Liquiritin ameliorates painful diabetic neuropathy in SD rats by inhibiting NLRP3-MMP-9-mediated reversal of aquaporin-4 polarity in the glymphatic system.

Background: Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain. Methods: This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques. Results: The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements. Conclusion: Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.

Preparation and Characterization of Nanostructured Lipid Carriers (NLCs) Containing Glycyrrhiza glabra Extract for the Treatment of Skin Hyperpigmentation.

PURPOSE: This study aimed to prepare, characterize, and in vitro and in vivo evaluate a novel nanostructured lipid carriers (NLCs) formulation containing two fractions of Glycyrrhiza glabra L. (licorice) extract for the treatment of hyperpigmentation. METHODS: Two fractions, one enriched with glabridin (FEG) and the other enriched with liquiritin (FEL), were obtained by partitioning the methanol (MeOH) extract of licorice roots with ethyl acetate (EtOAc) and partitioning the EtOAc fraction with butanol (n-BuOH) and water. The quantities of glabridin (Glab) and liquiritin (LQ) in the fractions were determined by high-performance liquid chromatography (HPLC). FEG and FEL were loaded in different NLC formulations, and surface characterization and long-term stability were studied using Dynamic Light Scattering (DLS). The best formulation was chosen for further surface characterization, including Transmission Electron Microscopy (TEM), Differential Scanning Calorimetry (DSC), and Fouriertransform infrared (FTIR) spectroscopy. Moreover, entrapment efficiency percentage (EE%), in vitro drug release, in vivo skin penetration, cytotoxicity on B16F10 melanoma cells, effect on melanin production, and anti- tyrosinase activity were tested for the selected formulation. RESULTS: Based on HPLC results, FEG contained 34.501 mg/g of Glab, and FEL contained 31.714 mg/g of LQ. Among 20 different formulations, NLC 20 (LG-NLCs) showed desirable DLS results with a Z-average size of 185.3 ± 1.08 nm, polydispersity index (PDI) of 0.229 ± 0.35, and zeta potential of -16.2 ± 1.13 mV. It indicated good spherical shape, high EE% (79.01% for Glab and 69.27% for LQ), two-stage release pattern (an initial burst release followed by sustained release), efficient in vivo skin penetration, and strong anti-tyrosinase activity. LG-NLCs had acceptable physiochemical stability for up to 9 months and were non-cytotoxic. CONCLUSION: The LG-NLC formulation has revealed desirable surface characterization, good physiochemical stability, efficient drug release pattern and in vivo penetration, and high EE%. Therefore, it can be a suitable nanosystem for the delivery of licorice extract in the treatment of hyperpigmentation.

The Anticancer Journey of Liquiritin: Insights into Its Mechanisms and Therapeutic Prospects.

Liquiritin (LIQ), a bioactive flavonoid from Glycyrrhiza species, has shown significant potential in cancer therapy. LIQ exhibits potent inhibitory effects on various cancer cell types, including breast, lung, liver, and colon cancers, while demonstrating low toxicity towards healthy cells. Its anticancer mechanisms include inducing cell cycle arrest, promoting apoptosis, and modulating inflammation-related pathways. Additionally, LIQ impedes angiogenesis and enhances the efficacy of conventional chemotherapies through sensitization and synergistic effects with other natural compounds and targeted therapies. These multifaceted actions highlight LIQ as a promising candidate for further development as an anticancer agent. This abstract provides an overview of LIQ's chemistry, biological effects, and underlying mechanisms.

Therapeutic Effect of Liquiritin Carbomer Gel on Topical Glucocorticoid-Induced Skin Inflammation in Mice.

Glucocorticoids are often used and highly effective anti-inflammatory medications, but prolonged topical application may alter the epidermis' normal structure and function, potentially resulting in a number of adverse effects. Topical glucocorticoid-induced skin inflammation is a dangerous condition that develops after topical glucocorticoid use. The patients become dependent on the medication and, even after the medication is stopped, the dermatitis symptoms recur, severely impairing their quality of life. Thus, the need to aggressively confront Topical glucocorticoid-induced skin inflammation is critical. Prior research has demonstrated that topical administration of licorice's flavonoid component liquiritin stimulates epidermal proliferation, which in turn enhances the creation of collagen and the healing of wounds. Therefore, the purpose of this work was to determine if topical use of liquiritin carbomer gel can treat glucocorticoid-induced changes in mice skin epidermal function, and the mechanisms involved. The findings demonstrated that, in the mice model of topical glucocorticoid-induced skin inflammation, liquiritin carbomer gel aided in the restoration of skin barrier function. These outcomes may have been caused by enhanced expression of the proteins Aquaporin 3, Keratin 10, and Claudin-1, as well as the restoration of epidermal hyaluronan content. In the meantime, liquiritin carbomer gel dramatically decreased the expression of TNF-α, IL-1ß, IL-6, IFN-γ, and IgE in mice, according to ELISA tests. Furthermore, topical treatment of liquiritin carbomer gel boosted the expression of superoxide dismutase, catalase, and decreased malondialdehyde expression, potentially counteracting the detrimental effects of glucocorticoids on the epidermis. In summary, these findings imply that topical liquiritin carbomer gel can treat glucocorticoid-induced skin damage through various mechanisms of action.

Liquiritin exerts psoriasis therapy and prevention by regulating the YY1/RBP3 axis.

BACKGROUND: Psoriasis (PSO) poses a global health threat. The current research challenge in PSO is relapse. Liquiritin (LIQ), a major active compound from Glycyrrhiza inflata Batalin, has multiple pharmacological properties, including anti-inflammatory and anti-proliferative. Nonetheless, the precise mechanisms underlying LIQ's therapeutic actions in PSO and prevention abilities remain elusive. PURPOSE: The present study aimed to delve into the potential to treat and prevent PSO and the mechanism of LIQ. METHODS: The anti-inflammatory and anti-proliferative effects of LIQ were studied in vitro with the HaCaT cell line. Then, Transcriptional analysis and bioinformatic analysis were used to determine the internal associations of the target set. Subsequently, functional experiment, luciferase report assay, ChIP-PCR, and immunohistochemical validation of clinical samples were performed to investigate the mechanism of LIQ. Finally, the anti-psoriatic effects and prevention abilities of LIQ were verified in vivo with imiquimod (IMQ)-induced PSO-like mouse models. RESULTS: Here, we identified differentially expressed genes in LIQ-stimulated HaCaT cells and Retinol-Binding Protein 3 (RBP3) as the core target, whereas YY1 was a predicted upstream transcription factor of RBP3. The YY1/RBP3 axis was obviously altered after administering LIQ at optimal doses of 20 µM in vitro and 100 µg/ml in vivo. LIQ can significantly inhibit the progression of PSO in vivo. Notably, LIQ also prevented the relapse of psoriatic lesions induced by the second round of low-dose IMQ. Mechanistically, we observed that LIQ could increase the promotion of YY1 for RBP3 by enhancing the binding affinity between them. CONCLUSION: These findings revealed that the YY1/RBP3 axis is a potential psoriatic target, and LIQ is a promising and innovative therapeutic candidate for the treatment and prevention of PSO.

Metabolite profiling of liquiritin in acute myocardial infarction model rat after intragastric administration using an information-dependent acquisition-mediated ultra-high-performance liquid chromatography-tandem mass spectrometry method.

Liquiritin (LQ), a kind of flavonoid isolated from licorice, was proven to have great potential in treating heart failure. Pharmacokinetic evaluation is important for demonstrating clinical efficacy and mechanisms, and the prototype drug and its metabolite profiling are important for drug discovery and development. However, the metabolism of LQ in acute myocardial infarction (AMI) model rats still needs to be studied in depth. An information-dependent acquisition (IDA)-ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was applied to profile LQ metabolites in AMI model rat plasma. Protein precipitation and extraction were used for sample preparation. Chromatographic separation was achieved using an XSelect BEH C18 column (2.1 × 150 mm, 2.5 µm) using gradient elution method combining 0.1% formic acid and acetonitrile with a flow rate of 0.3 mL/min. Twelve metabolites were identified in IDA mode, sulfation, glucuronidation, methylation, methyl esterification, glutamine conjugation, and valine conjugation, and their composite reactions were presumed as the primary pathways of LQ metabolism. The variation in the peak areas showed that the time to reach the peak drug concentration of LQ and 12 metabolites was within 5 h. In summary, IDA-bridged UHPLC-MS/MS from characteristic fragment ions toward confidence-enhanced identification could effectively screen and profile metabolites.

Liquiritin Alleviates Inflammation in Lipopolysaccharide-Induced Human Corneal Epithelial Cells.

PURPOSE: This research was designed to elucidate the anti-inflammatory impacts of liquiritin on lipopolysaccharide (LPS)-activated human corneal epithelial cells (HCECs). METHODS: The Cell Counting kit-8 (CCK-8) assay was adopted to assess cell viability. The enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion levels of the proinflammatory cytokines IL-6, IL-8, and TNF-α. Transcriptome analysis was conducted to identify the genes that exhibited differential expression between different treatment. The model group included cells treated with LPS (10 µg/mL), the treatment group comprised cells treated with liquiritin (80 µM) and LPS (10 µg/mL), and the control group consisted of untreated cells. To further validate the expression levels of the selected genes, including CSF2, CXCL1, CXCL2, CXCL8, IL1A, IL1B, IL24, IL6, and LTB, quantitative real-time PCR was performed. The expression of proteins related to the Akt/NF-κB signaling pathway was assessed through western blot analysis. NF-κB nuclear translocation was evaluated through immunofluorescence staining. RESULTS: The secretion of IL-6, IL-8, and TNF-α in LPS-induced HCECs was significantly downregulated by liquiritin. Based on the transcriptome analysis, the mRNA expression of pro-inflammatory cytokines, namely IL-6, IL-8, IL-1ß, IL-24, TNF-α, and IL-1α was overproduced by LPS stimulation, and suppressed after liquiritin treatment. Furthermore, the Western blot results revealed a remarkable reduction in the phosphorylation degrees of NF-κB p65, IκB, and Akt upon treatment with liquiritin. Additionally, immunofluorescence analysis confirmed liquiritin's inhibition of LPS-induced p65 nuclear translocation. CONCLUSIONS: Collectively, these findings imply that liquiritin suppresses the expression of proinflammatory cytokines, and the anti-inflammatory impacts of liquiritin may be caused by its repression of the Akt/NF-κB signaling pathway in LPS-induced HCECs. These data indicate that liquiritin could provide a potential therapeutic application for inflammation-associated corneal diseases.

Liquiritin Carbomer Gel Cold Paste Promotes Healing of Solar Dermatitis in Mice.

Ultraviolet radiation (UVR) has various effects on human cells and tissues, which can lead to a variety of skin diseases and cause inconvenience to people's lives. Among them, solar dermatitis is one of the important risk factors for malignant melanoma, so prevention and treatment of solar dermatitis is very necessary. Additionally, liquiritin (LQ) has anti-inflammatory effects. In this study, we aimed to evaluate the anti-inflammatory and pro-wound healing effects of liquiritin carbomer gel cold paste (LQ-CG-CP) in vitro and in vivo. The results of MTT experiments showed no cytotoxicity of LQ at concentrations of 40 µg/mL and below and cell damage at UVB irradiation doses above 60 mJ/cm2. Moreover, LQ can promote cell migration. ELISA results also showed that LQ inhibited the elevation of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) after UVB irradiation. In the mouse model of solar dermatitis, 2% LQ-CG-CP showed the best therapeutic efficacy for wound healing and relief of itching compared to MEIBAO moist burn moisturizer (MEBO). What is more, the results of skin histopathological examination show that LQ-CG-CP promotes re-epithelialization, shrinks wounds, and promotes collagen production, thus promoting wound healing. Simultaneously, LQ-CG-CP reduced TNF-α, IL-1ß, and IL-6 expression. In addition, LQ-CG-CP was not observed to cause histopathological changes and blood biochemical abnormalities in mice. Overall, LQ-CG-CP has great potential for the treatment of solar dermatitis.

Green Synthesis of Gold Nanoparticles Using Liquiritin and Other Phenolics from Glycyrrhiza glabra and Their Anti-Inflammatory Activity.

Phenolic compounds are the main phytochemical constituents of many higher plants. They play an important role in synthesizing metal nanoparticles using green technology due to their ability to reduce metal salts and stabilize them through physical interaction/conjugation to the metal surface. Six pure phenolic compounds were isolated from licorice (Glycyrrhiza glabra) and employed in synthesizing gold nanoparticles (AuNPs). The isolated compounds were identified as liquiritin (1), isoliquiritin (2), neoisoliquiritin (3), isoliquiritin apioside (4), liquiritin apioside (5), and glabridin (6). The synthesized AuNPs were characterized using UV, zeta sizer, HRTEM, and IR and tested for their stability in different biological media. The phenolic isolates and their corresponding synthesized NP conjugates were tested for their potential in vitro cytotoxicity. The anti-inflammatory effects were investigated in both normal and inflammation-induced settings, where inflammatory biomarkers were stimulated using lipopolysaccharides (LPSs) in the RAW 264.7 macrophage cell line. LPS, functioning as a mitogen, promotes cell growth by reducing apoptosis, potentially contributing to observed outcomes. Results indicated that all six pure phenolic isolates inhibited cell proliferation. The AuNP conjugates of all the phenolic isolates, except liquiritin apioside (5), inhibited cell viability. LPS initiates inflammatory markers by binding to cell receptors and setting off a cascade of events leading to inflammation. All the pure phenolic isolates, except isoliquiritin, neoisoliquiritin, and isoliquiritin apioside inhibited the inflammatory activity of RAW cells in vitro.

Liquiritin reduces chondrocyte apoptosis through P53/PUMA signaling pathway to alleviate osteoarthritis.

AIMS: The main pathological features of osteoarthritis (OA) include the degeneration of articular cartilage and a decrease in matrix synthesis. Chondrocytes, which contribute to matrix synthesis, play a crucial role in the development of OA. Liquiritin, an effective ingredient extracted from Glycyrrhiza uralensis Fisch., has been used for over 1000 years to treat OA. This study aims to investigate the impact of liquiritin on OA and its underlying mechanism. MATERIALS AND METHODS: Gait and hot plate tests assessed mouse behavior, while Micro-CT and ABH/OG staining observed joint morphological changes. The TUNEL kit detected chondrocyte apoptosis. Western blot and immunofluorescence techniques determined the expression levels of cartilage metabolism markers COL2 and MMP13, as well as apoptosis markers caspase3, bcl2, P53, and PUMA. KEGG analysis and molecular docking technology were used to verify the relationship between liquiritin and P53. KEY FINDINGS: Liquiritin alleviated pain sensitivity and improved gait impairment in OA mice. Additionally, we found that liquiritin could increase COL2 levels and decrease MMP13 levels both in vivo and in vitro. Importantly, liquiritin reduced chondrocyte apoptosis induced by OA, through decreased expression of caspase3 expression and increased expression of bcl2 expression. Molecular docking revealed a strong binding affinity between liquiritin and P53. Both in vivo and in vitro studies demonstrated that liquiritin suppressed the expression of P53 and PUMA in cartilage. SIGNIFICANCE: This indicated that liquiritin may alleviate OA progression by inhibiting the P53/PUMA signaling pathway, suggesting that liquiritin is a potential strategy for the treatment of OA.

Mechanistic investigation of the ameliorative effect of liquiritin on hypoxia/reoxygenation­induced cardiomyocyte injury based on network pharmacology and in vitro validation.

Liquiritin (LIQ) is a flavonoid known for its cardioprotective properties, extracted from Glycyrrhiza uralensis Fisch. The purpose of the present study was to investigate the protective mechanism of LIQ against hypoxia/reoxygenation (H/R) injury through in vitro experiments, with the goal of enhancing its pharmacological effects. Initially, network pharmacology was employed to explore the targets and mechanisms of LIQ. Subsequently, an in vitro H/R model was established using H9c2 cells. Potential targets for LIQ and myocardial ischemia-reperfusion injury (MIRI) were identified through online databases. The STRING, Cytoscape and DAVID databases were used to extract intersecting targets and mechanisms. In vitro experiments were conducted to validate these findings, assessing cardiac enzymes, oxidative stress indicators, mitochondrial fluorescence, apoptotic fluorescence, inflammation and related protein expression. The network pharmacological analysis revealed that the protective effects of LIQ on MIRI involve oxidative stress, inflammation and apoptosis. The results of in vitro experimental validation demonstrated that LIQ significantly reduced the activities of lactated dehydrogenase and creatine kinase isoenzyme-MB (P<0.05 or 0.01), as well as the level of malondialdehyde (P<0.01). It also inhibited the production of reactive oxygen species (P<0.01), the release of inflammatory factors (P<0.05 or 0.01) and apoptosis (P<0.01). By contrast, the LIQ pre-treatment group exhibited a significant increase in mitochondrial membrane potential level (P<0.05 or 0.01) and the activities of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase (P<0.05 or 0.01). Furthermore, LIQ reduced the protein expressions of TNF-α receptor type 1 (TNFR1) and MMP9, along with the level of NF-κB phosphorylation (P<0.05 or 0.01). In conclusion, LIQ mitigated H/R-induced cardiomyocyte injury through mechanisms that may involve antioxidants, anti-apoptotic effects, protection against mitochondrial damage and suppression of inflammatory levels. These effects are achieved via inhibition of the TNFR1/NF-κB/MMP9 pathway.

Effects of ultrasonic power on drying kinetics and product quality of licorice extract during ultrasound-assisted vacuum drying.

BACKGROUND: Licorice extract is an important raw material for food additives and medicine. The quality of licorice extract is dictated by the drying process. The commonly used drying methods of licorice extract are not efficient in obtaining high-quality products so alternative techniques need to be developed and researched. In this study, ultrasound-assisted vacuum drying (UAVD) was first utilized to improve drying efficiency and produce a higher-quality product. The changes in water mobility of licorice extract during drying were characterized using low-field nuclear magnetic resonance. In addition, the effects of ultrasonic power on the drying dynamics, the contents of liquiritin and glycyrrhizic acid, the antioxidant capacity and the microstructure formation of licorice extract during the whole drying process were investigated. RESULTS: The drying times for licorice extract to reach equilibrium moisture content were reduced by 9.09-69.70% with UAVD at 40-200 W compared with that without ultrasonic treatment (0 W). Moreover, the proportions of bound water and semi-bound water in fresh concentrate were 3.75% and 96.25%. It was also found that high ultrasonic power promoted the flow of water and the formation of porous structure in licorice extract, which led to the improvement of drying efficiency. The contents of liquiritin (2.444%) and glycyrrhizic acid (6.514%) were retained to a large degree in the dried product at an ultrasonic power of 80 W. The DPPH inhibition rate of UAVD samples with different ultrasonic powers ranged from 84.07 ± 0.46% to 90.65 ± 0.22%. CONCLUSION: UAVD has the advantages of high efficiency and low energy consumption, which may be an alternative technology for vacuum drying widely used in industry. © 2024 Society of Chemical Industry.

Liquiritin targeting Th17 cells differentiation and abnormal proliferation of keratinocytes alleviates psoriasis via NF-κB and AP-1 pathway.

Psoriasis is a common immune-mediated inflammatory skin disease, caused by disturbed interactions between keratinocytes and immune cells. Chinese medicine shows potential clinical application for its treatment. Liquiritin is a flavone compound extracted from licorice and shows potential antitussive, antioxidant and antiinflammatory effects, and therefore may have potential as a psoriasis therapeutic. The aim of this work was to examine the possible roles that liquiritin may have in treating psoriasis. HaCaT cells were stimulated by TNF-α with or without liquiritin, harvested for analysis by western blots and RT-qPCR, and the cellular supernatants were collected and analyzed by ELISA for cytokines. In addition, 4 groups of mice were examined: Normal, Vehicle, LQ-L and LQ-H. The mice were sacrificed after 6 days and analyzed using IHC, ELISA, RT-qPCR and flow cytometry. The results showed that liquiritin could significantly inhibit the progression of psoriasis both in vitro and in vivo. Liquiritin strongly suppressed the proliferation of HaCaT keratinocytes but did not affect cell viability. Moreover, liquiritin alleviated imiquimod-induced psoriasis-like skin inflammation and accumulation of Th17 cells and DCs in vivo. In TNF-α-induced HaCaT keratinocytes, both protein and mRNA expression levels of inflammatory cytokines were sharply decreased. In imiquimod-induced mice, the activation of NF-κB and AP-1 was reduced after treatment with liquiritin. Collectively, our results show that liquiritin might act as a pivotal regulator of psoriasis via modulating NF-κB and AP-1 signal pathways.

Modeling the Antiviral Activity of Ginkgo biloba Polyphenols against Variola: In Silico Exploration of Inhibitory Candidates for VarTMPK and HssTMPK Enzymes.

BACKGROUND: The aim of this study is to use modeling methods to estimate the antiviral activity of natural molecules extracted from Ginkgo biloba for the treatment of variola which is a zoonotic disease posing a growing threat to human survival. The recent spread of variola in nonendemic countries and the possibility of its use as a bioterrorism weapon have made it a global threat once again. Therefore, the search for new antiviral therapies with reduced side effects is necessary. METHODS: In this study, we examined the interactions between polyphenolic compounds from Ginkgo biloba, a plant known for its antiviral activity, and two enzymes involved in variola treatment, VarTMPK and HssTMPK, using molecular docking. RESULTS: The obtained docking scores showed that among the 152 selected polyphenolic compounds; many ligands had high inhibitory potential according to the energy affinity. By considering Lipinski's rules, we found that Liquiritin and Olivil molecules are the best candidates to be developed into drugs that inhibit VarTMPK because of their high obtained scores compared to reference ligands, and zero violations of Lipinski's rules. We also found that ginkgolic acids have good affinities with HssTMPK and acceptable physicochemical properties to be developed into drugs administered orally. CONCLUSION: Based on the obtained scores and Lipinski's rules, Liquiritin, Olivil, and ginkgolic acids molecules showed interesting results for both studied enzymes, indicating the existence of promising and moderate activity of these polyphenols for the treatment of variola and for possible multi-targeting. Liquiritin has been shown to exhibit anti-inflammatory effects on various inflammation- related diseases such as skin injury, hepatic inflammatory injury, and rheumatoid arthritis. Olivil has been shown to have antioxidant activity. Olivil derivatives have also been studied for their potential use as anticancer agents. Ginkgolic acids have been shown to have antimicrobial and antifungal properties. However, ginkgolic acids are also known to cause allergic reactions in some people. Therefore, future studies should consider these results and explore the potential of these compounds as antiviral agents. Further experimental studies in-vitro and in-vivo are required to validate and scale up these findings.

Trypsin is inhibited by phytocompounds liquiritin and terpinen-4-ol from the herb Glycyrrhiza glabra: in vitro and in silico studies.

Serine proteases are a class of hydrolytic enzymes involved in various physiological functions like digestion, coagulation, fibrinolysis and immunity. The present study evaluates the serine protease inhibitory potential of phytochemicals liquiritin and terpinen-4-ol present in the herb Glycyrrhiza glabra L. using trypsin as the model enzyme. In silico studies showed that both the compounds have a significant binding affinity towards trypsin with a binding energy of -26.66 kcal/mol and -19.79 kcal/mol for liquiritin and terpinen-4-ol, respectively. Their binding affinity was confirmed through in vitro enzyme inhibition assays. The mode of inhibition was found to be uncompetitive. In order to explain the mode of inhibition, docking of the ligands to the enzyme-substrate complex was also done and binding energy was calculated after MD simulation. The energy values showed that the binding affinities of these compounds towards the enzyme substrate complex are more than that towards the enzyme alone. This explains the uncompetitive mode of inhibition.Communicated by Ramaswamy H. Sarma.

Antidepressant effect of licorice total flavonoids and liquiritin: A review.

With the development of society and changes in lifestyle, major depressive disorder (MDD) has become a significant disease that plagues many people. Licorice, an excellent natural medicine with a long history of cultivation and application, is found in classical antidepressant prescriptions such as Chaihu Shugan Powder, Ganmai Dazao Decoction, Suanzaoren Decoction, etc. Licorice mainly contains triterpenoids and flavonoids, among which licorice total flavonoids (LF) and liquiritin are the main active components with good antidepressant effects. The pharmacological effects of licorice have been extensively investigated in current studies. However, a review of the antidepressant effects of LF and liquiritin has not been conducted. This article reviews the antidepressant effects of LF and liquiritin, including the biological characteristics of licorice and the pharmacological mechanism of LF and liquiritin in treating MDD. Studies have shown that LF and liquiritin can exert their antidepressant effects by improving depressive behavior, regulating endocrine and hypothalamic-pituitary-adrenal (HPA) axis function, affecting the brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling pathway, enhancing synaptic plasticity, increasing monoamine neurotransmitter levels, protecting nerve cells, reducing inflammation, preventing apoptosis, reducing oxidation and other ways. This lays a theoretical foundation for the development of antidepressant drugs.

A novel Glycyrrhiza glabra extract liquiritin targeting NFATc1 activity and ROS levels to counteract ovariectomy-induced osteoporosis and bone loss in murine model.

Osteoporosis, a prevalent osteolytic condition worldwide, necessitates effective strategies to inhibit excessive bone resorption by curbing osteoclast hyperactivation. Liquiritin (LIQ), an flavanone derivative employed in acute lung injury and rheumatoid arthritis treatment, possesses an unclear role in addressing excessive bone resorption. In this investigation, we found that LIQ demonstrates the ability to inhibit osteoclast formation and the bone-resorbing activity induced by RANKL. At a specific concentration, LIQ significantly attenuated NF-κB-Luc activity induced by RANKL and curtailed NF-κB activation in RANKL-stimulated RAW264.7 cells, resulting in reduced IκB-α breakdown and diminished nuclear NF-κB levels. Furthermore, LIQ markedly inhibited RANKL-induced NFATc1 activation, as evidenced by diminished NFATc1 luciferase activity, reduced NFATc1 mRNA levels, and decreased nuclear NFATc1 protein levels. Subsequent experiments demonstrated that LIQ effectively restrained the RANKL-induced elevation of intracellular calcium as well as reactive oxygen species. Additionally, LIQ exhibited a downregulating effect on the expression of osteoclast-specific genes, which include Acp5, Cathepsin K, Atp6v0d2, Nfatc1, c-Fos, and Mmp9. Notably, our findings revealed the potential of LIQ to counteract decreased bone density in mice that underwent ovariectomy. Collectively, the data indicate that LIQ impedes osteoclast formation triggered by RANKL and the subsequent reduction in bone mass by mitigating ROS levels and suppressing the Ca2+/MAPK-NFATc1 signaling pathway, suggesting its promising candidacy as a therapeutic agent for RANKL-mediated osteoporosis.

Liquiritin apioside alleviates colonic inflammation and accompanying depression-like symptoms in colitis by gut metabolites and the balance of Th17/Treg.

BACKGROUND: Inflammatory bowel disease (IBD) is a significant global health concern that can lead to depression in affected patients. Liquiritin apioside (LA) possesses anti-oxidative and anti-inflammatory properties. However, its anti-inflammatory mechanism in IBD has not been extensively studied. PURPOSE: This study elucidates the pivotal role of LA in alleviating inflammation by regulating gut metabiota-derived metabolites and evaluating its regulative effects on promoting a balance of Th17/Treg cells in colitis mice. METHODS: To evaluate the effect of LA on IBD,16S rRNA gene sequencing and UPLC-QTOF-MS analysis were used to identify the changes of intestinal bacteria and their metabolites. Cytokines levels were determined by ELISA and qPCR, while immune cell ratios were evaluated via flow cytometry. RESULTS: Our findings revealed that LA treatment ameliorated general states of DSS-induced colitis mice and their accompanying depressive behaviors. Moreover, LA restricted the expression of pro-inflammatory cytokines and revised the imbalanced Treg/Th17 differentiation, while promoting SCFAs production in inflamed colon tissues. Fecal microbiota transplantation from LA-fed mice also corrected the imbalanced Treg/Th17 differentiation, indicating that LA-mediated restoration of the colonic Treg/Th17 balance mainly depends on the changes in gut metabolites. CONCLUSION: These results provide scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols, and suggesting that LA could be used as a potential dietary supplement for the prevention and improvement of IBD.

Glycyrrhizae Radix suppresses lipopolysaccharide- and diazepam-induced nerve inflammation in the hippocampus, and contracts the duration of pentobarbital- induced loss of righting reflex in a mouse model.

Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1ß, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24 h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1ß, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders.

Liquiritin exhibits anti-acute lung injury activities through suppressing the JNK/Nur77/c-Jun pathway.

BACKGROUND: Licorice (Glycyrrhiza uralensis Fisch.), a well-known traditional medicine, is traditionally used for the treatment of respiratory disorders, such as cough, sore throat, asthma and bronchitis. We aim to investigate the effects of liquiritin (LQ), the main bioactive compound in licorice against acute lung injury (ALI) and explore the potential mechanism. METHODS: Lipopolysaccharide (LPS) was used to induce inflammation in RAW264.7 cells and zebrafish. Intratracheal instillation of 3 mg/kg of LPS was used for induction an ALI mice model. The concentrations of IL-6 and TNF-α were tested using the enzyme linked immunosorbent assay. Western blot analysis was used to detect the expression of JNK/Nur77/c-Jun related proteins. Protein levels in bronchoalveolar lavage fluid (BALF) was measured by BCA protein assay. The effect of JNK on Nur77 transcriptional activity was determined by luciferase reporter assay, while electrophoretic mobility shift assay was used to examine the c-Jun DNA binding activity. RESULTS: LQ has significant anti-inflammatory effects in zebrafish and RAW264.7 cells. LQ inhibited the expression levels of p-JNK (Thr183/Tyr185), p-Nur77 (Ser351) and p-c-Jun (Ser63), while elevated the Nur77 expression level. Inhibition of JNK by a specific inhibitor or small interfering RNA enhanced the regulatory effect of LQ on Nur77/c-Jun, while JNK agonist abrogated LQ-mediated effects. Moreover, Nur77-luciferase reporter activity was suppressed after JNK overexpression. The effects of LQ on the expression level of c-Jun and the binding activity of c-Jun with DNA were attenuated after Nur77 siRNA treatment. LQ significantly ameliorated LPS-induced ALI with the reduction of lung water content and BALF protein content, the downregulation of TNF-α and IL-6 levels in lung BALF and the suppression of JNK/Nur77/c-Jun signaling, which can be reversed by a specific JNK agonist. CONCLUSION: Our results indicated that LQ exerts significant protective effects against LPS-induced inflammation both in vivo and in vitro via suppressing the activation of JNK, and consequently inhibiting the Nur77/c-Jun signaling pathway. Our study suggests that LQ may be a potential therapeutic candidate for ALI and inflammatory disorders.