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The first description of the medical use of licorice appeared in “Shennong Bencao Jing”, one of the well-known Chinese herbal medicine classic books dated back to 220–280 AD. As one of the most commonly prescribed Chinese herbal medicine, licorice is known as “Guo Lao”, meaning “a national treasure” in China. Modern pharmacological investigations have confirmed that licorice possesses a number of biological activities, such as antioxidation, anti-inflammatory, antiviral, immune regulation, and liver protection. 18β-glycyrrhetinic acid is one of the most extensively studied active integrants of licorice. Here, we provide an overview of the protective effects of 18β-glycyrrhetinic acid against various acute and chronic liver diseases observed in experimental models, and summarize its pharmacological effects and potential toxic/side effects at higher doses. We also make additional comments on the important areas that may warrant further research to support appropriate clinical applications of 18β-glycyrrhetinic acid and avoid potential risks.

18β-Glycyrrhetinic acid liposomes (18β-GA-Lips) were developed to enhance lung-specific drug delivery and optimize the therapeutic management of pulmonary arterial hypertension (PAH). 18β-GA-Lips of varying particle sizes were formulated using the film-dispersion method and the thin-film dispersion-probe ultrasonic technique. Their characteristics, pharmacokinetics, and tissue distribution were thoroughly investigated, followed by an inhalation subacute toxicological analysis. Anti-PAH effects were assessed through hemodynamic measurements, right ventricular hypertrophy evaluation, echocardiography, histomorphometric, and morphological analyses. The 18β-GA-Lips, with varying particle sizes, exhibited a uniform spherical morphology, achieved entrapment efficiencies exceeding 80%, and had average particle sizes ranging from 150 to 1183 nanometers. These were categorized into four distinct size groups. The drug release profile demonstrated favorable sustained-release characteristics in vitro, and the formulation remained stable for up to 15 days when stored at 4°C. Pharmacokinetic analyses revealed that, compared with the 18β-GA-solution group, the AUC , MRT , t , t , and clearance rate of 18β-GA-Lips in each group were 4.42, 3.27, 4.28, 5.07, 2.10, 3.41, 1.73, 1.46, 1.53, 1.32, 1.79, 1.67, 0.61, 2.11, 0.71, 1.71, 1.15, 0.62, 0.96, and 0.90 times higher, respectively. Tissue distribution studies revealed that B-18β-GA-Lips exhibited the highest lung-targeting efficiency, with a Te value of 54.13%. No apparent signs of toxicity were observed. In vivo data demonstrate that rats treated with 18β-GA in different formulations (solution and liposomal) and with NO exhibited significantly lower mPAP and RVSP compared to the SuHx group, with no statistically significant differences observed among the treatment groups. Notably, 18β-GA-Lips exhibited a more pronounced reduction in RVHI compared to oral solutions and significantly attenuated pulmonary vascular remodeling. Furthermore, pharmacodynamic evaluations indicated that 18β-GA-Lips exhibited superior inhibitory effects on PAH in rats compared to both atomized and intragastric 18β-GA solutions. These findings confirm that 18β-GA-Lips exhibit outstanding lung-targeting capabilities and lack inhalation toxicity, thereby significantly enhancing the therapeutic efficacy of treatments for PAH.

Fluorescently labelled small molecule probes (fluorescent probes) play an important role in cell imaging and are often used in combination with light-affinity probes to determine the subcellular localisation of target proteins. To investigate the target proteins of 18 -glycyrrhetinic acid (18 -GA), which regulates the macrophage inflammatory response, we designed and synthesised three types of fluorescent probes. We analysed its structure-activity relationship by evaluating the biological activity and screening for fluorescent probes with high activity. Our results showed that modifying C-3 hydroxyl and C-30 carboxyl groups enhanced the anti-inflammatory activity of 18 -GA, and found that two preferred probes had similar effects on LPS-induced, inflammation-related factor release (IL-1β, TNF-α, IL-6, HDAC8, P-STAT3, and SOCS3) to those of 18 -GA. Fluorescence signals of the preferred probes and were observed in the cytoplasm. The above results indicated that the anti-inflammatory site of 18 -GA may be located in proteins in the cytoplasm, which would provide useful information for research on the anti-inflammatory targets of 18 -GA.

Glycyrrhetinic Acid (GA), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity.

At present, the chemotherapy of advanced inoperable liver cancer is limited with serious side effects. Curcumin possesses multiple cancer preventive activities and low safety concerns. However, its poor solubility and instability in water pose significant pharmacological barriers to its clinical application. In this study, we presented a novel delivery system - the glycyrrhetinic acid modified curcumin-loaded cationic liposomes (GAMCLCL) and investigated its antitumor activities on HepG2 cells in vitro and in H22 tumor-bearing mice. The experimental results demonstrated that GAMCLCL was a cationic liposome and could be Intravenous administration. Compared to free curcumin, GAMCLCL exhibited stronger antitumor activities in vitro and in vivo. The antitumor results of GAMCLCL after intravenous administration were very similar to those after intratumoral administration. The main activities of GAMCLCL and curcumin included inhibition of HepG2 cell proliferation, inhibition of tumor growth, reduction of tumor microvascular density, down-regulation of the expression of VEGF protein, and up-regulation of the expression of Caspases3 protein in H22 tumor tissues. Furthermore, GAMCLCL improved the parameters of WBC, RBC, ALT, CRE, LDH of H22 tumor-bearing mice. Curcumin is a nontoxic natural compound with definite antitumor activities, its antitumor effects can be enhanced by preparation of GAMCLCL.

Licorice (Glycyrrhiza spp.), a traditional Chinese herb, contains glycyrrhetinic acid derivatives with neuroprotective properties but limited bioavailability. YCY-20 is a novel derivative synthesized by structural modification of 18β-glycyrrhetinic acid. The aim of this study is to explore its therapeutic effect and potential molecular mechanism on cerebral ischemia-reperfusion injury (CIRI). Pharmacokinetic profiling was performed to compare plasma exposure and brain distribution of YCY-20 and its parent compound 18β-GA. Neuroprotection was assessed using middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced HT22 cells. Evaluations included infarct volume (TTC staining), apoptosis (TUNEL, flow cytometry), and protein dynamics (Western blot). Network pharmacology identified potential targets, and in vivo experiments are conducted to validate the relevant molecular pathways. YCY-20 exhibited improved pharmacokinetic properties, with higher and more stable plasma concentrations and detectable brain levels after oral administration, compared with 18β-GA. YCY-20 administration significantly attenuated body weight loss, cerebral infarct volume, and neuronal apoptosis in MCAO/R rats. Mechanistically, YCY-20 suppressed the MCAO/R-induced upregulation of pro-apoptotic proteins (Bax, caspase-3, cleaved caspase-3) while restoring anti-apoptotic Bcl-2 expression. In vitro OGD/R models corroborated these anti-apoptotic effects. Network analysis identified AGE-RAGE/MAPK signaling as the predominant pathway modulated by YCY-20, with subsequent in vivo validation demonstrating its capacity to downregulate key mediators in this pathway. YCY-20 confers protection against CIRI, at least partially through apoptosis inhibition mediated by AGE-RAGE/MAPK signaling pathway modulation. This study provides preclinical evidence for developing licorice-derived agents in stroke management.

Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhizaglabra were chemically investigated, which resulted in the isolation and characterization of 18β-glycyrrhetinic acid (GA) as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69 µg/ml) anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock) score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68-100% at doses of 62.5-250 mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.

Lung cancer ranks among the most commonly diagnosed malignancies worldwide, with dismal prognosis largely due to its intrinsic drug resistance and high recurrence rate. Herein, we synthesized 30 glycyrrhetinic acid derivatives and evaluated their anti-lung cancer potential both in vitro and in vivo. The biological effects of compound 17 on A549 cells were determined using MTT, colony formation, and Transwell assays. Flow cytometry, transcriptomic profiling, and RT-qPCR were performed to identify differentially expressed genes, followed by GO and KEGG enrichment analyses and molecular docking validation. A mouse xenograft tumor model was employed to assess therapeutic efficacy and systemic toxicity. Compound 17 exhibited dose-dependent inhibition of A549 cell proliferation, migration, and invasion, achieving an IC50 value of 0.6011 ± 0.05 μM. It induced G1-phase cell cycle arrest and apoptosis by inhibiting the TNF signaling pathway and modulating apoptosis-related proteins. In vivo experiments demonstrated that compound 17 exerted a tumor inhibition rate of 80.61% without observable toxic side effects. This study is the first to demonstrate that compound 17 exerts potent anti-lung cancer activity by targeting the TNF signaling pathway and activating the mitochondrial apoptosis pathway, providing a critical experimental foundation for its development as a novel therapeutic agent against lung cancer.

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

The combination of nanoplatform-based chemotherapy and photodynamic therapy (PDT) is a promising way to treat cancer. Celastrol (Cela) exhibits highly effective anti-hepatoma activity with low water solubility, poor bioavailability, non-tumor targeting, and toxic side effects. The combination of Cela-based chemotherapy and PDT via hepatoma-targeting and reactive oxygen species (ROS)-responsive polymeric micelles (PMs) could solve the application problem of Cela and further enhance antitumor efficacy. In this study, Cela and photosensitizer chlorin e6 (Ce6) co-loaded glycyrrhetinic acid-modified carboxymethyl chitosan-thioketal-rhein (GCTR) PMs (Cela/Ce6/GCTR PMs) were prepared and characterized. The safety, ROS-sensitive drug release, and intracellular ROS production were evaluated. Furthermore, the in vitro anti-hepatoma effect and cellular uptaken in HepG2 and BEL-7402 cells, and in vivo pharmacokinetic, tissue distribution, and antitumor efficacy of Cela/Ce6/GCTR PMs in H22 tumor-bearing mice were then investigated. Cela/Ce6/GCTR PMs were successfully prepared with nanometer-scale particle size, favorable drug loading capacity, and encapsulation efficiency. Cela/Ce6/GCTR PMs exhibited a strong safety profile and better hemocompatibility, exhibiting less damage to normal tissues. Compared with Cela-loaded GCTR PMs, the ROS-responsiveness of Cela/Ce6/GCTR PMs was increased, and the release of Cela was accelerated after combination with PDT. Cela/Ce6/GCTR PMs can efficiently target liver tumor cells by uptake and have a high cell-killing effect in response to ROS. The combination of GCTR PM-based chemotherapy and PDT resulted in increased bioavailability of Cela and Ce6, improved liver tumor targeting, and better anti-hepatoma effects in vivo. Hepatoma-targeting and ROS-responsive GCTR PMs co-loaded with Cela and Ce6 combined with PDT exhibited improved primary hepatic carcinoma therapeutic effects with lower toxicity to normal tissues, overcoming the limitations of monotherapy and providing new strategies for tumor treatment.