NDC80/HEC1 promotes macrophage polarization and predicts glioma prognosis via single-cell RNA-seq and in vitro experiment.

INTRODUCTION: Glioma is the most frequent and lethal form of primary brain tumor. The molecular mechanism of oncogenesis and progression of glioma still remains unclear, rendering the therapeutic effect of conventional radiotherapy, chemotherapy, and surgical resection insufficient. In this study, we sought to explore the function of HEC1 (highly expressed in cancer 1) in glioma; a component of the NDC80 complex in glioma is crucial in the regulation of kinetochore. METHODS: Bulk RNA and scRNA-seq analyses were used to infer HEC1 function, and in vitro experiments validated its function. RESULTS: HEC1 overexpression was observed in glioma and was indicative of poor prognosis and malignant clinical features, which was confirmed in human glioma tissues. High HEC1 expression was correlated with more active cell cycle, DNA-associated activities, and the formation of immunosuppressive tumor microenvironment, including interaction with immune cells, and correlated strongly with infiltrating immune cells and enhanced expression of immune checkpoints. In vitro experiments and RNA-seq further confirmed the role of HEC1 in promoting cell proliferation, and the expression of DNA replication and repair pathways in glioma. Coculture assay confirmed that HEC1 promotes microglial migration and the transformation of M1 phenotype macrophage to M2 phenotype. CONCLUSION: Altogether, these findings demonstrate that HEC1 may be a potential prognostic marker and an immunotherapeutic target in glioma.

Surveillance of adverse events following immunisation in Australia, COVID-19 vaccines, 2021.

Abstract: This report summarises Australia's spontaneous (passive) surveillance data for adverse events following immunisation (AEFI) for coronavirus disease 2019 (COVID-19) vaccines in 2021 reported to the Therapeutic Goods Administration (TGA). The TGA strongly promoted and facilitated adverse event reporting in preparation for, and during, the COVID-19 vaccine rollout as a core component of the most intensive vaccine safety monitoring ever conducted in Australia. There were 111,348 AEFI reports for COVID-19 vaccines administered in 2021, an annual AEFI reporting rate of 271.4 per 100,000 doses of COVID-19 vaccines administered to people aged ≥ 12 years. The annual AEFI reporting rate for non-COVID-19 vaccines in 2021 was 30.6 per 100,000 doses administered to people of all ages. Overall, the most frequently reported symptoms were headache, adverse events classified as 'gastrointestinal nonspecific symptoms and therapeutic procedures', myalgia, pyrexia and fatigue, which were consistent with common expected adverse events following COVID-19 vaccines used in Australia. The most commonly reported adverse events of special interest were myocarditis and/or pericarditis, followed by thrombosis and thromboembolism, and anaphylaxis. Of all COVID-19 vaccine AEFI reports, 762 (0.7%) included a fatal outcome, of which over 80% were in people aged ≥ 60 years. Thirteen deaths reported in 2021 were assessed as likely to be causally linked to vaccination. This report confirms the value of spontaneous post-marketing vaccine pharmacovigilance, especially in the context of new vaccines using novel vaccine technologies and near whole-of-population pandemic vaccination programs. The most frequently reported AEFI for COVID-19 vaccines were common, mild and temporary (lasting 1 or 2 days), and consistent with clinical trial and active surveillance data. Ongoing safety monitoring detected rare, unexpected conditions, such as myocarditis/pericarditis and thrombosis with thrombocytopenia syndrome (TTS), which were investigated and confirmed as safety signals, resulting in changes to vaccine recommendations and product information. The outcomes of TGA monitoring were published in weekly vaccine safety reports. Overall, COVID-19 vaccine safety monitoring provided critical information on the risks of vaccine related adverse events that enabled decisionmakers to undertake informed risk-benefit assessments.

Surveillance of adverse events following immunisation in Australia annual report, 2021.

Abstract: This report summarises Australia's spontaneous surveillance data for adverse events following immunisation (AEFI) for 2021 reported to the Therapeutic Goods Administration (TGA) and describes reporting trends over the 22-year period 1 January 2000 to 31 December 2021. This report excludes AEFI reports featuring pandemic coronavirus disease 2019 (COVID-19) vaccines, which are reported separately. There were 3,452 AEFI reports for non-COVID-19 vaccines administered in 2021, an annual AEFI reporting rate of 13.4 per 100,000 population compared with 14.9 per 100,000 population in 2020. This small decrease in the AEFI reporting rate in 2021 could potentially be related to an increased focus on COVID-19 vaccines and related AEFI, which are not included in this report. AEFI reporting rates for individual vaccines in 2021 were similar to 2020, as were the most commonly reported adverse events. Of the six deaths following vaccination in 2021 reported to the TGA, none were found to have a causal relationship with vaccination.

Comparison between oral dydrogesterone versus micronized vaginal progesterone gel in clinical outcome within the first HRT-FET cycle: a retrospective analysis.

OBJECTIVE: The purpose of this study is to compare the clinical efficacy of oral dydrogesterone and micronized vaginal progesterone (MVP) gel during the first HRT-FET cycle. METHODS: A retrospective cohort study based on a total of 344 women undergoing their first HRT-FET cycles without Gonadotropin-Releasing Hormone agonist (GnRH-a) pretreatment was conducted. All the cycles were allocated to two groups in the reproductive medical center at the University of Hong Kong-Shenzhen Hospital. One group (n = 193) received oral dydrogesterone 30 mg/d before embryo transfer, while the other group (n = 151) received MVP gel 180 mg/d. RESULTS: The demographics and baseline characteristics of two groups were comparable. We found no statistically significant difference in live birth rate (24.35% vs. 31.13%, P = 0.16), clinical pregnancy rate (34.72% vs. 36.42%, P = 0.74), embryo implantation rate (25.09% vs. 28.36%, P = 0.43), positive pregnancy rate (42.49% vs 38.41%, P = 0.45), miscarriage rate (9.33% vs 3.97%, P = 0.05), or ectopic pregnancy rate (0.52% vs. 0.66%, P = 0.86) between the oral dydrogesterone group and MVP gel group. In the multivariate logistic regression analysis for covariates, medication used for luteal support was not associated with live birth rate (OR = 0.73, 95% CI: 0.32-1.57, P = 0.45). And the different luteal support medication did not have a significant positive association with the live birth rate in the cycles with day 2 embryo transferred (OR = 1.39, 95% CI:0.66-2.39, P = 0.39) and blastocyst transferred (OR = 1.31 95% CI:0.64-2.69, P = 0.46). CONCLUSION: 30 mg/d oral dydrogesterone and 180 mg/d MVP gel revealed similar reproductive outcomes in HRT-FET cycles in the study.

Comparative Transcriptomic Analysis of Largemouth Bass (Micropterus salmoides) Livers Reveals Response Mechanisms to High Temperatures.

High temperatures are considered one of the most significant limitations to subtropical fishery production. Largemouth bass (Micropterus salmoides) is an economically important freshwater species grown in subtropical areas, which are extremely sensitive to heat stress (HS). However, comprehensive transcriptomic data for the livers of largemouth bass in response to HS are still lacking. In this study, a comparative transcriptomic analysis was performed to investigate the gene expression profiles of the livers of largemouth bass under HS treatment. As a result, 6114 significantly differentially expressed genes (DEGs), which included 2645 up-regulated and 3469 down-regulated genes, were identified in response to HS. Bioinformatics analyses demonstrated that the 'ECM-receptor interaction' pathway was one of the most dramatically changed pathways in response to HS, and eight DEGs assigned to this pathway were taken as hub genes. Furthermore, the expression of these eight hub genes was determined by quantitative reverse transcription PCR, and all of them showed a significant change at the transcriptional level, suggesting a crucial role of the 'ECM-receptor interaction' pathway in the response of largemouth bass to HS. These findings may improve our understanding of the molecular mechanisms underlying the response of largemouth bass to HS.

Tuning Local Structural Configurations to Improve Oxygen-Redox Reversibility of Li-Rich Layered Oxides.

Li-rich layered oxides (LLOs) are regarded as one of the most desirable cathode materials due to their high specific capacity. Nevertheless, the irreversible oxygen release associated with low oxygen stability prevents their widespread application. Herein, an improved oxygen redox reversibility was achieved by constructing Ni2+-O2--Ni2+ configurations. Superconducting Quantum Interference Device (SQUID) magnetometry measurements are used to track the evolution of the Ni2+-O2--Ni2+ configuration during the electrochemical process. The strongest 180° superexchange interaction in the Ni2+-O2--Ni2+ configuration, derived from the inevitable Li/Ni mixing in LLOs, regulates the local structure to form the ferrimagnetic (FiM) structural units. Consequently, the FiM structural units prevent the irreversible oxygen release and endow LLOs with high initial Coulombic efficiency (ICE). This work emphasizes the importance of the Ni2+-O2--Ni2+ configuration for LLOs with high reversible capacity and proposes a synthesis approach to modulate the amount of FiM structural units.

Mapping the regulatory effects of herbal organic compounds on gut bacteria.

Herbal organic compounds (HOCs) are bioactive natural products from medicinal plants and some traditional Chinese medicines (TCMs). Recently, ingestion of a few HOCs with low bioavailability has been associated with alterations in gut microbiota, but the extent of this phenomenon remains unclear. Here, we systematically screened 481 HOCs against 47 representative gut bacterial strains in vitro and found that almost one-third of the HOCs exhibited unique anticommensal activity. Quinones showed a potent anticommensal activity, while saturated fatty acids exhibited stronger inhibition of the Lactobacillus genus. Flavonoids, phenylpropanoids, terpenoids, triterpenoids, alkaloids and phenols displayed weaker anticommensal activity, but steroids, saccharides and glycosides had hardly any effect on strain growth. Notably, S-configuration HOCs demonstrated stronger anticommensal activity than R-configuration HOCs. The strict screening conditions ensured high accuracy (95%) through benchmarking validation. Additionally, the effects of HOCs on human fecal microbiota profiling were positively correlated with their anticommensal activity against bacterial strains. Molecular and chemical features such as AATS3i and XLogP3 were correlated with the anticommensal activity of the HOCs in the random forest classifier. Finally, we validated that curcumin, a polyhydric phenol with anticommensal activity, improved insulin resistance in HFD mice by modulating the composition and metabolic function of gut microbiota. Our results systematically mapped the profile of HOCs directly affecting human gut bacterial strains, offering a resource for future research on HOC-microbiota interaction, and broadening our understanding of natural product utilization through gut microbiota modulation.

ATAGI Targeted Review 2022: Vaccination for prevention of herpes zoster in Australia.

Abstract: In November 2016, herpes zoster (HZ) vaccination for older adults, using the live-attenuated zoster vaccine (Zostavax; ZVL) was added to the Australian National Immunisation Program (NIP) with the aim of reducing morbidity from HZ and its complications, particularly for people at increased risk. Prior to the program, there were on average 5.6 cases of HZ per 1,000 persons annually in Australia, with highest risk of disease in older and in immunocompromised people. The burden of complications of HZ, such as post-herpetic neuralgia (PHN), was also highest in older and immunocompromised groups. No formal comprehensive program evaluation has been undertaken since program commencement. This review examined published literature and available vaccine administration data to summarise the evidence and considerations underpinning current use of HZ vaccines and potential future program directions in Australia. There have been modest reductions in the incidence of HZ and its complications since program introduction. However, five years into the program, challenges remain, including suboptimal vaccine coverage and significant safety concerns arising from inadvertent use of ZVL in immunocompromised people, who are contraindicated to receive this vaccine. This reduces opportunities to offset the burden of HZ-related disease. The recombinant subunit zoster vaccine (Shingrix; RZV), first registered in Australia in 2018, became available on the Australian market in June 2021. This vaccine has higher efficacy than ZVL and, as a non-live vaccine, can be used in both immunocompetent and immunocompromised people. RZV has potential to address the unmet needs of at-risk population groups. However, it has not yet demonstrated cost-effectiveness for inclusion as a funded vaccine under the NIP. The Australian HZ vaccination program has had limited effectiveness in meeting its aim in highest risk groups. Future options and challenges anticipated in using vaccination to reduce the burden of HZ and its complications are discussed in this review.

Transitional Learning: Exploring the Transition States of Degradation for Blind Super-resolution.

Being extremely dependent on iterative estimation of the degradation prior or optimization of the model from scratch, the existing blind super-resolution (SR) methods are generally time-consuming and less effective, as the estimation of degradation proceeds from a blind initialization and lacks interpretable representation of degradations. To address it, this article proposes a transitional learning method for blind SR using an end-to-end network without any additional iterations in inference, and explores an effective representation for unknown degradation. To begin with, we analyze and demonstrate the transitionality of degradations as interpretable prior information to indirectly infer the unknown degradation model, including the widely used additive and convolutive degradations. We then propose a novel Transitional Learning method for blind Super-Resolution (TLSR), by adaptively inferring a transitional transformation function to solve the unknown degradations without any iterative operations in inference. Specifically, the end-to-end TLSR network consists of a degree of transitionality (DoT) estimation network, a homogeneous feature extraction network, and a transitional learning module. Quantitative and qualitative evaluations on blind SR tasks demonstrate that the proposed TLSR achieves superior performances and costs fewer complexities against the state-of-the-art blind SR methods. The code is available at github.com/YuanfeiHuang/TLSR.

Monkeypox: A clinical update for paediatricians.

The global spread of human monkeypox disease, a zoonotic infection related to smallpox and endemic to West and Central Africa, presents serious challenges for health systems. As of July 2022, 14 533 cases have been reported world-wide, leading to designation as a Public Health Emergency of International Concern. Monkeypox disease is spread from animals to humans through infected lesions or fluids; human-human transmission occurs through fomites, droplets or direct contact. Illness is usually self-limiting, but severe disease can occur in specific groups - particularly children, and people who are immunocompromised or pregnant. Clinical presentation may include fever, lymphadenopathy and skin rash, but the rash may occur without other symptoms. Complications can include secondary bacterial infection of skin lesions, vision loss from corneal involvement, pneumonia, sepsis and encephalitis. Diagnosis of monkeypox requires consideration of epidemiological, clinical and laboratory findings, with sensitive history-taking, to elicit close contacts, critical. Supportive management is usually sufficient, but treatment options (where required) include antivirals and vaccinia immune globulin. A paucity of safety data for relevant antivirals may limit their use. There are two types of monkeypox vaccines: a replication-competent vaccinia vaccine, the use of which is logistically and clinically complex, and a replication-deficient modified vaccinia Ankara virus vaccine. Preparedness of health systems for addressing the current outbreak is constrained by historic underfunding for research, and compounded by stigma and discrimination against cases and affected communities. Key challenges in halting transmission include improving vaccine equity and countering discrimination against men who have sex with men to aid diagnosis and treatment.

Dissecting the role of cell signaling versus CD8+ T cell modulation in propranolol antitumor activity.

Preclinical and early clinical mechanistic studies of antitumor activity from the beta-adrenergic receptor (ß-AR) blocker propranolol have revealed both cell signaling and immune function pathway effects. Intertumoral studies were performed using propranolol, a ß1-AR selective agent (atenolol), and a ß2-AR selective agent (ICI 118,551) in a preclinical in vivo model, as a step to dissect the contribution of cell signaling and CD8+ immunological effects on anticancer activity. We found that repression of ß2-AR but not ß1-AR signaling selectively suppressed cell viability and inhibited xenograft growth in vivo. Moreover, western blot analysis indicated that the phosphorylation levels of AKT/MEK/ERK were significantly decreased following the inhibition of ß2-AR. Furthermore, propranolol was found to activate the tumor microenvironment by inducing an increased intratumoral frequency of CD8+ T cells, whereas neither selective ß1 nor ß2-AR blockers had a significant effect on the tumor immune microenvironment. Thus, the results of this mechanistic dissection support a predominant role of tumor cell signaling, rather than the accumulation of CD8+ T cells, as the basis for propranolol antitumor activity. KEY MESSAGES : Molecular signaling of AKT/MAPK pathway contributes to propranolol caused cancer control. CD8+ T cells in tumor microenvironment were activated upon propranolol exposure. The basis for propranolol antitumor activity was predominantly dependent on cell signaling, rather than the activation of CD8+ T cells.

Interpretable Detail-Fidelity Attention Network for Single Image Super-Resolution.

Benefiting from the strong capabilities of deep CNNs for feature representation and nonlinear mapping, deep-learning-based methods have achieved excellent performance in single image super-resolution. However, most existing SR methods depend on the high capacity of networks that are initially designed for visual recognition, and rarely consider the initial intention of super-resolution for detail fidelity. To pursue this intention, there are two challenging issues that must be solved: (1) learning appropriate operators which is adaptive to the diverse characteristics of smoothes and details; (2) improving the ability of the model to preserve low-frequency smoothes and reconstruct high-frequency details. To solve these problems, we propose a purposeful and interpretable detail-fidelity attention network to progressively process these smoothes and details in a divide-and-conquer manner, which is a novel and specific prospect of image super-resolution for the purpose of improving detail fidelity. This proposed method updates the concept of blindly designing or using deep CNNs architectures for only feature representation in local receptive fields. In particular, we propose a Hessian filtering for interpretable high-profile feature representation for detail inference, along with a dilated encoder-decoder and a distribution alignment cell to improve the inferred Hessian features in a morphological manner and statistical manner respectively. Extensive experiments demonstrate that the proposed method achieves superior performance compared to the state-of-the-art methods both quantitatively and qualitatively. The code is available at github.com/YuanfeiHuang/DeFiAN.

Epigallocatechin­3­gallate modulates long non­coding RNA and mRNA expression profiles in lung cancer cells.

(­)­Epigallocatechin­3­gallate (EGCG), a major constituent of green tea, is a potential anticancer agent, but the molecular mechanisms of its effects are not well­understood. The present study was conducted to examine the mechanism of EGCG in lung cancer cells. Alterations in long non­coding RNAs (lncRNAs) and mRNAs were investigated in lung cancer cells treated with EGCG by lncRNA microarray analysis. Furthermore, the functions and signaling pathways regulated by EGCG were predicted by bioinformatics analysis. A total of 960 lncRNAs and 1,434 mRNAs were significantly altered following EGCG treatment. These lncRNAs were distributed across nearly all human chromosomes and the mRNAs were involved in the cell cycle and the mitotic cell cycle process. Through a combination of microarray and bioinformatics analysis, 20 mRNAs predicted to serve a key role in the EGCG regulation were identified, and certain regulatory networks involving EGCG­regulated lncRNAs were predicted. In conclusion, EGCG affects the expression of various lncRNAs and mRNAs in the cells, therefore affecting cell functions. The results of the present study provide an insight into the mechanism of EGCG, which may be useful for therapeutic development.

Modelling brain-wide neuronal morphology via rooted Cayley trees.

Neuronal morphology is an essential element for brain activity and function. We take advantage of current availability of brain-wide neuron digital reconstructions of the Pyramidal cells from a mouse brain, and analyze several emergent features of brain-wide neuronal morphology. We observe that axonal trees are self-affine while dendritic trees are self-similar. We also show that tree size appear to be random, independent of the number of dendrites within single neurons. Moreover, we consider inhomogeneous branching model which stochastically generates rooted 3-Cayley trees for the brain-wide neuron topology. Based on estimated order-dependent branching probability from actual axonal and dendritic trees, our inhomogeneous model quantitatively captures a number of topological features including size and shape of both axons and dendrites. This sheds lights on a universal mechanism behind the topological formation of brain-wide axonal and dendritic trees.

Single Image Super-Resolution via Multiple Mixture Prior Models.

Example learning-based single image super-resolution (SR) is a promising method for reconstructing a high-resolution (HR) image from a single-input low-resolution (LR) image. Lots of popular SR approaches are more likely either time-or space-intensive, which limit their practical applications. Hence, some research has focused on a subspace view and delivered state-of-the-art results. In this paper, we utilize an effective way with mixture prior models to transform the large nonlinear feature space of LR images into a group of linear subspaces in the training phase. In particular, we first partition image patches into several groups by a novel selective patch processing method based on difference curvature of LR patches, and then learning the mixture prior models in each group. Moreover, different prior distributions have various effectiveness in SR, and in this case, we find that student-t prior shows stronger performance than the well-known Gaussian prior. In the testing phase, we adopt the learned multiple mixture prior models to map the input LR features into the appropriate subspace, and finally reconstruct the corresponding HR image in a novel mixed matching way. Experimental results indicate that the proposed approach is both quantitatively and qualitatively superior to some state-of-the-art SR methods.

1H NMR based pharmacometabolomics analysis of metabolic phenotype on predicting metabolism characteristics of losartan in healthy volunteers.

Inter-individual variability in drug metabolism and disposition is common in both preclinical and clinical researches. Losartan and its active metabolite EXP3174 present a high degree of inter-individual differences in blood concentrations that affect drug efficacy and side effect. Pharmacometabolomics has been increasingly applied on predicting the drug responses by analyzing the differences in metabolic profile. A pre-dose metabolic phenotype was investigated to interpret inter-individual variations in the metabolism characteristics of losartan. 1H Nuclear Magnetic Resonance (NMR) spectroscopy-based metabolic profiles were performed on 36 healthy Chinese male volunteers by measuring their pre-dose plasma samples. After oral administration of losartan, the concentrations of losartan and its bioactive metabolite EXP3174 were monitored by liquid chromatography-mass spectrometry (LC-MS). Orthogonal partial least-squares (O-PLS) model was conducted to select potential biomarkers that substantially contributed to the inter-individual variations in the metabolism features via analyzing the ratio of pharmacokinetics (PK) parameters of its metabolite to parent drug. Potential metabolites such as glycine, phosphorylcholine, choline, creatine, creatinine, lactate, citrate, α-glucose, and lipids showed strong correlations with metabolism features of losartan. In addition, the pathway analysis revealed that baseline lipid metabolism, the glycine, serine and threonine pathway, and glycolysis or gluconeogenesis metabolism pathway were significantly associated with the ratio of PK parameters of EXP3174 to losartan. Step-wise multiple linear regression (MLR) was constructed to investigate the potential roles of the selected biomarkers in predicting individualized metabolism characteristics of losartan. These results showed that the pre-dose individual metabolic traits may be a useful approach for characterizing individual differences in losartan metabolism characteristics and therefore for expediting personalized dose-setting in further clinical studies.

Multiclass screening of >200 pharmaceutical and other residues in aquatic foods by ultrahigh-performance liquid chromatography-quadrupole-Orbitrap mass spectrometry.

A quick screening method of more than 200 pharmaceutical and other residues in aquatic foods based on ultrahigh-performance liquid chromatography-quadrupole-Orbitrap mass spectrometry (UHPLC-Q/Orbitrap MS) was established. In this method, after the addition of 200 µL of 1 M EDTA-Na2, 2 g of each sample homogenate was extracted successively with 10 mL of acetonitrile and 10 mL of ethyl acetate. The extracts were combined, dried under nitrogen flow, and redissolved in 0.1% formic acid in acetonitrile/water (4:6, v/v) for analysis. The prepared samples were analyzed by UHPLC- Q/Orbitrap MS system in Full MS/ddMS2 (full-scan data-dependent MS/MS) mode. Compound identification was performed through comparison of the sample data with the database for standard chemicals, including the retention time, precursor ion, product ions, and isotope pattern for all 206 compounds. Five different aquatic food matrices (carp, shrimp, crab, eel, and mussel) spiked with the analytes at 1, 10, and 50 ng/g were evaluated to assess recoveries, precision, matrix effects, stability, and detection limits using the method. UHPLC analyses required 25 min, and 178-200 analytes met identification criteria at 50 ng/g depending on the matrix. Furthermore, practical application of this method for real samples displayed strong screening capability. Graphical abstract A quick screening method of >200 pharmaceutical and other residues in aquatic foods based on ultrahighperformance liquid chromatography-quadrupole-Orbitrap mass spectrometer was established. Fivedifferent aquatic food matrices, including carp, shrimp, crab, eel and mussel, were studied to evaluatescreen limit at 1, 10 and 50 µg·kg-1 level. Results suggest the high reliability, high time-efficiency and goodsimplicity of the method.

A robust anonymous biometric-based authenticated key agreement scheme for multi-server environments.

In order to improve the security in remote authentication systems, numerous biometric-based authentication schemes using smart cards have been proposed. Recently, Moon et al. presented an authentication scheme to remedy the flaws of Lu et al.'s scheme, and claimed that their improved protocol supports the required security properties. Unfortunately, we found that Moon et al.'s scheme still has weaknesses. In this paper, we show that Moon et al.'s scheme is vulnerable to insider attack, server spoofing attack, user impersonation attack and guessing attack. Furthermore, we propose a robust anonymous multi-server authentication scheme using public key encryption to remove the aforementioned problems. From the subsequent formal and informal security analysis, we demonstrate that our proposed scheme provides strong mutual authentication and satisfies the desirable security requirements. The functional and performance analysis shows that the improved scheme has the best secure functionality and is computational efficient.

Effect of glycyrrhizin on the activity of CYP3A enzyme in humans.

BACKGROUND: Glycyrrhizin is a major ingredient of licorice which is widely used in the treatment of various diseases such as chronic hepatitis. Licorice or glycyrrhizin has been shown to alter the activity of CYP3A in rodents. The influence of glycyrrhizin on CYP3A has not been elucidated in humans. OBJECTIVE: To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of midazolam, a probe drug for CYP3A activity in humans. METHODS: Sixteen healthy adult male subjects were enrolled in a two-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days. On the 15th day, midazolam was administered and blood samples were obtained to determine midazolam plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMRs) and 90% confidence intervals (90% CI). RESULTS: The geometric mean (geometric coefficient of variation) for the AUC(0-infinity) of midazolam in the placebo group was 196.4 ng x h/ml (30.3%) and after glycyrrhizin treatment, 151.3 ng x h/ml (34.7%). The GMRs and 90% CI for AUC(0-infinity) and Cmax of midazolam in the presence/ absence of glycyrrhizin were 0.77 (0.70, 0.89) and 0.83 (0.74, 1.01), respectively. The 90% CI for AUC(0-infinity) and Cmax for the GMR of glycyrrhizin over placebo were both out of the no-effect boundaries of 0.80-1.25. CONCLUSIONS: Administration of glycyrrhizin resulted in a modest induction of CYP3A that was clinically relevant according to the bioequivalence analysis.