Ring-Contracted Artemisinin Derivatives as Novel CDK 4/6 Inhibitors: Synthesis and Anti-Breast Cancer Evaluation.

The endoperoxide group of artemisinins is universally accepted an essential group for their anti-cancer effects. In this study, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, 1H-NMR and 13C NMR. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to those of the positive control Palbociclib, with GI50 values of 4.87±0.23 µM and 9.97±1.44 µM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 was the most potent compound against CDK6/cyclin D3 kinase, with an IC50 value of 0.135±0.041 µM, and its activity was approximately 1/3 of the positive control Palbociclib.

From bonds to interactions: comprehensive molecular characterization via polarizable bond-dipole approach.

Accurately characterizing molecular interactions stands as a pivotal requirement for ensuring the reliability of molecular dynamics simulations. In line with our bond-dipole-based interaction model proposed by Gao et al. [X.-C. Gao, Q. Hao and C.-S. Wang, J. Chem. Theory Comput., 2017, 13, 2730-2741.], we have implemented an efficient and concise approach to compute electrostatic potential. This methodology capitalizes on the polarizable nature of chemical bond dipoles, resulting in a model of remarkable simplicity. In this study, we have revised the polarizable bond-dipole-based force field (PBFF) through the meticulous curation of quantum chemical data sets. These data sets encompass a comprehensive collection of 40 000 conformations, including those of water, methylamine, methanol, and N-methylacetamide. Additionally, we incorporate 520 hydrogen-bonded dimers into our data sets. In pursuit of enhanced accuracy in molecular dynamics simulations and a more faithful representation of potential energy landscapes, we undertook the re-optimization of the nonbonded parameters within the PBFF framework. Concurrently, we intricately fine-tuned the bonded parameters. The results of our comprehensive evaluation denote that this newly optimized force field method adeptly and efficiently computes structural characteristics, harmonic frequencies, and interaction energies. Overall, this study provides further validation for the applicability of PBFF in molecular dynamics simulations.

A scheme for rapid evaluation of the intermolecular three-body polarization effect in water clusters.

The ability to accurately and rapidly evaluate the intermolecular many-body polarization effect of the water system is very important for computer simulations of biomolecule in aqueous. In this paper, a scheme is proposed based on the polarizable dipole-dipole interaction model and used to rapidly estimate the intermolecular many-body polarization effect in water clusters. We use a bond-dipole-based polarization function to evaluate the polarization energy. We regard two OH bonds of a water molecule as two bond-dipoles and set the permanent OH bond-dipole moment of a water molecule to be 1.51 Debye. We estimate the induced OH bond-dipole moment via a simple formula in which only one correction factor is needed. This scheme is then applied to tens of water clusters to calculate the three- and four-body interaction energies. The three-body interaction energies of 93 water clusters produced by our scheme are compared with those produced by the counterpoise-corrected CCSD(T)/aug-cc-pVDZ, MP2/aug-cc-pVDZ, M06-2X/jul-cc-pVTZ methods, by the AMOEBApro13, iAMOEBA, AMOEBA+, AMOEBA+(CF) methods, and by the MB-pol method. The four-body interaction energies of 47 water clusters yielded by our scheme are compared with those yielded by the counterpoise-corrected MP2/aug-cc-pVDZ and M06-2X/ jul-cc-pVTZ methods, by the AMOEBApro13, AMOEBA+, AMOEBA+(CF) methods, and by the MB-pol method. The comparison results show that the scheme proposed in this paper can reproduce the counterpoise-corrected CCSD(T)/aug-cc-pVDZ three-body interaction energies and reproduce the counterpoise-corrected MP2/aug-cc-pVDZ four-body interaction energies both accurately and efficiently. We anticipate the scheme proposed here can be useful for computer simulations of liquid water and aqueous solutions.

Fibrinogen-like protein 2 promotes the accumulation of myeloid-derived suppressor cells in the hepatocellular carcinoma tumor microenvironment.

The tumor microenvironment in hepatocellular carcinoma can be classified into cellular and non-cellular components. Myeloid-derived suppressor cells (MDSCs) are cellular components of this microenvironment that serve an important role in the progression of hepatocellular carcinoma. Fibrinogen-like protein 2 (FGL2) has been demonstrated to promote tumor progression by regulating cellular components of the tumor microenvironment in various types of malignant tumor. The present study aimed to determine the expression of FGL2 in hepatocellular carcinoma and its effect on the tumor microenvironment in order to determine novel targets for liver cancer treatment. Immunohistochemistry and reverse transcription quantitative PCR were performed to determine the expression level of FGL2 and the correlation with surface markers of human MDSCs in hepatocellular carcinoma. Furthermore, a mouse hepatocellular carcinoma cell line overexpressing FGL2 was established by stable transfection of a lentivirus expressing FGL2. In addition, fresh bone marrow cells extracted from mouse femurs were in vitro cultured using conditioned medium derived from the cell line overexpressing FGL2. An orthotopic hepatocellular carcinoma mouse model was also established. The results demonstrated that FGL2 expression level in hepatocellular carcinoma tissues was closely associated with tumor size. FGL2 level was positively correlated with the expression level of the MDSC surface markers CD11b and CD33 in hepatocellular carcinoma. The in vitro results demonstrated that FGL2 could maintain the undifferentiated state of bone marrow cells, therefore promoting MDSC accumulation. Furthermore, in the orthotopic hepatocellular carcinoma mouse model, we observed that overexpression of FGL2 could promote tumor growth and significantly increase the number of MDSCs in the tumors and spleen. Taken together, these findings suggested that FGL2 may promote hepatocellular carcinoma tumor growth by promoting the accumulation of MDSCs in the tumor microenvironment.

Effect of high pressure homogenization treatment on the rheological properties of citrus peel fiber/corn oil emulsion.

BACKGROUND: Citrus fiber is a main component in the peel of citrus and contains natural dietary fiber. It is often used as a functional additive to improve the texture or nutritional property of food. It is also widely used to reduce the content of absorbable fat in sausages and other meat products, and to improve food stability as an emulsifier. In this research, the dynamic rheological properties (linear and non-linear) of citrus peel fiber/corn oil (CF/CO) emulsion system under high pressure homogenization (HPH) treatment was investigated. RESULT: Rheological results illustrated HPH treatment significantly increased the apparent viscosity of the emulsion, reduced the activation energy of the emulsion and distinctly improved the viscoelasticity of the emulsion. Meanwhile, HPH treatment increased the linear viscoelastic region of the sample, and the behavior of the emulsion converted from strain thinning (without HPH treatment) to weak strain overshoot (with HPH treatment). Lissajous curves indicated the viscosity of the sample increased first and then decreased with strain increasing and the third harmonic contributed much more to the first harmonic compared with the fifth harmonic. Chebyshev stress decomposition revealed that, as strain increased, the samples with HPH treatment showed internal-cycle strain hardening behavior first, then turned to internal-cycle softening behavior. CONCLUSION: HPH treatment can significantly improve the processing performance of CF/CO emulsion as well as the stability against large periodic oscillations in food processing. © 2020 Society of Chemical Industry.

Copy Number Aberrations of Multiple Genes Identified as Prognostic Markers for Extrahepatic Metastasis-free Survival of Patients with Hepatocellular Carcinoma.

Extrahepatic metastasis confers unfavorable patient prognosis in patients with hepatocellular carcinoma (HCC), however, reliable markers allowing prediction of extrahepatic metastasis at the time of initial diagnosis are still lacking. This study was to identify gene-level copy number aberrations (CNAs) related to extrahepatic metastasis-free survival of HCC patients, and further examine the associations between CNAs and gene expression. Array comparative genomic hybridization (aCGH) and expression array were used to analyze gene CNAs and expression levels, respectively. The associations between CNAs of a panel of 20 genes and extrahepatic metastasis-free survival were analyzed in 66 patients with follow-up period of 1.6-90.5 months. The gene expression levels between HCCs with and without gene CNA were compared in 109 patients with HCC. We observed that gains at MDM4 and BCL2L1, and losses at APC and FBXW7 were independent prognostic markers for extrahepatic metastasis-free survival of HCC patients. Integration analysis of aCGH and expression data showed that MDM4 and BCL2L1 were significantly upregulated in HCCs with gene gain, while APC and FBXW7 were significantly downregulated in HCCs with gene loss. We concluded that gene gains at MDM4 and BCL2L1, and losses at APC and FBXW7, with concordant expression changes, were associated with extrahepatic metastasis-free survival of HCC patients and have potential to act as novel prognostic markers.

Effect of temperature on the microflora community composition in the digestive tract of the veined rapa whelk (Rapana venosa) revealed by 16S rRNA gene sequencing.

The veined rapa whelk, Rapana venosa, a poikilotherm that is susceptible to temperature, is an important and valuable fishery resource in China but a major invader around the world. We studied the effects of abnormal temperature on the digestive tract microflora of R. venosa to investigate how temperature impacts its digestion and ingestion. We characterized the microflora in nine samples by sequencing the 16S rRNA gene. To assess the species diversity within the samples, effective tags were clustered at 97% similarity by default. Mycoplasma was the most abundant genus among the three groups, and the Proteobacteria phylum had the highest diversity. However, the microflora structure in the digestive tract was significantly different at different temperatures. The top five most abundant genera in the samples housed at 16 °C were Mycoplasma, Phyllobacterium, Aliivibrio, Psychromonas, and Delftia, whereas those in the samples housed under 22 °C were Mycoplasma, Phyllobacterium, Delftia, Spirochaeta_2, and Sphingomonas, and those in the samples housed at 28 °C were Mycoplasma, Phyllobacterium, Vibrio, Delftia, and Aliivibrio. The family Flavobacteriaceae was more abundant in R. venosa housed at 22 °C and 28 °C, whereas a significant decrease in Flavobacteriaceae abundance and a substantial increase in Mycoplasmataceae abundance were observed in R. venosa housed at 16 °C. The alteration in the digestive tract microflora might further affect the function of the R. venosa digestive tract. The results presented herein might provide further insight into investigations on the effects of temperature on the digestion and ingestion of gastropods.

A Panel of Genes Identified as Targets for 8q24.13-24.3 Gain Contributing to Unfavorable Overall Survival in Patients with Hepatocellular Carcinoma.

Copy number aberrations (CNAs) in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma (HCC). This study was to identify correlation of CNAs in 8q with clinical outcomes of HCC patients, and further screen for differentially expressed genes in outcome-related CNAs. Array comparative genomic hybridization and expression arrays were performed to detect CNAs and expression levels, respectively. The correlations between CNAs in 8q and outcomes were analyzed in 66 patients, with a median follow-up time of 45.0 months (range, 2.6-108.6 months). One hundred and nine cases were further evaluated to identify differentially expressed genes in the potential outcome-related CNAs. Copy number gain in 8q was observed in 22 (33.3%) of the 66 HCC cases. The most recurrent gains (with frequencies >20%) were 8q13.3-21.3,8q21.3-23.3,8q23.3-24.13,8q24.13-24.3, and 8q24.3. Survival analysis showed that 8q24.13-24.3 gain was significantly associated with reduced overall survival (jP=0.010). Multivariate Cox analysis identified 8q24.13-24.3 gain as an independent prognostic factor for poor overall survival (HR=2.47; 95% CI=1.16-5.26; Р=0.019). Apanel of 17 genes within the 8q24.13-24.3 region, including ATAD2,SQLE,PVT1,ASAP1, and NDRG1 were significantly upregulated in HCCs with 8q24.13-24.3 gain compared to those without. These results suggest that copy number gain at 8q24.13-24.3 is an unfavorable prognostic marker for HCC patients, and the potential oncogenes ATAD2,SQLE, PVT1, ASAP1,and NDRG1 within the regional gain, may contribute coordinately to the 8q24.13-24.3 gain-related poor prognosis.

Biomass-Based Mechanically Strong and Electrically Conductive Polymer Aerogels and Their Application for Supercapacitors.

A novel biomass-based mechanically strong and electrically conductive polymer aerogel was fabricated from aniline and biodegradable pectin. The strong hydrogen bonding interactions between polyaniline (PANI) and pectin resulted in a defined structure and enhanced properties of the aerogel. All the resultant aerogels exhibited self-surppoted 3D nanoporous network structures with high surface areas (207-331m(2)/g) and hierarchical pores. The results from electrical conductivity measurements and compressive tests revealed that these aerogels also had favorable conductivities (0.002-0.1 S/m) and good compressive modulus (1.2-1.4 MPa). The aerogel further used as electrode for supercapacitors showed enhanced capacitive performance (184 F/g at 0.5 A/g). Over 74% of the initial capacitance was maintained after repeating 1000 cycles of the cylic voltammetry test, while the capacitance retention of PANI was only 57%. The improved electrochemical performance may be attributed to the combinative properties of good electrical conductivity, BET surface areas, and stable nanoporous structure of the aerogel. Thus, this aerogel shows great potential as electrode materials for supercapacitors.

Metal-free (Boc)2O-mediated C4-selective direct indolation of pyridines using TEMPO.

Direct metal-free C-4-selective indolation of pyridines is achieved for the first time using TEMPO and (Boc)2O. A variety of substituents on both indoles and pyridines are tolerated to give 3-(pyridin-4-yl)-1H-indole derivatives in moderate to excellent yields. This finding provides a novel approach for developing metal-free C-H functionalization of pyridines.

EEG-based emotion recognition with manifold regularized extreme learning machine.

EEG signals, which can record the electrical activity along the scalp, provide researchers a reliable channel for investigating human emotional states. In this paper, a new algorithm, manifold regularized extreme learning machine (MRELM), is proposed for recognizing human emotional states (positive, neutral and negative) from EEG data, which were previously evoked by watching different types of movie clips. The MRELM can simultaneously consider the geometrical structure and discriminative information in EEG data. Using differential entropy features across whole five frequency bands, the average accuracy of MRELM is 81.01%, which is better than those obtained by GELM (80.25%) and SVM (76.62%). The accuracies obtained from high frequency band features (ß, γ) are obviously superior to those of low frequency band features, which shows ß and γ bands are more relevant to emotional states transition. Moreover, experiments are conducted to further evaluate the efficacy of MRELM, where the training and test sets are from different sessions. The results demonstrate that the proposed MRELM is a competitive model for EEG-based emotion recognition.

Cu(II)-catalyzed highly regio- and stereoselective construction of C-C double bonds: an efficient method for the ketonization-olefination of indoles.

A general and efficient method for the cross-coupling of indoles with ß-keto esters by using TEMPO/CuSO4·5H2O in air as oxidant has been developed. This reaction features high functional-group compatibility and an excellent selectivity. This methodology provides an alternative approach for the ketonization-olefination of indoles in moderate to good yields.

[DNA methylation-mediated regulation of OsMAPK2 gene expression in rice callus formation].

A DNA segment with DNA methylation site was detected from rice callus with or without 5-azaC treatment by MSAP. This segment was located on the first exon of gene OsMAPK2 and its 5' non-coding region. Gene OsMAPK2 had a CpG island in the 5' region and was homologous to AtMAPK12. Real-time quantitative PCR and Hpa II-McrBC PCR were conducted to detect the gene expression and DNA methylation of OsMAPK2 in the process of callus formation. The results showed that the DNA methylation was able to control the expression of OsMAPK2. The additon of 2.0 mg/L 2,4-D could induce DNA demethylation in the 5' region and activate the expression of OsMAPK2 gene. However, after long-time stimulation (100 h), the gene was methylated again, and the gene expression level was decreased. The trends of DNA methylation and gene expression stimulated by low concentrations of 2,4-D (0.5 and 1.0 mg/L) were similar to 2.0 mg/L 2,4-D, but the expression levels in each time point were low. On the other hand, high concentration of 2,4-D (5.0 mg/L) completed the processes of induction and suppression of the gene in a shorter time.