Drug metabolism and transport mediated the hepatotoxicity of Pleuropterus multiflorus root: a review.

Pleuropterus multiflorus root (PMR, Polygoni Multiflori Radix) is an herbal medicine widely used in East Asia, particularly China. However, the potential hepatotoxicity has hindered its rational and safe application of PMR in clinical practice. Recently, the hepatotoxic study of PMR have made great progress, especially drug metabolism and transport-mediated liver injury. In this review, we summarized the advancement of drug metabolism and transport regluated hepatic injury of PMR, pointed out the key role of drug metabolizing enzymes and transporters in regulating hepatic injury of PMR, and emphasized the main hepatotoxic substances, toxicity promoter, and hepatic toxic substance-toxicity promoter interactions in PMR. On this basis, the clinical prospect of preventing and treating hepatic injury of PMR from the perspective of metabolism and transporter was discussed, to provide a useful reference and theoretical basis for the prevention and treatment of hepatic injury of PMR.

Downregulation of the m6A reader YTHDC2 upregulates exosome content in lung adenocarcinoma via inhibiting IFIT and OAS family members.

N6-Methyladenosine (m6A) is the most prevalent mRNA modification. Its biological function primarily relies on its "Reader" protein, such as YTHDC2. Previous studies have shown that YTHDC2 downregulation is a pro-carcinogenic phenomenon in lung adenocarcinoma (LUAD). However, further investigation is needed to understand the molecular mechanisms of downstream genes and the associated biological phenomena following YTHDC2 downregulation. Here, we found that YTHDC2 knockout upregulated exosome content in LUAD. Following YTHDC2 knockout, the mRNA levels of OAS family members (OASs) and IFIT family members (IFITs) also decreased; and inhibition of OASs and IFITs could promote exosome content. Several m6A modification sites on the NT domain of OASs and the TPR12 domain of IFITs were found to increase the stability of OASs and IFITs in a YTHDC2-dependent manner. OASs and IFITs affected exosome content through target genes including RAB5A, RAB7 and RAB11A, and three arginine (R) amino acids on IFITs were critical for combination IFITs with targeted RAB mRNAs and subsequent degradation. Simultaneously, OASs degraded targeted RABs through RNAseL. Additionally, mutual bindings between OASs and IFITs were critical for their target gene degradation. Collectively, the above findings might provide a theoretical basis for the treatment of LUAD patients with low YTHDC2 expression.

Binding uric acid: a pure chemical solution for the treatment of hyperuricemia.

Hyperuricemia, characterized by elevated uric acid levels and subsequent crystal deposition, contributing to conditions such as gout, cardiovascular events, and kidney injury, poses a significant health threat, particularly in developed countries. Current drug options for treatment are limited, with safety concerns, leading to suboptimal therapeutic outcomes in symptomatic hyperuricemia patients and a lack of pharmaceutical interventions for asymptomatic cases. Distinguishing from the previous drug design strategies, we directly target uric acid, the pathological molecule of hyperuricemia, resulting in a pyrimidine derivative capable of increasing the solubility and excretion of uric acid by forming a complex with it. Its prodrug showed an anti-hyperuricemia activity comparable to benzbromarone and a favorable safety profile in vivo. Our finding provides a strategy purely based on organic chemistry to address the largely unmet therapeutic needs on novel anti-hyperuricemia drugs.

Milk vetch returning combined with lime materials alleviates soil cadmium contamination and improves rice quality in soil-rice system.

Milk vetch (Astragalus sinicus L.) returning and lime materials is employed as an effective strategy for remediating cadmium (Cd)-contaminated paddy fields. However, the combined effects of them on alleviating Cd pollution and the underlying mechanisms remain poorly explored. Therefore, this study investigated the impact of these combined treatments on soil properties, iron oxides, iron plaque, mineral elements, and amino acids through a field experiment. The following treatments were employed: lime (LM), limestone (LS), milk vetch (MV), MV + LM (MVLM), and MV + LS (MVLS), and a control (CK) group with no materials. Results demonstrated that treatments significantly decreased soil available Cd by 19.40-32.55 %, 10.20-39.58 %, and 25.36-40.66 % at tillering, filling, and maturing stages compared to CK, respectively. Moreover, exchangeable Cd was transformed into more stable fractions. Compared with individual treatments, MVLM and MVLS treatments further decreased available Cd and exchangeable Cd. Overall, Cd in brown rice was reduced by 18.97-77.39 % compared with CK. And the Cd in iron plaque decreased by 14.12-31.14 %, 24.65-61.60 %, 2.6-38.28 % across three stages. Furthermore, soil pH, dissolved organic carbon, and cation exchange capacity increased, along with 0.22-62.09 % and 0.57-10.66 % increases in free and amorphous iron oxide contents at all stages, respectively. Compared with lime alone, the integration of MV returning facilitated increased formation of Fed, Feo and enhanced the antagonistic effect among grain Ca with Cd; Additionally, it increased AAs in brown rice, improving rice quality and potentially reducing Cd transport. Mantel tests and Partial least squares path modeling revealed a significant positive correlation between Cd in IP and rice Cd uptake and a significant negative correlation between available Cd, Fed and Feo. These findings provide valuable insights into the mechanisms involved in mitigating soil Cd bioavailability using integrated approaches with MV returning and lime materials.

Joint utilization of Chinese milk vetch and lime materials mitigates soil cadmium risk and improves soil health in a double-cropping rice system.

Cadmium (Cd) in paddy soil poses significant risks to humans due to its strong biological migration and toxicity. Chinese milk vetch (MV) is commonly used as green manure in the paddy fields of southern China and its potential to decrease the availability of Cd has been identified. Nevertheless, the effects of MV combined with lime materials (lime, L; limestone, LS) on Cd availability, soil properties, enzyme activity and comprehensive benefits are still not fully understood in double-cropping rice system. A field study was conducted to investigate these changes. The results indicated that all treatments notably decreased soil available Cd (Avail-Cd) by 19.3-44.3% and 14.9-43.1% during early and late rice, compared with CK. Moreover, the Cd fractions transformed to more stable forms. Compared to CK, all treatments reduced brown rice Cd content by 34.6-64.2% and 12.7-52.5% during the two periods. Furthermore, the translocation factors root to shoot, as well as shoot to brown rice, decreased. The combination led to improvements in soil properties, soil enzyme activity. Meantime, Cd in iron-manganese plaque (IMP) decreased by 31.9-51.1% and 29.0-42.7% respectively during two periods in amendments treatments. Soil pH and DOC were more important factors for Cd bioavailability than other properties. Additionally, rice Cd uptake was positively correlated with Cd in IMP. Enzyme activity exhibited a negative correlation with soil active Cd. Partial Least Squares Path Model (PLS-PM) indicated that the mitigation of Cd pollution helped to improve soil enzyme activity. Grey correlation analysis (GRA) indicated that MVLS showed the best comprehensive benefits in soil-plant system. Overall, the combination of MV and lime materials could reduce Cd availability, enhance soil properties and enzyme activity. And this could be strengthened by the combination. These findings will provide valuable insights for Cd-contaminated soil remediation.

Diopter detection method based on optical imaging.

The peripheral retinal refractive state plays an important role in eye growth and development and is closely related to the development of myopia. Existing methods for measuring the peripheral retinal refractive state are cumbersome and can only detect in a limited range. To address the above shortcomings, this paper proposes a retinal refractive state detection method using optical refractive compensation imaging. First, a series of defocus images is captured using an optical system, and then the images are enhanced and filtered. Subsequently, the Sobel function is applied to calculate sharpness, and the asymmetric Gaussian (AG) model is employed for peak fitting, allowing for the determination of the fundus retina's overall refractive compensation value. We performed consistency analysis on the central and peripheral diopters with autorefractor KR-8900 (Topcon, Japan) and WAM-5500 (Grand Seiko, Japan), respectively. The intraclass correlation coefficients (ICCs) are all greater than 0.9, showing good consistency. This is a promising alternative to the current techniques for assessing the refraction of the peripheral retina.

Biocontrol and Growth Promotion Potential of Bacillus subtilis CTXW 7-6-2 against Rhizoctonia solani that Causes Tobacco Target Spot Disease.

Fungal diseases form perforated disease spots in tobacco plants, resulting in a decline in tobacco yield and quality. The present study investigated the antagonistic effect of Bacillus subtilis CTXW 7-6-2 against Rhizoctonia solani, its ability to promote the growth of tobacco seedlings, and the expression of disease resistance-related genes for efficient and eco-friendly plant disease control. Our results showed that CTXW 7-6-2 had the most vigorous growth after being cultured for 96 h, and its rate of inhibition of R. solani growth in vitro was 94.02%. The volatile compounds produced by CTXW 7-6-2 inhibited the growth of R. solani significantly (by 96.62%). The fungal growthinhibition rate of the B. subtilis CTXW 7-6-2 broth obtained after high-temperature and no-high-temperature sterile fermentation was low, at 50.88% and 54.63%, respectively. The lipopeptides extracted from the B. subtilis CTXW 7-6-2 fermentation broth showed a 74.88% fungal growth inhibition rate at a concentration of 100 mg/l. Scanning and transmission electron microscopy showed some organelle structural abnormalities, collapse, shrinkage, blurring, and dissolution in the R. solani mycelia. In addition, CTXW 7-6-2 increased tobacco seedling growth and improved leaf and root weight compared to the control. After CTXW 7-6-2 inoculation, tobacco leaves showed the upregulation of the PDF1.2, PPO, and PAL genes, which are closely related to target spot disease resistance. In conclusion, B. subtilis CTXW 7-6-2 may be an efficient biological control agent in tobacco agriculture and enhance plant growth potential.

A Comparative Study of Three Systems for Liver Magnetic Resonance Elastography.

BACKGROUND: Different MR elastography (MRE) systems may produce different stiffness measurements, making direct comparison difficult in multi-center investigations. PURPOSE: To assess the repeatability and reproducibility of liver stiffness measured by three typical MRE systems. STUDY TYPE: Prospective. POPULATION/PHANTOMS: Thirty volunteers without liver disease history (20 males, aged 21-28)/5 gel phantoms. FIELD STRENGTH/SEQUENCE: 3.0 T United Imaging Healthcare (UIH), 1.5 T Siemens Healthcare, 3.0 T General Electric Healthcare (GE)/Echo planar imaging-based MRE sequence. ASSESSMENT: Wave images of volunteers and phantoms were acquired by three MRE systems. Tissue stiffness was evaluated by two observers, while phantom stiffness was assessed automatically by code. The reproducibility across three MRE systems was quantified based on the mean stiffness of each volunteer and phantom. STATISTICAL TESTS: Intraclass correlation coefficients (ICC), coefficients of variation (CV), and Bland-Altman analyses were used to assess the interobserver reproducibility, the interscan repeatability, and the intersystem reproducibility. Paired t-tests were performed to assess the interobserver and interscan variation. Friedman tests with Dunn's multiple comparison correction were performed to assess the intersystem variation. P values less than 0.05 indicated significant difference. RESULTS: The reproducibility of stiffness measured by the two observers demonstrated consistency with ICC > 0.92, CV < 4.32%, Mean bias < 2.23%, and P > 0.06. The repeatability of measurements obtained using the electromagnetic system for the liver revealed ICC > 0.96, CV < 3.86%, Mean bias < 0.19%, P > 0.90. When considering the range of reproducibility across the three systems for liver evaluations, results ranged with ICCs from 0.70 to 0.87, CVs from 6.46% to 10.99%, and Mean biases between 1.89% and 6.30%. Phantom studies showed similar results. The values of measured stiffness differed across all three systems significantly. DATA CONCLUSION: Liver stiffness values measured from different MRE systems can be different, but the measurements across the three MRE systems produced consistent results with excellent reproducibility. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Viscoelastic parameters derived from multifrequency MR elastography for depicting hepatic fibrosis and inflammation in chronic viral hepatitis.

OBJECTIVES: The capability of MR elastography (MRE) to differentiate fibrosis and inflammation, and to provide precise diagnoses is crucial, whereas the coexistence of fibrosis and inflammation may obscure the diagnostic accuracy. METHODS: In this retrospective study, from June 2020 to December 2022, chronic viral hepatitis patients who underwent multifrequency MRE (mMRE) were included in, and further divided into, training and validation cohorts. The hepatic viscoelastic parameters [shear wave speed (c) and loss angle (φ) of the complex shear modulus] were obtained from mMRE. The logistic regression and receiver operating characteristic (ROC) curves were generated to evaluate performance of viscoelastic parameters for fibrosis and inflammation. RESULTS: A total of 233 patients were assigned to training cohort and validation cohorts (mean age, 52 years ± 13 (SD); 51 women; training cohort, n = 170 (73%), and validation cohort, n = 63 (27%)). Liver c exhibited superior performance in detecting fibrosis with ROC (95% confidence interval) of ≥ S1 (0.96 (0.92-0.99)), ≥ S2 (0.86 (0.78-0.92)), ≥ S3 (0.89 (0.84-0.95)), and S4 (0.88 (0.83-0.93)). Similarly, φ was effective in diagnosing inflammation with ROC values of ≥ G2 (0.72 (0.63-0.81)), ≥ G3 (0.88 (0.83-0.94)), and G4 (0.92 (0.87-0.98)). And great predictive discrimination for fibrosis and inflammation were shown in validation cohort (all AUCs > 0.75). CONCLUSION: The viscoelastic parameters derived from multifrequency MRE could realize simultaneous detection of hepatic fibrosis and inflammation. CRITICAL RELEVANCE STATEMENT: Fibrosis and inflammation coexist in chronic liver disease which obscures the diagnostic performance of MR elastography, whereas the viscoelastic parameters derived from multifrequency MR elastography could realize simultaneous detection of hepatic fibrosis and inflammation. KEY POINTS: • Hepatic biomechanical parameters derived from multifrequency MR elastography could effectively detect fibrosis and inflammation. • Liver stiffness is useful for detecting fibrosis independent of inflammatory activity. • Fibrosis could affect the diagnostic efficacy of liver viscosity in inflammation, especially in early-grade of inflammation.

Three-Dimensional Multifrequency MR Elastography for Microvascular Invasion and Prognosis Assessment in Hepatocellular Carcinoma.

BACKGROUND: Pretreatment identification of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is important when selecting treatment strategies. PURPOSE: To improve models for predicting MVI and recurrence-free survival (RFS) by developing nomograms containing three-dimensional (3D) MR elastography (MRE). STUDY TYPE: Prospective. POPULATION: 188 patients with HCC, divided into a training cohort (n = 150) and a validation cohort (n = 38). In the training cohort, 106/150 patients completed a 2-year follow-up. FIELD STRENGTH/SEQUENCE: 1.5T 3D multifrequency MRE with a single-shot spin-echo echo planar imaging sequence, and 3.0T multiparametric MRI (mp-MRI), consisting of diffusion-weighted echo planar imaging, T2-weighted fast spin echo, in-phase out-of-phase T1-weighted fast spoiled gradient-recalled dual-echo and dynamic contrast-enhanced gradient echo sequences. ASSESSMENT: Multivariable analysis was used to identify the independent predictors for MVI and RFS. Nomograms were constructed for visualization. Models for predicting MVI and RFS were built using mp-MRI parameters and a combination of mp-MRI and 3D MRE predictors. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, chi-squared or Fisher's exact tests, multivariable analysis, area under the receiver operating characteristic curve (AUC), DeLong test, Kaplan-Meier analysis and log rank tests. P < 0.05 was considered significant. RESULTS: Tumor c and liver c were independent predictors of MVI and RFS, respectively. Adding tumor c significantly improved the diagnostic performance of mp-MRI (AUC increased from 0.70 to 0.87) for MVI detection. Of the 106 patients in the training cohort who completed the 2-year follow up, 34 experienced recurrence. RFS was shorter for patients with MVI-positive histology than MVI-negative histology (27.1 months vs. >40 months). The MVI predicted by the 3D MRE model yielded similar results (26.9 months vs. >40 months). The MVI and RFS nomograms of the histologic-MVI and model-predicted MVI-positive showed good predictive performance. DATA CONCLUSION: Biomechanical properties of 3D MRE were biomarkers for MVI and RFS. MVI and RFS nomograms were established. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.