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.

A systematic review and meta-analysis of efficacy and safety of compound glycyrrhizin combined with second-generation non-sedated antihistamine for the treatment of chronic urticaria.

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.

Blockade of HMGB1 Reduces Inflammation and Pruritus in Atopic Dermatitis by Inhibiting Skin Fibroblasts Activation.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsed eczema and serious pruritus. High-mobility group box 1 protein (HMGB1) is a nuclear-binding protein and serves as an alarmin to promote inflammatory responses. METHODS: In this study, we established an AD mouse model by topical use of MC903 on ears and then used a specific HMGB1-binding peptide cIY8 and a HMGB1 inhibitor of glycyrrhizin to investigate HMGB1 on fibroblast activation in the pathogenesis of AD-like symptoms. RESULTS: Topical use of cIY8 and oral use of glycyrrhizin significantly improved the MC903-induced AD-like symptoms and pathological changes of the ears and scratching behavior in an AD mouse model; cIY8 treatment inhibited the higher mRNAs of IL-1α, IL-4, IL-5, IL-13, and IL-31 in the ears. In human fibroblasts, HMGB1 caused nuclear translocation of NF-kB, and the nuclear translocation could be inhibited by pre-treatment of HMGB1 with cIY8, suggesting that NF-κB signaling pathway participates in the HMGB1-induced inflammation of AD in fibroblasts and that cIY8 effectively impedes the function of HMGB1. Glycyrrhizin inhibited the Ca2+ signaling induced by ionomycin in mouse primary fibroblasts. The fibroblast-related proteins of α-SMA, Hsp47, and vimentin and the pruritus-related proteins of IL-33 and periostin were increased in the ears of the AD mouse model, the ratio of EdU incorporation became higher in mouse fibroblasts treated with MC903, and the higher proliferation and inflammatory responses of the fibroblasts could be reversed by glycyrrhizin treatment. CONCLUSIONS: Fibroblast activation by HMGB1 is one of the critical processes in the development of inflammation and pruritus in the AD mouse model. The specific HMGB1-binding peptide cIY8 and the HMGB1 inhibitor glycyrrhizin inactivate skin fibroblasts to alleviate the inflammation and pruritus in the AD mouse model. Peptide cIY8 may be topically used to treat AD patients in the future.

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.

[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.

Effects of mesotherapy introduction of compound glycyrrhizin injection on the treatment of moderate to severe acne.

BACKGROUND: Compound glycyrrhizin has achieved outstanding results in the treatment of various skin diseases. However, the use of mesotherapy to inject compound glycyrrhizin into the skin to treat acne is still understudied. AIMS: This paper aims to explore the effects of mesotherapy introduction of compound glycyrrhizin injection on the acne. MATERIALS & METHODS: A total of 108 patients were included in this study and divided into the control group (n = 54) and the observation group (n = 54). The control group was treated with topical clindamycin gel, while the study group was treated with topical clindamycin gel + mesotherapy and compound glycyrrhizin injection. Skin transepidermal water loss (TEWL), cuticle water content, acne severity, adverse reactions, and inflammatory reactions were documented before and after treatment in the two groups. RESULTS: The usage of mesotherapy to inject compound glycyrrhizin into the skin of acne patients more effectively treat acne than traditional clindamycin gel. The mesotherapy compound glycyrrhizin can more effectively protect the skin barrier of patients and reduce the loss of skin moisture. Compared with the traditional clindamycin gel, the combination of mesotherapy and compound glycyrrhizin more effectively inhibit the inflammatory reaction in acne patients and reduce skin damage in acne patients. DISCUSSION/CONCLUSION: Mesoderm introduction of compound glycyrrhizin injection has better effects on the treatment of moderate to severe acne than clindamycin gel.

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.

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.

An analysis of the efficacy and safety of compound glycyrrhizin injections in the treatment of drug-induced liver injury using a nationwide database.

Background Drug-induced liver injury (DILI) refers to liver damage caused by drugs. DILI poses a significant challenge in the development of new drugs. The management of DILI mainly involves the withdrawal of the offending drug, and there is a lack of specific therapy. This study sought to evaluate the efficacy and safety of compound glycyrrhizin (CG) injections in DILI patients. Aim To evaluate the efficacy and safety of compound glycyrrhizin injections in DILI treatment. Methods The clinical data of DILI patients were collected from a nationwide DILI database. Patients were divided into two groups: the compound glycyrrhizin (CG) group who received CG injections, and the control group who received no treatment. The propensity score matching (PSM) method was applied to obtain an even distribution of characteristics between the two groups. The efficacy of the CG injections was assessed by the analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels between the two groups. Results There were 152 patients in the compound glycyrrhizin group and 512 patients in the control group. The PSM method was used to acquire 152 matched pairs. The compound glycyrrhizin group had a significantly higher overall ALT and AST normalization rate than the control group (43.42% vs. 24.34%, p = 0.0004 and 63.82% vs. 38.82%, p ≤ .0001). There was no difference in the levels of renal and serum biochemical parameters between the two groups. Conclusions CG injections are effective in reducing ALT and AST levels in DILI patients, and their safety is comparable to the control group.

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).

Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial.

Recent evidence points to a potential therapeutic role for glycyrrhizin(GR) and boswellic acids (BA) in the treatment of COVID-19 but conclusive evidence is lacking. Our aim is to investigate the efficacy of GR + BA versus placebo for the treatment of hospitalized patients with moderate SARS-CoV-2 or COVID-19 variants infection. The current study is a randomized, double-blind, placebo-controlled, single-center trial. Patients with SARS-CoV-2 or COVID-19 variants diagnosed by PCR test who were admitted to Sohag University hospital were eligible if they were at least 18 years of age and had moderate symptoms. Patients were randomly assigned to receive oral GR capsule (60 mg) and BA (200 mg) twice daily for 14 days or a matching placebo. All patients also received treatment with the institutional protocol for COVID-19. The primary outcome was mortality and time to recovery. Secondary outcome was clinical status score, 14 days after receiving study drugs. Adverse events from use of study drugs have been evaluated for up to 14 days. The trial is registered at ClinicalTrials.gov (Identifier NCT04487964). During the 6-month enrollment period (June-November, 2021) only 50 patients (54% women; median age 60 years, IQR 54-65) met eligibility and were randomly assigned. Evaluation of the primary outcome at 14 days showed that there were five deaths in the placebo group and no deaths in the GR + BA group. With regard to recovery time, it was significantly shorter (p = 0.0001) in the group receiving GR + BA capsule compared to the placebo group (median 7.0; IQR 6.0-8.0 days vs. median 12.5; IQR 12-20 days). Clinical status on the ordinal score scale as a secondary outcome showed a significant difference between the GR + BA group (median (IQR) score, 2 [2-3]) and placebo groups (mean (IQR) score, 3 [3-5.5]). There was a significant decrease in CRB (p = 0.000041) in GR + BA compared with the placebo group. In conclusion, this safe, inexpensive, antiviral, immunomodulating and anti-inflammatory combination may be considered for use in mild to moderate infections of SARS-CoV-2 or COVID-19 variants. The study is limited by the small sample size; therefore, larger randomized trials are required.

Preparation of Oral Core-Shell Zein Nanoparticles to Improve the Bioavailability of Glycyrrhizic Acid for the Treatment of Ulcerative Colitis.

In this study, oral colon-targeted adhesion core-shell nanoparticles were designed by applying FA-Zein as the core and using pectin as the shell to enhance the low bioavailability exhibited by glycyrrhizic acid (GA) and the anti-inflammatory effect in specific parts of the intestine. As indicated by the results, the nanoparticles (NPs) remained stable in the stomach and small intestine, while pectins began to degrade and release GA in considerable amounts in the colon with the abundant flora. Subsequently, folate-acid targeting was further assessed with Raw 264.7 and NCM 460 cells. Lastly, NPs were reported to exhibit high adhesion on the colon by using the DSS-induced ulcerative colitis mouse model. Moreover, as indicated by in vitro and in vivo studies, nanoparticles could decrease the levels of MPO and TNF-α by reducing macrophages and neutrophils. In brief, this study provides an ideal loaded natural anti-inflammatory drug delivery system to treat ulcerative colitis.

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.

Exploration for the real causative agents of licorice-induced pseudoaldosteronism.

I investigated the causative agents of licorice-induced pseudoaldosteronism, which is a frequent side effect of Japanese traditional Kampo medicines. Glycyrrhizin (GL), the main ingredient of licorice, is absorbed after being metabolized to glycyrrhetinic acid (GA) by intestinal bacteria, and then metabolized in liver to 3-monoglucuronyl-glycyrrhetinic acid (3MGA). In normal condition, 3MGA is excreted into bile via a multidrug resistance-related protein (Mrp) 2, therefore, 3MGA does not appear in blood circulation. However, under the dysfunction of Mrp2, 3MGA appears in the blood circulation and is excreted into the urine by not glomerular filtration but tubular secretion via organic anion transporter (OAT) 1 and 3. At this time, 3MGA inhibits type 2 11ß-hydroxysteroid dehydrogenase (11ßHSD2) in tubular cells to cause pseudoaldosteronism. Since GA is not the substrates of these transporters, GA cannot inhibit 11ßHSD2 in tubular cells. Therefore, it was considered that 3MGA was the causative agents of licorice-induced pseudoaldosteronism. After that, I isolated and identified three other GL metabolites, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate (2), and 18ß-glycyrrhetyl-3-O-sulfate (3) from the urine of Mrp2-deficient rats orally treated with GA, and found that their blood and urinary concentrations were much higher than 3MGA and that their pharmacokinetic behaviors were similar to 3MGA. 3MGA was not detected in the blood of patients with pseudoaldosteronism who developed rhabdomyolysis due to licorice, and compound 3 was detected at a high concentration. In addition, a multicenter retrospective study was conducted using the serum and urine of 97 patients who took Kampo medicines containing licorice. Of a total of 97 patients, 67 detected GA in the serum (median 122 nM, 5 nM-1.8 µM) and 68 detected compound 3 (median 239 nM, 2 nM-4.2 µM), and there were no cases of detection of GL, 3MGA, compounds 1, and 2. High blood concentrations of compound 3 were associated with low plasma renin activity, plasma aldosterone levels, and serum potassium levels. It is highly probable that compound 3 is the true causative agent of pseudoaldosteronism.

Compound glycyrrhizin combined with antihistamines for chronic urticaria: A protocol for systematic review and meta analysis.

BACKGROUND: To investigate the efficacy and safety of compound glycyrrhizin (CG) combined with antihistamines in the treatment of chronic urticaria (CU). METHODS: We will use computers to search all databases including Medline, Embase, Pubmed, Web of Science and Cochrane Central Register of Controlled Trials and China's 4 databases: China National Knowledge Infrastructure Database, China Biomedical Literature Database, China Science Journal Database, and Wanfang Database. Find data from creation date to July 2020. In addition, we will manually search the list of medical journals as a supplement. The scope of the search included randomized controlled clinical studies related to CG combined with antihistamines for CU. The primary outcome is the disease activity control. Secondary outcomes include response rate, adverse events, and recurrence rates. The Cochrane RevMan V5.3 Deviation Assessment Tool will be used to assess bias assessment risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). The average difference, standard mean difference, and binary data will be used to represent continuous results. RESULTS: This study will comprehensively review the existing evidence on CG combined with antihistamines for CU. CONCLUSION: This systematic review will provide a basis for judging the effectiveness and safety of CG combined with antihistamines in the treatment of CU. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020156153.