Histamine H / 中国药理学通报

Aim To determine the effect of histamine H

Usefulness of Noncontrast MRI-Based Radiomics Combined Clinic Biomarkers in Stratification of Liver Fibrosis.

Purpose: To develop and validate a radiomic nomogram based on texture features from out-of-phase T1W images and clinical biomarkers in prediction of liver fibrosis. Materials and Methods: Patients clinically diagnosed with chronic liver fibrosis who underwent liver biopsy and noncontrast MRI were enrolled. All patients were assigned to the nonsignificant fibrosis group with fibrosis stage <2 and the significant fibrosis group with stage ≥2. Texture parameters were extracted from out-of-phase T1-weighted (T1W) images and calculated using the Artificial Intelligent Kit (AK). Boruta and LASSO regressions were used for feature selection and a multivariable logistic regression was used for construction of a combinational model integrating radiomics and clinical biomarkers. The performance of the models was assessed by using the receiver operator curve (ROC) and decision curve. Results: ROC analysis of the radiomics model that included the most discriminative features showed AUCs of the training and test groups were 0.80 and 0.78. A combinational model integrating RADscore and fibrosis 4 index was established. ROC analysis of the training and test groups showed good to excellent performance with AUC of 0.93 and 0.86. Decision curves showed the combinational model added more net benefit than radiomic and clinical models alone. Conclusions: The study presents a combinational model that incorporates RADscore and clinical biomarkers, which is promising in classification of liver fibrosis.

[Anti-obesity and lipid-lowering mechanism of Corydalis Bungeanae Herba: based on intestinal microflora and metabolomics].

This study aims to explore anti-obesity and lipid-lowering mechanism of Corydalis Bungeanae Herba(CB) based on intestinal microflora and metabolomics. Specifically, high-fat high-sugar diet(HFHS, 10 weeks) was used to induce obesity in rats. Then the model rats were randomized into the model group, low-dose(0.18 g·kg~(-1)), medium-dose(0.9 g·kg~(-1)), and high-dose(1.8 g·kg~(-1)) CBH groups, and orlistat group(0.03 g·kg~(-1)), 12 in each group. Rats which received normal diet were used as control. The body weight and feed intake of rats were recorded every week. After 6 weeks of administration, rats were killed and gastric emptying and small intestinal propulsion were examined. Enzyme-linked immunosorbent assay(ELISA) was employed to analyze serum indexes, and liver and perirenal fat were collected for haematoxilin-eosin(HE) staining. Rat feces and serum were gathered for 16 S rDNA sequencing and metabolomics analysis and Spearman's correlation analysis was performed to explore the correlation between differential microflora and differential metabolites. The result showed that CBH extract decreased body weight, feed intake, and serum cholecystokinin(CCK), triglyceride(TG), and total cholesterol(TC), delayed gastric emptying, and reduced fat accumulation in liver and perirenal adiposity as compared with rats in the model group. In addition, Lachnospiraceae and Sutterellaceaecan significantly decreased in the model group, but CBH extract up-regulated their abundance. Moreover, the abundance of Prevotellaceae was significantly raised by HFHS, but CBH decreased it. Glutaric acid, glyceric acid, hippuric acid, malic acid, glyceric acid, oxoglutaric acid, fumaric acid/succinic acid, oxoglutaric acid/isocitric acid, D-glucuronic acid, cholic acid were the main deferentially expressed metabolites and significantly correlated with Sutterellaceae and Prevotellaceae. These key metabolites and microbiota mainly involved in tricarboxylic acid(TCA) cycle, glucose metabolism, amino acid metabolism, and energy metabolism. This study proved that CBH can efficiently improve body weight and blood lipids, reduce adipocyte volume, and positively regulate the intestinal microflora and serum metabolites, thereby achieving the anti-obesity and lipid-owering effect.

Use of Texture Analysis on Noncontrast MRI in Classification of Early Stage of Liver Fibrosis.

Purpose. To compare the diagnostic value of texture analysis- (TA-) derived parameters from out-of-phase T1W, in-phase T1W, and T2W images in the classification of the early stage of liver fibrosis. Methods. Patients clinically diagnosed with hepatitis B infection, who underwent liver biopsy and noncontrast MRI scans, were enrolled. TA parameters were extracted from out-of-phase T1-weighted (T1W), in-phase T1W, and T2-weighted (T2W) images and calculated using Artificial Intelligent Kit (AK). Features were extracted including first-order, shape, gray-level cooccurrence matrix, gray-level run-length matrix, neighboring gray one tone difference matrix, and gray-level differential matrix. After statistical analyses, final diagnostic models were constructed. Receiver operating curves (ROCs) and areas under the ROC (AUCs) were used to assess the diagnostic value of each final model and 100-time repeated cross-validation was applied to assess the stability of the logistic regression models. Results. A total of 57 patients were enrolled in this study, with 27 in the fibrosis stage < 2 and 30 in stages ≥ 2. Overall, 851 features were extracted per ROI. Eight features with high correlation were selected by the maximum relevance method in each sequence, and all had a good diagnostic performance. ROC analysis of the final models showed that all sequences had a preferable performance with AUCs of 0.87, 0.90, and 0.96 in T2W and in-phase and out-of-phase T1W, respectively. Cross-validation results reported the following values of mean accuracy, specificity, and sensitivity: 0.98 each for out-of-phase T1W; 0.90, 0.89, and 0.90 for in-phase T1W; and 0.86, 0.88, 0.84 for T2W in the training set, and 0.76, 0.81, and 0.72 for out-of-phase T1W; 0.74, 0.72, and 0.75 for in-phase T1W; and 0.63, 0.64, and 0.63 for T2W for the test group, respectively. Conclusion. Noncontrast MRI scans with texture analysis are viable for classifying the early stages of liver fibrosis, exhibiting excellent diagnostic performance.

Clinical Study of the Prediction of Malignancy in Thyroid Nodules: Modified Score versus 2017 American College of Radiology's Thyroid Imaging Reporting and Data System Ultrasound Lexicon.

The clinical importance of thyroid nodules rests with the need to exclude thyroid cancer. In the present study, we developed a modified Thyroid Imaging Reporting and Data System (TI-RADS) score using gray-scale ultrasound, contrast-enhanced ultrasound (CEUS) and shear-wave elastography (SWE) images to predict malignancy of thyroid nodules and compared this modified score system with the subjective scoring criteria based on the Thyroid Imaging Reporting and Data System (TI-RADS, 2017 edition). The results revealed that by using SWE and CEUS (enhanced pattern) to downgrade TI-RADS category 4 and 5 nodules, the malignancy rate for TI-RADS category 4 and 5 nodules increased from 47.6% with American College of Radiology (ACR) TI-RADS assessment alone to 49.4% with ACR TI-RADS combined with shear wave elastography (SWE) and CEUS (enhanced pattern). Likewise, by using the modified TI-RADS to adjust TI-RADS category 3 nodules, the malignancy rate for TI-RADS category 3 nodules increased from 13.9%-20.0%. The discriminating power for detection of malignancy of the variable score 2 (ACR TI-RADS + SWE + CEUS), with an area under the curve (AUC) of 0.899 (95% confidence interval [CI]: 86.1%-93.6%), was higher than that of score 1 (ACR TI-RADS), with an AUC of 0.862 (95% CI: 81.9%-90.6%; p > 0.05). With a point 4.5 as the optimal cutoff value, a score of 1 predicted malignancy with an accuracy of 75.6%, sensitivity of 85.0% and specificity of 71.6%. However, with a point 5.5 as the optimal cutoff value, a score of 2 predicted malignancy with an accuracy of 84.9%, sensitivity of 81.0% and specificity of 86.6%. The modified TI-RADS based on ACR TI-RADS + SWE + CEUS (enhanced pattern) could contribute to a reduction in the number of biopsies performed on benign nodules and the implementation of consistent follow-up in clinical practice.

An examination of the potential effect of lipids on the first-pass metabolism of the lipophilic drug anethol trithione.

In this study, an examination of the potential effect of lipids on the first-pass metabolism of anethol trithione (ATT) was investigated. ATT is metabolized rapidly and extensively in liver into 4-hydroxy-anethole trithione (ATX), which was confirmed using the rat intestinal perfusion with the mesenteric cannulation model. Male Sprague-Dawley rats were orally administered of the lipid-based formulations (prepared by medium chain triglycerides (MCT)), the cyclodextrin formulation and the suspension formulation, respectively. For 6.75 mg/kg groups, ATX/ATT area under the plasma concentration-time curve (AUC) ratio decreased by 87% and 76% after administration of the MCT-based formulations and the cyclodextrin formulation, when compared with the suspension formulation (p < 0.05), respectively; for 2.25 mg/kg groups, it decreased by 53% in the MCT group when compared with the cyclodextrin group (p < 0.05). The saturation of pre-system metabolism of ATT was observed after administration of the MCT-based formulations and the cyclodextrin formulation, likely as a result of enhanced absorption and therefore presentation of higher drug concentrations to liver, when compared with the suspension formulation. A trend toward lower systemic metabolite to parent ratios was evident after administration of the lipid formulations, when compared with the cyclodextrin formulation; however, this was not statistically significant. Further studies on the potential for lipids to inhibit hepatic metabolism are therefore warranted.

Reversible inhibitory effects of saturated and unsaturated alkyl esters on the carboxylesterases activity in rat intestine.

This study was conducted to investigate the relationship between the carbon chain length/double bonds of alkyl esters and their inhibitory potency/mechanism on carboxylesterases (CESs). CESs activity was evaluated by inhibition of adefovir dipivoxil (ADV) metabolism in rat intestinal homogenates. Furthermore, the inhibitory effect of BNPP and ethyl (E)-hex-2-enoate (C8:1) on drug absorption was evaluated in situ intestinal perfusion model. The results showed that the rank order of the inhibitory potency on CESs was C10:0 > C8:0 > C6:0 > C4:0 > C12:0, C8:1 > C8:0, C6:1 > C6:0, while the esters (C14:0, C13:1, C16:0, C18:0, C17:1, C20:0) were found to have no inhibitory effect at investigated concentrations. However, the unsaturated esters (C20:1, C20:2, C20:3) displayed the inhibitory effect on CESs. Moreover, the double reciprocal plots indicated that alky esters inhibited the CESs in competitive and mixed competitive ways which were reversible. In addition, the result of most effective CESs inhibitor C8:1 from in situ experiment showed that C8:1 can inhibit the CESs-mediated intestinal metabolism and improve the drug absorption. And the inhibition had no time-dependent effect, compared with that of BNPP groups. The study suggested that alkyl esters can be served as effective and reversible CESs inhibitors, besides that their inhibitory potency/mechanism can be affected by their carbon chain length/double bonds.

Absorption enhancement of adefovir dipivoxil by incorporating MCT and ethyl oleate complex oil phase in emulsion.

AIM: To improve the oral absorption of adefovir dipivoxil (ADV) by employing MCT and the esterase inhibitor ethyl oleate (EO) as a complex oil phase in emulsion. METHODS: EO was used as the esterase inhibitor, and its inhibitory effect on esterase activity was assessed in rat intestinal homogenates. ADV emulsions with or without EO were prepared. The emulsions' protective effect against intestinal metabolism was evaluated in rat luminal contents, ex vivo, as well as in vivo. RESULTS: The IC(50) of EO in intestinal mucosal homogenates was 2.2 mg/mL. The emulsions exhibited significant protective effects in rat luminal contents compared to a simple suspension (98.7%, 96.3%, 95.7% vs 74.7%, P<0.01). The permeability calculated from the emulsion containing EO was significantly different (11.4 x 10(-6) vs 7.4/8.0 x 10(-6), P<0.05) from the simple suspension or the emulsion without EO in an ex vivo assay. A bioavailability study in vivo revealed that emulsions containing both EO and MCT as a complex oil phase demonstrated 1.6- and 1.5-fold enhancements in area under the curve (AUC(0-12)) values (5358 vs 3386/3618, P<0.05), respectively, when compared with emulsions containing EO or MCT as a single oil phase. CONCLUSION: Heterotic lipid formulations (emulsions) with an esterase inhibitor (ie, EO) may be useful in protecting ester prodrugs from intestinal metabolism and increasing their oral bioavailability.

Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: effects of lipid composition and formulation.

This study has explored the use of lipid-based formulations to enhance the oral bioavailability of the poorly water-soluble drug anethol trithione (ATT), and compared the performance of different formulations. Two groups of lipid-based formulations, sub-microemulsion (SME) and oil solution, were prepared using short (SCT), medium (MCT) and long (LCT) chain triglycerides respectively; aqueous suspension was used as the reference formulation. In vitro and in vivo studies were conducted to investigate the impact of lipid composition and formulation on drug absorption. In vitro digestion was used to analyze lipid digestion rates and drug distribution/solubilization. After in vitro digestion, the performance rank order for drug solubilization was SCT