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Ethnopharmacological Relevance: Paeonol (PAE) and glycyrrhizic acid (GLY) are predominate components of 14 blood-entering ones of Piantongtang No. 1, which is a traditional Chinese medicine prescription for chronic migraine with minimal side effects. Both paeonol and glycyrrhizic acid exhibit analgesic, neuroprotective and anti-inflammatory properties individually. Our previous research has highlighted their combined effect (PAE + GLY) in ameliorating migraine symptoms. However, there are not yet any studies exploring the mechanism of action of PAE + GLY in the treatment of migraine., Aim of the Study: This research aimed to determine the mechanism of PAE + GLY in ameliorating the recurrent nitroglycerin-induced migraine-like phenotype in rats., Materials and Methods: Using a nitroglycerin-induced migraine model via subcutaneous injection in the neck, we evaluated the effect of PAE + GLY on migraine-like symptoms. Behavioural tests and biomarkers analysis were employed, alongside transcriptome sequencing (RNA-seq). Mechanistic insights were further verified utilising reverse transcription quantitative PCR (RT-qPCR), Western blot (WB), ELISA and immunofluorescence (IF) techniques., Results: Following treatment with PAE + GLY, hyperalgesia threshold and 5-hydroxytryptamine (5-HT) levels increased, and migraine-like head scratching, histamine and calcitonin gene-related peptide (CGRP) levels were reduced. RNA-Seq experiments revealed that PAE + GLY upregulated the expression of Glutamate decarboxylase 2 (GAD2) and γ-aminobutyric acid type B receptor subunit 2 (GABBR2) genes. This upregulation activated the GABAergic synapse pathway, effectively inhibiting migraine attacks. Further validation demonstrated an increase in γ-aminobutyric acid (GABA) content in cerebrospinal fluid post PAE + GLY treatment, coupled with increased expression of dural GAD2, GABBR2 and transient receptor potential channel M8 (TRPM8). Consequently, this inhibited the expression of dural cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) and transient receptor potential channel type 1 (TRPV1), subsequently downregulating p-ERK1/2, p-AKT1, IL-1β and TNF-α., Conclusions: Our findings underscore that PAE + GLY ameliorates inflammatory hyperalgesia migraine by upregulating inhibitory neurotransmitters and modulating the GABBR2/TRPM8/PRKACA/TRPV1 pathway., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare, and all the authors have approved this manuscript for publication., (Copyright © 2024. Published by Elsevier B.V.)

As one of the most common malignancies, colorectal cancer (CRC) usually starts with a benign lesion and accumulates DNA damage as it progresses to full-fledged cancer. Glycyrrhizin (GL) has been found to alleviate tumor growth and inflammation, while the role of GL influences DNA damage response (DDR) in colorectal cancer remains unclear. GL exposure significantly reduced cell colony formation and viability with a concomitant increase in DNA fragmentation in CRC, meanwhile GL induced apoptosis by activating caspase-3. Moreover, GL induced cell cycle arrest in CRC cells at S phase, which was associated with decreased cyclin D1 in vitro. GL treatment significantly ameliorated tumor growth and promoted DDR in vivo. Mechanism analysis revealed that GL significantly downregulated the NHEJ pathway via inhibiting HMGB1. Finally, the expression of HMGB1 was abnormal regulated in CRC tissue than in adjacent normal tissues and associated with TNM stage and overall survival. Our findings indicate that HMGB1 may be a novel therapeutic target in CRC, a result that GL may serve as a promising drug for CRC treatment., (© 2024. The Author(s).)

Acne Vulgaris or Acne is a multifactorial bacterial infection caused by Propionibacterium acne, leading to inflammation and decreased quality of life, especially in adolescence. Currently, antibiotics and retinoids are preferred for treating acne. However, their continuous usage may lead to anti-microbial resistance and other side effects. Therefore, research on developing effective strategies to reduce antimicrobial resistance and improve acne healing is ongoing. The current work reports the synthesis and evaluation of near-infrared light-absorbing copper sulfide (CuS) nanoparticles loaded with a biomolecule, Glycyrrhizin (Ga). The photothermal efficacy studies, and in-vitro and in-vivo experiments indicated that the Ga-CuS NPs generated localized hyperthermia in acne-causing bacteria, leading to their complete growth inhibition. The results indicated that the Ga-Cus NPs possess excellent antibacterial and anti-inflammatory properties in the acne and inflammatory models. This could be from the synergistic effect of CuS NPs mediated mild Photothermal effect and inherent pharmacological properties of Ga. Further detailed studies of the formulations can pave the way for application in cosmetic clinics for the effective and minimally invasive management of Acne-like conditions., (© 2024. Controlled Release Society.)

Glycyrrhizic acid (GA) has effects on anti-hepatic fibrosis, anti-tumor and prevention from hepatocellular carcinoma (HCC) progression. Yet, the capacity of GA to ameliorate the advance of HCC pertinent to nonalcoholic fatty liver disease (NAFLD) remains to be clarified. We used the CCK-8 method to detect the optimal treatment concentration and time for L-02 cells, palmitic acid (PA)-induced L-02 cells and HepG2 cells, and selected 40 μM and 48 h to treat PA-induced L-02 cells and 60 μM for 24 h to treat HepG2 cells. Moreover, functional associations of HepG2 cells were elucidated through various assays. The results showed that GA demonstrated enhances lipid deposition and alleviates the inflammatory response in L-02 cells induced by palmitic acid. Simultaneously, we found that GA inhibits the proliferation, migration, and invasion while promoting apoptosis in HepG2 cells. In pursuit of constructing of HCC model rats, a combination of high-fat diets and diethylnitrosamine was utilized. The results showed that GA significantly decreased the liver index, body weight, liver weight, and the number of nodules in HCC model rats. Moreover, GA mitigated infiltration and heightened apoptosis in these rats. Mechanistically, GA notably attenuated the KKβ/NF-κB pathway in both HepG2 cells and the HCC model rats. In conclusion, GA functions as an inhibitor in the progression of NAFLD-related HCC cells, which might be relevant to the KKβ/NF-κB pathway. Therefore, GA is a potential drug for NAFLD-related HCC treatment., (© 2024 Wiley Periodicals LLC.)

Background: Chronic urticaria (CU) is a prevalent dermatologic disease that negatively affects life, current therapies remain suboptimal. Hence, there is an urgent need to identify effective and safe treatment., Objective: Assess the efficacy and safety of compound glycyrrhizin (CG) combined with second-generation nonsedated antihistamine for the treatment of CU., Methods: Nine databases were queried to screen RCTs related. Two reviewers independently assessed the risk of bias using Cochrane Collaboration. Primary objective was the total efficiency rate, while secondary was rate of recurrence, adverse events, and cure. Statistical analyses using Review Manager 5.4 and Stata17., Results: Twenty-four RCTs were identified. Significant differences were noted in rate of total efficiency ( n  = 2649, RR = 1.36, 95%CI:1.30-1.43, p  < 0.00001), cure ( n  = 2649, RR = 1.54, 95%CI:1.42-1.66, p  < 0.00001) and recurrence ( n  = 446, RR = 0.34, 95%CI:0.20-0.58, p  < 0.00001) between the combination of CG with second-generation non-sedated antihistamine and antihistamine monotherapy. Contrastingly, adverse events rate ( n  = 2317, RR = 0.76, 95% CI:0.59-0.97, p  = 0.03) was comparable between the two groups. Our results indicated that CG combined with second-generation non-sedated antihistamine could significantly mitigate the symptoms in CU compared with antihistamine monotherapy. No serious adverse events were reported., Conclusions: CG combined with second-generation nonsedated antihistamine is effective for CU. Nevertheless, higher-quality studies are warranted to validate our results.

Glycyrrhizin (GL) has immunoregulatory effects on various inflammatory diseases including hepatitis and nephritis. However, the mechanisms underlying the anti-inflammatory effect of GL on renal inflammation are not fully understood. Hepatorenal syndrome (HRS) is a functional acute renal impairment that occurs in severe liver disease, and we found that kidney injury also occurs in Con A-induced experimental hepatitis in mice. We previously found that GL can alleviate Con A-induced hepatitis by regulating the expression of IL-25 in the liver. We wanted to investigate whether GL can alleviate Con A-induced nephritis by regulating IL-25. IL-25 regulates inflammation by modulating type 2 immune responses, but the mechanism by which IL-25 affects kidney disease remains unclear. In this study, we found that the administration of GL enhanced the expression of IL-25 in renal tissues; the latter promoted the generation of type 2 macrophages (M2), which inhibited inflammation in the kidney caused by Con A challenge. IL-25 promoted the secretion of the inhibitory cytokine IL-10 by macrophages but inhibited the expression of the inflammatory cytokine IL-1β by macrophages. Moreover, IL-25 downregulated the Con A-mediated expression of Toll-like receptor (TLR) 4 on macrophages. By comparing the roles of TLR2 and TLR4, we found that TLR4 is required for the immunoregulatory effect of IL-25 on macrophages. Our data revealed that GL has anti-inflammatory effects on Con A-induced kidney injury and that the GL/IL-25/M2 axis participates in the anti-inflammatory process. This study suggested that GL is a potential therapeutic for protecting against acute kidney injury.

Varicellovirus bovinealpha 1 (BoAHV-1) is a significant pathogen responsible for respiratory disease in cattle, capable of inducing lung damage independently or co-infection with bacteria. The widespread spread of BoAHV-1 in cattle herds has caused substantial economic losses to the cattle industry. The pathogenic mechanisms of BoAHV-1 are often relevant to robust inflammatory responses, increased oxidative burden, and the initiation of apoptosis. Glycyrrhizin (GLY) is a small-molecule triterpenoid saponin compound obtained from the herb liquorice, which has a broad spectrum of pharmacological properties such as antiviral, anti-inflammatory, and antioxidant effects. Furthermore, GLY regulates lung physiology by modulating oxidative stress, inflammatory response, and cell apoptosis through interference with the NF-κB/NLRP3 and Nrf2/HO-1 Signaling pathways. However, the potential of GLY to mitigate lung injury induced by BoAHV-1 and its underlying mechanism remains unclear. Therefore, in this study, we investigated the protective effect of GLY against pulmonary injury induced by BoAHV-1 in a guinea pig model by reducing viral load and suppressing the inflammatory response, oxidative stress, and apoptosis. The results of this study demonstrated that GLY exerted a protective effect against BoAHV-1-induced lung injury in guinea pigs. Specifically, GLY reduced the levels of pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and interleukin (IL)-8 in guinea pig tissues while suppressing the expression of Caspase-1. Additionally, GLY reduced BoAHV-1 load and the number of TUNEL-positive lung cells in guinea pig lungs while inhibiting Caspase 3 protein expression. Furthermore, GLY significantly enhanced lung antioxidant capacity by increasing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity while simultaneously reducing malondialdehyde (MDA) levels. Lung histological observation and score further validated the protective effect of GLY on BoAHV-1-induced lung injury. Furthermore, we observed that the expression of phosphorylated NF-κB p65 (p-NF-κB p65) and NLRP3 proteins in the lung tissue of BoAHV-1-infected guinea pigs decreased after GLY treatment while the expression of Nrf2 and HO-1 proteins increased. These results indicated that GLY inhibited the NF-κB/NLRP3 Signaling pathway and activated the Nrf2/HO-1 Signaling pathway during BoAHV-1 infection. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Importantly, this study provides a compelling argument for the GLY in combating respiratory disease in cattle caused by BoAHV-1., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Ulcerative colitis (UC) is a persistent inflammatory condition that specifically targets the colon and rectum. Existing therapies fail to adequately address the clinical requirements of people suffering from this ailment. Despite the acknowledged potential of nanomedicines in the field of anti-inflammatory treatment, their widespread use in clinical settings is impeded by their expensive nature and the uncertainty surrounding their safety profiles. This study illustrates that two naturally occurring phytochemicals, Costunolide (COS) and Glycyrrhizic acid (GA), form carrier-free, multifunctional spherical nanoparticles (NPs) through noncovalent interactions, such as π-π stacking and hydrogen bonding. The COS-GA NPs displayed a synergistic anti-inflammatory effect, providing much more evidently improved therapeutic benefits for dextran sodium sulfate (DSS)-induced UC mice due to more effective reduction in inflammation and oxidative stress than did equal dosages of COS or GA used alone. In addition, COS-GA NPs have biocompatibility and biosafety properties unique to them. This study will serve as affirmation of the potential of COS-GA NPs as innovative natural anti-inflammatory and antioxidant activities and also such agents as drug discovery in UC, leading possibly to better outcomes in people living with this disabling condition., (© 2024. The Author(s).)

Porcine reproductive and respiratory syndrome (PRRS) is endemic worldwide, seriously affecting the development of the pig industry, but vaccines have limited protective effects against PRRSV transmission. The aim of this study was to identify potential anti-PRRSV drugs. We examined the cytotoxicity of seven compounds formulated based on the mass ratio of glycyrrhizic acid to matrine and calculated their inhibition rates against PRRSV in vitro. The results showed that the seven compounds all had direct killing and therapeutic effects on PRRSV, and the compounds inhibited PRRSV replication in a time- and dose-dependent manner. The compound with the strongest anti-PRRSV effect was selected for subsequent in vivo experiments. Pigs were divided into a control group and a medication group for the in vivo evaluation. The results showed that pigs treated with the 4:1 compound had 100% morbidity after PRRSV challenge, and the mortality rate reached 75% on the 8th day of the virus challenge. These results suggest that this compound has no practical anti-PRRSV effect in vivo and can actually accelerate the death of infected pigs. Next, we further analyzed the pigs that exhibited semiprotective effects following vaccination with the compound to determine whether the compound can synergize with the vaccine in vivo. The results indicated that pigs treated with the compound had higher mortality rates and more severe clinical reactions after PRRSV infection (p < 0.05). The levels of proinflammatory cytokines (IL-6, IL-8, IL-1β, IFN-γ, and TNF-α) were significantly greater in the compound-treated pigs than in the positive control-treated pigs (p < 0.05), and there was no synergistic enhancement with the live attenuated PRRSV vaccine (p < 0.05). The compound enhanced the inflammatory response, prompted the body to produce excessive levels of inflammatory cytokines and caused body damage, preventing a therapeutic effect. In conclusion, the present study revealed that the in vitro effectiveness of these agents does not indicate that they are effective in vivo or useful for developing anti-PRRSV drugs. Our findings also showed that, to identify effective anti-PRRSV drugs, comprehensive drug screening is needed, for compounds with solid anti-inflammatory effects both in vitro and in vivo. Our study may aid in the development of new anti-PRRSV drugs., (© 2024. The Author(s).)

Background: Severe acute pancreatitis (SAP) is a potential fatal gastrointestinal disease that is usually complicated by myocardial injury and dysfunction. Due to the lack of understanding of the mechanism of SAP-associated cardiac injury (SACI), there is still no complete treatment., Aims: To explore the alleviative effect and anti-ferroptosis mechanism against SACI of glycyrrhizin (GL), an inhibitor of oxidative stress., Methods: The SAP model was established by perfusing 5% sodium taurocholate into biliopancreatic duct in rats. H&E staining and serum assays were used to assess the injury changes of pancreas and heart. Echocardiography was used to evaluate the cardiac function. Transmission electron microscopy (TEM) and oxidative stress assays were used to investigate the ferroptosis-related morphological and biochemical changes. Western blot and immunofluorescence were performed to analyzed the expression of ferroptosis-related proteins., Results: Significant myocardial impairment was found in SAP rats according to increased histopathological scores, serum creatine kinase-MB (CK-MB) and cardiac troponin-I (cTnI) levels, and a decreased fractional shortening and ejection fraction. The decreased mitochondrial cristae and significant expression changes of ferroptosis-related proteins confirmed the presence of ferroptosis in SACI. GL treatment attenuated above-mentioned cardiac tissues damage by inhibiting ferroptosis via restoring the expression of Nrf2 and HO-1 in vivo and in vitro. Treating with ML385 (a Nrf2 inhibitor) or transfecting with siRNA-Nrf2 reversed the protective effect of GL., Conclusions: Our findings demonstrate the involvement of ferroptosis in SACI and suggest a potential role for GL in the treatment of SACI by supressing ferroptosis via Keap1/Nrf2/HO-1 pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: As a traditional Chinese medicinal herb, Glycyrrhiza., Uralensis: Fisch. (licorice root, chinese name: Gancao) has a variety of medicinal values and is widely used clinically. Its main active ingredient, glycyrrhizic acid (GA), is believed to have a neuroprotective effect. However, the underlying biological mechanisms of GA on stress-induced anxiety disorders are still unclear., Aim of the Study: To investigate the anti-anxiety effect of GA and its underlying mechanism., Methods: We selected the anxiety model induced by repeated chronic restraint stress (CRS) for 2 h on each of 7 consecutive days. GA (4, 20, 100 mg/kg) was injected intraperitoneally once daily for 1 week. The potential GA receptors were identified using whole-cell patches and computer-assisted docking of molecules. High-throughput RNA sequencing, adeno-associated virus-mediated gene regulation, Western blotting, and RT-qPCR were used to assess the underlying molecular pathways., Results: GA alleviate depression-like and anxiety-like behaviors in CRS mice. GA decreased synaptic transmission by facilitating glutamate reuptaking in mPFC. Meanwhile, long-term GA treatment increased the expression of clock genes Per1 and Per2. Suppressing both Per1 and Per2 abolished the anxiolytic effects of GA treatment., Conclusion: Our study suggests that GA may be developed for the treatment of stress-induced anxiety disorders, and its mechanism is related to GLT1 and Per1/2-dependent pathways. This presents a novel approach to discovering potent therapeutic drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: This study was done to clinically investigate the efficacy of glycyrrhizin-based intracanal medication (ICM) compared to calcium hydroxide Ca(OH) 2 and Ledermix on the bacterial counts inside the root canals of necrotic teeth with chronic periapical periodontitis., Methodology: Thirty-six patients having single-rooted and single-canaled necrotic teeth with chronic periapical periodontitis were enrolled in this research. Aseptic control measures were taken before clinical steps. Access cavity preparation was done. First bacteriological samples (S1) were collected immediately after access cavity preparation and before cleaning and shaping inside the root canals. Cleaning and shaping were performed on the root canals. Patients were randomly allocated into 3 groups according to the type of intracanal medicament used [Ca(OH) 2 , Ledermix, Glycyrrhizin]. Second bacteriological samples (S2) were collected after 1 week from placing the ICMs. S1 and S2 were transferred to the lab of microbiology for culturing on blood agar dishes in anaerobic conditions, and the bacteria on the plates were enumerated as colony-forming units (CFUs) by the manual counting method. The anti-bacterial efficacy of the ICM was estimated by the percentage reduction in the bacterial colonies from S1 to S2., Results: All tested ICM documented a significant reduction in the CFUs from S1 to S2 ( p < 0.05). Regarding S1, there was no significant difference between the three tested materials ( p > 0.05). Regarding S2, Glycyrrhizin and Ledermix showed significantly lower CFUs than Ca(OH) 2 . There was no significant difference between Glycyrrhizin and Ledermix., Conclusion: Under the conditions of the present study, Glycyrrhizin and Ledermix showed comparable antimicrobial effects that were better than the commonly used Ca(OH) 2 ICM. Glycyrrhizin may be a promising ICM., Clinical Significance: Herbal medicine can be considered as an alternative antimicrobial material for root canal disinfection because it has many benefits, like low toxicity, absence of microbial resistance, and favorable antimicrobial efficacy. This study highlights the clinical efficacy of Glycyrrhizin as a promising ICM. How to cite this article: Eltantawi AR, Abdel-Razik GM, Elhawary YM, et al. Efficacy of Glycyrrhizin as an Intracanal Medicament on Bacterial Load Reduction in Primary Infected Root Canals: A Randomized Clinical Trial. J Contemp Dent Pract 2024;25(6):540-546.

Background: Hepatocellular carcinoma (HCC) is the most malignant cancer worldwide. Sorafenib (SRF) is a common therapeutic drug used for patients with advanced HCC. Nevertheless, drug resistance frequently occurs in patients treated with sorafenib. Glycyrrhizic acid (GRA) is a natural compound that is identified to exhibit anti-cancer effects. In this work, we aimed to investigate the effects of GRA on SRF-resistant HCC cells and the potential regulatory mechanisms., Methods: We established SRF-resistant HCC cell lines and administrated GRA treatment. We performed CCK-8 and colony formation experiments to detect cell proliferation. The accumulation of lipid reactive oxygen species (ROS) and iron levels were measured to evaluate ferroptosis. The protein levels of ferroptosis suppressor glutathione peroxidase 4 (GPX4) and SLC7A11, and the activation of AKT and mTOR were measured with western blotting assay., Results: GRA treatment notably suppressed the viability and proliferation of SRF-resistant HCC cells. SRF-resistant HCC cells exhibited repressed ferroptosis level activated AKT/mTOR cascade, and GRA treatment reversed these effects. Inhibition of ferroptosis and activation of mTOR reversed the anti-proliferation effects of GRA on SRF-resistant HCC cells., Conclusion: Treatment with GRA could effectively reverse the SRF resistance of HCC cells via inducing ferroptosis and inactivating the AKT/mTOR cascade.

Abstract: Currently, the coronavirus disease 2019 (COVID-19) is becoming a serious threat to human health worldwide. Therefore, there is a great need to develop effective drugs against viral pneumonia. Diammonium glycyrrhizinate (DG), derived from Glycyrrhiza glabra L., has been demonstrated with significant anti-inflammatory properties. However, the therapeutic effects and mechanisms of DG on pneumonia require further clarification. In this study, mice received intratracheal injection of polyinosinic-polycytidylic acid (poly(I:C)) to induce pneumonia and were treated with DG. First, we evaluated the therapeutic potential of DG on poly(I:C)-induced pneumonia. Second, the anti-inflammatory and antioxidative activities and the impact of DG on the toll-like receptor 3 (TLR3) pathway were investigated. Third, the mechanism of DG was analyzed through untargeted metabolomics techniques. Our results revealed that DG intervention decreased permeability and reduced abnormal lung alterations in poly(I:C)-induced pneumonia model mice. DG intervention also downregulated cytokine levels in bronchoalveolar lavage fluid. Moreover, DG treatment inhibited the activation of TLR3 pathway. Furthermore, untargeted metabolomics analysis revealed that DG intervention could modulate serum metabolites involved in amino and nucleotide sugar metabolism, fructose and mannose metabolism, tyrosine metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In conclusion, our study showed that DG could ameliorate poly(I:C)-induced pneumonia by inactivating the TLR3 pathway and affecting amino and nucleotide sugar, fructose and mannose metabolism, as well as tryptophan, phenylalanine, and tyrosine biosynthesis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Neutrophils and T lymphocytes are closely related to occurrence of immunosuppression in sepsis. Studies have shown that neutrophil apoptosis decreases and T lymphocyte apoptosis increases in sepsis immunosuppression, but the specific mechanism involved remains unclear. In the present study, we found Toll-like Receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) were significantly activated in bone marrow neutrophils of wild-type mice after LPS treatment and that they were attenuated by treatment with C29, an inhibitor of TLR2. PD-L1 activation inhibits neutrophil apoptosis, whereas programmed death protein 1 (PD-1)activation promotes apoptosis of T lymphocytes, which leads to immunosuppression. Mechanistically, when sepsis occurs, pro-inflammatory factors and High mobility group box-1 protein (HMGB1) passively released from dead cells cause the up-regulation of PD-L1 through TLR2 on neutrophils. The binding of PD-L1 and PD-1 on T lymphocytes leads to increased apoptosis of T lymphocytes and immune dysfunction, eventually resulting in the occurrence of sepsis immunosuppression. In vivo experiments showed that the HMGB1 inhibitor glycyrrhizic acid (GA) and the TLR2 inhibitor C29 could inhibit the HMGB1/TLR2/PD-L1 pathway, and improving sepsis-induced lung injury. In summary, this study shows that HMGB1 regulates PD-L1 and PD-1 signaling pathways through TLR2, which leads to immunosuppression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The neurotoxicity of Semen Strychni has been reported recently in several clinical cases. Therefore, this study was conducted to investigate the role of HMGB1 in a model of neurotoxicity induced by Semen Strychni and to assess the potential alleviating effects of glycyrrhizic acid (GA), which is associated with the regulation of HMGB1 release. Forty-eight SD rats were intraperitoneally injected with Semen Strychni extract (175 mg/kg), followed by oral administration of GA (50 mg/kg) for four days. After treatment of SS and GA, neuronal degeneration, apoptosis, and necrosis were observed via histopathological examination. Inflammatory cytokines (TNF-α and IL-1β), neurotransmitter associated enzymes (MAO and AChE), serum HMGB1, nuclear and cytoplasmic HMGB1/ph-HMGB1, and the interaction between PP2A, PKC, and HMGB1 were evaluated. The influence of the MAPK pathway was also examined. As a result, this neurotoxicity was characterized by neuronal degeneration and apoptosis, the induction of pro-inflammatory cytokines, and a reduction in neurotransmitter-metabolizing enzymes. In contrast, GA treatment significantly ameliorated the abovementioned effects and alleviated nerve injury. Furthermore, Semen Strychni promoted HMGB1 phosphorylation and its translocation between the nucleus and cytoplasm, thereby activating the NF-κB and MAPK pathways, initiating various inflammatory responses. Our experiments demonstrated that GA could partially reverse these effects. In summary, GA acid alleviated Semen Strychni-induced neurotoxicity, possibly by inhibiting HMGB1 phosphorylation and preventing its release from the cell., (© 2024. The Author(s).)

Varicellovirus bovinealpha 1 (BoAHV-1) is one of the crucial pathogens of bovine respiratory diseases, and its pathogenic mechanism involves oxidative stress, inflammation response, and apoptosis. Glycyrrhizin (GLY) possesses powerful antiviral, antioxidant, anti-inflammatory, and anti-apoptotic bioactivities. However, the anti-BoAHV-1 activity of GLY and its role in BoAHV-1-induced oxidative stress, inflammation, and apoptosis remain unclear. Therefore, the current study investigated the anti-BoAHV-1 effect of GLY and its ability to alleviate BoAHV-1-induced oxidative stress, inflammation, and apoptosis using an in vitro model (MDBK cells). Our results showed that BoAHV-1 titers significantly increased in MDBK cells after infection, and GLY reduced the BoAHV-1 titers in MDBK cells exposed to it. Furthermore, Interleukin (IL)-1β, IL-8, tumor necrosis factor (TNF)-α, phosphorylated NF-κB p65 (p-NF-κB p65), the NLR pyrin domain containing 3 (NLRP3), Caspase-1, and Cleaved Caspase-3 levels were significantly upregulated when MDBK cells were challenged with BoAHV-1. In BAY 11-7085 (a specific NF-κB inhibitor) treated MDBK cells, IL-1β, IL-8, TNF-α, p-NF-κB p65, NLRP3, Caspase-1, and Cleaved Caspase-3 levels were downregulated. Notably, GLY treatment had the same trend as the BAY 11-7085 treatment. Thus, these results suggested that GLY exerted anti-inflammatory and anti-apoptotic activities by blocking NF-κB/NLRP3 axis. In addition, after BoAHV-1 infection, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and p-NF-κB p65 and apoptosis rate were increased, and catalase (CAT) and glutathione peroxidase (GSH-Px) enzyme activities, as well as NF-E2-related nuclear factor erythroid-2 (Nrf2) protein expression were repressed. Compared with BoAHV-1-infected MDBK cells, GLY treatment significantly downregulated intracellular ROS, MDA, and p-NF-κB p65 levels and apoptotic rates and significantly increased intracellular CAT and GSH-Px enzyme activities and Nrf2 expression. Additionally, ML385 (a specific Nrf2 inhibitor) abolished the enhancing effect of GLY on Nrf2 and the attenuating effect on ROS, p-NF-κB p65, and apoptosis. These results suggested that GLY had an anti-BoAHV-1 effect and could mitigate BoAHV-1-induced oxidative stress, inflammation, and apoptosis by activating the Nrf2 signalling and restraining NF-κB/NLRP3 axis., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Glycyrrhizic acid (GA), one of the major active components derived from licorice root, exerts liver-protecting activity. Its molecular mechanisms of action, however, remain not completely understood. The angiotensin (Ang) converting enzyme (ACE) 2/Ang-(1-7)/Mas axis, regulated by ACE2 through converting Ang II into Ang-(1-7) to activate Mas receptor, counteracts the pro-inflammatory and pro-steatotic effects of the ACE/Ang II/Ang II receptor type 1 (AT1) axis. Here, it was found that pretreatment with GA suppressed LPS/D-galactosamine-induced serum hyperactivities of alanine aminotransferase and aspartate aminotransferase, hepatomegaly, pathological changes, and over-accumulation of triglycerides and fatty droplets in the liver of mice. GA also diminished LPS/free fatty acid-induced inflammation and steatosis in cultured hepatocytes. Mechanistically, GA restored hepatic protein hypoexpression of ACE2 and Mas receptor, and the decrease in hepatic Ang-(1-7) content. Hepatic overexpression of angiotensin II and AT1 was also suppressed. However, GA did not alter hepatic protein expression of renin and ACE. In addition, GA inhibited hepatic protein over-phosphorylation of the p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor κB at Ser 536 . Hepatic overexpression of tumor necrosis factor α, interleukin 6, interleukin 1β, sterol regulatory element-binding protein 1c, and fatty acid synthase was also inhibited. GA-elicited recovery of ACE2 and Mas protein hypoexpression was further confirmed in the hepatocyte. Thus, the present results demonstrate that GA restores the downregulated hepatic ACE2-mediated anti-inflammatory and anti-steatotic signaling in the amelioration of steatohepatitis. We suggest that GA may protect the liver from injury by regulating the hepatic ACE2-mediated signaling., Competing Interests: Declaration of competing interest The authors (Longyue Zhou, Shankang Chen, Yuanyi Wei, Yihui Sun, Yifan Yang, Bingqi Lin, Yuhao Li, and Chunxia Wang) declare no duality of competing financial interests or personal relationships to influence this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Previous research has demonstrated that glycyrrhizic acid (GA) exhibits antioxidant, anti-inflammatory, and antiapoptotic characteristics. Using myocardial ischemia/reperfusion injury as a case study, this study aims to clarify the functional significance of GA and to elucidate the mechanisms involved., Materials and Methods: In this study, an MI/R injury model was established both in vivo and in vitro to investigate the impact of GA on MI/R injury. The viability of H9c2 cells was evaluated using the Cell Counting Kit-8. Myocardial damage was assessed through the measurement of creatine kinase myocardial band (CK-MB) levels and lactate dehydrogenase (LDH), HE staining, and MASSON staining. Inflammatory cytokine levels (IL-6, IL-1β, IL-10, and TNF-α) were measured to determine the presence of inflammation. Cellular oxidative stress was evaluated by measuring ROS and MMP levels, while cardiac function was assessed using cardiac color Doppler ultrasound. Immunofluorescence staining to determine the nuclear translocation of YAP, TUNEL to determine apoptosis, and western blotting to determine gene expression., Results: GA treatment effectively alleviated myocardial injury induced by MI/R, as evidenced by reduced levels of inflammatory cytokines (IL-1β, IL-6, IL-10, and TNF-α) and cardiac biomarkers (CK-MB, LDH) in MI/R rats. Moreover, There was a significant increase in cell viability in vitro after GA treatment and inhibited reactive oxygen species (ROS) during oxidative stress, while also increasing mitochondrial membrane potential (MMP) in vitro. The Western blot findings indicate that GA treatment effectively suppressed apoptosis in both in vivo and in vitro settings. Additionally, GA demonstrated inhibitory effects on the activation of the Hippo/YAP signaling pathway triggered by MI/R and facilitated YAP nuclear translocation both in vitro and in vivo. It has been found, however, in vitro, that silencing the YAP gene negates GA's protective effect against hypoxia/reoxygenation-induced myocardial injury., Conclusion: This study suggests that GA regulates YAP nuclear translocation by inhibiting the Hippo/YAP signaling pathway, which protects ists against MI/R injury. This finding may present a novel therapeutic approach for the treatment of MI/R., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Glycyrrhizin (GA) and its derivative Enoxolone (18β), isolated from the Glycyrrhiza glabra plant, are two potential molecules for treating viral diseases. Both demonstrate to regulate immune system with antiviral and anti-inflammatory activities, with the latter mainly due to modulation of inflammatory cytokines. The aim of this clinical trial was to evaluate the safety and efficacy of a nebulized GA/18β drug for treating COVID-19 patients., Methods: An open label, randomized, placebo-controlled clinical trial was conducted in Mexico City from January-August 2022 (Registration No. PROTAP-CLI-00). Clinical and biochemical parameters were recorded. Blood samples from patients were regularly collected to evaluate interleukins IL-4, IL-2, IL-1b, TNF-α, IL-17A, IL-6, IL-10,IFN-γ, IL-12, IL-8 and TGF-β1, as well as IgM and IgG against SARS-CoV-2. Two doses of the drug were used - 30/2 mg (dose A) and 90/4 mg (dose B)., Results and Discussion: Both GA/18β doses modulated inflammatory response by reducing mainly IL-17A expression, which in turn kept IL-1β, IL-6, IL-8 and TNF-α interleukins unchanged, indicating significant modulation of key interleukin levels to prevent exacerbation of the immune response in COVID-19 patients. Early on, dose A increased IgM, while dose B induced expression of the antiviral IFN-γ. No severe side effects were seen with either dose, indicating nebulized GA/18β is a safe treatment that could be used for COVID-19 and potentially other viral infections involving inflammatory response., Competing Interests: UZ-H and NA-M were employed by SPV TIMSER company. FV were employed by SPV TIMSER company as independent investigator. DT-V was employed by Columbia Biotech Laboratories as independent investigator. UZ-H has a patent pending for GA/18β compound. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zendejas-Hernandez, Alcántara-Martínez, Vivar, Valenzuela, Sosa Espinoza and Cervera Ceballos.)

Paeoniflorin (PF) and glycyrrhizic acid (GL) have skin beautifying effects of anti-inflammation, anti-oxidation, inhibition of melanin formation, and reduction of skin pigmentation. To improve the transdermal permeability of PF and GL in transdermal drug delivery system (TDDS) and enhance their anti-melasma efficacy, PF-GL transethosome (PF-GL-TE) was prepared by ethanol injection method, and finally gelled with carbomer-940 to form PF-GL-TE gel. Consequently, the obtained PF-GL-TE is small and uniform, with an average particle size and a PDI value of about 167.9 nm and 0.102. PF-GL-TE gel showed sustained release behavior and high transdermal permeability in vitro release and transdermal tests. Meanwhile, PF-GL-TE gel played significant preventive effects on melasma induced by progesterone injection and ultraviolet radiation B (UVB) irradiation. According to the results of H&E staining and Masson staining of rat skin, PF-GL-TE gel can alleviate the skin inflammation of and reduce the loss of collagen fibers of back skin in the melasma model rats. Compared with the PF-GL mixture gel, PF-GL-TE gel significantly attenuated the oxidative damage of liver and skin by increasing the activity of SOD and reducing the content of MDA. The results of Western blot showed that PF-GL-TE gel might down-regulate melanin-related proteins expressions of MITF/TYR/TRP1 and TRP2 to prevent and treat melasma. These findings indicate that PF-GL-TE gel is an effective TDDS for delivering PF and GL into the skin, providing a promising preparation for effective prevention and treatment of melasma., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Liver diseases and their related complications endanger the health of millions of people worldwide. The prevention and treatment of liver diseases are still serious challenges both in China and globally. With the improvement of living standards, the prevalence of metabolic liver diseases, including non-alcoholic fatty liver disease and alcoholic liver disease, has increased at an alarming rate, resulting in more cases of end-stage liver disease. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently needed. Glycyrrhizin (GL), a triterpene glycoside from the roots of licorice plants, possesses a wide range of pharmacological and biological activities. Currently, GL preparations (GLPs) have certain advantages in the treatment of liver diseases, with good clinical effects and fewer adverse reactions, and have shown broad application prospects through multitargeting therapeutic mechanisms, including antisteatotic, anti-oxidative stress, anti-inflammatory, immunoregulatory, antifibrotic, anticancer, and drug interaction activities. This review summarizes the currently known biological activities of GLPs and their medical applications in the treatment of liver diseases, and highlights the potential of these preparations as promising therapeutic options and their alluring prospects for the treatment of liver diseases.

Glycyrrhizin (GL) is one of the antagonists of highly conserved nuclear protein (HMGB1). The researches have shown that the glycosyl of GL is an important pharmacophore for GL binding to HMGB1, and it is the determinant factor for mechanism of action. To get the HMGB1 inhibitors with higher activity and good pharmacokinetic properties, two classes of GL analogues containing C-N glycoside bond were synthesized, and their anti-inflammatory, anti-oxidative stress and anti-septic kidney injury were evaluated. The results are as follows. First, in the anti-inflammatory assay, all the compounds inhibited NO release in some degree; among them, compound 6 displayed the strongest NO inhibitory effect with IC50 value of 15.9 μM, and compound 15 with IC50 of 20.2 μM. The two compounds not only decreased IL-1β and TNF-α levels in RAW264.7 cells and HK-2 cells, but also downregulated the levels of NLRP3, P-NF-κB p65 and HMGB1 in activated HK-2 cells in a dose-dependent manner. Second, in the renal protection assay with H2O2-stimulated HK-2 cell line, they reduced MDA level and increased SOD in HK-2 cells; additionally, they also inhibited the HK-2 cell apoptosis and downregulated the Caspase-1 p20 level. Third, in the in vivo activity tests of the septic mouse, they also showed good activities just like in vitro, decreasing the IL-1β, TNF-α, MDA, blood creatinine (Scr) and urea nitrogen (BUN) in serum, and increasing SOD levels in a dose-dependent manner. The immunoblotting results showed the two compounds downregulated the levels of HMGB1, P-NF-κB p65, NLRP3 and Caspase-1 p20 protein. All in all, the two compounds improved the renal injury of septic mice, and alleviated the tube wall structure damage and renal tubular dilation in kidney, which further proved by H&E staining. This suggests the two compounds have septic acute kidney injury activity, and they will be potential therapeutic drugs for septic acute kidney injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Riehl's melanosis is a hyperpigmentation disorder that has a significant psychological and social impact on individuals. In the past 10 years, new categories have been developed, raising questions about how to classify Riehl's melanosis. The mechanism of this disease remains unclear, although the type IV hypersensitivity response caused by allergic sensitization, as well as genetic, ultraviolet radiation, and autoimmune factors, is to blame. Clinical manifestation, dermoscopy, reflectance confocal microscopy, patch/photopatch testing, histopathology, and a novel multimodality skin imaging system have been used for the diagnosis. A variety of therapies including topical skin-lightening agents, oral tranexamic acid, glycyrrhizin compound, chemical peels, and lasers and light therapies (intense pulsed light, 1064-nm Q-Switched Nd: YAG laser, 755-nm PicoWay laser, nonablative 1927-nm fractional thulium fiber laser, new pulsed-type microneedling radiofrequency), with improved effectiveness. The latest findings on possible biomarkers and their relationship to other autoimmune diseases were also summarized., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Vitiligo is an acquired chronic depigmentary disorder affecting approximately 0.5% to 1% of individuals worldwide. The compound glycyrrhizin (CG), a complementary medicine, has been reported for treatment of vitiligo, but the evidence has not been systematically evaluated. We systematically assessed the efficacy and safety of CG in combination with conventional therapy for the treatment of vitiligo., Methods: We searched Embase, Web of Science, PubMed, The Cochrane Library, Chinese BioMedical Literature Database (CBM), Wanfang Data, China National Knowledge Infrastructure (CNKI), and VIP information from inception to July 2022. Randomized controlled trials comparing CG combined with conventional therapy with conventional therapy alone for vitiligo were included in our analysis. The primary outcome was treatment response, which defined as >50% repigmentation rate of vitiligo after treatment. The secondary outcome was incidence of adverse events. Meta-analysis was performed using the Review Manager 5.4 software. Statistical heterogeneity was evaluated with chi-square and I2 statistics, dichotomous data were expressed as risk ratios (RR) with 95% confidence intervals using the Mantel-Haenszal method., Results: Thirty-nine studies enrolling with 3994 participants were subjected to this review. The results of our meta-analysis indicated that addition of CG had superior effectiveness on repigmentation rate than phototherapy (RR = 1.28; P < .001), immunosuppressant (RR = 1.76; P < .001), traditional Chinese medicine (RR = 1.38; P < .001), combination of phototherapy and immunosuppressant (RR = 1.42; P < .001), and combination of phototherapy and traditional Chinese medicine (RR = 1.37; P < .001). In addition, CG did not increase the incidence of adverse events for vitiligo (RR = 0.79; P = .05)., Conclusions: CG as a complementary medicine has a potential benefit in treatment of vitiligo. However, since the methodological flaws in the studies we included, more high-quality randomized controlled trials are warranted., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Glycyrrhetinic acid, a drug with anti-inflammatory effects, enhanced the activity of antipsoriatic efficacy. In this research, an ointment with glycyrrhetinic acid was prepaired as the major component and several other herbal monomers (astilbin, osthole, and momordin Ic) have antipsoriatic activity as minor components. Then an Imiquimod-induced psoriasis-like mouse model was established and the damaged skin condition of the administered group, the changes in the spleen index and the secretion of inflammatory factors in mouse skin were observed. Calcipotriol ointment was used as a positive control to compare the efficacy. Glycyrrhizic acid compound ointment significantly improved imiquimod-induced psoriasis in mice and reduced the secretion of TNF-α, IL-12, IL-17, and IL-23 in mouse skin, and showed a stronger therapeutic effect than calcipotriol ointment. Calcipotriol ointment did not significantly alleviate imiquimod-induced splenomegaly and did not significantly reduce the expression of IL-17 and IL-23 in mouse skin. Glycyrrhetinic acid compound ointment was more effective than calcipotriol and was dose-dependent in the treatment of imiquimod-induced psoriatic dermatitis in mice. Meanwhile,calcipotriol was not suitable for the treatment of Imiquimod -induced psoriasis-like mice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objectives: Entecavir (ETV) has disadvantages, such as poor improvement in liver function, during the treatment of Chronic hepatitis B (CHB). Thus ETV is often used in clinical therapy with glycyrrhizic acid (GA) preparations. However, due to the lack of reliable and direct clinical studies, it remains controversial whether glycyrrhizic acid preparations have the best efficacy in CHB. Therefore, we aimed to compare and rank the different GA preparations in the treatment of CHB using network meta-analysis (NMA)., Methods: We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Science, China national knowledge internet (CNKI), Wanfang, VIP, and SinoMed databases as of August 4, 2022. Literature was screened according to predefined inclusion and exclusion criteria to extract meaningful information. A Bayesian approach was used for random effects model network meta-analysis, and Stata 17 software was used for data analysis., Results: From 1074 papers, we included 53 relevant randomized clinical trials (RCTs). For the primary outcome, we used the overall effective rate in assessing the effectiveness of treatment for CHB (31 RCTs including 3007 patients): CGI, CGT, DGC and MgIGI significantly reduced the incidence of overall response compared to controls (RRs range from 1.16 to 1.24); SUCRA results showed that MgIGI was the best (SUCRA 0.923). In terms of secondary outcomes, we assessed the effect of treatment for CHB according to the level of reduction in ALT and AST: for ALT (37 RCTs including 3752 patients), CGI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to controls (MD range from 14.65 to 20.41); SUCRA results showed that CGI was the best (SUCRA 0.87); for AST, GI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to the control group (MD range from 17.46 to 24.42); SUCRA results showed that MgIGI was the best (SUCRA 0.871)., Conclusion: In this study, we verified that the combination of GA and Entecavir is more effective than entecavir monotherapy in the treatment of hepatitis B. MgIGI and CGI showed clinically significant effects on liver function recovery compared with other GA preparations. MgIGI appeared to be the best choice among all GA preparations for the treatment of CHB. Our study provides some references for the treatment of CHB., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests related to this publication., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Particulate matter (PM) is a major environmental pollutant that contributes considerably to deaths worldwide. The pathogenesis of PM-induced lung injury (PILI) is far from elucidated and warrants effective intervention. An effective component of licorice, glycyrrhizin (GL), has been the subject of much research due to its anti-inflammatory and anti-oxidative capabilities. Although preventive properties of GL are well-known, the precise mechanism of GL in PILI has not yet been investigated. A mouse model of PILI was used to examine the protective effects of GL in vivo, and a human bronchial epithelial cells (HBECs) model was used in vitro. In order to determine whether GL mitigates PILI, its effects on endoplasmic reticulum (ER) stress, NLRP3 inflammasome-mediated pyroptosis and the oxidative response were examined. According to the findings, GL reduced PILI and activate anti-oxidative Nrf2/HO-1/NQO1 signaling in mice. Notably, the effect of GL on PM-induced ER stress and NLRP3 inflammasome-mediated pyroptosis was significantly attenuated by the Nrf2 inhibitor ML385. The data suggest that via the anti-oxidative Nrf2 signaling, GL may reduce oxidative stress-mediated ER stress and NLRP3 inflammasome-mediated pyroptosis. Therefore, GL may serve as a promising treatment for PILI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: This study aimed to evaluate the effects of glycyrrhizin, as a potential therapeutic agent in endodontic surgery, on the proliferation and viability of diabetic human bone marrow-derived mesenchymal stem cells (hBM-MSCs)., Materials and Methods: Diabetic human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were isolated and characterized by flow cytometry. The cells were treated with different concentrations of Glycyrrhizin (Gly) (12.5, 25, 50, and 100 µg/mL) and 0.1% dimethyl sulfoxide (DMSO) as the control group. MTT assay was performed to evaluate the cell proliferation and viability after 24, 48, and 72 hours of the cell treatment with Gly. The optical density (OD) was measured at 570 nm. Each assay was repeated three times. The corrected OD and cell viability were determined. ANOVA followed by the Bonferroni post hoc test evaluated the statistical significance at p < 0.05., Results: Flow cytometric analysis of the isolated cells showed positive expression of mesenchymal markers (CD105 and CD90) and negative expression of hematopoietic markers (CD34 and CD14). After 24 and 48 hours of cell treatment, Gly in 100 µg/mL concentration significantly decreased the diabetic hBM-MSC proliferation as compared with the control ( p < 0.05). Gly in 12.5-50 µg/mL concentrations significantly increased the cell proliferation after 72 hours of treatment as compared with the control ( p < 0.05). The diabetic hBM-MSC proliferation and viability at 12.5-50 µg/mL concentrations were significantly greater than that at 100 µg/mL concentration ( p < 0.05)., Conclusion: Under the present study conditions, Gly (in 12.5-50 µg/mL concentrations) did not show cytotoxicity to diabetic hBM-MSCs and enhanced their proliferation. Gly may represent a potential therapeutic agent in endodontic surgery in diabetic patients., Clinical Significance: Preclinical assessment of Gly effects on diabetic hBM-MSCs is important for determining its effective concentration range, anticipating its therapeutic potential, and designing future in vivo studies.

Hyperthermia using magnetic nanoparticles enables tumor-specific heating and can destroy tumor tissues. This approach works as in situ vaccination with tumor antigens released from dying tumor cells. However, in situ vaccination caused by magnetic hyperthermia is often insufficient to induce complete regression of poorly immunogenic tumors surrounded by an immunosuppressive microenvironment. In this study, we explored a novel strategy for immunotherapy using magnetic hyperthermia to regress poorly immunogenic melanoma. Magnetic hyperthermia induced tumor cell death in a B16-F10 melanoma mouse model. After hyperthermia treatment, we found elevated levels of HMGB1, which is known to be released from dying cells to promote inflammation, and the proinflammatory cytokine TNF-α was increased in serum of the mice. Systemic administration of glycyrrhizin, an HMGB1 inhibitor, reduced the levels of TNF-α in serum and successfully delayed the regrowth of tumors after magnetic hyperthermia. To achieve complete tumor regression, TLR9 activation by intratumor injection of CpG was combined with systemic administration of anti-PD-1 antibody and anti-CTLA-4 antibody. The combination therapy of magnetic hyperthermia at 46°C with the immunomodulators (glycyrrhizin+CpG+anti-PD-1+anti-CTLA-4) achieved complete tumor regression in 80% of growing 5-mm B16-F10 tumors. These findings have important implications for the development of novel cancer immunotherapy using magnetic hyperthermia for poorly immunogenic tumors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.

Objectives: This study aims to introduce compound glycyrrhizin injection for the treatment of rosacea by mesoderm therapy, and further analyze the therapeutic and aesthetic effects of this treatment method and its impact on the dermatological quality of life index, which provides new ideas and methods for cosmetic dermatology treatment of rosacea., Methods: The recruited rosacea patients were divided into Control group (n = 58) and observation group (n = 58) according to the random number table. The control group was treated with topical metronidazole clindamycin liniment, and the study group was additionally used mesoderm introduction of compound glycyrrhizin injection. The transepidermal water loss (TEWL), water content in corneum, and dermatology life quality index (DLQI) in rosacea patients were evaluated., Results: Our results showed that the scores of erythema, flushing, telangiectasia, and papulopustule were significantly reduced in the observation group. In addition, the observation group significantly decreased TEWL and increased the water content of the stratum corneum. Furthermore, the observation group significantly reduced the DLQI of rosacea patients compared to the control group., Conclusion: The use of mesoderm therapy combined with compound glycyrrhizic acid has a therapeutic effect on facial rosacea and improves patient satisfaction., (© 2023 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Bioactive hydrogels self-assembled from naturally occurring herbal small molecules are attracting growing interest for applications in wound healing, due to their versatile intrinsic biological activities, excellent biocompatibility, as well as facile, sustainable, and eco-friendly processes. However, the development of supramolecular herb hydrogels with sufficient strength and multifunctionality as an ideal wound dressing in clinical practice remains a challenge. In this work, inspired by the efficient clinic therapy and directed self-assembly of natural saponin glycyrrhizic acid (GA), we create a novel GA-based hybrid hydrogel to promote full-thickness wound healing and bacterial-infected wound healing. This hydrogel possesses excellent stability and mechanical performance and multifunctional properties, including injectable, shape-adaptation and remodeling, self-healing, and adhesive abilities. This is attributed to the hierarchical dual-network that comprises the self-assembled hydrogen-bond fibrillar network of aldehyde-contained GA (AGA) and the dynamic covalent network through Schiff base reaction between AGA and a biopolymer carboxymethyl chitosan (CMC). Notably, benefiting from the inherent strong biological activity of GA, the AGA-CMC hybrid hydrogel exhibits unique and significant anti-inflammation effects and antibacterial ability, especially toward the Gram-positive Staphylococcus aureus ( S. aureus ). In vivo experiments demonstrate that the AGA-CMC hydrogel promotes uninfected skin wound healing and S. aureus -infected skin wound healing by enhancing the formation of granulation tissue, facilitating collagen deposition, reducing bacterial infection, and downregulating inflammatory response. This study highlights the design of new and multifunctional bioactive herb hydrogels from natural drug-food homologous small molecules, which can serve as a promising wound-healing dressing for biomedical applications.

Background: Helicobacter pylori is a key agent for causing gastric complications linked with gastric disorders. In response to infection, host cells stimulate autophagy to maintain cellular homeostasis. However, H. pylori have evolved the ability to usurp the host's autophagic machinery. High mobility group box1 (HMGB1), an alarmin molecule is a regulator of autophagy and its expression is augmented during infection and gastric cancer. Therefore, this study aims to explore the role of glycyrrhizin (a known inhibitor of HMGB1) in autophagy during H. pylori infection., Main Methods: Human gastric cancer (AGS) cells were infected with the H. pylori SS1 strain and further treatment was done with glycyrrhizin. Western blot was used to examine the expression of autophagy proteins. Autophagy and lysosomal activity were monitored by fluorescence assays. A knockdown of HMGB1 was performed to verify the effect of glycyrrhizin. H. pylori infection in in vivo mice model was established and the effect of glycyrrhizin treatment was studied., Results: The autophagy-lysosomal pathway was impaired due to an increase in lysosomal membrane permeabilization during H. pylori infection in AGS cells. Subsequently, glycyrrhizin treatment restored the lysosomal membrane integrity. The recovered lysosomal function enhanced autolysosome formation and concomitantly attenuated the intracellular H. pylori growth by eliminating the pathogenic niche. Additionally, glycyrrhizin treatment inhibited inflammation and improved gastric tissue damage in mice., Conclusion: This study showed that inhibiting HMGB1 restored lysosomal activity to ameliorate H. pylori infection. It also demonstrated the potential of glycyrrhizin as an antibacterial agent to address the problem of antimicrobial resistance., (© 2023. The Author(s).)

Influenza A virus (IVA) has been continuously causing pandemics in several animal hosts and has become a worldwide public health threat. Currently, antiviral drugs have become associated with a lot of side effects and limited activity against emerging drug-resistant influenza viruses. Therefore, the development of novel antiviral drugs is of great importance. In this study, we synthesized a kind of carbon dots (CDs) with high dispersibility from glycyrrhizic acid (GA) using a simple dry heating method. Compared with glycyrrhizic acid alone, GA-CDs exhibit superior solubility and significantly improve the antiviral property against IVA. Investigation of the mechanism revealed that GA-CDs act against IVA mainly by inhibiting viral internalization, replication of the viral genome, neuraminidase activity, and host inflammatory responses. More importantly, in a mouse model, GA-CDs can significantly alleviate the clinical symptoms and decrease mortality and lung viral titers. In vitro and in vivo experiments demonstrate that GA-CDs possess extraordinary therapeutic effects; therefore, we propose that GA-CDs may be a promising alternative therapy for IVA infection.

Wound healing is characterized by a systemic and complex process of cellular and molecular activities. Dipotassium Glycyrrhizinate (DPG), a side product derived from glycyrrhizic acid, has several biological effects, such as being antiallergic, antioxidant, antibacterial, antiviral, gastroprotective, antitumoral, and anti-inflammatory. This study aimed to evaluate the anti-inflammatory effect of topical DPG on the healing of cutaneous wounds by secondary intention in an in vivo experimental model. Twenty-four male Wistar rats were used in the experiment, and were randomly divided into six groups of four. Circular excisions were performed and topically treated for 14 days after wound induction. Macroscopic and histopathological analyses were performed. Gene expression was evaluated by real-time qPCR. Our results showed that treatment with DPG caused a decrease in the inflammatory exudate as well as an absence of active hyperemia. Increases in granulation tissue, tissue reepithelization, and total collagen were also observed. Furthermore, DPG treatment reduced the expression of pro-inflammatory cytokines ( Tnf-α , Cox-2 , Il-8 , Irak-2 , Nf-kB , and Il-1 ) while increasing the expression of Il-10 , demonstrating anti-inflammatory effects across all three treatment periods. Based on our results, we conclude that DPG attenuates the inflammatory process by promoting skin wound healing through the modulation of distinct mechanisms and signaling pathways, including anti-inflammatory ones. This involves modulation of the expression of pro- and anti-inflammatory cytokine expression; promotion of new granulation tissue; angiogenesis; and tissue re-epithelialization, all of which contribute to tissue remodeling.

Temporal lobe epilepsy (TLE) leads to extensive degradation of the quality of life of patients. Glycyrrhizic acid (GA) has been reported to exert neuroprotective effects on status epilepticus. Herein, the current study set out to explore the functional mechanism of GA in TLE young rats. Firstly, TLE young rat models were established using the lithium chloride and pilocarpine regimen and then subjected to treatment with different doses of GA, miR-194-5p-antagomir, or/and sh-prostaglandin-endoperoxide synthase 2 (PTGS2) to observe changes in iron content, glutathione and malondialdehyde levels, and GPX4 (glutathione peroxidase 4) and PTGS2 protein levels in the hippocampus. Neuronal injury and apoptosis were assessed through HE, Nissl, and TUNEL staining. Additionally, the expression patterns of miR-194-5p were detected. The binding site of miR-194-5p and PTGS2 was verified with a dual-luciferase assay. Briefly, different doses of GA (20, 40, and 60 mg/kg) reduced the epileptic score, frequency, and duration in TLE young rats, along with reductions in iron content, lipid peroxidation, neuronal injury, and apoptosis in the hippocampus. Silencing of miR-194-5p partly annulled the action of GA on inhibiting ferroptosis and attenuating neuronal injury in TLE young rats. Additionally, PTGS2 was validated as a target of miR-194-5p. GA inhibited ferroptosis and ameliorated neuronal injury in TLE young rats via the miR-194-5p/PTGS2 axis. Overall, our findings indicated that GA exerts protective effects on TLE young rats against neuronal injury by inhibiting ferroptosis through the miR-194-5p/PTGS2 axis., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

In recent decades, studies have reported that inflammation serves key roles in epilepsy and that high mobility group box protein‑1 (HMGB1) may be involved in status epilepticus. However, it has not been reported whether HMGB1 participates in the pathogenesis of status epilepticus through the regulation of the p38 mitogen‑activated protein kinase (p38MAPK) signalling pathway. In the present study, Sprague‑Dawley rats were randomly divided into four groups as follows: Control, status epilepticus (SE), dimethyl sulfoxide treatment (DMSO + SE), and glycyrrhizin treatment (GL + SE) groups. Behavioural changes were then evaluated using the Racine score. In the hippocampus, the protein expression levels of HMGB1 were assessed using western blotting, the neuronal damage was evaluated using haematoxylin and eosin staining and transmission electron microscopy, and the activation of microglia was assessed using immunochemistry and immunofluorescence. The results demonstrated that, in the hippocampal region, HMGB1 existed in neurons and astrocytes and the protein expression levels of HMGB1, p38MAPK and phosphorylated‑p38MAPK were significantly inhibited after treatment with GL. Furthermore, GL could alleviate neuronal injury in the CA1 region of the hippocampus and prevented HMGB1 translocation from the nucleus into the cytoplasm in these areas. These findings expand the understanding of how HMGB1 may participate in SE and lay a foundation for evaluation of HMGB1 as a drug target.

Background: Emerging virus infections provoke health problems in people and animals, which generate social and economic issues worldwide. This has spurred the search for new pharmacological strategies to confront them., Summary: The purpose of this review is to draw the reader's attention to pharmacological evaluations of glycyrrhizic acid (GA) and its analogs on the broad range of viruses known in human and veterinary medicine. GA is the main water-soluble constituent extracted from the roots of plants from the genus Glycyrrhiza, commonly known as licorice root. It has long been used due to its broad spectrum of bioactivities, including anti-inflammatory, antiulcer, and antitumor properties. It has also been proposed as an antiviral agent. Medicines derived from GA are currently being used to combat acute and chronic hepatitis and herpes viruses., Key Messages: This review suggests that GA could be a new broad-spectrum antiviral due to its ability to inhibit DNA or RNA viruses both in vitro and in vivo. GA could be a potential drug for preventing and/or treating various viral diseases., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

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Breakthrough infections have been reported in fully vaccinated persons. Furthermore, rebound symptoms have been reported following the new FDA granted emergency use to combat SARS-CoV-2. Glycyrrhizin (GR) and boswellic acids (BAs) combination has been shown to have highly successful actions against COVID-19 in our recent clinical trial. However, the study is limited by the small sample size, and therefore, the aim of this article is to comprehensively evaluate recent evidence on the efficacy of GR and BAs in preventing the development of COVID-19 in patients with mild and moderate infections and in preventing post-COVID-19 cognitive impairment, which is the most important symptom after recovery from Covid-19 disease. We have reviewed and discussed information published since the outbreak of the COVID-19 pandemic until July 2022 on preclinical (in vivo, in vivo and bioinformatics) and clinical studies related to the antiviral, anti-inflammatory and immunomodulatory activity of Gr and BAs. Sixteen studies were performed to determine the efficacy of GR against SARS-CoV-2. Ten studies were used primarily for in vitro and in vivo assays and six used molecular docking studies. However, the antiviral activity of BAs against SARS-CoV-2 was determined in only five studies using molecular modeling and bioinformatics. All these studies confirmed that GR n and BAs have strong antiviral activity and can be used as a therapeutic agent for COVID-19 and as a protective agent against SARS-CoV-2. They may act by inhibiting the main protease SARS-CoV-2 (Mpro) responsible for replication and blocking spike protein-mediated cell entry. Only seven rigorously designed clinical trials regarding the usefulness of GR, BAs or their combinations in the treatment of COVID-19 have been published as of July 2022. Although there is no clinical study regarding the treatment of cognitive impairment after COVID-19 that has been published so far, several preclinical and clinical studies have demonstrated the potential effect of GR and BAs in the prevention and treatment of cognitive impairment by inhibiting the activity of several molecules that activate inflammatory signaling pathway. In conclusion, the findings of our study documented the beneficial use of GR and BAs to treat SARS-CoV-2 and its variants and prevent post-COVID cognitive impairment. However, it warrants further studies with a larger randomized sample size to ensure that the studies have sufficient evidence of benefits against COVID-19 and post-COVID-19 symptoms., (© 2022. The Author(s).)

Glycyrrhizin, a bioactive constituent of Glycyrrhiza glabra has been reported to ameliorate diabetes. Here, the effects of liposome-encapsulated glycyrrhizin on STZ-induced diabetes and associated oxidative stress were investigated. Wistar rats were grouped as control (NC, received placebo), diabetic (DC, STZ-induced), diabetic treated with free glycyrrhizin (DTG, 3 i.v. doses, 1.6 mg/0.5 ml), empty liposomes (DTl, 3 i.v. doses), and liposome-encapsulated glycyrrhizin (DTbd, 3 i.v. doses, 1.6 mg/0.5 ml). Serum glucose, insulin, intraperitoneal glucose tolerance test and glycohemoglobin were estimated. Free iron and iron-mediated oxidative stress were examined. Histological examinations of the kidney and liver were performed. Liposomal-glycyrrhizin treatment caused significant improvement of hyperglycemia (DC vs. DTbd p  < .05), glucose intolerance (DC vs. DTG p  < .01 and DC vs. DTbd p  < .05), insulin (DC vs. DTG p  < .1, DTbd vs. DC p  < .05 and DTbd vs. DTG p  < .1) and glycohemoglobin (DC vs. DTG p  < .1 and DC vs. DTbd p  < .05) levels in the DTbd group. Alleviation of free iron release (DC vs. DTbd p  < .05), lipid peroxidation (DC + H 2 O 2 vs. DTbd + H 2 O 2 p  < .05), deoxyribose (DC + H 2 O 2 vs. DTbd + H 2 O 2 , p  < .05), and DNA degradation occurred in the DTbd group. The abnormalities of the kidney and liver were abolished in the DTbd group. The inhibitory effects were more pronounced compared to free glycyrrhizin. Liposome-encapsulated glycyrrhizin treatment caused inhibition of diabetic complications through its antioxidant effects and can be exploited for effective treatment of diabetes.

Background: Glycyrrhizin, an active component of liquorice root extract, exhibits antiviral and immunomodulatory properties by direct inhibition of the pro-inflammatory alarmin HMGB1 (High-mobility group box 1)., Objective: The aim of this study was to explore the role of liquorice intake on the viral entry receptor ACE2 (angiotensin-converting enzyme 2) and the immunoregulatory HMGB1 in healthy individuals and to explore HMGB1 expression in coronavirus disease 2019 (COVID-19) or non-COVID-19 in ARDS (acute respiratory distress syndrome patients)., Material and Methods: This study enrolled 43 individuals, including hospitalised patients with i) acute respiratory distress syndrome (ARDS) due to COVID-19 (n = 7) or other underlying causes (n = 12), ii) mild COVID-19 (n = 4) and iii) healthy volunteers (n = 20). Healthy individuals took 50 g of liquorice (containing 3% liquorice root extract) daily for 7 days, while blood samples were collected at baseline and on day 3 and 7. Changes in ACE2 and HMGB1 levels were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. Additionally, HMGB1 levels were measured in hospitalised COVID-19 patients with mild disease or COVID-19 associated acute respiratory distress syndrome (ARDS) and compared with a non-COVID-19-ARDS group., Results: Liquorice intake significantly reduced after 7 days both cellular membranous ACE2 expression (-51% compared to baseline levels, p = 0.008) and plasma HMGB1 levels (-17% compared to baseline levels, p<0.001) in healthy individuals. Half of the individuals had a reduction in ACE2 levels of at least 30%. HMGB1 levels in patients with mild COVID-19 and ARDS patients with and without COVID-19 were significantly higher compared with those of healthy individuals (+317%, p = 0.002), but they were not different between COVID-19 and non-COVID-19 ARDS., Conclusions: Liquorice intake modulates ACE2 and HMGB1 levels in healthy individuals. HMGB1 is enhanced in mild COVID-19 and in ARDS with and without COVID-19, warranting evaluation of HMGB1 as a potential treatment target and glycyrrhizin, which is an active component of liquorice root extract, as a potential treatment in COVID-19 and non-COVID-19 respiratory disease., Competing Interests: RB reports grants and consulting fees from AstraZenica, grants and consulting fees from Boehringer Ingelheim, personal fees from GlaxoSmithKline, consulting fees from Grifols, grants and consulting fees from Novartis, personal fees from CSL Behring, grants from German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), grants from Sander Stiftung, grants from Schwiete Stiftung, grants from Krebshilfe, grants from Mukoviszidose eV. FM is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche (SFB TRR219), and Deutsche Herzstiftung. He has received scientific support from Medronic and ReCor Medical and speaker honoraria from Astra-Zeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, and ReCor Medical. MB is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939) and reports personal fees from Abbott, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier and Vifor during the conduct of the study. The grants and fundings indicated are however not related to this publication. Therefore, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Cognitive dysfunction, sickness-like behavior, for instance, anxiety, and depression are common aspects of neuropsychiatry often associated with neurodegenerative disorders. Growing evidence suggests that high mobility group box 1 (HMGB1) may act as a proinflammatory cytokine that aggravates neurobehavioral dysfunction. However, the detailed underlying mechanism is still elusive. Here we focus on determining the relationship between lipopolysaccharide (LPS)-induced neuroinflammation (in both in vitro and in vivo models), cognitive dysfunction, sickness-like behavior and thus decode the impact of HMGB1 inhibition (using Glycyrrhizin; Gcy as an antagonist). Using a mice model of repeated LPS (1 mg/kg, i.p. for 4 days) injections, we found that LPS induced neurobehavioral deficit and a strong proinflammatory response with increased proinflammatory markers, including tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and iNOS (inducible nitric oxide synthase) at 7 days after the final dose of LPS compared to control animals. Our findings suggest that neurobehavioral dysfunction strongly correlates with the proinflammatory immune response following LPS stimulation. In vitro Gcy pretreatment to LPS-activated BV2 microglia cells significantly reduced nitrite and reactive oxygen species production, along with diminished expression of classical proinflammatory cytokines (TNF-α, IL-1β, IL-6, iNOS). These key proinflammatory changes with LPS and Gcy treatment are also found in vivo mice model and correlate with improved cognitive function and reduced anxiety/depression. Together, these results show that blocking HMGB1 using Gcy abrogated the cognitive dysfunction, sickness-like behavior of anxiety and depression induced by LPS which can be a promising avenue for crucial neurobehavioral dysfunction., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Matrine and glycyrrhizin are representative active ingredients of traditional Chinese medicine (TCM) used in clinical practice. Studies have demonstrated that matrine has antitumor pharmacological effects and that glycyrrhizin protects liver function. However, the potential bioactive compounds and mechanisms remain unknown, as well as whether they have synergistic effects in killing cancer cells and protecting liver cells. To investigate the synergistic effects and mechanism of matrine combined with glycyrrhizin in hepatocellular carcinoma (HCC) treatment, we used both network pharmacology and bioinformatics analyses. First, the chemical gene interaction information of matrine and glycyrrhizin was obtained from the PubChem database. The pathogenic genes of HCC were accessed from five public databases. The RNA sequencing data and clinical information of HCC patients were downloaded from The Cancer Genome Atlas (TCGA). Next, the overlapping genes among the potential targets of matrine and glycyrrhizin and HCC-related targets were determined using bioinformatics analysis. We constructed the drug-target interaction network. Prognosis-associated genes were acquired through the univariate Cox regression model and Lasso-Cox regression model. The results were verified by the International Cancer Genome Consortium (ICGC) database. Finally, we predicted the immune function of the samples. The drug-target interaction network consisted of 10 matrine and glycyrrhizin targets. We selected a Lasso-Cox regression model consisting of 3 differentially expressed genes (DEGs) to predict the efficacy of the combination in HCC. Subsequently, we successfully predicted the overall survival of HCC patients using the constructed prognostic model and investigated the correlation of the immune response. Matrine and glycyrrhizin have synergistic effects on HCC. The model we obtained consisted of three drug-target genes by Lasso-Cox regression analysis. The model independently predicted the combined effect of matrine and glycyrrhizin in HCC treatment and OS, which will be helpful for guiding clinical treatment. The prognostic model was correlated with the immune cells and immune checkpoints of patients, which had an adjuvant effect on HCC immunotherapy. Matrine and glycyrrhizin can have therapeutic effects on HCC by promoting the production or enhancing the core gene activity in the drug network and improving the immune system function of patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Tao Han et al.)

The senescence and dysfunction of vascular endothelial cells are important features of diabetic vascular disease. High mobility group box-1(HMGB1) may be involved in vascular injury in response to high glucose. Glycyrrhizin (GL) is an HMGB1 inhibitor that significantly reduces HMGB1. However, the relationship between HMGB1 and vascular ageing in diabetes is not clear, the protective mechanism of GL against vascular injury in type 2 diabetes mellitus (T2DM) is unclear too. This study aims to examine the role of HMGB1 in vascular endothelial cell senescence and the protective effects of GL on vascular aging in high fat diet/streptozotocin (HFD/STZ) induce type 2 diabetic rats.After induction of diabetes, GL (150 mg/kg/d) was treated by gavage for 4 weeks. Results showed that compared with the Control group, the serum level of HMGB1 was increased in rats with type 2 diabetes, while the expression of HMGB1 mRNA and protein in the thoracic aorta was upregulated, with a decrease in endothelium-dependent vasodilation function and an increase in aging degree in the thoracic aorta. However, the above indicators were significantly improved after GL treatment. In HUVECs, we found that treated with HMGB1 (50, 100 and 200 ng/ml) for 48 h induced cells senescence and GL (50, 100 mg/L) significantly inhibited high-glucose-induced endothelial cell senescence, meanwhile GL (50, 100 mg/L) significantly inhibited the high-glucose-induced HMGB1 release and upregulated p53 expression. In conclusion, GL as an HMGB1 inhibitor, attenuates endothelium-dependent relaxation impairment and vascular ageing in an animal model of diabetes and high-glucose-induced endothelial cell senescence., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

In bovine mastitis, antimicrobial treatment is often initiated before the causative organism is identified a problem in the prudent use of antimicrobials. In this study, we aimed to reduce the total amount of antimicrobials used in mastitis treatment by administering glycyrrhizin, an anti-inflammatory drug, instead of antimicrobials at the onset of clinical mastitis without systemic symptoms, followed by symptom-based antimicrobial selection therapy (ST), to examine the effect of this treatment strategy on treatment outcomes and antimicrobial use. Comparisons between cases that received antimicrobial treatment starting from the day of diagnosis (blanket antibiotic therapy [BT] group: 33 cases) and cases that received ST starting from the day after the diagnosis (ST group: 57 cases) revealed no difference in the cure rate, milk withholding period, or recurrence rate. However, the ST group had a significantly lower amount of antimicrobials than the BT group. Additionally, a single administration of glycyrrhizin before ST significantly relieved the udder symptoms and reduced the antimicrobial amount when compared with cases without glycyrrhizin administration. Thus, a single administration of glycyrrhizin followed by ST can reduce the total antimicrobial use.

Portal hypertension (PHT) is a complication of liver diseases. Increased intrahepatic vascular resistance is attributed to reduced bioavailability of vasodilator substances. The macrophage activation and superoxide dismutase 3 (SOD3) involve in the pathogenesis of PHT. Diammonium glycyrrhizinate (DG) is the salt form of glycyrrhizin derived from Radix glycyrrhizae, exerting anti-oxidant activities and be beneficial for liver injury. Here, we aimed to investigate effects of DG on PHT and explore its underlying mechanisms on regulation of macrophages and SOD3. The carbon tetrachloride induced PHT rats received administration of liposome-encapsulated clodronate for hepatic macrophage depletion, or PBS liposomes for matched control. DG (25 mg/kg) or vehicle was gavaged. Portal pressure in vivo, and serum biomarkers of macrophage activation were measured. The nitric oxide (NO) and prostacyclin (PGI 2 ) bioavailability was evaluated in the isolated portal perfused rat livers. Liver tissues were collected to evaluate cirrhosis, macrophage oxidation, and SOD3 activity. Depletion of hepatic macrophages decreased portal pressure, increased bioavailability of NO and PGI 2 , and restored SOD3 activity. DG effectively decreased portal pressure, relieved cirrhosis, inhibited macrophage activation. DG increased bioavailability of NO and PGI 2 to relax portal veins. DG relieved portal macrophage oxidation through decreasing nicotinamide adenine dinucleotide phosphate oxidase 2 and inducible NO synthase expressions, elevated SOD3 activities and increased SOD3 expressions at portal triads. These findings indicated that DG restored SOD3 activity, against portal macrophage oxidation, protected bioavailability of NO and PGI 2 , thereby reduced portal pressure. It suggested a potential use of DG for PHT treatment., (Copyright © 2022. Published by Elsevier B.V.)

Liver injury refers to a pathological condition that causes dysfunction to hepatic parenchymal cells. And diammonium glycyrrhizinate (DG) is clinically prescribed for hepatoprotection. To date, detailed information regarding DG against liver injury in molecular mechanisms remains unrevealed totally. In the present study, we applied network pharmacology and molecular docking to decipher substantial genes, biological functions of DG for treating liver injury. Furthermore, preclinical experiments using perfluorooctanoic acid (PFOA)-induced liver injury in mice were used to validate the bioinformatic findings. Our results showed that the target network of DG and liver injury predominantly shared 90 genes. Eleven core genes of DG treating liver injury including ALB, TP53, TNF, CASP3, PTGS2, JUN, TLR4, IL10, STAT3, NOS3, FOS. The gene ontology and KEGG enrichment further highlighted their importance in regulation of cell proliferation, regulation of transcription, inflammatory response, regulation of NF-kappaB import into nucleus, regulation of apoptotic process, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. Moreover, DG treatment was found to rescue the PFOA-induced liver injury through the modulation of identified genes including TNF, CASP3, PTGS2, and ALB. Current integrated data from bioinformatics method and experimental validation uncovered that DG exerts potent actions to treat liver injury through regulating core targets associated with inflammation and immunomodulation., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)