Colon-targeted piperine-glycyrrhizic acid nanocrystals for ulcerative colitis synergetic therapy via macrophage polarization.

Ulcerative colitis (UC) is a chronic inflammatory disease that affects the gastrointestinal tract and is characterized by immune dysregulation. Oral administration of nanoformulations containing immunomodulators is a desirable approach to treating UC. However, low drug-loading (<10%, typically), premature drug release, and systemic absorption of these nanoformulations continue to be significant challenges restricting clinical applications. Herein, we developed colon-targeted piperine-glycyrrhizic acid nanocrystals (ES100-PIP/GA NCs) to treat UC through the regulation of macrophages. The ES100-PIP/GA NCs exhibited ultra-high drug loading and colon-specific drug release. In vitro studies demonstrated that the ES100-PIP/GA NCs could effectively be internalized by lipopolysaccharide (LPS)-induced RAW 264.7 and Caco-2 cells. More importantly, the ES100-PIP/GA NCs could downregulate pro-inflammatory factors (IL-1ß, IL-17A), upregulate anti-inflammatory factors (TGF-ß1), and repair the intestinal mucosal barrier. In a murine model of acute colitis induced by dextran sodium sulfate (DSS), ES100-PIP/GA NCs could protect PIP and GA from gastric acid destruction, reach the colon, and significantly inhibit colitis. Surprisingly, ES100-PIP/GA NCs enhance M2 macrophages by increasing the mammalian target of rapamycin (mTOR), and inhibit M1 macrophages by reducing hypoxia-inducible factor-1α (HIF-1α). Overall, this study shows that ES100-PIP/GA NCs have synergistic immunotherapy capabilities with macrophage regulation, which offers a promising blueprint for the oral delivery of multicomponent drugs in UC therapy.

Efficacy and safety of compound glycyrrhizin in the patients with vitiligo: a systematic review and meta-analysis.

OBJECTIVE: Compound glycyrrhizin (CG) is widely used to treat vitiligo in China, and the efficacy and adverse events (AEs) of CG for vitiligo need further analysis. This study aimed to systematically reevaluate the efficacy and safety of CG in the patients with vitiligo. RESEARCH DESIGN AND METHODS: Eight literature databases were searched up to 31 December 2022, and randomized controlled trials which compared CG plus conventional treatments with conventional treatments alone were included. RESULTS: 17 studies with 1492 patients were included. The pooled results showed that the combination of CG and conventional treatments was superior to conventional treatments alone in the total efficacy rate (risk ratio (RR) = 1.54, 95% confidence interval (CI) = 1.40 to 1.69, P < 0.00001), cure rate (RR = 1.62, 95%CI = 1.32 to 1.99, P < 0.00001), the levels of serum IL-6, TNF-α, IL-17, and TGF-ß, and the ratio of CD4+/CD8+ T cell in blood. Moreover, few patients suffered from the mild and tolerable AEs of CG. CONCLUSIONS: CG plus conventional treatments is an effective treatment for vitiligo with mild and tolerable AEs. More high-quality and large-sample studies are required in the future to provide more evidence of CG for vitiligo. PROSPERO REGISTRATION: CRD42023401166.

Glycyrrhizin ameliorates impaired glucose metabolism and ovarian dysfunction in a polycystic ovary syndrome mouse model.

The aim of this study was to determine the impact of glycyrrhizin, an inhibitor of high mobility group box 1, on glucose metabolic disorders and ovarian dysfunction in mice with polycystic ovary syndrome. We generated a polycystic ovary syndrome mouse model by using dehydroepiandrosterone plus high-fat diet. Glycyrrhizin (100 mg/kg) was intraperitoneally injected into the polycystic ovary syndrome mice and the effects on body weight, glucose tolerance, insulin sensitivity, estrous cycle, hormone profiles, ovarian pathology, glucolipid metabolism, and some molecular mechanisms were investigated. Increased number of cystic follicles, hormonal disorders, impaired glucose tolerance, and decreased insulin sensitivity in the polycystic ovary syndrome mice were reverted by glycyrrhizin. The increased high mobility group box 1 levels in the serum and ovarian tissues of the polycystic ovary syndrome mice were also reduced by glycyrrhizin. Furthermore, increased expressions of toll-like receptor 9, myeloid differentiation factor 88, and nuclear factor kappa B as well as reduced expressions of insulin receptor, phosphorylated protein kinase B, and glucose transporter type 4 were restored by glycyrrhizin in the polycystic ovary syndrome mice. Glycyrrhizin could suppress the polycystic ovary syndrome-induced upregulation of high mobility group box 1, several inflammatory marker genes, and the toll-like receptor 9/myeloid differentiation factor 88/nuclear factor kappa B pathways, while inhibiting the insulin receptor/phosphorylated protein kinase B/glucose transporter type 4 pathways. Hence, glycyrrhizin is a promising therapeutic agent against polycystic ovary syndrome.

[Adverse effects of licorice consumed as food: An update]. / Toxicités de l'exposition alimentaire à la réglisse : mise au point.

The word "licorice" refers to the plant, its root, and its aromatic extract. From a commercial point of view, Glycyrrhiza glabra is the most important species with a wide range of uses (herbal medicine, tobacco industry, cosmetics, food and pharmaceutical). Glycyrrhizin is one of the main constituents of licorice. Glycyrrhizin is hydrolyzed in the intestinal lumen by bacterial ß-glucuronidases to 3ß-monoglucuronyl-18ß-glycyrrhetinic acid (3MGA) and 18ß-glycyrrhetinic acid (GA), which are metabolized in the liver. Plasma clearance is slow due to enterohepatic cycling. 3MGA and GA can bind to mineralocorticoid receptors with very low affinity, and 3MGA induces apparent mineralocorticoid excess syndrome through dose-dependent inhibition of 11ß-hydroxysteroid dehydrogenase type 2 in renal tissue. The cases of apparent mineralocorticoid excess syndrome reported in the literature are numerous and sometimes severe, even fatal, most often in cases of chronic high dose consumption. Glycyrrhizin poisonings are characterized by hypertension, fluid retention, and hypokalemia with metabolic alkalosis and increased kaliuresis. Toxicity depends on the dose, the type of product consumed, the mode of consumption (acute or chronic) and a very large inter-individual variability. The diagnosis of glycyrrhizin-induced apparent mineralocorticoid excess syndrome is based on the history, clinical examination, and biochemical analysis. Management is primarily based on symptomatic care and stopping licorice consumption.

Efficacy and Safety of Glycyrrhizic Acid in Treatment of Autoimmune Hepatitis.

To compare the long-term efficacy and safety of glycyrrhizic acid preparation and hormone treatment in patients with autoimmune hepatitis, we enrolled 377 patients in a study that lasted from January 2009 to January 2020. After performing propensity score matching, we included 58 patients in the hormone group and 58 in the glycyrrhizic acid preparation group in statistical analysis. We then compared the ratio of sustained biochemical responses at 48 weeks after treatment. Adverse events, including some incidence of decompensated liver cirrhosis and liver cancer, were evaluated. The results showed that a total of 61.8% of treated patients achieved complete biochemical remission. The cumulative biochemical remission rate in the hormone group and glycyrrhizic acid preparation group showed no significant difference (62.3% vs. 60.7%, [Formula: see text], [Formula: see text]). At the end of follow-up, the total bile acid in the hormone group was significantly higher than that in the glycyrrhizic acid preparation group (8.9[Formula: see text][Formula: see text]mol/L vs. 5.6[Formula: see text][Formula: see text]mol/L, [Formula: see text], [Formula: see text]). The incidence of adverse reactions in the hormone group was significantly higher than that in the glycyrrhizic acid preparation group (31.03% vs. 15.52%, [Formula: see text], [Formula: see text]). In conclusion, compared with the hormone treatment, glycyrrhizic acid preparation might be a safe and effective treatment for autoimmune hepatitis.

Efficacy of diammonium glycyrrhizinate in the treatment of rosacea with papules and pustules: A randomized, double-blind, placebo-controlled study.

Rosacea is a kind of chronic inflammatory skin disease that usually occurs in the middle of the face. Diammonium glycyrrhizinate (DG), an effective monomer component extracted from licorice, has extensive anti-inflammatory, antioxidant, anti-allergic, and immunomodulatory effects. There is no research on its therapeutic effect on rosacea. In this study, we divided rosacea patients mainly characterized by papules and pustules randomly into three groups. Group A received clarithromycin 500 mg once a day, isotretinoin 10 mg once a day; Group B received DG 150 mg three times a day, other medicines were the same as Group A; Group C received clarithromycin 250 mg once a day, isotretinoin 10 mg once every 2 days, and DG 150 mg three times a day. All patients' symptom scores and laboratory tests were evaluated when followed up. We found that DG combined with clarithromycin and isotretinoin in the treatment of rosacea was more effective and quicker than clarithromycin and isotretinoin alone. Moreover, half common dosage of clarithromycin and isotretinoin combined with DG could achieve the same therapeutic effect as the conventional dose, and brought about lower incidences of adverse events (AEs). Therefore, it is recommended to use half common dosage of routine medication combined with DG for rosacea patients mainly characterized by papules and pustules.

Glycyrrhizic acid suppresses atopic dermatitis-like symptoms by regulating the immune balance.

BACKGROUND: Glycyrrhiza is one of the most widely used traditional Chinese medicines in China. Its main bioactive ingredient glycyrrhizic acid (GA) has the potential to be used as a treatment for atopic dermatitis (AD) because it has similar actions to steroids, but with relatively few side effects. AIMS: The objective of this study was to explore the potential mechanisms of GA on AD mice model. METHODS: Calcipotriol, a vitamin D3 analogue (MC903) was applied topically to establish AD mouse model. Mice were intraperitoneally administrated with 2 mg/kg dexamethasone (DEX), 25 or 50 mg/kg GA for 15 days. After mice were executed, skin tissues were collected and detected the expression levels of IL-4, IFN-γ, TNF-α and thymic stromal lymphopoietin (TSLP). The percentages of Th1, Th2, Th17, langerhans cells (LCs) in draining lymph nodes (dLNs) were measured by flow cytometry. RESULTS: Our data demonstrated that GA improved the symptoms of AD by exerting anti-inflammatory and anti-allergic functions in vivo. We found that GA treatment decreased the level of total IgE in serum, suppressed ear swelling, reduced the infiltration of mast cells in skin lesions and decreased expressions of IL-4, IFN-γ, TNF-α and TSLP in skin lesions. Furthermore, our experimental results demonstrated that GA suppressed the Th1/Th2/Th17-immune responses in the dLNs, inhibited the migration of LCs in dLNs. CONCLUSIONS: In conclusion, our findings suggested potential therapeutic effects of GA against MC903-induced AD-like skin lesions in mice.

Therapeutic Management of Idiosyncratic Drug-Induced Liver Injury and Acetaminophen Hepatotoxicity in the Paediatric Population: A Systematic Review.

INTRODUCTION: Drug-induced liver injury (DILI) is a rare but serious adverse event that can progress to acute liver failure (ALF). The evidence for treatment of DILI in children is scarce. OBJECTIVE: We aimed to comprehensively review the available literature on the therapies for both acetaminophen overdose (APAP) and idiosyncratic DILI in the paediatric population. METHODS: We included original articles conducted in a paediatric population (< 18 years) in which a therapeutic intervention was described to manage APAP or idiosyncratic DILI. Findings were summarized based on age groups (preterm newborn neonates, term and post-term neonates, infants, children and adolescents). RESULTS: Overall, 25 publications (fifteen case reports, six case series and four retrospective cohort studies) were included, including a total of 140 paediatric DILI cases, from preterm newborn neonates to adolescents. N-acetylcysteine was used to treat 19 APAP cases. N-acetylcysteine (n = 14), ursodeoxycholic acid (n = 3), corticosteroids (n = 31), carnitine (n = 16) and the combination of glycyrrhizin, reduced glutathione, polyene phosphatidylcholine and S-adenosylmethionine (n = 31) were the therapeutic options for treating idiosyncratic DILI. The molecular adsorbent recirculating system was used in the management of either APAP (n = 4) or idiosyncratic DILI (n = 2), while 20 paediatric ALF cases received continuous renal replacement therapy. CONCLUSIONS: This systematic review identified DILI in the paediatric population who have received specific treatment. These interventions appear to be mainly extrapolated from low-quality evidence from the adult population. Thus, there is a need for high-quality studies to test the efficacy of known and novel therapies to treat DILI specifically addressed to the paediatric population. PROSPERO registration number CRD42021214702.

Desloratadine citrate combined with compound glycyrrhizin in the treatment of subacute eczema: A randomized trial.

To investigate the efficacy of desloratadine citrate combined with compound glycyrrhizin in the treatment of subacute eczema. 100 patients with subacute eczema who were admitted in our hospital from June 2019 to June 2020 were selected according to the order of admission, and divided into experimental groups (n=50, using a single compound glycyrrhizin) and control group (n=50, using compound glycyrrhizin combined with desloratadine citrate); the curative effect was compared between the two groups. After treatment, the inflammatory factors in the experimental group were lower than those in the control group [TNF-α (ng/L) (35.16±3.31), IL-2 (pg/ml) (24.39±3.11), IL-4 (pg/ml) (39.82± 4.48) vs TNF-α (ng/L) (44.24±3.87), IL-2 (pg/ml) (41.68±3.89), IL-4 (pg/ml) (49.88±5.74)] (P<0.05). After treatment the adverse reaction rate of the experimental group was lower than that of the control group (P<0.05). After treatment,the experimental group yielded higher total effective rate in relative to the control group (P<0.05). Desloratadine citrate plus compound glycyrrhizinfor might be a preferable option for clinical treatment of patients with subacute eczema, with an ideal effectiveness profile.

Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.

BACKGROUND: Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. AIMS: To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. METHODS: This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. RESULTS: Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. CONCLUSION: This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).

Effect of Monoammonium Glycyrrhizinate on the Development of Hepatotoxicity After Initial Intrathecal Chemotherapy for Leukemia.

BACKGROUND/AIM: Chemotherapy for acute leukemia includes agents known to cause hepatotoxicity. This study evaluated the role of monoammonium glycyrrhizinate for the prevention of hepatotoxicity after the first methotrexate-containing intrathecal chemotherapy (ITC) in children and adolescents with leukemia. PATIENTS AND METHODS: Patients with newly diagnosed acute leukemia (age 0-18 years) who received ITC during the first week of induction therapy at our hospital between April 2016 and March 2021 were enrolled. Intravenous monoammonium glycyrrhizinate (IVMG) was defined as the intravenous administration of monoammonium glycyrrhizinate initiated on the day before or the day of the first ITC. RESULTS: Overall, 39 of 118 patients (33%) developed grade 3-4 hepatotoxicity. The inverse probability of treatment weighting logistic regression model showed that IVMG was not associated with the development of grade 3-4 hepatotoxicity (OR=1.9, 95%CI=0.808-4.468). CONCLUSION: IVMG did not protect against the development of grade 3-4 hepatotoxicity after the first methotrexate-containing ITC for leukemia.

Hypertensive crisis with 2 target organ impairment induced by glycyrrhizin: A case report.

RATIONALE: Glycyrrhizin is the main active component of licorice. Licorice and glycyrrhizin induced hypertension has been widely reported, yet licorice and glycyrrhizin induced hypertensive crisis has been rarely known. PATIENT CONCERNS: The case of this report was a 47-year-old woman, who took 225 mg of glycyrrhizin daily for 3 years due to primary biliary cholangitis. She was found to have a dramatically elevated blood pressure of about 230/110 mmHg without a history of hypertension and was referred to the emergency department. DIAGNOSES: Hypokalemia, hypertensive retinopathy, and nephropathy were found during the following work-up. Since no other risk factors of hypertension were identified, she was suspected to have glycyrrhizin induced pseudo-hyperaldosteronism. INTERVENTIONS: Glycyrrhizin was discontinued. Intravenous sodium nitroprusside was used during the first few days. Nifedipine and irbesartan were taken after discharge, and the dosage was reduced gradually under supervision. OUTCOMES: She stopped all the anti-hypertensive drugs 6 months since glycyrrhizin was stopped. Her blood pressure was about 110/60 mmHg after repetitive measurement. Her serum potassium and urine albumin/creatinine ratio were also normalized. LESSONS: Licorice and glycyrrhizin induced hypertension due to pseudo-hyperaldosteronism has been widely reported, yet only 3 cases reported that excessive consumption of licorice could lead to hypertensive emergencies. This is the first case that glycyrrhizin induced hypertensive crisis with target organ impairment. By presenting this case, we remind clinicians of glycyrrhizin induced hypertension, a condition which could lead to medical emergencies.

Gas chromatographic-mass spectrometric analysis of urinary glycyrrhetinic acid: an aid in diagnosing liquorice abuse.

OBJECTIVES: Liquorice abuse can lead to severe clinical complications, caused by its active compound 18beta-glycyrrhetinic acid (18betaGA). 18betaGA inhibits dehydrogenase activity of 11beta-hydroxysteroid dehydrogenase (11betaHSD). This enzyme catalyses the interconversion between cortisol and cortisone and normally protects the mineralocorticoid receptor from being activated by cortisol. Diagnosing liquorice abuse can be notoriously difficult. The aim of our study was to develop an accurate and clinically applicable 18betaGA urinary assay. DESIGN: We developed a urinary 18betaGA assay based on gas chromatography and mass spectrometry (GCMS) with sufficient sensitivity to detect 18betaGA at low concentrations. The assay was validated in four volunteers consuming different amounts of liquorice. We applied its use in two patients with hypokalaemic hypertension and suppressed plasma renin activity and serum aldosterone, who were suspected of liquorice abuse. RESULTS: The detection limit for 18betaGA of the GC assay was 10 microg L-1, which was lowered to 3 microg L-1 by subsequent application of MS. In all volunteers, urinary 18betaGA was detected during liquorice intake. Urinary 18betaGA remained detectable until 5 days after stopping continued liquorice intake and until at least 51 h after ingestion of a single large amount. Urinary 18betaGA was demonstrated in both patients, establishing a diagnosis of liquorice abuse. One patient showed changes in urinary cortisol metabolites, consistent with 11betaHSD inhibition. Changes in cortisol metabolites were less pronounced in the other patient. CONCLUSION: Liquorice abuse can result in hypokalaemic hypertension with prolonged suppression of plasma renin activity and aldosterone concentration. This is caused by 18betaGA-mediated inhibition of 11betaHSD, resulting in activation of the renal mineralocorticoid receptor by cortisol. Urinary 18betaGA measurement by GCMS is a useful aid in establishing liquorice abuse.