treat peptic ulcers. ...
Article
Full-text available
Nonsteroidal anti-inflammatory drug-induced small bowel injuries (NSIs) have been largely ignored for decades due to the focus on nonsteroidal anti-inflammatory drug gastropathy. With the visualization of the small intestines enabled by video capsule endoscopy, the frequency and severity of NSIs have become more evident. NSIs have a complex pathophysiology, and no effective preventive or treatment options have been proven. Complementary and alternative medicine (CAM) has been used to treat disorders of the small intestine, and more research on its effectiveness for NSIs has been conducted. We reviewed the current evidence and mechanisms of action of CAMs on NSI. Clinical and experimental studies on the effect of CAMs on NSIs were performed using 10 databases. Twenty-two studies (3 clinical and 19 in vivo experimental studies) were included in the final analysis involving 10 kinds of CAMs: bovine colostrum, Orengedokuto (coptis), muscovite, licorice, grape seed, wheat, brown seaweed, Ganoderma lucidum fungus mycelia, Chaenomeles speciosa (sweet) Nakai (muguasantie), and Jinghua Weikang capsule. The mechanisms of CAM include an increase in prostaglandin E2, reparation of the enteric nervous system, inhibition of pro-inflammatory cytokines, reduction of intestinal permeability and enteric bacterial numbers, decrease in oxidative stress, and modulation of small intestinal motility. CAM may be a novel alternative option for treating and preventing NSI, and further studies on human and animal models with relevant comorbidities are warranted.
... However, glycyrrhizin, the main active phytochemical in RG (proportion = 19%), can increase CYP3A4 activity by approximately 30% [86]. Some of the key active phytochemicals, especially those in RG, can lower the activity of P-gp, potentially inhibiting efflux transport of potential substrate phytochemicals [87]. P-gp is also expressed in the synovial tissue and can influence the joint disposition of drugs [88]. ...
Article
Full-text available
Osteoarthritis (OA), a highly prevalent chronic joint disease, involves a complex network of inflammatory mediators that not only triggers pain and cartilage degeneration but also accelerates disease progression. Traditional Chinese medicinal shenjinhuoxue mixture (SHM) shows anti-inflammatory and analgesic effects against OA with remarkable clinical efficacy. This study explored the mechanism underlying anti-OA properties of SHM and evaluated its efficacy and safety via in vivo experiments. Through network pharmacology and published literature, we identified the key active phytochemicals in SHM, including β-sitosterol, oleanolic acid, licochalcone A, quercetin, isorhamnetin, kaempferol, morusin, lupeol, and pinocembrin; the pivotal targets of which are TLR-4 and NF-κB, eliciting anti-OA activity. These phytochemicals can enter the active pockets of TLR-4 and NF-κB with docking score≤−3.86 kcal/mol, as shown in molecular docking models. By using surface plasmon resonance assay, licochalcone A and oleanolic acid were found to have good TLR-4-binding affinity. In OA rats, oral SHM at mid and high doses (8.72 g/kg and 26.2 g/kg) over 6 weeks significantly alleviated mechanical and thermal hyperalgesia (P
... Glycyrrhiza glabra Linn., Glycyrrhiza echinata Linn., Glycyrrhiza inflata Batalin or Glycyrrhiza uralensis Fisch. It has been used as a food additive and for medicinal purposes for thousands of years [2][3][4]. The use of the liquorice extract in foods has been approved by the US Food and Drug Administration, the Council of Europe, and the Joint FAO/WHO Expert Committee on Food Additives [5]. ...
Article
In the search for novel drugs for health preservation, the active ingredients of medicinal herbs have been used since time immemorial. Liquorice, a potent medicinal herb derived from the root and rhizomes of Glycyrrhiza species, has been used worldwide for the treatment of various diseases. A number of compounds have been isolated from the liquorice root, including retrochalcones, viz. echinatin, licochalcone A, B, C, D and E, having a diverse range of pharmacological applications such as antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, anti-diabetic, anti-obesity, anti-parasitic, to name a few. This review highlights the different synthetic procedures for retrochalcones and their in vitro, in vivo, ex vivo and in silico studies, along with the underlying molecular mechanisms. In addition, the total syntheses of licochalcone F and H, the regioisomers of licochalcone E and C, respectively, have also been included. Herein, the maximum possible biological applications of retrochalcones cited so far in the literature have been reviewed. The insights from this review will further advance the role and application of retrochalcones in the field of medicinal chemistry.
... The chemical constituents of Gancao are complex, including triterpenoids, flavonoids, polysaccharides, lignin, proteins, trace elements, etc. (Jiang et al., 2020;Li et al., 2020). These chemical constituents contribute a variety of pharmacological activities, such as antitussive, anti-asthmatic, anti-inflammatory, antibacterial, analgesic, immunoregulatory, hepatoprotective, antioxidant and other effects (Lam et al., 2016;Li et al., 2020;Wang et al., 2013). Gancao, based on its natural properties and sweet taste, has the functions in TCM of strengthening the spleen and replenishing qi, relieving spasms and pain, and regulating the properties of other herbal ingredients (Lv et al., 2018). ...
Article
A method combining ultra-high-performance liquid chromatograph/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and chemometrics was established to evaluate the difference in chemical composition between Aconiti Lateralis Radix (Fuzi in Chinese) before and after combination with Glycyrrhizae Radix et Rhizoma (Gancao in Chinese). UPLC-Q-TOF-MS was used to characterize the chemical components, before and after the combination of Fuzi with Gancao, and genetic algorithm selection variables were applied to extract important variables. Partial least square discriminant analysis was used to verify the reliability of the variables obtained by genetic algorithm selection, in differentiating Fuzi and combinations with Gancao, and nine potential chemical markers were obtained by partial least square discriminant analysis. The content changes of chemical markers in Fuzi, before and after combination, were visualized using a heat map and hierarchical cluster analysis. Based on the chemical markers, characteristic profiling of UPLC-Q-TOF-MS data was developed, then unsupervised principal components analysis and a supervised counter-propagation artificial neural network, were used to validate the characteristic profiling approach, and showed that it performed well in differentiating between Fuzi and combinations with Gancao.
... Licorice derivatives are often used to treat cases of suspected DILI in Japan, China, and other Asian countries. 18β-Glycyrrhetinic acid, the main ingredient in licorice, is a staple of Chinese medicine, and is widely prescribed for its antioxidation, anti-inflammation, antiviral, and immune regulation properties [190]. Studies in mice and cells suggest that 18β-glycyrrhetinic acid has protective effects on the liver such as inhibition of hepatic fibrosis, attenuation of acute liver injury, reducing oxidative stress, and inflammation [191]. ...
Article
Drug-induced liver injury (DILI) remains an important, yet challenging diagnosis for physicians. Each year, additional drugs are implicated in DILI and this year was no different, with more than 1400 articles published on the subject. This review examines some of the most significant highlights and controversies in DILI-related research over the past year and their implications for clinical practice. Several new drugs were approved by the US Food and Drug Administration including a number of drugs implicated in causing DILI, particularly among the chemotherapeutic classes. The COVID-19 pandemic was also a major focus of attention in 2020 and we discuss some of the notable aspects of COVID-19-related liver injury and its implications for diagnosing DILI. Updates in diagnostic and causality assessments related to DILI such as the Roussel Uclaf Causality Assessment Method are included, mindful that there is still no single biomarker or diagnostic tool to unequivocally diagnose DILI. Glutamate dehydrogenase received renewed attention as being more specific than alanine aminotransferase. There were a few new reports of previously unrecognized hepatotoxins, including immune modulators and novel gene therapy drugs that we highlight. Updates and new developments of previously described hepatotoxins, such as immune checkpoint inhibitors and anti-tuberculosis drugs are reviewed. Finally, novel technologies such as organoid culture systems to better predict DILI preclinically may be coming of age and determinants of hepatocyte loss, such as calculating PALT are poised to improve our current means of estimating DILI severity and the risk of acute liver failure.
... Other phytochemicals of licorice including glycyrrhizin, glycyrrhetinic acid (GA), (3R)-vestitol, liquiritigenin-3,4-diglucoside, and 4-hydroxyguaiacol apioglucoside potentially inhibited major CYP isoforms (Lv et al., 2016;Pandit et al., 2011;Tsukamoto et al., 2005;Wang et al., 2013). Glabridin is a chief phytochemical of G. glabra. ...
Article
Full-text available
Since the beginning, human beings have consistently been using plants and their components for the prevention and treatment of various ailments. However, in the last few decades, plant-based medicines and health supplements are gaining more acceptability and rapid popularity. Licorice (Glycyrrhiza sp.) is a terrestrial herb belonging to the family Fabaceae and primarily cultivated in European, Middle Eastern, and South Asian countries. Ethnomedicinal uses of licorice have frequently been described in the world's renowned medical systems, including Ayurveda, Unani, Chinese, Korean, Japanese, African, and European traditional medical systems. To date, 30 species of licorice are known, and among them, G. glabra, G. inflata, and G. uralensis are significantly explored for nutritional and pharmacological benefits. The wide range of commercially available products, including herbal preparations, health supplements, cosmetics, and food and feeds preparations use licorice as active ingredient. Glabridin, licochalcone A, glycyrrhizin, and 18-glycyrrhetinic acid are the notable phytochemicals isolated from licorice and immensely explored for biological and pharmacological activities. Nevertheless, the excessive intake of licorice has also been associated with a wide spectrum of adverse effects on human health. Among them, several are reported to be mediated by modulation of drug-metabolizing cytochrome P-450 enzymes. In the present review, we provide a comprehensive description of the current knowledge of licorice, including historical development, phytoconstituents, species-specific marker metabolites, herb–drug interaction, pharmacological uses, food additive application, and toxicities. We believe this review will provide excellent information to physicians, researchers, and personnel of different scientific regulatory bodies.
... Licorice (Glycyrrhiza uralensis Fisch) has been used for medicinal and health purposes in the human digestive, immune, and respiratory systems for thousands of years [1]. It is primarily effective for relieving asthma by coughing, fatigue and debilitation, excessive phlegm, and drug toxicity [2]. Moreover, licorice and its metabolites have significant therapeutic potential for treating diabetes mellitus [3]. ...
Article
Recently, the use of stimuli-responsive ionic liquids (ILs) as extractants has received close attention due to their retrievability. In this study, a temperature-responsive ionic liquid (TR-IL) was synthesized and used for the extraction and subsequent separation of liquiritin (LQ) and glycyrrhizic acid (GA) from licorice (Glycyrrhiza uralensis Fisch) root. This TR-IL was used as the extractant below its lower critical solution temperature (LCST), whereas it became hydrophobic to form a biphasic system to separate the two target compounds above its LCST. LQ and GA were distributed in the IL and aqueous phases, respectively. Moreover, the factors influencing the extraction and separation processes were studied to optimize the experimental conditions. The extraction yields of 9.63 and 28.51 mg/g and the distribution coefficients of 3.2 and 4.42 were obtained for LQ and GA, respectively. The selectivity coefficient of this biphasic system for LQ and GA was 14.2. Finally, the TR-IL was recycled and reused after extraction and separation. This study developed an efficient, green and sustainable strategy for the extraction and selective separation of bioactive ingredients from natural products.
... It has a unique effect on moderating and complementing the characteristics of other herbs in low dosage. 32 The reduction of the oral ulcer may be caused by many factors. Combination with CSE may provide strong antioxidant and antibacterial properties and accelerate complete healing. ...
Article
Introduction: Stomatitis is the most common oral mucosal lesions characterized by round ulcers with yellow-white color and usually heals up to 14 days. Many recent studies have demonstrated that glycyrrhizin (GL) and C. sappan extract (CSE) exhibits anti-inflammatory, anti-ulcer and antioxidant action but no study has demonstrated the effect on the oral mucosal ulcer. Objectives: To evaluate the effect of GL and CSE in experimentally chemically induced oral mucosal ulcers using rats. Methods: Male Sprague-Dawley rats were randomly distributed into seven groups: the control group, the comparison group of 0.1% triamcinolone acetonide (TCA), a single treatment group of 3% GL and 3% CSE, combination groups of 3% GL + CSE (1:1, 1:2, 2:1). The oral ulcer model was induced by 15 μL of 50% acetic acid. The clinical healing was evaluated by measuring the ulcer size and body weight from day 0–14 and evaluate the leukocyte number on days 0, 4, 9 and 14. Histological examination was conducted at the end of the treatment. Results: The group of 0.1% TCA and GL:CSE (2:1) showed greater ulcer closure (>80%) and decreased leukocyte number since day 4 (p<0.05). Body weight loss was observed after ulcer initiation and started to increase after day 4 of treatment. While the histological examination showed similar tissue regeneration profile only from the GL:CSE (2:1) group with the healthy oral mucosa. Conclusion:Combination treatment of GL:CSE (2:1) enhanced the closure of oral mucosal ulcer and demonstrate complete tissue regeneration.
Article
Full-text available
This study aimed to examine the in vivo and in vitro therapeutic effects of glycyrrhizic acid (GA) on steroid-induced osteonecrosis of the femoral head (SONFH), which is caused by the overuse of glucocorticoids (GCs). Clinically, we identified elevated oxidative stress (OS) levels and an imbalance in osteolipogenic homeostasis in SONFH patients compared to femoral neck fracture (FNF) patients. In vivo, we established experimental SONFH in rats via lipopolysaccharides (LPSs) combined with methylprednisolone (MPS). We showed that GA and Wnt agonist-S8320 alleviated SONFH, as evidenced by the reduced microstructural and histopathological alterations in the subchondral bone of the femoral head and the decreased levels of OS in rat models. In vitro, GA reduced dexamethasone (Dex)-induced excessive NOX4 and OS levels by activating the Wnt/β-catenin pathway, thereby promoting the osteogenic differentiation of mesenchymal stem cells (MSCs) and inhibiting lipogenic differentiation. In addition, GA regulated the expression levels of the key transcription factors downstream of this pathway, Runx2 and PPARγ, thus maintaining osteolipogenic homeostasis. In summary, we demonstrated for the first time that GA modulates the osteolipogenic differentiation commitment of MSCs induced by excessive OS through activating the Wnt/β-catenin pathway, thereby ameliorating SONFH.
Article
Ethnopharmacological relevance: As a traditional Chinese medicine, Euodiae Fructus (EF) has been used to treat stomachache, belching, and emesis for more than a thousand years. Ancient records and modern research have shown that EF has mild toxicity, which needs to be processed with licorice juice to reduce its toxicity. Research suggested that the toxicity of EF can be caused by in vivo metabolism, but whether its metabolites are related to hepatotoxicity and whether licorice can affect the metabolism of EF have not been reported, which needed an effective strategy to clarify the correlation between metabolites and toxicity and the attenuation mechanism of licorice processing. Aim of the study: The poisonous substances and metabolic pathways were clarified by comparing the mechanism in vivo process of the main alkaloids of EF in normal rats and rats treated with dexamethasone (DXMS), ketoconazole (KTC), and EF processed with licorice (EFP). Materials and methods: Rats were given EF and EFP by oral administration, respectively. The EF + DXMS and EF + KTC groups were pretreated with DXMS and KTC, respectively, by i. p. for seven days, and their toxicity differences were compared. The comprehensive strategy based on UPLC-Q-Exactive-MS and OPLS-DA analysis was developed to compare the types and contents of metabolites and clarify the metabolic pathways of alkaloids among EF, EFP, EF + KTC, and EF + DXMS groups. Results: EF + DXMS group significantly increased the hepatotoxicity, whereas the EF + KTC and EFP groups reduced the hepatotoxicity compared with the EF group. One hundred and thirty-five metabolites were detected, and the metabolic pathways of the main alkaloid components related to toxicity were inferred in the plasma, urine, feces, and bile of rats. KTC and licorice similarly inhibited the production of toxic metabolites, changed metabolism in vivo, and produced many new II and a few phases I metabolites, while the contents of toxic metabolites increased in the DXMS group. Conclusion: Licorice and KTC could inhibit the production of metabolites of EF related to toxicity, increase the production of other metabolites and promote the excretion of alkaloids, which may be why licorice and KTC can minimize EF toxicity.
Article
Background and purpose: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The development of novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products (NPs) have played a fundamental role and provided an abundant pool in drug discovery. Experimental approach: A compound library containing 160 NPs was used to screen potential anti-inflammatory compounds. Mice with lipopolysaccharide (LPS)-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. Key results: Licochalcone A (LA) was discovered from the anti-inflammatory screening of NPs in macrophages. A qPCR array validated the inflammation-regulatory effects of LA and indicated that the potential targets of LA may be the upstream proteins in LPS pro-inflammatory signaling. Further studies showed that LA directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to LA. In vivo, LA treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway, and inflammatory cytokine induction. Conclusion and implications: In summary, our study identified MD2 as a direct target of LA for its anti-inflammatory activity and suggested that LA might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy.
Article
Ethnopharmacologic relevance Licorice is a traditional Chinese medicine that has been used for cardiovascular diseases. Recent studies found that supplementation with licorice extracts attenuated the development of atherosclerosis (AS) in hypercholesterolemic patients. Many studies have shown that licorice flavonoids, the main active components of licorice, have a variety of pharmacological effects, including anti-inflammation, regulation of lipid metabolism, and antioxidation. However, the key active components against AS in licorice flavonoids are still unclear. Aim of the study The aim of this paper is to investigate the active components of licorice flavonoids that exert anti-atherosclerotic effects and the underlying mechanisms. Materials and methods Network pharmacology was used to screen the active components of licorice flavonoids that have anti-atherosclerotic effects. Combining bioinformatics analysis and in vitro studies, the effects and underlying mechanisms of the active component isoliquiritigenin (ISL) on cell pyroptosis were further investigated in tumor necrosis factor (TNF)-α-treated human umbilical vein endothelial cells (HUVECs). Results We constructed a compound-target network and screened 3 active components, namely, ISL, glabridin, and naringenin in licorice flavonoids. The half maximal effective concentration values of these 3 components suggested that ISL was the key active component against TNF-α-induced endothelial cell injury. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that ISL could potentially treat AS via the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway. An in vitro study verified that ISL suppressed TNF-α-induced NLRP3 activation and pyroptosis in HUVECs. The molecular docking and cellular thermal shift assay showed good compatibility between ISL and class III histone deacetylase sirtuin 6 (SIRT6). Moreover, we found that ISL upregulated the expression of SIRT6 in TNF-α-treated HUVECs. Further study found that SIRT6 knockdown reduced the inhibitory effect of ISL on pyroptosis, whereas the NLRP3 inhibitor reversed this process in TNF-α-treated HUVECs. Conclusions Our results demonstrate that ISL is a key active component of licorice flavonoids. ISL attenuates NLRP3-mediated vascular endothelial cell pyroptosis via SIRT6, and SIRT6 may be a potential target of ISL for the treatment of AS.
Article
Full-text available
The roots of licorice (Glycyrrhiza glabra L.) have been widely used in traditional and officinal medicines for the treatment of different diseases. Natural deep eutectic solvents (NADES) have become popular for the extraction of active principles from medicinal plants. However, the ability of NADES to co-extract trace elements during the isolation of target active compounds is rarely investigated. The aim of this study was to analyze the content of trace elements in acid-based NADES extracts from the roots of G. glabra and the health risks associated with them. In this study, we have tested for the first time the ability of several acid-based NADES to co-extract glycyrrhizic acid (GA) and trace elements from the roots of G. glabra. GA has been identified as the dominant phytochemical in G. glabra NADES extracts (0.145–0.495 mg/g). Due to the close pKa of lactic acid and GA, the yield of GA in lactic acid-based NADES was higher in comparison with other tested NADES. The yield of GA in NADES3-NADES5 was statistically significant and surpassed the yield of GA in water. The recovery of all elements (except Li) by all tested NADES was low (less than 6%). According to an ANOVA test, the hydrogen bond donor type plays a decisive role in the extraction of elements. A strong positive correlation between the recovery of GA and MPI was noted. The metal pollution index, hazard quotient, hazard index, and chronic daily intake were calculated and suggest that all tested NADES extracts of G. glabra roots were nontoxic and possess no health risk for both ingestion and topical application.
Article
Full-text available
Melanoma skin cancer is a malignant melanocyte tumor considered the most invasive and dangerous skin cancer, with an average five-year survival rate of less than 5% after metastasis. Thus, a new strategy for preventing and treating cancer from the natural product is required. Medicinal plants are the potential as an alternative against cancer. This review article aims to determine natural products from medicinal plants which have the potential as an anticancer in melanoma skin cancer in vitro and in vivo. 40 plants have been selected based on the selection criteria for anticancer compounds. In vitro studies showed that the plant can reduce cell viability through cell cycle inhibition and apoptosis induction and inhibit angiogenesis, invasion, and metastasis in human melanoma skin cancer. Therefore, further research is required to explore more plants, especially medicinal plants, their active compounds, and the mechanism of anticancer action to be used as standard herbal medicines.
Article
Objective: This study compared the ability of Liquorice roots aqueous extract (LRE) and its ingredient, isoliquiritigenin (ISL), in alleviating high-fat diet (HFD)-induced hepatic steatosis and examined if this effect involves activation of AMPK. Materials and methods: Control or HFD-fed rats were treated with the vehicle, LRE (200 mg/kg), or ISL (30 mg/kg) for 8 weeks orally. Results: ISL and LRE reduced HFD-induced hyperglycaemia, improved liver structure, lowered serum and hepatic lipids, and attenuated hepatic oxidative stress and inflammation. In the control and HFD-fed rats, ISL and LRE significantly stimulated the muscular and hepatic mRNA and protein levels of AMPK, improved oral glucose tolerance, reduced hepatic mRNA levels of SREBP1/2, and upregulated hepatic levels of PPARα and Bcl2. These effects were comparable for ISL and LRE and were prevented by co-administration of compound C, an AMPK inhibitor. Discussion and conclusion: ISL and LRE provide an effective theory to alleviate hepatic steatosis through activating AMPK.
Article
The study aimed to investigate the effects of dietary licorice (Glycyrrhiza uralensis) on the growth performance, muscle quality, and immunity of common carp (Cyprinus carpio haematopterus). Five diets were formulated to contain 0.0%, 0.5%, 1.5%, 2.5%, and 4.0% licorice, respectively. Each diet was randomly distributed to triplicate groups of 60 juvenile (average weight 21.27 ± 0.13 g) per aquarium. After 15 weeks of feeding, the licorice had positive effects on body growth and feed utilization, the FBW, WGR, PER and SGR reached a maximum in the 4.0% treatment group (P
Article
Emodin (EMO), the main bioactive component of Polygonum multiflorum, Rheum palmatum, Aloe vera and Cassia acutifolia, can cause severe hepatotoxicity. Isoliquiritigenin (ISL), a flavonoid compound from the Glycyrrhiza, has been reported to be the most potent antioxidant response element (ARE)-luciferase inducer among the main components of licorice. But the protective effect and underlying mechanism of ISL on liver injury induced by EMO has not been reported. This study aims to explore the role of nuclear transcription factor 2 (Nrf2) in EMO-induced hepatotoxicity and the protective effect of ISL. EMO treatment caused cytotoxicity in L-02 cells. Combined treatment of EMO with ISL effectively reversed changes in cell viability, reduced reactive oxygen species (ROS) generation and malondialdehyde (MDA) generation, enhanced the levels of glutathione (GSH) and super oxide dismutase (SOD) induced by EMO in L-02 cells. Furthermore, ISL could also phosphorylate mitogen-activated protein kinases (MAPKs) and up-regulate Kelth-like ECH-associated protein (Keap1). The pathways of MAPKs and Keap1 lead to the separation of Keap1 and Nrf2. Free Nrf2 transferred to the nucleus and enhanced the expression of phase II detoxification enzymes. In conclusion, our results are the first to highlight the beneficial role and relevant mechanisms of ISL in EMO-induced liver injury and provide novel insight into its application.
Article
Chronic gastritis (CG) has become a major threat to human health. Banxia Xiexin Decoction (BXXXD) has been used clinically to treat gastritis by acting on the spleen and stomach for thousands of years. Baicalin, wogonoside, liquiritin and liquiritigenin, are the main bioactive flavonoids of BXXXD. A rapid, sensitive and selective HPLC‐TQ‐MS/MS method was developed to simultaneously quantify the four flavonoids in rat plasma in this study. With salidroside as internal standard (IS), plasma samples were extracted and separated on a Welch HPLC XB‐C18 column (2.1 × 50 mm, 1.8 μm) using gradient elution. An optimized gradient of mobile phase consisted of water (containing 0.1% formic acid) (A) and methanol (B) was used. Detection was implemented in MRM mode with an electrospray negative ionization source. Comparative pharmacokinetics of four analytes in normal and CG rats after oral administration of BXXXD or its different compatibilities were firstly investigated. Results indicated that the pharmacokinetic behaviors of analytes were obviously changed in CG rats. From the comparison between the whole prescription group and the compatibility groups, it was found that the pharmacokinetic behavior of analytes also changed to some extent. The pharmacokinetic alterations of analytes might be due to the pathological conditions of CG.
Article
Full-text available
Excessive oxygen free radicals can lead to aging, cancer, and other diseases. Therefore, searching for effective antioxidants to scavenge oxygen free radicals has become the focus of modern medicine. In this study, the molecular mechanism of Licorice Green Tea Beverage (LGTB) in scavenging oxygen free radicals was investigated by means of network pharmacology, molecular docking and experimental verification. Network pharmacology studies have shown that paeonol, eugenol, cinnamaldehyde, swertisin, rutin, glycyrrhetinic acid, oleic, pelargonidin‐3‐O‐glucoside and quercetin, kaferempol were the main active components of LGTB, and SOD and CAT are important targets for LGTB in scavenging oxygen free radicals. The results of molecular docking showed that these representative compounds had good affinity to SOD and CAT target proteins. In vitro free radical scavenging experiments showed that LTGB had significant scavenging effects on both DPPH and ABTS radicals, and had strong total reducing power. In vitro cell experiments showed that LGTB could protect HaCaT cells from oxidative stress induced by H2O2. The mechanism of LGTB was related to the increase of SOD and CAT activity. Western blotting showed that LGTB could inhibit PI3K/AKT/HIF‐1 signaling pathway and improve the antioxidant capacity of HaCaT cells. In vivo experiments showed that LGTB could significantly increase mouse visceral index, increase serum SOD and GSH‐Px activity, decrease the content of MDA, and improve liver and kidney pathological state. This study reported the molecular mechanism of LTGB scavenging oxygen free radicals, which provided scientific basis for the treatment and clinical research of aging and other diseases caused by excessive free radicals. Practical applications Free radicals are produced by the normal response of cells during aerobic respiration and perform various functions, such as signaling and providing protection against infection. However, excessive free radicals can lead to aging, cancer, and other diseases. The antioxidant can overcome the harm caused by excessive free radicals. In this study, we investigated the molecular mechanism of scavenging oxygen free radicals of Licorice Green Tea Beverage (LGTB) through network pharmacology and molecular docking, and its efficacy was verified by free radical scavenging experiment in vitro, HaCaT cell oxidative stress injury induced by H2O2, D‐galactose to establish an aging model in mice and Western blotting experiment. It not only elucidates its mechanism at the system level, but also proves its validity at the biological level. It provides the theoretical basis and experimental evidence for the follow‐up research and promotion of the product.
Article
The aim of this study was to evaluate the effects of dietary Glycyrrhiza polysaccharide (GCP) supplementation on growth performance, intestinal antioxidants, immunity and microbiota in weaned piglets. One hundred and twenty 28-day-old weaned piglets were randomly assigned into five groups (four replicates per group) and fed a basal diet with GCP at 0, 500, 1000, 2000 and 4000 mg/kg for four weeks, respectively. Results showed that 1000 mg/kg GCP improved piglets’ ADG and ADFI and reduced FCR (p <.05). Thus, the 0 and 1000 mg/kg GCP dose were selected for subsequent experiments. We found that 1000 mg/GCP increased SOD and T-AOC and decreased MDA in the jejunal mucosa (p <.05). Dietary 1000 mg/kg GCP also resulted in high levels of sIgA, IL-10 and TGF-β, whereas IL-2 dropped dramatically (p <.05). The relative expression levels of ZO-1, CLDN, OCLDN, TLR-4, IL-10, TGF-β, Nrf-2, SOD1 and CAT increased in the jejunal mucosa, whereas INF-γ decreased (p <.05). 1000 mg/kg GCP treatment altered the diversity and community composition of cecal microbiota in pigs, with increasing relative abundance of Bacteroidota and Lactobacillus at phylum and genus levels (p <.05), respectively. The results suggested that dietary 1000 mg/kg GCP could improve growth performance and intestinal health of weaned piglets.
Article
Uridine diphosphate glucose dehydrogenase (UGDH) has a crucial role for the synthesis of UDP-glucuronic acid (UDPGA), which is the important sugar donor in the glucuronosylation of bioactive triterpene saponins in the traditional Chinese medicine Glycyrrhiza uralensis Fisch. UGDHs usually exist as isoforms in plants, but knowledge of their unique binding sites and patterns remain largely incomplete. Here, we mined five UGDH isoforms in G. uralensis transcriptome that catalyze the oxidation of UDP-glucose (UDPG) to UDPGA and had different catalytic efficiencies. Molecular modeling and molecular dynamics simulation revealed the potential catalytic residues for the catalytic efficiencies of the isoforms. Moreover, the UGDH isoforms exhibited substrate promiscuity by catalyzing two structurally diverse UDPG derivatives, which was further demonstrated by docking studies. This work gives new insights into the UGDH isoforms involved the biosynthesis of glucuronides in G. uralensis, and extends the understanding of the versatility of UGDHs.
Article
Background Misusage of pyrrolizidine alkaloid (PA)-containing plants or unaware intake of PA-contaminated foodstuffs causes thousands of PA poisoning cases in humans. PA intoxication is accompanied by oxidative stress and subsequent extensive hepatocellular damage. Our previous study has demonstrated that 18β-glycyrrhetinic acid (GA), a bioactive constituent of liquorice, prevented PA-induced hepatotoxicity in rats, however the underlying mechanisms remain unclear. Objective This study aims to explore the mechanisms underlying the hepato-protective effect of GA in combating retrorsine (RTS, a representative toxic PA)-induced liver injury. Methods Histological and biochemical assessments were employed to evaluate the protective effect of GA on RTS-induced hepatotoxicity in rats. Sulforhodamine B assay, real-time PCR, western blotting, and immunostaining were used to explore the underlying mechanisms in human hepatocytes and rats. Results Our findings demonstrated that GA alleviated RTS-induced elevation of serum ALT and bilirubin levels, as well as hepatocytes necrosis and sinusoidal endothelial cells (SECs) damage in rats. GA also enhanced the activities and expressions of several antioxidant enzymes through upregulating nuclear factor-erythroid 2-related factor2 (Nrf2). Moreover, inhibition of Nrf2 blocked the hepatoprotective effect of GA against RTS intoxication. Mechanistically, GA increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and enhanced glycogen synthase kinase 3 beta (GSK3β) inhibitory phosphorylation at serine 9, thus promoting the nuclear accumulation of Nrf2 and activating its downstream targets. Conclusion This study for the first time demonstrated that GA exerted protective effects against RTS-induced liver injury by potentiating the Nrf2-mediated antioxidant system through PI3K/Akt/GSK3β pathway. The findings indicated that GA may serve as a potential candidate drug for the treatment of PA intoxication.
Article
Full-text available
Magnetic solid-phase extraction (MSPE) strategy based on the Fe3O4@PDA/MIL-101(Cr) has been proposed to separate and purify five common mycotoxins in licorice, including aflatoxin B1, aflatoxin G1, sterigmatocystin, zearalenone, and ochratoxin A. Integrating the MSPE and solid–liquid extraction/partitioning, a modified QuEChERS was established to adapt to the complex licorice samples. The Fe3O4@PDA/MIL-101(Cr) was successfully synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption–desorption isotherms. Sorbents with superior advantages for exclusion of matrix interference and extraction of target analytes in a short time were obtained, according to their ability of magnetic separation, high surface area (287.75 m²/g), large pore volume (0.61 cm³/g), and nanosized structure with mesopores. Prior to analysis with ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), several key parameters that would affect the sorbents’ extraction efficiency were extensively investigated. Under the optimized conditions, the practicality of the developed method for analysis of mycotoxins in licorice samples was confirmed by adequate linearity (R² ≥ 0.9967), high sensitivity (LODs and LOQs, respectively, in the ranges 0.01–0.09 and 0.02–0.30 μg/kg), acceptable recovery (78.53%–116.28%), satisfactory reusability, and good interbatch precision of the sorbents (RSDs in the ranges 6.70%–11.20% and 6.02%–10.35%, respectively). The results indicated that the established method was feasible and reliable for the environment-friendly and rapid screening of mycotoxins in complex licorice samples. © 2022 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.
Article
The dried roots and rhizomes of Glycyrrhiza species (G. glabra, G. uralensis and G. inflata), commonly known as licorice, have long been used in traditional medicine. In addition, two other species, G. echinata and G. lepidota are also considered “licorice” in select markets. Currently, licorice is an integral part of several botanical drugs and dietary supplements. To probe the botanicals’ safety, herb-drug interaction potential of the hydroethanolic extracts of five Glycyrrhiza species and their key constituents was investigated by determining their effects on pregnane X receptor, aryl hydrocarbon receptor, two major cytochrome P450 isoforms (CYP3A4 and CYP1A2), and the metabolic clearance of antiviral drugs. All extracts enhanced transcriptional activity of PXR and AhR (>2-fold) and increased the enzyme activity of CYP3A4 and CYP1A2. The highest increase in CYP3A4 was seen with G. echinata (4-fold), and the highest increase in CYP1A2 was seen with G. uralensis (18-fold) and G. inflata (16-fold). Among the constituents, glabridin, licoisoflavone A, glyasperin C, and glycycoumarin activated PXR and AhR, glabridin being the most effective (6- and 27-fold increase, respectively). Licoisoflavone A, glyasperin C, and glycycoumarin increased CYP3A4 activity while glabridin, glyasperin C, glycycoumarin, and formononetin increased CYP1A2 activity (>2-fold). The metabolism of antiretroviral drugs (rilpivirine and dolutegravir) was increased by G. uralensis (2.0 and 2.5-fold) and its marker compound glycycoumarin (2.3 and 1.6-fold). The metabolism of dolutegravir was also increased by G. glabra (2.8-fold) but not by its marker compound, glabridin. These results suggest that licorice and its phytochemicals could affect the metabolism and clearance of certain drugs that are substrates of CYP3A4 and CYP1A2. Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2050875 .
Article
Full-text available
Background: Hua-Feng-Dan is a patent Chinese medicine for stroke recovery and various diseases. This study used GC-MS to profile its ingredients and RNA-Seq to analyze the induced adaptive response in the liver. Methods: Hua-Feng-Dan was subjected to steam distillation and solvent extraction, followed by GC-MS analysis. Mice were orally administered Hua-Feng-Dan and its “Guide drug” Yaomu for 7 days. Liver pathology was examined, and total RNA isolated for RNA-Seq, followed by bioinformatic analysis and quantitative real-time PCR (qPCR). Results: Forty-four volatile and fifty liposoluble components in Hua-Feng-Dan were profiled and analyzed by the NIST library and their concentrations quantified. The major components (>1%) in volatile (5) and liposoluble (10) were highlighted. Hua-Feng-Dan and Yaomu at hepatoprotective doses did not produce liver toxicity as evidenced by histopathology and serum enzyme activities. GO Enrichment revealed that Hua-Feng-Dan affected lipid homeostasis, protein folding, and cell adhesion. KEGG showed activated cholesterol metabolism, bile secretion, and PPAR signaling pathways. Differentially expressed genes (DEGs) were identified by DESeq2 with p < 0.05 compared to controls. Hua-Feng-Dan produced more DEGs than Yaomu. qPCR on selected genes largely verified RNA-Seq results. Ingenuity Pathways Analysis of the upstream regulator revealed activation of MAPK and adaptive responses by Hua-Feng-Dan, and Yaomu was less effective. Hua-Feng-Dan-induced DEGs were highly correlated with the Gene Expression Omnibus database of chemical-induced adaptive transcriptome changes in the liver. Conclusion: GC-MS primarily profiled volatile and liposoluble components in Hua-Feng-Dan. Hua-Feng-Dan at the hepatoprotective dose did not produce liver pathological changes but induced metabolic and signaling pathway activations. The effects of Hua-Feng-Dan on liver transcriptome changes point toward induced adaptive responses to program the liver to produce hepatoprotective effects.
Article
In conclusion, this case should remind clinicians of the potential dangers of glycyrrhizin (high blood pressure, low blood potassium and abnormal changes in ECG, among other effects). The timely detection and effective treatment of glycyrrhizin-induced PsHA can prevent the occurrence of serious complications. The importance of taking a detailed medical history is also emphasized.
Article
Full-text available
An efficient and environmentally friendly ultrasound-assisted (UAE) natural deep eutectic solvent (NADES) extraction method was applied for the extraction of five bioactive compounds (liquiritin, isoliquiritin, liquiritigenin, glycyrrhizic acid and isoliquiritigenin) from compound liquorice tablets (CPLTs), and the antioxidant activities of these compounds were evaluated. In this study, eighteen different NADES systems based on either two or three components were tested and a 1,4-butanediol-levulinic acid system (1 : 3 molar ratio) was selected as a topgallant solvent for maximizing analyte extraction yields. Various extraction parameters, such as water content, liquid/solid ratio, extraction time and temperature, were systematically optimized by single-factor and response surface methodology (RSM) experiments. The results indicated that the optimum extraction conditions for the analytes featured a water content of 17%, a liquid/solid ratio of 42 mL g⁻¹and an extraction time of 30 min. The extracted amounts of liquiritin, isoliquiritin, liquiritigenin, glycyrrhizic acid and isoliquiritigenin reached 5.60, 3.17, 1.27, 74.62 and 1.34 mg g⁻¹, respectively, under optimized conditions, which were much higher than those extracted using conventional organic solvents. In addition, antioxidant tests revealed that the NADES extracts showed higher DPPH and hydroxyl radical-scavenging capacity than the conventional solvent extracts used for comparison. This study provides a suitable approach for efficiently extracting the bioactive compounds of CPLTs. Meanwhile, NADESs can be extended to other natural products as green extraction media.
Article
Full-text available
Historically, liquorice (Leguminosae Glycyrrhiza Sp. 1) has been added as culinary ingredient, chewed whole as a sabbatical medicinal, used in most TCM formulae as a harmonising herb in decoction. Components of the root and leaves can also be found in expectorant OTC pharmaceutical cough preparations, commercial nutraceuticals, commercial teas and one formulation is even the active ingredient in a pharmaceutical diuretic. Chinese Materia Medica refer to liquorice root as "Gan Cao" (Sweet Weed) due to its sweetness exceeding cane sugar more than 50%. As such it is often included as a healthier alternative to sweeten food and beverages. Liquorice is also consumed extensively as a tea on its own and marketed in many herbal formulas sprucing its anti-inflammatory and hormonal balancing qualities. In low concentrations, Liquorice does seem to exert an antioxidant effect, however at high concentrations some of its chemical constituents can inhibit important pharmacokinetic processes and antagonise others which flip the antioxidant qualities of liquorice to a toxic sequale of accumulation of Redox metabolites and overconcentration of mineralocorticoids which over time cause potentially fatal effects. The scope of this ingredient being used across many medicinal, food, beverage, vitamin and drug formulations has shown an increase in literature recommending the consumer be informed about the quantity of intake to avoid adverse and even toxic effects. This article focuses on the pharmacokinetic and pharmacodynamic properties of Glycyrrhizic 2 acid and glycyrrhitic acid, two of the most studied components found in liquorice outlining the toxicological effects of overconsumption in vulnerable populations and the interactions that can occur with co-consumption of some contraceptive medications.
Article
Licorice (Glycyrrhiza glabra L.), Fabaceae, has a wide range of medicinal properties due to the metabolites found in the plant tissues. Callus cultures from Glycyrrhiza glabra were previously initiated in vitro using leaf as an explant and the current study was designed to examine the possible role of various elicitors (biotin, adenine sulphate, salicylic acid, putrescine, spermine, or spermidine) at different concentrations (25, 50, 75, and 100 mg L−1) on the stimulation of biomass and their effects on the content of different metabolites such as total carbohydrates, protein, proline, phenol, alkaloids, flavonoids, and glycyrrhizin. Elicitation with different concentrations of elicitors increased the biomass and metabolite content in callus culture of G. glabra at different rates. The optimum concentration of adenine sulphate for maximum biomass accumulation (16.79 g flask−1) was found to be at 50 mg L−1 after incubation for 20 d. Adenine sulphate and putrescine were also found to stimulate the metabolite content to 3- to fourfold in the callus cultures as compared to that of control showing that metabolite content and antioxidant enzyme of Glycyrrhiza glabra can be enhanced by appropriate elicitation.
Preprint
Full-text available
Purpose: This study aimed to investigate the effect of essential ingredients of licorice on the chronic obstructive pulmonary disease (COPD). Method: The ingredients information were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/), related genes about COPD was collected from geneCards (http://www.genecards.org/). Network pharmacology was utilized in this study. Result: The intersection data set contains 20 molecular targets between COPD and liquorice. Protein-protein interaction network showed that there are a total of 58 nodes and 137 edges involved. The link number of AKT1 in PPI network was 39, which is the highest level of interaction. MAPK1 is an important target of Licorice on COPD. Conclusion: MAPK signaling pathway could be the important key target of main ingredients of licorice on COPD.
Article
Ethnopharmacological relevance: The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is one of the most promising therapeutic targets for cancer immunotherapy, but several challenges remain in current anti-PD-1/PD-L1 therapy. Natural products, mainly derived from traditional medicine, could improve and expand anti-PD-1/PD-L1 therapy because of their advantages such as large diversity and multi-target effects. Aim of the study: This review summarize natural products, raw extracts, and traditional medicines with pharmacological effects associated with the PD-1/PD-L1 axis, particularly PD-L1. Materials and methods: Electronic literature databases, including Web of Science, PubMed, and ScienceDirect, and online drugs and chemicals databases, including DrugBank, ZINC, PubChem, STITCH, and CTD, were searched without date limitation by February 2021. 'Natural product or herb or herbal plant or traditional medicine' and 'PD-L1' and 'Cancer immunotherapy' were used as the search keywords. Among 112 articles identified in database searching, 54 articles are full text articles, reporting in silico, in vitro, in vivo and clinical trials. 68 articles included are review articles and grey literature such as thesis and congress abstracts. Results: Several natural products and traditional medicines have exhibited diverse and multi-functional effects including direct blockade of PD-1/PD-L1 interactions, modulation of PD-L1 expression, and cooperation with PD-1/PD-L1 inhibitors. Conclusion: Natural products and traditional medicines can facilitate the development of more effective and acceptable diverse strategies for anti-PD-1/PD-L1 therapy, but further exploration of natural products and pharmaceutical techniques is required.
Article
Full-text available
The novel Coronavirus (COVID-19) has spread rapidly across the globe and has involved more than 215 countries and territories. Due to a lack of effective therapy or vaccine, urgent and concerted efforts are needed to identify therapeutic targets and medications. COVID-19 main protease represents a major target for drug treatment to inhibit viral function. The present study sought to evaluate medicinal plant compounds as potential inhibitors of the COVID-19 main protease using molecular docking and molecular dynamic analysis. The PDB files of COVID-19 main protease and some medicinal plant compounds were retrieved from the Protein Data Bank (http://www.rcsb.org) and Pubchem server, respectively. The Gromacs software was used for simulation studies, and molecular docking analysis was done using Autodock 4.2. The COVID-19 main protease simulation, compared with some phytochemicals docked to the COVID-19 main protease, were analyzed. Glabridin, catechin, and fisetin had the greatest tendency to interact with the COVID-19 main protease by hydrogen and hydrophobic interactions. Docking of these phytochemicals to COVID-19 main protease led to an increase in the radius of gyration (Rg), decrease in the Root mean square fluctuation (RMSF), and induced variation in COVID-19 main protease secondary structure. The high tendency interaction of glabridin, catechin, and fisetin to COVID-19 main protease induced conformational changes on this enzyme. These interactions can lead to enzyme inhibition. This simulated study indicates that these phytochemicals may be considered as potent inhibitors of the viral protease; however, more investigations are required to explore their potential medicinal use. Communicated by Ramaswamy H. Sarma
Article
The intestinal mucosa is the largest mucosal surface of the human body and contains a large number of immune cells, which can resist the invasion of foreign antigens, toxins, pathogens, and bacteria while allowing the absorption of nutrients. Numerous studies have shown that intestinal mucosal injury is associated with many diseases. The active ingredients of traditional Chinese medicine are complex and diverse, and new active metabolites are generated after metabolic transformation by intestinal bacteria in the intestine, which in turn exert different biological effects. Many Chinese herbal ingredients can cause damage to the intestinal mucosa. This article discusses the intestinal mucosal injury caused by traditional Chinese medicine by affecting the mechanical barrier of the intestinal mucosa, intestinal mucosal immunity, and biological barrier, and the possible mechanism of intestinal mucosal injury by traditional Chinese medicine and how to reduce the toxic and side effects of traditional Chinese medicine on the intestinal mucosa, with an aim to provide a more scientific basis for the treatment of intestinal diseases by traditional Chinese medicine.
Article
Xiao-Chaihu-Decoction (XCHD), a classical traditional Chinese medicine with diverse biological activities, is widely applied to prevent and treat many human diseases. Effects of dietary XCHD on growth performance, immune response, detoxification system, intestinal microbiota and resistance against aflatoxin B1(AFB1) of Litopenaeus vannamei was studied. Four isonitrogenous and isolipidic diets were formulated to contain 0, 1, 2, and 5 g/kg (control, XCHD1, XCHD2 and XCHD3) of XCHD, respectively. Seven hundred and eighty shrimp (1.16 ± 0.09 g) were assigned randomly to 12 tanks (400 L, three tanks each group, 65 shrimp in each tank) for 6 weeks. After sampling, 25 shrimp from each tank were selected for a 2-week AFB1 (2500 μg/kg) challenge experiment. The results indicated that the final weight, weight gain and specific growth rate in XCHD2 and XCHD3 groups were significantly increased compared to control. The protease, amylase, superoxide dismutase (SOD), glutathione s-transferase (GST), sulfotransferase (SULT) activities, total antioxidant capacity (T-AOC) and glutathione (GSH) contents in hepatopancreas were significantly increased in XCHD3 groups and the expressions of immune-related genes (Toll, Dorsal and Cru) in hepatopancreas were significantly up-regulated in XCHD2 and XCHD3 groups. High-throughput sequencing analysis revealed that the abundance of Proteobacteria decreased and the abundances of Bacteroidetes increased in XCHD2 and XCHD3 groups. Additionally, AFB1 challenge experiments showed that AFB1 caused histological damage to the hepatopancreas and significantly increased the levels of malondialdehyde (MDA) and protein carbonylation (PC) in hepatopancreas as well as the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Nevertheless, XCHD could effectively alleviated the growth toxicity, immunosuppression and macromolecular damage caused by AFB1 to shrimp by inhibiting the Phase I enzyme and enhancing Phase II enzyme and antioxidant system.
Article
Full-text available
Angiogenesis is one of the crucial steps in the transition of a tumor from a small, harmless cluster of mutated cells to a large, malignant growth, capable of spreading to other organs throughout the body. Vascular endothelial growth factor (VEGF) that stimulates vasculogenesis and angiogenesis is thought to be as an anti-angiogenic target for cancer therapy. Liquiritigenin (LQ), a flavanone existing in Radix glycyrrhiza, shows extensive biological activities, such as anti-inflammatory and anti-cancer properties. In our studies, liquiritigenin effectively inhibited the growth of tumors xenografted in nude mice from human cervical cancer cell line HeLa cells, and microvascular density (MVD) of the tumor exposed to liquiritigenin was reduced in a dose dependent manner, especially in the high dose group. Moreover, the expression and secretion of VEGF were down-regulated by the drug in vivo and in vitro. Therefore, liquiritigenin can be further studied on cancer and other diseases associated with VEGF up-regulation.
Article
Full-text available
Saponins are a group of amphiphilic glycosides containing one or more sugar chains linked to a nonpolar triterpene or steroid aglycone skeleton, which are believed to be responsible for the pharmacological activities of many Chinese medicinal herbs. The purpose of this paper is to summarize the contemporary knowledge of the absorption, disposition, and pharmacokinetics of some important saponins, including ginsenosides, licorice saponins, dioscorea saponins, astragalosides, and saikosaponins. Poor intestinal absorption of saponins is mainly due to their unfavorable physicochemical traits, such as large molecular mass ( > 500 Da), high hydrogen-bonding capacity ( > 12), and high molecular flexibility ( > 10), that underlie poor membrane permeability. Rapid and extensive biliary excretion is another primary factor that limits the oral bioavailability of most saponins. However, several saponins, including ginsenosides Ra3, Rb1, Rc, and Rd, and dioscin, are excreted slowly into the bile and in turn have significantly long elimination half lives (7-25 h in rats). These longcirculating saponins may be used as pharmacokinetic markers to substantiate systemic exposure to the ingested herb extracts. In addition to biliary excretion for elimination of most saponins unchanged, renal excretion may also be important for certain saponins. Saponins can be hydrolyzed by the colonic microflora. After absorption, the deglycosylated aglycones undergo phase I and/or II metabolism by the host. In line with the poor permeability, saponin concentrations in most rat tissues are lower than the concurrent plasma level and the brain level is usually very low. However, the liver concentrations of many saponins, as well as the kidney levels of certain saponins, can be quite high, which involves transporter-mediated uptake mechanisms. Repeated p.o. ingestion of glycyrrhizin appears to be able to induce CYP3A in rodents and humans, while several deglycosylated products of ginsenosides can moderately inhibit CYP activities in vitro with IC50 values of 10-50 μM. More research is required for elucidation of the absorption, disposition, and pharmacokinetics of multiple saponins to enhance understanding which saponins are most likely to exert pharmacological effects in vivo, as well as influence of complex herb matrix. In addition, research is also needed to characterize the microbiotal deglycosylation and the subsequent aglycone metabolism by the host for a broader range of saponins, as well as the hepatobiliary transporter phenotyping for and the interaction with saponins. Furthermore, in vitro and in vivo studies of saponin-based herb-drug interactions are also warranted.
Article
Full-text available
To describe and evaluate spontaneous reports of suspected adverse reactions (ARs) associated with herbal laxatives received by the Italian Medicines Agency and the Italian National Institute of Health between April 2002 and January 2011. Spontaneous reports of suspected ARs were individually analyzed by a multidisciplinary group of experts, and a causality assessment was performed. Twenty-six reactions were reported during the study period. Of these, eight were associated with herbal medicinal products and 18 were related to herbal food supplements. Almost 80% of the reports on ARs involved women. The ARs, classified by System Organ Class, were associated with gastrointestinal, skin and subcutaneous tissue, and hepatobiliary disorders. Fifty percent of the reactions were serious, with the patients requiring hospitalization; of these, one was life-threatening. Most of the herbal remedies associated with the reported ARs contained liquorice, dandelion, and/or plants containing anthraquinones. Possible causes of the ARs were long-term use, idiosyncratic reactions or hypersensitivity, and interaction with other treatments. All of these factors and the presence of a large number of components in the same product increased the unpredictability of the final effect. The total number of 26 ARs recorded in 8 years is limited; however, the an under-reporting effect cannot be excluded. Moreover, taking into account the seriousness of the reported ARs, the low number of reports does not represent a guarantee of safety. To reduce the risk of an adverse outcome, herbal laxatives should be used only over the short term.
Article
Full-text available
To evaluate the hypotensive effects of glycyrrhizin (GL) on a rabbit model of ocular hypertension (OH) induced by triamcinolone acetonide (TA). Forty New Zealand White Rabbits were divided as follows: control (intravitreal injection of sterile saline solution); GL (intravitreal injection of sterile saline solution, then fed with 25mg GL/day); TA (intravitreal TA injection); TA+GL (intravitreal TA injection, then fed with GL) and GL+TA (pre-treated with GL for 3 days, then got TA injection and the following GL treatment). Intraocular pressure (IOP), flash electroretinogram (flash ERG) and flash visual evoked potential (flash VEP) were measured during the follow-up (28 days). The aqueous humor was analyzed, using (1)H-nuclear magnetic resonance spectroscopy and principal components analysis (PCA). IOP elevation was observed in the TA group during the follow-up, compared to the controls (p<0.01). The IOP was decreased in the TA+GL group and the GL+TA group, compared to the TA group (p<0.05). Both in flash ERG and VEP, the amplitudes were decreased, and the implicit time was prolonged in the TA group, compared to the controls (p<0.05); and the parameters were improved after intervention of GL, compared to the TA group (p<0.05). PCA results indicated that TA could affect ocular metabolism (especially the sugar metabolism), and GL could inhibit it. The administration of GL could suppress OH induced by TA in rabbits, and improve their electrophysiological parameters. Metabolomics is a useful tool in ophthalmology research. Our results indicate that TA-induced ocular metabolism changes could be compensated by GL.
Article
To reduce the limit on the relevant parameters during constructing zero correlation zone (ZCZ) sequences, a novel construction method was proposed to design the near-optimal sequence set with ZCZ. Using the interleaving technique and recursive algorithm, a new ZCZ sequence set can be generated from an arbitrary perfect sequence with a period longer than 4. With the size (i.e. the number of sequences) of the new sequence set kept unchanged, the length and ZCZ width of the new sequence can be doubled by each recursive operation. The constructed near-optimal ZCZ sequence set can approach the mathematical bound, and can successfully provide quasi-synchronous CDMA communication without co-channel interference.
Article
The alkaloid components in Strychnos nux-vomical L. uncombined and combined with Glycyrrhiza uralensis Fisch have been investigated by electrospray ionization tandem mass spectrometry ( ESI-MS o) and HPLC. The experimental results demonstrated that the number of strychnine and brucine all declined in combined Strychnos nux-vomical L. with Glycyrrhiza uralensis Fisch, and the concentration level of strychnine fell obviously. The results of ESI-MS were identical to those of HPLC, which provided scientific basis for explanation of detoxicity of Glycyrrhiza uralensis Fisch and the reasonable combination of Strychnos nux-vomical L. .
Article
Herbal medicinals are being used by an increasing number of patients who typically do not advise their clinicians of concomitant use. Known or potential drug-herb interactions exist and should be screened for. If used beyond 8 weeks, Echinacea could cause hepatotoxicity and therefore should not be used with other known hepatoxic drugs, such as anabolic steroids, amiodarone, methotrexate, and ketoconazole. However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatoxicity of pyrrolizidine alkaloids. Nonsteroidal anti-inflammatory drugs may negate the usefulness of feverfew in the treatment of migraine headaches. Feverfew, garlic, Ginkgo, ginger, and ginseng may alter bleeding time and should not be used concomitantly with warfarin sodium. Additionally, ginseng may cause headache, tremulousness, and manic episodes in patients treated with phenelzine sulfate. Ginseng should also not be used with estrogens or corticosteroids because of possible additive effects. Since the mechanism of action of St John wort is uncertain, concomitant use with monoamine oxidase inhibitors and selective serotonin reuptake inhibitors is ill advised. Valerian should not be used concomitantly with barbiturates because excessive sedation may occur. Kyushin, licorice, plantain, uzara root, hawthorn, and ginseng may interfere with either digoxin pharmacodynamically or with digoxin monitoring. Evening primrose oil and borage should not be used with anticonvulsants because they may lower the seizure threshold. Shankapulshpi, an Ayurvedic preparation, may decrease phenytoin levels as well as diminish drug efficacy. Kava when used with alprazolam has resulted in coma. Immunostimulants (eg, Echinacea and zinc) should not be given with immunosuppressants (eg, corticosteroids and cyclosporine). Tannic acids present in some herbs (eg, St John wort and saw palmetto) may inhibit the absorption of iron. Kelp as a source of iodine may interfere with thyroid replacement therapies. Licorice can offset the pharmacological effect of spironolactone. Numerous herbs (eg, karela and ginseng) may affect blood glucose levels and should not be used in patients with diabetes mellitus.
Article
A rationally designed motion system with four Mecanum wheels can move in omni-direction on flat floor, but not any arbitrarily composed system with four Mecanum wheels can do so. In order to find the conditions of the system with four Mecanum wheels to move in omni-direction, the motion model of the general system is put forward and the inverse velocity Jacobian matrix is analyzed, considering the request of the system driving and controllability. The conclusion is presented that the omi-directional motion conditions not only depend on the full rank of inverses Jacobian matrix, but also depend on the wheel structure and the layout of the four wheels of the system. Then six typical layouts of four Mecanum wheels are illustrated and the optimal layout is picked out by calculating the Jacobian matrix rank of the six typical layouts.
Article
This paper reviews our investigations on the chemical constituents of several kinds of botanically identified licorice roots, which led to the characterization of 13 then-new glu- curonide-saponins named licorice-saponins (A-L), apioglycyrrhizin, and araboglycyrrhizin, together with glycyrrhizin and 18α-glycyrrhizin and also of 49 kinds of phenolic compounds and their glycosides (11 then-new). The restoration-promoting activity of licorice-saponin B2 for CCl 4 -intoxicated hepatocyte function and the structure-sweetness relationship of saponins were discussed. Biologically interesting, but isolable in minor quantities, several licorice-saponins were favorably synthesized from abundantly available glycyrrhizin. With 15 saponins and 49 phenolic compounds (including their glycosides) at hand, chemical eval- uation of licorice root processings was undertaken. It was shown that the cortex contained a rich amount of phenolic compounds, whereas the xylem was rich in phenolic glycosides and the saponins contained were richer in the xylem than in the cortex. It was also found that roasted licorice root contained an increased amount of glycyrrhetic acid monoglucuronide, which was secondarily formed from glycyrrhizin through thermal hydrolysis and was known to taste 5 times sweeter than glycyrrhizin.
Article
Glycyrrhizin (GL), a main component of the plant Glycyrrhiza glabra has shown various immunomodulatory activities that can interfere with immune responses by targeting the dendritic cells (DCs). In this study, the effects of GL on the maturation and function of mouse splenic DCs was investigated. The results of flow cytometry analysis showed that GL was able to up-regulate the expression of CD40, CD86 and MHC-ІІ maturation markers on DCs. This component increased the production of IL-12 by these cells. The capacity of treated DCs to stimulate allogenic T cells and secretion of cytokines was examined in mixed lymphocyte reaction. DCs treated with GL enhanced proliferation of allogenic T cells along with the production of IFN-γ and IL-10 cytokines and reduced IL-4 production. These data indicated that GL has the capacity to up-regulate allostimulatory activity of professional antigen presenting DCs and conduct immune responses toward a T helper 1 response.
Article
Allergic asthma is associated with Th2-mediated inflammation. Several flavonoids were isolated from Glycyrrhiza uralensis, one of the herbs in the anti-asthma herbal medicine intervention. The aim of this investigation was to determine whether Glycyrrhiza uralensis flavonoids have inhibitory effects on memory Th2 responses in vitro and antigen-induced Th2 inflammation in vivo. The effects of three Glycyrrhiza uralensis flavonoids on effector memory Th2 cells, D10.G4.1 (D10 cells), were determined by measuring Th2 cytokine production. Isoliquiritigenin, 7, 4'-dihydroxyflavone (7, 4'-DHF) and liquiritigenin significantly suppressed IL-4 and IL-5 production in a dose-dependent manner, 7, 4'-DHF being most potent. It was also evaluated for effects on D10 cell proliferation, GATA-3 expression and IL-4 mRNA expression, which were suppressed, with no loss of cell viability. Chronic treatment with 7, 4'-DHF in a murine model of allergic asthma not only significantly reduced eosinophilic pulmonary inflammation, serum IgE levels, IL-4 and IL-13 levels, but also increased IFN-γ production in lung cell cultures in response to antigen stimulation. Copyright © 2012 John Wiley & Sons, Ltd.
Article
Hepatic stellate cells (HSCs) have immunosuppressive capabilities and contribute to the occurrence and development of hepatocellular carcinoma (HCC). Thus, activated HSCs may be a suitable target for HCC therapy. Our study used mixed leukocyte reactions (MLR) in vitro to demonstrate that 18β-glycyrrhetinic acid (GA) could reverse HSC-mediated immunosuppression by reducing T-cell apoptosis and regulatory T (Treg) cells expression, thereby enhancing the ability of T cells to attack tumor cells and attenuating HCC cell invasiveness. Moreover, we established a HCC orthotopic implantation model in immunocompetent C57BL/6 mice, which suggested that GA played a protective role in HCC development by reducing immunosuppression mediated by HSCs in the tumor microenvironment.
Article
Liquorice (root of Glycyrrhiza uralensis FISCH) is an ingredient of candies and used as a popular medicine in Europe and oriental countries. Cyclosporine (CsA), an immunosuppressant with narrow therapeutic window, is widely used in transplant patients. The absorption and disposition of CsA were associated with P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effects of liquorice extract (LE) and its major ingredient, glycyrrhizin (GZ), on CsA pharmacokinetics in rats. The results indicated that LE and GZ significantly decreased the peak blood concentration and the areas under the curves of CsA in rats. Mechanism studies revealed that glycyrrhetic acid (GA), the major metabolite of GZ, significantly activated the functions of P-gp and CYP3A4. In conclusion, liquorice significantly reduced the oral bioavailability of CsA through activating P-gp and CYP3A4.
Article
The aims of this study were to elucidate the immunomodulatory effects of glycyrrhizin (GL) on CD4(+)T cell responses during liver fibrogenesis. To obtain in vivo evidence about the effects of GL on CD4(+)T cells in livers and spleens of concanavalin A (ConA)-induced mouse model, mice were administrated with ConA together with or without GL for 8weeks. Mice treated with GL dramatically prevented liver inflammation and fibrosis. Besides, GL inhibited the infiltration of T helper (Th) cell type 1, Th2, Th17 and regulatory T cells (Treg) in livers and spleens of mouse fibrosis models, and regulated the Th1/Th2 and Treg/Th17 balances respectively to a relative dominance of Th1 and Treg lineages in livers. Moreover, GL dramatically enhanced the antifibrotic cytokine interferon (IFN)-γ and interleukin (IL)-10. GL at a concentration of 10 or 100μg/mL was respectively incubated with ConA-stimulated splenic CD4(+)T cells in vitro, and JNK inhibitor (SP600125), ERK inhibitor (U0126), p38 inhibitor (SB203580) or PI3K/AKT inhibitor (LY29400225) was added during the incubation. Notably, GL not only inhibited ConA-induced proliferation of splenic CD4(+)T cells but also enhanced the mRNAs of IFN-γ and IL-10 in these cells. Be similar to the effects of GL, SP600125, U0126 and LY29400225, however not SB203580, also inhibited ConA-induced CD4(+)T cell proliferation, indicating the involvement of JNK, ERK and PI3K/AKT in this process. Moreover, GL significantly inhibited ConA-induced phosphorylation of JNK, ERK and PI3K/AKT in vitro. Collectively, GL might alleviate liver injury and fibrosis progression via regulation of CD4(+)T cell response in JNK, ERK and PI3K/AKT-dependent pathways.
Article
Recently we have studied the Lorentzian version of the IIB matrix model as a nonperturbative formulation of superstring theory. By Monte Carlo simulation, we have shown that the notion of time ---as well as space---emerges dynamically from this model, and that we can uniquely extract the real-time dynamics, which turned out to be rather surprising: after some "critical time", the SO(9) rotational symmetry of the nine-dimensional space is spontaneously broken down to SO(3) and the three-dimensional space starts to expand rapidly. In this paper, we study the same model based on the classical equations of motion, which are expected to be valid at later times. After providing a general prescription to solve the equations, we examine a class of solutions, which correspond to manifestly commutative space. In particular, we find a solution with an expanding behavior that naturally solves the cosmological constant problem.
Article
Licochalcone E was firstly isolated from licorice root in 2005, which belongs to the retrochalcone family. Studies on the biological activities of licochalcone E were in the initial stage. In the study, we demonstrated that licochalcone E has potent antimicrobial property against Staphylococcus aureus. Furthermore, via hemolysis, Western blot, and real-time RT-PCR assays, we have shown that subinhibitory concentrations of licochalcone E dosedependently reduces the production of alpha-toxin in both methicillin-sensitive S. aureus (MSSA) and methicillinresistant S. aureus (MRSA). The data suggest that licochalcone E may deserve further investigation as a potential therapeutic against S. aureus infections, or the structure of licochalcone E may be used as a basis for chemical synthesis of novel anti-S. aureus compounds.
Article
Licochalcone A (LA) has been shown to exert multiple pharmacological effects, including anti-inflammatory, antiparasitic, antifungal, anticancer, and osteogenic activities. The present study investigated the ability of LA to suppress the differentiation of 3T3-L1 preadipocytes, and its antiobesity activity was explored using high fat diet (HFD)-fed ICR mice. During the terminal differentiation process, 3T3-L1 preadipocytes were treated with LA, and the lipid contents were quantified along with any changes in the expression of biomarkers associated with adipocyte differentiation and lipogenesis. The results show that LA significantly reduced lipid accumulation and down-regulated the expression of peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein α, sterol regulatory element-binding protein 1c, and their target genes (fatty acid binding protein, fatty acid synthase, stearoyl-CoA desaturase 1, and glycerol-3-phosphate acyltransferase). In an animal study, body weight, triglyceride, cholesterol, and nonesterified fatty acid levels in the group given 10 mg/kg LA were significantly decreased by 14.0, 48.2, 58.9, and 73.5%, respectively. Transverse microcomputed tomography indicated that visceral fat depots in LA-treated mice were markedly reduced when compared with those of the HFD control group. In summary, these results suggest that LA exerts an antiobesity effect and that it is a candidate for future clinical trials.
Article
Liquiritigenin (LQ) is a flavanone extracted from Glycyrrhizae, which has multiple biological effects, such as antiinflammation and anticancer. This study is the first to investigate the effect of LQ on the migration of human lung adenocarcinoma A549 cells in vitro. First, LQ exhibited inhibitory effects on the adhesion and migration of A549 cells in the absence of cytotoxicity. Gelatin zymography and Western blot analysis showed that LQ significantly reduced the expression of promatrix metalloproteinase-2 (proMMP-2) in A549 cells in terms of both activity and protein level. Second, LQ inhibited the phosphorylation of Akt and activated the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2). Furthermore, the treatment of inhibitors specific for Akt (LY294002) and ERK1/2 (U0126) to A549 cells resulted in reduced activity of proMMP-2. These results suggested that the inhibition on proMMP-2 expression by LQ may be through suppression on PI3K/Akt signaling pathway, which in turn led to the inhibition of lung adenocarcinoma A549 cells migration. However, activation of ERK might not be involved in the regulation of proMMP-2. Taken together, LQ may be considered as a potential interfering agent of cancer progression.
Article
The purpose of the current study was to determine whether glycyrrhizin (GL) maintains hepatic glutathione (GSH) levels by inhibiting GSH biliary secretion in normal rats. The effects of glycyrrhizin on hepatic glutathione content, bile flow and biliary secretion of glutathione were examined. Because glutathione is a substrate for multidrug resistance associated protein-2 (Mrp2/ABCC2), the inhibitory effects of GL on Mrp2 in isolated perfused rat liver and in Mrp2-expressing Sf9 membrane vesicles were also examined using the Mrp2 substrate methotrexate (MTX) and estradiol-17-β-glucuronide (E2 17G). The hepatic content of glutathione in rats following GL perfusion (43.7 µmol/l) in isolated liver perfusion and GL intravenous treatment (25 mg/kg) was significantly higher than that for the control. A marked and dose-dependent decrease in the excretion of glutathione was observed. In addition, the secretion rate of MTX was decreased by 57% in isolated liver perfusion in GL-treated rats. Moreover the ATP-dependent uptake of E2 17G by Mrp2 membrane vesicles was decreased by 75.9% in the 20 µm GL group and by 60.5% in the 2 µm GL group. In conclusion, glycyrrhizin increases hepatic glutathione content possibly through inhibition of Mrp2 which then reduces the biliary excretion of glutathione.