Intratumoral and peritumoral radiomics based on contrast-enhanced MRI for preoperatively predicting treatment response of transarterial chemoembolization in hepatocellular carcinoma.

BACKGROUND: Noninvasive and precise methods to estimate treatment response and identify hepatocellular carcinoma (HCC) patients who could benefit from transarterial chemoembolization (TACE) are urgently required. The present study aimed to investigate the ability of intratumoral and peritumoral radiomics based on contrast-enhanced magnetic resonance imaging (CE-MRI) to preoperatively predict tumor response to TACE in HCC patients. METHODS: A total of 138 patients with HCC who received TACE were retrospectively included and randomly divided into training and validation cohorts at a ratio of 7:3. Total 1206 radiomics features were extracted from arterial, venous, and delayed phases images. The inter- and intraclass correlation coefficients, the spearman's rank correlation test, and the gradient boosting decision tree algorithm were used for radiomics feature selection. Radiomics models on intratumoral region (TR) and peritumoral region (PTR) (3 mm, 5 mm, and 10 mm) were established using logistic regression. Three integrated radiomics models, including intratumoral and peritumoral region (T-PTR) (3 mm), T-PTR (5 mm), and T-PTR (10 mm) models, were constructed using TR and PTR radiomics scores. A clinical-radiological model and a combined model incorporating the optimal radiomics score and selected clinical-radiological predictors were constructed, and the combined model was presented as a nomogram. The discrimination, calibration, and clinical utilities were evaluated by receiver operating characteristic curve, calibration curve, and decision curve analysis, respectively. RESULTS: The T-PTR radiomics models performed better than the TR and PTR models, and the T-PTR (3 mm) radiomics model demonstrated preferable performance with the AUCs of 0.884 (95%CI, 0.821-0.936) and 0.911 (95%CI, 0.825-0.975) in both training and validation cohorts. The T-PTR (3 mm) radiomics score, alkaline phosphatase, tumor size, and satellite nodule were fused to construct a combined nomogram. The combined nomogram [AUC: 0.910 (95%CI, 0.854-0.958) and 0.918 (95%CI, 0.831-0.986)] outperformed the clinical-radiological model [AUC: 0.789 (95%CI, 0.709-0.863) and 0.782 (95%CI, 0.660-0.902)] in the both cohorts and achieved good calibration capability and clinical utility. CONCLUSIONS: CE-MRI-based intratumoral and peritumoral radiomics approach can provide an effective tool for the precise and individualized estimation of treatment response for HCC patients treated with TACE.

Design, synthesis and biological evaluation of selective histone deacetylase 6 (HDAC6) inhibitors bearing benzoindazole or pyrazoloindazole scaffold as surface recognition motif.

A series of compounds were designed and synthesized based on the compound 11i bearing phenylpyrazole scaffold with histone deacetylase 6 (HDAC6) inhibitory activity. Most of the compounds showed considerable inhibitory activity against HDAC6 and compound A16 with good inhibitory activity was found therein. We further found that A16 had an inhibitory effect on inflammatory mediators (NO, TNF-α, IL-6) involved in inflammatory response and neuroendocrine regulation. In addition, A16 has a certain neuroprotective effect on PC12 cells injured by hydrogen peroxide. Acute toxicity assay showed that the LD50 of A16 was 274.47 mg/kg in mouse model. Furthermore, A16 displayed good stability properties in microsomes and plasma.

Synthesis and antitumor effects of novel 18ß-glycyrrhetinic acid derivatives featuring an exocyclic α,ß-unsaturated carbonyl moiety in ring A.

A series of novel 18ß-glycyrrhetinic acid (GA) derivatives featuring an exocyclic α,ß-unsaturated carbonyl moiety in ring A were synthesized and evaluated for their antitumor activities. Compounds 5c and 5l showed stronger cytotoxicity than other compounds and reported GA analogue CDODA-Me (methyl 2-cyano-3,11-dioxo-18ß-olean-1,12-dien-30-oate). 5c and 5l induced apoptosis in cancer cells accompanying with c-Flip reduction and Noxa induction, associated with decreased HDAC3 expression and increased acetylation of H3. 5l displayed better stability properties than 5c and CDODA-Me in microsomes and plasma, 5l also showed favorable pharmacokinetic profiles and inhibited tumor growth in mice. Compound 5l represents a new type of GA derivatives with improved antitumor activity.

Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents.

HDAC inhibitors and BRD4 inhibitors were considered to be potent anti-cancer agents. Recent studies have demonstrated that HDAC and BRD4 participate in the regulation of some signal paths like PI3K-AKT. In this work, a series of indole derivatives that combine the inhibitory activities of BRD4 and HDAC into one molecule were designed and synthesized through the structure-based design method. Most compounds showed potent HDAC inhibitory activity and moderate BRD4 inhibitory activity. In vitro anti-proliferation activities of the synthesized compounds were also evaluated. Among them, 19f was the most potent inhibitor against HDAC3 with IC50 value of 5 nM and BRD4 inhibition rate of 88% at 10 µM. It was confirmed that 19f could up-regulate the expression of Ac-H3 and reduce the expression of c-Myc by western blot analysis. These results indicated that 19f was a potent dual HDAC/BRD4 inhibitor and deserved further investigation.

Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif.

In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1' of pyrazol gave the most selectivity. The most compounds 11i (GI50=3.63µM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.

Kynurenine Attenuates Ulcerative Colitis Mediated by the Aryl Hydrocarbon Receptor.

The higher prevalence of ulcerative colitis (UC) and the side effects of its therapeutic agents contribute to finding novel treatments. This study aimed to investigate whether kynurenine (KYN), a tryptophan metabolite, has the possibility of alleviating UC and further clarifying the underlying mechanism. The effect of KYN on treating UC was evaluated by intestinal pathology, inflammatory cytokines, and tight-junction proteins in colitis mice and LPS-stimulated Caco-2 cells. Our results revealed that KYN relieved pathological symptoms of UC, improved intestinal barrier function, enhanced AhR expression, and inhibited NF-κB signaling pathway activation in the colon of colitis mice. Moreover, the improved intestinal barrier function, the decreased inflammasome production, and the inhibited activation of the NF-κB signaling pathway by KYN were dependent on AhR in Caco-2 cells. KYN could trigger AhR activation, inactivate the NF-κB signaling pathway, and inhibit NLRP3 inflammasome production, thus alleviating intestinal epithelial barrier dysfunction and reducing intestinal inflammation. In conclusion, the present study reveals that KYN ameliorates UC by improving the intestinal epithelial barrier and activating the AhR-NF-κB-NLRP3 signaling pathway, and it can be a promising therapeutic agent and dietary supplement for alleviating UC.

Amide proton transfer weighted combined with diffusion kurtosis imaging for predicting lymph node metastasis in cervical cancer.

OBJECTIVE: To investigate the value of amide proton transfer weighted (APTw) combined with diffusion kurtosis imaging (DKI) in quantitative prediction of lymph node metastasis (LNM) in cervical carcinoma (CC). METHODS: Data of 19 LNM(+) and 50 LNM(-) patients with CC were retrospectively analyzed. 3.0 T MRI scan was performed before the operation, including APTw and DKI. After post-processing, quantitative magnetization transfer ratio asymmetric at 3.5 ppm [MTRasym (3.5 ppm)], mean kurtosis (MK), and mean diffusivity (MD) maps were obtained. The MTRasym(3.5 ppm), MK, and MD values were respectively measured by two observers, and intra-class correlation coefficients (ICC) were used to test the consistency of the results. The independent samples t-test or Mann-Whitney U test was used to compare the differences in the values of each parameter. The ROC curve was used to analyze the predictive performance of parameters with significant differences and their combination parameter. RESULTS: The two observers had good agreement in the measurement of each data (ICC > 0.75). The MTRasym(3.5 ppm) and MK values of the LNM(+) group(3.260 ± 0.538% and 0.531 ± 0.202) were higher than those of the LNM(-) group(2.698 ± 0.597% and 0.401 ± 0.148) (P < 0.05), while there was no significant difference in MD values between the two groups(P > 0.05). The area under the curves (AUCs) of MTRasym(3.5 ppm), MK value, and MTRasym(3.5 ppm) + MK value were 0.763, 0.716, and 0.813, respectively, when predicting LNM status of CC. CONCLUSION: APTw and DKI can quantitatively predict LNM status of CC, which is of importance in clinical diagnosis and treatment.

Influence of Fibre Orientation on the Slotting Quality of CFRP Composites Using the Multi-Tooth Mill.

Carbon fibre-reinforced plastic (CFRP) composites, prized for their exceptional properties, often encounter surface quality issues during slotting due to their inherent heterogeneity. This paper tackles CFRP slotting challenges by employing multi-tooth mills in experiments with various fibre orientations and tool feed rates. In-plane scratching tests are performed under linearly varying loads; then, slotting experiments are conducted at different parameters. The scratching test results indicate that the fibre orientation and cutting angles have significant influences on forces and fracture process. The slotting experiments demonstrate that cutting forces and surface roughness Sa of the bottom slotting surface are notably affected by the fibre orientation, with disparities between up-milling and down-milling sides. Reorganising Sa data by local fibre cutting angle θ highlights consistent Sa variations between up-milling and down-milling sides for 0° ≤ θ ≤ 90°, with lower Sa on the up-milling side. However, for 90° < θ ≤ 150°, Sa variations diverge, with lower Sa on the down-milling side. Unexpectedly, Sa on the down-milling side decreases with increasing θ in this range. Additionally, the tool feed rate exerts a more pronounced influence on Sa on the up-milling side.

Nomogram based on dual-energy CT-derived extracellular volume fraction for the prediction of microsatellite instability status in gastric cancer.

Purpose: To develop and validate a nomogram based on extracellular volume (ECV) fraction derived from dual-energy CT (DECT) for preoperatively predicting microsatellite instability (MSI) status in gastric cancer (GC). Materials and methods: A total of 123 patients with GCs who underwent contrast-enhanced abdominal DECT scans were retrospectively enrolled. Patients were divided into MSI (n=41) and microsatellite stability (MSS, n=82) groups according to postoperative immunohistochemistry staining, then randomly assigned to the training (n=86) and validation cohorts (n=37). We extracted clinicopathological characteristics, CT imaging features, iodine concentrations (ICs), and normalized IC values against the aorta (nICs) in three enhanced phases. The ECV fraction derived from the iodine density map at the equilibrium phase was calculated. Univariate and multivariable logistic regression analyses were used to identify independent risk predictors for MSI status. Then, a nomogram was established, and its performance was evaluated by ROC analysis and Delong test. Its calibration performance and clinical utility were assessed by calibration curve and decision curve analysis, respectively. Results: The ECV fraction, tumor location, and Borrmann type were independent predictors of MSI status (all P < 0.05) and were used to establish the nomogram. The nomogram yielded higher AUCs of 0.826 (0.729-0.899) and 0.833 (0.675-0.935) in training and validation cohorts than single variables (P<0.05), with good calibration and clinical utility. Conclusions: The nomogram based on DECT-derived ECV fraction has the potential as a noninvasive biomarker to predict MSI status in GC patients.

A Lesion-Fusion Neural Network for Multi-View Diabetic Retinopathy Grading.

As the most common complication of diabetes, diabetic retinopathy (DR) is one of the main causes of irreversible blindness. Automatic DR grading plays a crucial role in early diagnosis and intervention, reducing the risk of vision loss in people with diabetes. In these years, various deep-learning approaches for DR grading have been proposed. Most previous DR grading models are trained using the dataset of single-field fundus images, but the entire retina cannot be fully visualized in a single field of view. There are also problems of scattered location and great differences in the appearance of lesions in fundus images. To address the limitations caused by incomplete fundus features, and the difficulty in obtaining lesion information. This work introduces a novel multi-view DR grading framework, which solves the problem of incomplete fundus features by jointly learning fundus images from multiple fields of view. Furthermore, the proposed model combines multi-view inputs such as fundus images and lesion snapshots. It utilizes heterogeneous convolution blocks (HCB) and scalable self-attention classes (SSAC), which enhance the ability of the model to obtain lesion information. The experimental results show that our proposed method performs better than the benchmark methods on the large-scale dataset.

Radiative cooling assisted self-sustaining and highly efficient moisture energy harvesting.

Harvesting electricity from ubiquitous water vapor represents a promising route to alleviate the energy crisis. However, existing studies rarely comprehensively consider the impact of natural environmental fluctuations on electrical output. Here, we demonstrate a bilayer polymer enabling self-sustaining and highly efficient moisture-electric generation from the hydrological cycle by establishing a stable internal directed water/ion flow through thermal exchange with the ambient environment. Specifically, the radiative cooling effect of the hydrophobic top layer prevents the excessive daytime evaporation from solar absorption while accelerating nighttime moisture sorption. The introduction of LiCl into the bottom hygroscopic ionic hydrogel enhances moisture sorption capacity and facilitates ion transport, thus ensuring efficient energy conversion. A single device unit (1 cm2) can continuously generate a voltage of ~0.88 V and a current of ~306 µA, delivering a maximum power density of ~51 µW cm-2 at 25 °C and 70% relative humidity (RH). The device has been demonstrated to operate steadily outdoors for continuous 6 days.

Boosting Evaporative Cooling Performance with Microporous Aerogel.

Hydrogel-based evaporative cooling with a low carbon footprint is regarded as a promising technology for thermal regulation. Yet, the efficiency of hydrogel regeneration at night generally mismatches with vapor evaporation during the day, resulting in a limited cooling time span, especially in arid regions. In this work, we propose an efficient approach to improve hydrogel cooling performance, especially the cooling time span, with a bilayer structure, which comprises a bottom hydrogel layer and an upper aerogel layer. The microporous aerogel layer can reduce the saturation vapor density at the hydrogel surface by employing daytime radiative cooling, together with increased convective heat transfer resistance by thermal insulation, thus boosting the duration of evaporative cooling. Specifically, the microstructure of porous aerogel for efficient radiative cooling and vapor transfer is synergistically optimized with a cooling performance model. Results reveal that the proposed structure with a 2-mm-thick SiO2 aerogel can reduce the temperature by 1.4 °C, meanwhile extending the evaporative cooling time span by 11 times compared to a single hydrogel layer.

A Hierarchically Nanofibrous Self-Cleaning Textile for Efficient Personal Thermal Management in Severe Hot and Cold Environments.

Climate change has recently caused more and more severe temperatures, inducing a growing demand for personal thermal management at outdoors. However, designing textiles that can achieve personal thermoregulation without energy consumption in severely hot and cold environments remains a huge challenge. Herein, a hierarchically nanofibrous (HNF) textile with improved thermal insulation and radiative thermal management functions is fabricated for efficient personal thermal management in severe temperatures. The textile consists of a radiative cooling layer, an intermediate thermal insulation layer, and a radiative heating layer, wherein the porous lignocellulose aerogel membrane (LCAM) as intermediate layer has low thermal conductivity (0.0366 W·m-1·K-1), ensuring less heat loss in cold weather and blocking external heat in hot weather. The introduction of polydimethylsiloxane (PDMS) increases the thermal emissivity (90.4%) of the radiative cooling layer in the atmospheric window and also endows it with a perfect self-cleaning performance. Solar absorptivity (80.1%) of the radiative heating layer is dramatically increased by adding only 0.05 wt% of carbon nanotubes (CNTs) into polyacrylonitrile. An outdoor test demonstrates that the HNF textile can achieve a temperature drop of 7.2 °C compared with white cotton in a hot environment and can be as high as 12.2 °C warmer than black cotton in a cold environment. In addition, the HNF textile possesses excellent moisture permeability, breathability, and directional perspiration performances, making it promising for personal thermal management in severely hot and cold environments.

Natural products in pursuing novel therapies of nonalcoholic fatty liver disease and steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are hepatic manifestations of systemic metabolic dysfunction, which affect one-quarter of the adult population worldwide as estimated, and exhibit high risk in progressing to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Current drug discovery focuses on modifying homeostasis of lipids, carbohydrates, and cholesterol, as well as inhibiting inflammation and fibrogenesis. Many natural products show promising activities on various molecular targets involving these mechanisms; however, they have not been fully exploited. Since some compounds are components of healthy food, they may be employed in chemoprevention as adjuvants to lifestyle modification, while natural products such as alkaloids and sesquiterpenoids could serve as promising starting points for structural modifications and deserve further development.

Simultaneous Passive Cooling and Humidity Control via the Fiber-Encapsulated Gel Structure.

Radiative cooling is a promising technology that offers benefits such as reducing cooling energy demand, mitigating climate change impacts, and contributing to sustainable development. However, previous radiative cooling technologies are unable to manage humidity, which is crucial and energy-intensive in many applications. Therefore, it is necessary to extend the capabilities of radiative coolers to include humidity control. Here, we demonstrate a fiber-encapsulated gel structure (FEGS) to realize simultaneous radiative cooling and humidity control. By employing a phase equilibrium-based strategy, the FEGS can control relative humidity to any value between 30 and 80%. The changes in temperature, thermal conductivity, and water content during the regeneration process of FEGS were studied. Field tests demonstrated that the FEGS can achieve 5 °C subambient temperature reduction under direct sunlight while maintaining the relative humidity at a controlled level of 58 ± 3% for a continuous period of 3 days. This work can potentially pave the way for the comanagement of temperature and humidity in a passive, low-cost, and scalable way.

Multi-parametric MRI-based radiomics for preoperative prediction of multiple biological characteristics in endometrial cancer.

Purpose: To develop and validate multi-parametric MRI (MP-MRI)-based radiomics models for the prediction of biological characteristics in endometrial cancer (EC). Methods: A total of 292 patients with EC were divided into LVSI (n = 208), DMI (n = 292), MSI (n = 95), and Her-2 (n = 198) subsets. Total 2316 radiomics features were extracted from MP-MRI (T2WI, DWI, and ADC) images, and clinical factors (age, FIGO stage, differentiation degree, pathological type, menopausal state, and irregular vaginal bleeding) were included. Intra-class correlation coefficient (ICC), spearman's rank correlation test, univariate logistic regression, and least absolute shrinkage and selection operator (LASSO) were used to select radiomics features; univariate and multivariate logistic regression were used to identify clinical independent risk factors. Five classifiers were applied (logistic regression, random forest, decision tree, K-nearest neighbor, and Bayes) to construct radiomics models for predicting biological characteristics. The clinical model was built based on the clinical independent risk factors. The combined model incorporating the radiomics score (radscore) and the clinical independent risk factors was constructed. The model was evaluated by ROC curve, calibration curve (H-L test), and decision curve analysis (DCA). Results: In the training cohort, the RF radiomics model performed best among the five classifiers for the three subsets (MSI, LVSI, and DMI) according to AUC values (AUCMSI: 0.844; AUCLVSI: 0.952; AUCDMI: 0.840) except for Her-2 subset (Decision tree: AUC=0.714), and the combined model had higher AUC than the clinical model in each subset (MSI: AUCcombined =0.907, AUCclinical =0.755; LVSI: AUCcombined =0.959, AUCclinical =0.835; DMI: AUCcombined = 0.883, AUCclinical =0.796; Her-2: AUCcombined =0.812, AUCclinical =0.717; all P<0.05). Nevertheless, in the validation cohort, significant differences between the two models (combined vs. clinical model) were found only in the DMI and LVSI subsets (DMI: AUCcombined =0.803, AUCclinical =0.698; LVSI: AUCcombined =0.926, AUCclinical =0.796; all P<0.05). Conclusion: The radiomics analysis based on MP-MRI and clinical independent risk factors can potentially predict multiple biological features of EC, including DMI, LVSI, MSI, and Her-2, and provide valuable guidance for clinical decision-making.

Parental exposure to 3-methylcholanthrene before gestation adversely affected the endocrine system and spermatogenesis in male F1 offspring.

The compound 3-methylcholanthrene (3-MC) is an environmental pollutant belonging to the PAHs, which reportedly have the potential to disrupt the endocrine systems of animals. In the present study, 4-week-old male and female mice were given 3-MC through their diet at a dose of 0.5 mg/kg of chow for 6 weeks before pregnancy. The first filial (F1) generation offspring of exposed or unexposed parental mice were sacrificed at the age of 5 or 10 weeks (F1-5 W or F1-10 W), and the potential effects on the F0 and F1 offspring were evaluated. The results showed that the serum and testicular testosterone (T) levels and the genes involved in T synthesis in F0 males and male F1-5 W individuals born from female mice exposed to 3-MC were significantly decreased. In addition, histological analysis suggested that exposure to 3-MC significantly disrupted testicular morphology in F0 mice and in the offspring of female mice exposed to 3-MC. Further investigation revealed that genes involved in spermatogenesis, such as Phosphoglycerate kinase 2 (Pgk2), Glial cell derived neurotrophic factor (Gdnf), Myeloblastosis oncogene (Myb), DEAD box helicase 4 (Ddx4) and KIT proto-oncogene receptor tyrosine kinase (Kit), were suppressed in these mice. However, the adverse effects of parental 3-MC exposure on the adolescent mice were mitigated when they grew to adulthood, which was verified by studies on F1-10 W mice. Our results suggest that female exposure to 3-MC has the potential to disrupt the endocrine system and spermatogenesis in male offspring; nevertheless, the adverse effects might be mitigated with age.

The fungicide prothioconazole and its metabolite prothioconazole-desthio disturbed the liver-gut axis in mice.

The triazole fungicide prothioconazole (PTC) can cause adverse effects in animals, and its main metabolite prothioconazole-desthio (PTC-d) is even much more harmful. However, the toxic effects of PTC and PTC-d on the liver-gut axis of mice are still unknown. In the present experiment, we found that oral exposure to PTC and PTC-d increased total bile acids (TBAs) levels in the serum, liver, and feces. Correspondingly, the transcription of genes involved in bile acids (BAs) disposition was significantly influenced by PTC or PTC-d exposure. Furthermore, the BAs composition of serum BAs was analyzed by LC-MS, and the results indicated that PTC and PTC-d exposure changed the BAs composition, lowered the ratio of conjugated/unconjugated BAs, elevated the ratio of CA/b-MCA, and enhanced the hydrophobicity of BAs pool. 16s RNA gene sequencing of the DNA from colonic contents uncovered that PTC and PTC-d exposure altered the relative abundance and constitution of intestinal microbiota, increasing the relative level of Lactobacillus with bile salt hydrolase (BSH) activity. Furthermore, PTC and PTC-d exposure impaired the gut barrier function, causing an increase in mucus secretion. In particular, the effects of PTC-d on some endpoints in the BAs metabolism and gut barrier function had been proven to be more significant than the parent compound PTC. All these findings draw attention to the health risk of PTC and PTC-d exposure in regulating BAs metabolism, which might lead to some metabolic disorders and occur of related diseases in animals.

Design, Synthesis, and Biological Evaluations of Pyridyl 4,5,6,7-Tetrahydro-4,7-Methanobenzo[d]isoxazoles as Potent and Selective Inhibitors of 11ß-Hydroxylase.

Inhibition of CYP11B1 is a promising therapy for severe diseases caused by excessive cortisol. Enantiomer discrimination provides clues to achieve selectivity that CYP11B1 and homologous CYP11B2 were selectively bound by S- and R-fadrozole, respectively, in distinct binding modes. Pyridyl 4,5,6,7-tetrahydro-4,7-methanobenzo[d]isoxazoles showing a similar binding mode to S-fadrozole in CYP11B1 were designed as potent and selective CYP11B1 inhibitors. Compound 7aa exhibited a highly potent CYP11B1 inhibition similar to that of the drug osilodrostat (IC50's of 9 and 6 nM, respectively) but was 1500-fold more selective over CYP11B2 compared to osilodrostat (selectivity factors of 125 versus 0.08, respectively). Strong reductions of plasma cortisol concentrations by compound 7aa were demonstrated in rats without interference in aldosterone production after oral application. It showed no inhibition against a panel of steroidogenic and hepatic CYP enzymes. Exhibiting a good pharmacokinetic profile, compound 7aa was considered as a drug candidate for further development.

Parental exposure 3-methylcholanthrene disturbed the enterohepatic circulation in F1 generation of mice.

3-methylcholanthrene (3 MC) is an environmental compound belonging to the PAHs and is reportedly thought to be a risk factor for the prevalence of hepatic function disorder. Here, a dose of 0.5 mg/kg of 3 MC was given to 4-week-old male and female mice (F0) in their diet for 6 weeks. After exposure, then the mice were mated between different groups. The first filial (F1) generation offspring of exposed or unexposed parental mice were sacrificed at the age of 5 weeks (F1-5 W), and the potential effects on the F0 and F1 offspring were evaluated. The results showed that the total bile acids (TBAs) in the serum and feces in F0 females and female F1-5 W individuals born from female mice exposed to 3 MC decreased, while the TBAs in the liver increased. The transcriptional levels of major genes participating in synthesis, regulation, transportation and apical uptake was also altered correspondingly. In addition, the transcription of some genes related to inflammation was enhanced in these mice. Further investigation revealed that in addition to distinct changes in the mucus secretion, tight junction proteins and ion transport were induced, and antimicrobial peptides were also disrupted in the intestine of F0 mice and F1-5 W female offspring of maternal mice exposed to 3 MC. Our results suggested that exposure to 3 MC, but not male exposure, had the potential to interfere with BAs metabolism, affecting gut barrier function. Females were more seriously affected than males.