Macrophage AHR-TLR4 cross-talk drives p-STAT3 (Ser727)-mediated mitochondrial oxidative stress and upregulates IDO/ICAM-1 in the steatohepatitis induced by aflatoxin B1.

Aflatoxin B1 (AFB1) is a major mycotoxin contaminant showing in the environment and foods. In this study, the molecular initiating events (MIEs) of AFB1-induced steatohepatitis were explored in mice and human cell model. We observed dose-dependent steatohepatitis in the AFB1-treated mice, including triglyceride accumulation, fibrotic collagen secretion, enrichment of CD11b + and F4/80+ macrophages/Kupffer cells, cell death, lymphocytes clusters and remarkable atrophy areas. The gut barrier and gut-microbiota were also severely damaged after the AFB1 treatment and pre-conditioned colitis in the experimental mice aggravated the steatohepatitis phenotypes. We found that macrophages cells can be pro-inflammatorily activated to M1-like phenotype by AFB1 through an AHR/TLR4/p-STAT3 (Ser727)-mediated mitochondrial oxidative stress. The phenotypes can be rescued by AHR inhibitors in the mice model and human cell model. We further showed that this signaling axis is based on the cross-talk interaction between AHR and TLR4. Gene knock-up experiment found that the signaling is dependent on AFB1 ligand-binding with AHR, but not protein expressions of TLR4. The signaling elevated NLRP3 and two immune metabolic enzymes ICAM-1 and IDO that are associated with macrophage polarization. Results from intervention experiments with natural anti-oxidant and AHR inhibitor CH223191 suggest that the macrophage polarization may rely on AHR and ROS. Our study provides novel and critical references to the food safety and public health regulation of AFB1.

Prediction of local tumor progression after microwave ablation for early-stage hepatocellular carcinoma with machine learning.

Objectives: Local tumor progression (LTP) is a major constraint for achieving technical success in microwave ablation (MWA) for the treatment of early-stage hepatocellular carcinoma (EHCC). This study aims to develop machine learning (ML)-based predictive models for LTP after initial MWA in EHCC. Materials and Methods: A total of 607 treatment-naïve EHCC patients (mean ± standard deviation [SD] age, 57.4 ± 10.8 years) with 934 tumors according to the Milan criteria who subsequently underwent MWA between August 2009 and January 2016 were enrolled. During the same period, 299 patients were assigned to the external validation datasets. To identify risk factors of LTP after MWA, clinicopathological data and ablation parameters were collected. Predictive models were developed according to 21 variables using four ML algorithms and evaluated based on the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CIs). Results: After a median follow-up time of 28.7 months (range, 7.6-110.5 months), 6.9% (42/607) of patients had confirmed LTP in the training dataset. The tumor size and number were significantly related to LTP. The AUCs of the four models ranged from 0.791 to 0.898. The best performance (AUC: 0.898, 95% CI: [0.842 0.954]; SD: 0.028) occurred when nine variables were introduced to the CatBoost algorithm. According to the feature selection algorithms, the top six predictors were tumor number, albumin and alpha-fetoprotein, tumor size, age, and international normalized ratio. Conclusions: Out of the four ML models, the CatBoost model performed best, and reasonable and precise ablation protocols will significantly reduce LTP.

Tributyltin reduces bone mineral density by reprograming bone marrow mesenchymal stem cells in rat.

Tributyltin (TBT), a proven endocrine disrupter, was widely used in industry and agriculture. Previous research showed that TBT could alter the balance between osteogenesis and adipogenesis, which may have significant consequences for bone health. Herein, we exposed male rats to TBT chloride (TBTCl) to evaluate the deleterious effects of TBT on bone. Exposure to 50 µg kg-1 TBT resulted in a significant decrease in bone mineral density (BMD) at the femur diaphysis region in the rat. A dose-dependent increase in lipid accumulation and adipocyte number was observed in the bone marrow (BM) of the femur. Meanwhile, TBTCl treatment significantly enhanced the expression of PPARγ and attenuated the expression of Runx2 and ß-catenin in BM. In addition, serum ALP activity of TBT-exposed rats also showed a dose-dependent decrease. These results suggest that TBT could reduce BMD via inhibition of the Wnt/ß-catenin pathway and skew the adipo-osteogenic balance in the BM of rats.

One immunoassay probe makes SERS and fluorescence two readout signals: Rapid imaging and determination of intracellular glutathione levels.

In this paper, one probe (TPPA-VCh) with fluorescence and Surface-enhanced Raman Scattering (SERS) two readout signals, which has high sensitivity and specificity to glutathione in both vitro and cell image applications, is designed and synthesized. Furthermore, the quenched emissions and intensified SERS signals is obtained by loading TPPA-VCh on the surfaces of gold nanoparticles.

T-box Transcription Factor Tbx3 Contributes to Human Hepatocellular Carcinoma Cell Migration and Invasion by Repressing E-Cadherin Expression.

Tbx3, a member of the T-box family of transcription factors, contributes directly to tumor formation, migration, and invasion. However, the role of Tbx3 in the metastasis of HCC remains unclear. In the present study, Tbx3 expression was detected in HCC tissues and cells by Western blot, and Tbx3 expression was regulated by use of siRNAs or lentivirus-mediated vectors. Here we found that Tbx3 protein expression increased in HCC tissues and cell lines. Tbx3 expression was positively associated with multiple tumor nodes, venous infiltration, and advanced TNM tumor stage. Survival analysis demonstrated that Tbx3 expression was an independent prognostic factor for HCC patients. In vitro assays further validated that Tbx3 indeed prompted HCC cell migration and invasion. In addition, Tbx3 expression was negatively related with E-cadherin expression in HCC tissues. Mechanically, Tbx3 inhibited the expression of E-cadherin, and then facilitated epithelial-mesenchymal transition (EMT) of HCC cells. Furthermore, the effect of Tbx3 knockdown on HCC cells was attenuated by E-cadherin knockdown. In conclusion, Tbx3 may be a novel prognostic factor, and it contributes to HCC cell migration, invasion, and EMT by repressing E-cadherin expression. Thus, Tbx3 may be recommended as a therapeutic target for HCC patients.

[Antitumor effect of DHA compound in vitro and in vivo and its mechanism].

OBJECTIVE: To study the anticancer effect in vitro and in vivo and mechanism of DHA compound. METHODS: Cervical cancer cell line HeLa cells, glioma cell line U251 cells and mouse hepatoma H(22) tumor were used in this study. Transmission electron microscopy and fluorescence microscopy were used to observe the morphological changes of cell apoptosis. Western blot was used to detect the expression of caspase-3. RT-PCR was used to determine the effect on Bcl-2 and Bax mRNA transcription in U251. RESULTS: Antitumor effect was observed in vivo and in vitro. Typical morphological changes were seen in cancer cells. The level of caspase-3 was significantly increased and the content of Bcl-2 mRNA was decreased significantly, while the content of Bax mRNA was significantly increased in the U251 cells after treatment with DHA compound. CONCLUSION: DHA compound can inhibit the growth of some types of tumors and the increase of caspase-3 and Bax mRNA and decrease of Bcl-2 mRNA may be involved in its mechanism of action.