Trifluoromethyl quinoline derivative targets inhibiting HDAC1 for promoting the acetylation of histone in cervical cancer cells.

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity. Therefore, in this work, combined with network pharmacology analysis and experimental validation, we investigated the anti-cervical cancer activity and molecular mechanism of a new trifluoromethyl quinoline (FKL) derivative in vivo and in vitro. FKL117 inhibited the proliferation of cervical cancer cells in a dose and time-dependent manner, induced apoptosis in HeLa cells, arrested the cell cycle in the G2/M phase, and regulated the expression of the apoptotic and cell cycle-related proteins Bcl-2, Bax, cyclin B1, and CDC2. We used online databases to obtain HDAC1 as one of the possible targets of FKL117 and the target binding and binding affinity were modeled by molecular docking. The results showed that FKL117 formed a hydrogen bond with HDAC1 and had good binding ability. We found that FKL117 targeted to inhibit the expression and function of HDAC1 and increased the acetylation of histone H3 and H4, which was also confirmed in vivo. The migration of HMGB1 from the nucleus to the cytoplasm further verified the above results. In conclusion, our study suggested that FKL117 might be used as a novel candidate for targeting the inhibition of HDAC1 against cervical cancer.

A genome-wide association study identifies genes associated with cuticular wax metabolism in maize.

The plant cuticle is essential in plant defense against biotic and abiotic stresses. To systematically elucidate the genetic architecture of maize (Zea mays L.) cuticular wax metabolism, 2 cuticular wax-related traits, the chlorophyll extraction rate (CER) and water loss rate (WLR) of 389 maize inbred lines, were investigated and a genome-wide association study (GWAS) was performed using 1.25 million single nucleotide polymorphisms (SNPs). In total, 57 nonredundant quantitative trait loci (QTL) explaining 5.57% to 15.07% of the phenotypic variation for each QTL were identified. These QTLs contained 183 genes, among which 21 strong candidates were identified based on functional annotations and previous publications. Remarkably, 3 candidate genes that express differentially during cuticle development encode ß-ketoacyl-CoA synthase (KCS). While ZmKCS19 was known to be involved in cuticle wax metabolism, ZmKCS12 and ZmKCS3 functions were not reported. The association between ZmKCS12 and WLR was confirmed by resequencing 106 inbred lines, and the variation of WLR was significant between different haplotypes of ZmKCS12. In this study, the loss-of-function mutant of ZmKCS12 exhibited wrinkled leaf morphology, altered wax crystal morphology, and decreased C32 wax monomer levels, causing an increased WLR and sensitivity to drought. These results confirm that ZmKCS12 plays a vital role in maize C32 wax monomer synthesis and is critical for drought tolerance. In sum, through GWAS of 2 cuticular wax-associated traits, this study reveals comprehensively the genetic architecture in maize cuticular wax metabolism and provides a valuable reference for the genetic improvement of stress tolerance in maize.

Design, synthesis and bioevaluation of novel trifluoromethylquinoline derivatives as tubulin polymerization inhibitors.

Aim: A series of novel trifluoromethylquinoline derivatives were designed, synthesized and evaluated for antitumor activities. Methodology: All compounds were evaluated for antiproliferative activity against four human cancer cell lines. Results: Among them, 5a, 5m, 5o and 6b exhibited remarkable antiproliferative activities against all the tested cell lines at nanomolar concentrations. Mechanism of action studies demonstrated that 6b targeted the colchicine binding site, potentially inhibiting tubulin polymerization, and further studies indicated that 6b could arrest LNCaP cells in the G2/M phase and induce cell apoptosis. Molecular docking confirmed that 6b could bind to the colchicine binding site. Conclusion: Results suggested that 6b could serve as a promising lead compound for the development of novel tubulin polymerization inhibitors and cancer therapy.

Hydrothermal synthesis of Bi2Se3 nanosheets by using gallic acid as a reductant.

In this work, a simple and reproducible hydrothermal synthesis was employed to synthesize two-dimensional Bi2Se3 nanosheets by using gallic acid as a reductant. Meanwhile, the effects of the amounts of gallic acid and sodium hydroxide and the surfactant Triton X-100 on phase composition and morphology of the obtained Bi2Se3 were also studied. The results reveal that gallic acid could effectively reduce Se4+ to Se2- and gave rise to the formation of Bi2Se3. Additionally, keeping the reaction conditions of molar ratio of gallic acid to the precursor elements (Bi + Se) at 1 to 1 (or higher) and using strong alkaline solutions were the key factors to synthesize high purity crystalline Bi2Se3 nanosheets. Furthermore, flower-like Bi2Se3 composed of nanosheets with a dozen nanometer thickness could be easily fabricated by adding appropriate amounts of Triton X-100. This work provides a novel approach for synthesis of ultra-thin Bi2Se3 nanosheets in a controllable manner.

Optimal body mass index cut-off points for prediction of incident diabetes in a Chinese population.

BACKGROUND: The current body mass index (BMI) classifications have been established based on the risk of obesity-related conditions, but not specifically on type 2 diabetes mellitus (T2DM). The aim of this study was to identify the optimal BMI cut-off points for assessing incident T2DM risk in the Chinese population. METHODS: The longitudinal study cohort consisted of 8735 non-diabetic participants aged 20-74 years at baseline, with a mean follow-up period of 6.0 years. Body mass index, 2-h plasma glucose after a 75-g oral glucose tolerance test, and HbA1c were measured at baseline and follow-up. RESULTS: During the follow-up period, 825 participants were diagnosed with T2DM. In multivariable Cox regression analyses, after adjusting for covariates, a strong positive association between BMI and incident T2DM was found in the whole population; however, when stratified by age groups (20-39, 40-59, and 60-74 years), the risk associations between BMI and incident T2DM decreased with increasing age and were no longer evident in the 60-74 years group (Pinteraction < 0.001). The optimal BMI cut-off points for predicting T2DM risk for men and women were 25.5 and 24.4 kg/m2 , respectively, in the 20-39 years group, and 23.5 and 23.0 kg/m2 , respectively, in the 40-59 years group. There was no predictive performance of BMI in the 60-74 years group for either sex. CONCLUSIONS: The results suggest that the performance of BMI in predicting T2DM risk was best in subjects of younger age and decreased with age. Age- and sex-specific BMI cut-off points should be considered for T2DM risk stratification in the Chinese population.

Postprandial Saturated Fatty Acids Increase the Risk of Type 2 Diabetes: A Cohort Study in a Chinese Population.

Context: Experimental evidence suggests saturated fatty acids (SFAs) are associated with insulin resistance, but results from epidemiological studies on fasting SFAs-diabetes risk are inconsistent. Objective: We investigated SFA (fasting and 2-hour postprandial) profiles and diabetes risk. Design Setting: A total of 8940 participants were recruited for the Harbin People's Health Study in 2008. Serum SFAs (fasting and 2-hour postprandial) at baseline in Chinese men and women without diabetes were profiled, and type 2 diabetes was ascertained using World Health Organization criteria after 4 to 7 years of follow-up. Outcome: Associations between 2-hour postprandial SFA (2h-SFA) and diabetes. Results: At baseline, incident cases of diabetes were older with a higher body mass index and waist circumference. After a mean follow-up of 6.7 years, 658 incident cases of diabetes occurred. After propensity score computation and inverse probability of treatment weighting (IPTW) estimation, fasting SFAs were unrelated to diabetes risk but IPTW-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the highest tertile of 2-hour postprandial stearic acid (2h-SA), 2-hour postprandial palmitic acid (2h-PA), and 2h-SFA for diabetes risk were 2.50 (2.08 to 3.16), 1.56 (1.23 to 2.02), and 1.70 (1.34 to 2.17), respectively (P-trend < 0.0001). Similarly, 2h-SA/fasting SA, 2h-PA/fasting PA, and 2h-SFA/fasting SFA ratios [IPTW-adjusted OR (95% CI): 2.94 (2.39 to 3.58), 2.31 (1.80 to 2.93), and 2.42 (1.91 to 3.11), respectively; P-trend < 0.0001] predicted the diabetes risk. Conclusions: Higher serum 2h-SFA (but not fasting SFA) independently predicted diabetes risk.