Ameliorative effects of silybin against avermectin-triggered carp spleen mitochondrial dysfunction and apoptosis through inhibition of PERK-ATF4-CHOP signaling pathway.

The aim of this study was to investigate the splenic tissue damage of environmental biological drug avermectin to freshwater cultured carp and to evaluate the effect of silybin on the splenic tissue damage of carp induced by avermectin. A total of 60 carp were divided into 4 groups with 15 carp in each group, including the control group fed with basic diet, experimental group fed with basal diet and exposed to avermectin (avermectin group), experimental group fed with basal diet supplement silybin (silybin group), and experimental group fed with basal diet supplement silybin and exposed to avermectin (silybin + avermectin group). The whole test period lasted for 30 days, and spleen tissue was collected for analysis. In this study, H&E staining, mitochondrial purification and membrane potential detection, ATP detection, DHE staining, biochemical tests, qPCR, immunohistochemistry, and apoptosis staining were used to evaluate the biological processes of spleen tissue injury, mitochondrial function, oxidative stress, apoptosis, and endoplasmic reticulum stress. The results show that silybin protected carp splenic tissue damage caused by chronic avermectin exposure, decreased mitochondrial membrane potential, decreased ATP content, ROS accumulation, oxidative stress, apoptosis, and endoplasmic reticulum stress. Silybin may ameliorate the splenic tissue damage of cultured freshwater carp caused by environmental biopesticide avermectin by alleviating mitochondrial dysfunction and inhibiting PERK-ATF4-CHOP-driven mitochondrial apoptosis. Adding silybin into the diet becomes a feasible strategy to resist the pollution of avermectin and provides a theoretical basis for creating a good living environment for freshwater carp.

Development and Validation of a Model for Predicting Diabetic Nephropathy in Chinese People.

OBJECTIVE: To develop a risk model for predicting later development of diabetic nephropathy (DN) in Chinese people with type 2 diabetes mellitus (T2DM) and evaluate its performance with independent validation. METHODS: We used data collected from the project 'Comprehensive Research on the Prevention and Control of Diabetes', which was a community-based study conducted by the Jiangsu Center for Disease Control and Prevention in 2013. A total of 11,771 eligible participants were included in our study. The endpoint was a clear diagnosis of DN. Data was divided into two components: a training set for model development and a test set for validation. The Cox proportional hazard regression was used for survival analysis in men and women. The model's performance was evaluated by discrimination and calibration. RESULTS: The incidence (cases per 10,000 person-years) of DN was 9.95 (95% CI; 8.66-11.43) in women and 11.28 (95% CI; 9.77-13.03) in men. Factors including diagnosis age, location, body mass index, high-density-lipoprotein cholesterol, creatinine, hypertension, dyslipidemia, retinopathy, diet control, and physical activity were significant in the final model. The model showed high discrimination and good calibration. CONCLUSION: The risk model for predicting DN in people with T2DM can be used in clinical practice for improving the quality of risk management and intervention.

Toll-like receptor 2-mediated MAPKs and NF-κB activation requires the GNAO1-dependent pathway in human mast cells.

Toll-like receptors (TLRs) expressed on mast cells are essential for effective host defense against a wide variety of pathogens. Previous studies have demonstrated that both TLR2 agonists Pam3CSK4 and PGN stimulated IL-8 release in human mast cells. To determine the molecular basis for this phenomenon, we utilized human mast cell line LAD2 cells. We found that only the release of IL-8 stimulated by Pam3CSK4 was TLR2-mediated, which was confirmed by specific TLR2 shRNA. Heterotrimeric G proteins have been previously implicated in TLR signaling in macrophages and monocytes. In the current study, we showed that PamCSK4 induced the activation of MAPKs, NF-κB, PI3K-Akt and Ca(2+)-calcineurin-NFAT signaling cascades in LAD2 cells. Go proteins were required for the activation of MAPKs and NF-κB in TLR2 stimulated LAD2 cells. Therefore, the genetic depletion of Gαo proteins also led to the reduction of the release of IL-8 in LAD2 cells. Taken together, the data presented here suggest that TLR2 activation in human mast cells promotes the release of inflammatory mediators via distinct signaling pathways that partially depend on the action of Go proteins.

Design, synthesis and biological evaluation of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives.

Based on our previous work, a series of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that some compounds possessed significant antiproliferative activities against four cancer cell lines, HepG2, HCT116, PC-3, and Hela. Particularly, the most promising compound 8d displayed 184-, 18-, and 17-fold improvement compared to fluorouracil in inhibiting HCT116, Hela and PC-3 cell proliferation with IC50 values of 0.37, 2.94, and 31.31µM, respectively. Most interestingly, the compound did not affect the normal human embryonic kidney cells, HEK-293. Moreover, mechanistic investigation showed that the representative compound 8d induced apoptosis and blocked cell cycle in G2/M phase in Hela cells in a dose-dependent manner. These findings suggest that compound 8d may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs.

Polycyclic Aromatic Hydrocarbons Concentrations in Drinking Water in Villages along the Huai River in China and Their Association with High Cancer Incidence in Local Population.

This study aims to evaluate the carcinogenic risk of PAHs in the drinking water of counties along the Huai River in China and study their associations with high cancer incidence in local population. We investigated 20 villages with high cancer incidence rates as the risk group and 20 villages with low rates as the control group. Water samples from each village were collected in the winter and summer seasons to analyze the concentrations of 16 PAHs. The carcinogenic risks of the PAHs were calculated for each village using a health risk assessment approach. Results showed that PAHs concentrations in 27.2% of the water samples were higher than the allowable values in China. However, no significant difference in water PAHs concentrations was observed between the risk and control groups (P > 0.05), and no correlation was found between water PAHs concentrations and cancer incidence in these villages. The average upper bound carcinogenic risks were less than 1 × 10(-4) in both groups. In conclusion, PAHs were present in the drinking water of the studied villages, but their carcinogenic risks remained within acceptable limits. PAHs in local drinking water might not be the major environmental cause of the high cancer incidences.

Design, synthesis and biological evaluation of novel 1,2,4-triazolo [3,4-b][1,3,4] thiadiazines bearing furan and thiophene nucleus.

Twenty-six novel 1,2,4-triazolo [3,4-b][1,3,4] thiadiazines containing furan and thiophene nucleus were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that most of the compounds showed moderate to potent antiproliferative activities against four cancer cell lines, PC-3, HepG2, A549, and MCF-7. Particularly, compound 32 showed eleven-, three-, and two-fold improvement compared to positive control fluorouracil in inhibiting HepG2, PC-3, and A549 cell proliferation with IC50 values of 5.09, 3.70 and 12.74 µM, respectively. Further flow-activated cell sorting analysis revealed that the most promising compound 32 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in PC-3 cells. These encouraging results should provide important information for the development of new anticancer agents.

Diagnosis and treatment of mediastinal enterogenous cysts in children.

OBJECTIVE: To investigate the diagnosis and therapy of mediastinal enterogenous cysts in children. METHODS: Clinical data of 17 cases with mediastinal enterogenous cysts within 19 years in our hospital were retrospectively analyzed. RESULTS: One case was intramural esophageal cyst and 16 cases were enteric cysts, two among which were complicated with abdominal enteric duplications. Most cases presented with symptoms of respiratory distress. Twelve cases were complicated with vertebral anomalies. Ultrasound of 12 cases and magnetic resonance imaging of 4 cases were helpful in confirming the cystic nature of these lesions. Eight cases had technetium-99m pertechnetate scintigraphy of posterior mediastinum. CONCLUSIONS: Most patients present with symptoms of respiratory distress, complicated with vertebral anomalies. Ultrasonography and magnetic resonance imaging may be helpful in confirming the cystic nature of these lesions. Technetium-99m pertechnetate scintigraphy is the most effective method for differentiation of the disease from other mediastinal cysts.