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Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of Glycyrrhiza species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.

Sigal peptides have garnered remarkable efficacy in rejuvenating photoaged skin and delaying senescence. Nevertheless, their low solubility and poor permeability bring about a formidable challenge in their transdermal delivery. To address this challenge, bioactive ionic liquids (ILs) synthesized from natural glycyrrhizic acid (GA) and oxymatrine (OMT) with eminent biocompatibility is first prepared. The components ratios and inherent forming mechanisms of GA‐OMT (GAO) are optimized by molecular dynamics simulations and density functional theory calculations. Remarkably, GAO can significantly improve the sparingly soluble properties of palmitoyl pentapeptide‐4 (PAL‐4), a model peptide drug. Subsequently, GAO self‐assembled micelles loading PAL‐4 (GAO/PAL‐4‐SM) are fabricated without additional auxiliary materials. The permeation and subcutaneous retention of PAL‐4 are significantly promoted with 10wt.% GAO‐SM. Moreover, GAO ILs facilitated PAL‐4 permeation by enhancing its miscibility and interaction with stratum corneum (SC), offering a pulling effect and micellar structures for PAL‐4, as elucidated by computational simulations. In cellular and animal photoaging experiments, GAO/PAL‐4‐SM possessed remarkable capabilities in boosting collagen and hyaluronic acid regeneration, mitigating inflammation and apoptosis, accelerating macrophage M2 polarization, thereby lessening skin wrinkles and leveraging elasticity. Collectively, the research innovatively designed an ILs self‐assembled nano‐micellar transdermal delivery system to enhance the permeability and anti‐photoaging effect of signal peptides. The ionic hydrogen bonding interaction between N+‐O‐ and ‐COOH predominantly drive the formation of GAO. GAO ILs can be self‐assembled into micelles with PAL‐4 (GAO/PAL‐4‐SM). GAO‐SM micelles possessed high capabilities to dissolve, load PAL‐4, and then deliver PAL‐4 to deeper skin layers. Moreover, GAO‐SM promoted the anti‐photoaging effect of PAL‐4 at the cellular and animal levels.

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.

Glycyrrhhizic acid (GA), including 18α-glycyrrhizic acid (18α-GA) and 18β-glycyrrhizic acid (18β-GA), is the main active ingredient of licorice. GA is generally considered an effective pharmacological strategy protecting against hepatic disease; however, the optimal compatibility proportion of 18α-GA and 18β-GA against alcoholic liver disease (ALD) and the underlying mechanism are not well established. Hence, this study was designed to explore the optimal compatibility proportion of 18α-GA and 18β-GA against ALD, followed by investigating the underlying mechanisms. SD rats were administered 40% ethanol once a day, accompanied by treatment with different proportions of 18α-GA and 18β-GA for four weeks. Then all rats were anesthetized with chloral hydrate and blood samples were taken from the abdominal aorta for biochemical assay. Livers were also collected and the liver function, lipid profile, ROS production, and mRNA and protein levels of related genes involved in lipid metabolism were assessed. The results showed that 18α-GA and 18β-GA, particularly at a proportion of 4:6, significantly reduced liver damage, lipid accumulation, and oxidative stress in ethanol-induced rats, as indicated by the decreased levels of alanine aminotransferase (ALT) and aminotransferase (AST) in serum, improvement of liver histopathological changes, regulation of total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), and modulation of superoxide dismutase (SOD), glutathione (GSH), and malonaldehyde (MDA). Moreover, the combination treatment with 18α-GA and 18β-GA substantially reduced the mRNA and protein levels of sterol regulatory element-binding protein-1c (SREBP-1c) and acetyl-coal carboxylase (ACC); meanwhile, increased levels of peroxisome proliferators activated receptor-α (PPAR-α) and carnitine palmitoy transferase-1 (CTP-1) in the liver tissues of ethanol-induced rats. In conclusion, our results indicated that the optimal compatibility proportion of 18α-GA and 18β-GA protecting against ALD was 4:6, and the mechanism was associated with the regulation of oxidative stress and lipid metabolism.

To fabricate and evaluate the therapeutic efficacy of glycyrrhizic acid (GA)-loaded pH-sensitive nanoformulations that specifically target and combat mucosal inflammation of the colon. GA-loaded Eudragit S100/poly-(lactic-co-glycolic acid) nanoparticles were developed through modified double-emulsion evaporation coupled with solvent evaporation coating techniques and analyzed for physicochemical characteristics, surface chemistry, release kinetics, site-retention and therapeutic effectiveness. Nanoparticles have a particle size of approximately 200 nm, high encapsulation efficiency, desired surface chemistry with pH-dependent and sustained drug release behavior following the Gompertz kinetic model. retention and therapeutic effectiveness in the inflamed colon tissues were confirmed by macroscopic and microscopic indices, cytokine analysis and antioxidant assays. GA-loaded Eudragit S100/poly-(lactic-co-glycolic acid) nanoparticles could efficiently deliver GA to the colon and ameliorate the mucosal inflammation for a prolonged duration.

This study provides the scientific basis for the anti-inflammatory effects of licorice extract in a t-BHP (tert-butyl hydrogen peroxide)-induced liver damage model and the effects of its ingredients, glycyrrhizic acid (GA), liquiritin (LQ) and liquiritigenin (LG), in a lipopolysaccharide (LPS)-stimulated microglial cell model. The GA, LQ and LG inhibited the LPS-stimulated elevation of pro-inflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and interleukin (IL)-6 in BV2 (mouse brain microglia) cells. Furthermore, licorice extract inhibited the expression levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the livers of t-BHP-treated mice models. This result suggested that mechanistic-based evidence substantiating the traditional claims of licorice extract and its three bioactive components can be applied for the treatment of inflammation-related disorders, such as oxidative liver damage and inflammation diseases.

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.

Background Open skin wounds increase the risk of infections and can compromise health. Therefore, applying medications to promote healing at the injury site is crucial. In practice, direct drug delivery is often difficult to maintain for a long time due to rapid absorption or wiping off, which reduces the efficiency of wound healing. Consequently, the development of bioactive materials with both antibacterial and wound‐healing properties is highly desirable. Methods This study synthesized liposomes loaded with glycyrrhizic acid (GA) and asiaticoside (AS) by film dispersion‐ultrasonication method, which were then incorporated into a GelMA solution and cross‐linked by ultraviolet light to form a bioactive composite hydrogel for wound dressings. Results This hydrogel is conducive to the transport of nutrients and gas exchange. Compared with GelMA hydrogel (swelling rate 69.8% ± 5.7%), the swelling rate of GelMA/Lip@GA@AS is lower, at 52.1% ± 1.0%. GelMA/Lip@GA@AS also has better compression and rheological properties, and the in vitro biodegradability is not significantly different from that of the collagenase‐treated group. In addition, the hydrogel polymer has a stable drug release rate, good biocompatibility, and an angiogenic promoting effect. In vitro experiments prove that, at concentrations of 0.5, 1, 2, and 3 mg/mL, GelMA/Lip@GA@AS can inhibit the growth of Staphylococcus aureus. Conclusion We synthesized GelMA/Lip@GA@AS hydrogel and found it possesses advantageous mechanical properties, rheology, and biodegradability. Experimental results in vitro showed that the bioactive hydrogel could efficiently release drugs, exhibit biocompatibility, and enhance angiogenesis and antimicrobial effects. These results suggest the promising application of GelMA/Lip@GA@AS hydrogel in wound‐dressing materials.

With unknown etiology and limited treatment options, neonatal hypoxic-ischemic brain damage (HIBD) remains a major cause of mortality in newborns. Ferroptosis, a recently discovered type of cell death triggered by lipid peroxidation, is closely associated with HIBD. High-mobility group box 1 (HMGB1), a molecule associated with inflammation damage, can induce neuronal death in HIBD. However, it remains unknown whether HMGB1 contributes to neuronal ferroptosis in patients with HIBD. Herein, glycyrrhizin (GL), an HMGB1 inhibitor, was used to investigate the relationship between ferroptosis and HMGB1. RAS-selective lethal 3(RSL3), a ferroptosis agonist, was administered to further confirm the changes in the signaling pathway between HMGB1 and ferroptosis. Western blot analysis revealed that GL markedly suppressed the expression of HMGB1 and increased the level of GPX4 in the context of HIBD. We observed changes in neuronal ultrastructure via transmission electron microscopy to further confirm the occurrence of ferroptosis. Real-time PCR indicated that GL inhibited the expression of ferroptosis-related genes and inflammatory factors. Immunofluorescence and immunohistochemistry staining confirmed GL inhibition of neuronal damage and ferroptosis in HIBD associated with GPX4 and ROS. GL not only inhibited ferroptosis induced by RSL3 and oxygen-glucose deprivation in vitro but also inhibited ferroptosis induced by HIBD in vivo. More importantly, GL may improve oxidative stress imbalance and mitochondrial damage, alleviate the downstream production of inflammatory factors, and ultimately reduce ferroptosis and damage to cortical neurons following HIBD via the HMGB1/GPX4 pathway. In conclusion, we showed for the first time that GL could suppress the occurrence of neuronal ferroptosis and reduce neuronal loss in HIBD via the HMGB1/GPX4 pathway. These findings highlight the potential of HMGB1 signaling antagonists to treat neuronal damage by suppressing ferroptosis, provide new and unique insights into GL as a neuroprotective agent, and suggest new prevention and treatment strategies for HIBD.

Background Glycyrrhizin is a major ingredient of licorice which is widely used in the treatment of various diseases such as chronic hepatitis. Licorice or glycyrrhizin has been shown to alter the activity of CYP3A in rodents. The influence of glycyrrhizin on CYP3A has not been elucidated in humans. Objective To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of midazolam, a probe drug for CYP3A activity in humans. Methods Sixteen healthy adult male subjects were enrolled in a two-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days. On the 15th day, midazolam was administered and blood samples were obtained to determine midazolam plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMRs) and 90% confidence intervals (90% CI). Results The geometric mean (geometric coefficient of variation) for the [graphic removed] of midazolam in the placebo group was 196.4 ng·h/ml (30.3%) and after glycyrrhizin treatment, 151.3 ng·h/ml (34.7%). The GMRs and 90% CI for [graphic removed] and Cmax of midazolam in the presence/absence of glycyrrhizin were 0.77 (0.70, 0.89) and 0.83 (0.74, 1.01), respectively. The 90% CI for [graphic removed] and Cmax for the GMR of glycyrrhizin over placebo were both out of the no-effect boundaries of 0.80-1.25. Conclusions Administration of glycyrrhizin resulted in a modest induction of CYP3A that was clinically relevant according to the bioequivalence analysis.