Distinctive Neurophysiological Signatures of Analgesia after Inflammatory Pain in the ACC of Freely Moving Mice.

Preclinical assessments of pain have often relied upon behavioral measurements and anesthetized neurophysiological recordings. Current technologies enabling large-scale neural recordings, however, have the potential to unveil quantifiable pain signals in conscious animals for preclinical studies. Although pain processing is distributed across many brain regions, the anterior cingulate cortex (ACC) is of particular interest in isolating these signals given its suggested role in the affective ("unpleasant") component of pain. Here, we explored the utility of the ACC toward preclinical pain research using head-mounted miniaturized microscopes to record calcium transients in freely moving male mice expressing genetically encoded calcium indicator 6f (GCaMP6f) under the Thy1 promoter. We verified the expression of GCaMP6f in excitatory neurons and found no intrinsic behavioral differences in this model. Using a multimodal stimulation paradigm across naive, pain, and analgesic conditions, we found that while ACC population activity roughly scaled with stimulus intensity, single-cell representations were highly flexible. We found only low-magnitude increases in population activity after complete Freund's adjuvant (CFA) and insufficient evidence for the existence of a robust nociceptive ensemble in the ACC. However, we found a temporal sharpening of response durations and generalized increases in pairwise neural correlations in the presence of the mechanistically distinct analgesics gabapentin or ibuprofen after (but not before) CFA-induced inflammatory pain. This increase was not explainable by changes in locomotion alone. Taken together, these results highlight challenges in isolating distinct pain signals among flexible representations in the ACC but suggest a neurophysiological hallmark of analgesia after pain that generalizes to at least two analgesics.

Dietary palm oil enhances Sterol regulatory element-binding protein 2-mediated cholesterol biosynthesis through inducing endoplasmic reticulum stress in muscle of large yellow croaker (Larimichthys crocea).

Sterol regulatory element-binding protein 2 (SREBP2) is considered to be a major regulator to control cholesterol homoeostasis in mammals. However, the role of SREBP2 in teleost remains poorly understand. Here, we explored the molecular characterisation of SREBP2 and identified SREBP2 as a key modulator for 3-hydroxy-3-methylglutaryl-coenzyme A reductase and 7-dehydrocholesterol reductase, which were rate-limiting enzymes of cholesterol biosynthesis. Moreover, dietary palm oil in vivo or palmitic acid (PA) treatment in vitro elevated cholesterol content through triggering SREBP2-mediated cholesterol biosynthesis in large yellow croaker. Furthermore, our results also found that PA-induced activation of SREBP2 was dependent on the stimulating of endoplasmic reticulum stress (ERS) in croaker myocytes and inhibition of ERS by 4-Phenylbutyric acid alleviated PA-induced SREBP2 activation and cholesterol biosynthesis. In summary, our findings reveal a novel insight for understanding the role of SREBP2 in the regulation of cholesterol metabolism in fish and may deepen the link between dietary fatty acid and cholesterol biosynthesis.

Modality-specific sensory and decisional carryover effects in duration perception.

BACKGROUND: The brain uses recent history when forming perceptual decisions. This results in carryover effects in perception. Although separate sensory and decisional carryover effects have been shown in many perceptual tasks, their existence and nature in temporal processing are unclear. Here, we investigated whether and how previous stimuli and previous choices affect subsequent duration perception, in vision and audition. RESULTS: In a series of three experiments, participants were asked to classify visual or auditory stimuli into "shorter" or "longer" duration categories. In experiment 1, visual and auditory stimuli were presented in separate blocks. Results showed that current duration estimates were repelled away from the previous trial's stimulus duration, but attracted towards the previous choice, in both vision and audition. In experiment 2, visual and auditory stimuli were pseudorandomly presented in one block. We found that sensory and decisional carryover effects occurred only when previous and current stimuli were from the same modality. Experiment 3 further investigated the stimulus dependence of carryover effects within each modality. In this experiment, visual stimuli with different shape topologies (or auditory stimuli with different audio frequencies) were pseudorandomly presented in one visual (or auditory) block. Results demonstrated sensory carryover (within each modality) despite task-irrelevant differences in visual shape topology or audio frequency. By contrast, decisional carryover was reduced (but still present) across different visual topologies and completely absent across different audio frequencies. CONCLUSIONS: These results suggest that serial dependence in duration perception is modality-specific. Moreover, repulsive sensory carryover effects generalize within each modality, whereas attractive decisional carryover effects are contingent on contextual details.

Screening and application of aptamers as fluorescent biosensors for selective and sensitive detection of hepatocellular carcinoma and in vivo targeted delivery studies.

The incidence of primary hepatocellular carcinoma (HCC) has recently ranked fifth in the world, and the incidence rate is increasing year by year worldwide. Therefore, early diagnosis is the highest priority in the treatment of HCC. In this paper, four anti-HCC aptamers were obtained using magnetic bead SELEX technology. Among them, Apt-1 had the smallest Kd value(5.9 nM) and the highest affinity. Flow cytometry results showed that the FITC-aptamers only specifically recognized HCC serum. Circular dichronism (CD) spectral characterization showed a positive peak near 275 nm and a negative peak near 250 nm for all aptamers, elucidating that the secondary structure formed by the candidate aptamers was a stem-loop B-DNA structure. In addition, molecular docking simulations showed that the binding of the HCC target to the candidate aptamer sequences was mainly dominated by hydrogen bonding. The results of the aptamer sensing performance analysis showed that under the optimized assay conditions, a linear relationship (ranging from 1 nM to 1 µM) was achieved, with a limit of detection (LOD) down to 0.75 nM and a LOQ of 2.32 nM. This was further validated in clinical samples, with a positive detection rate of more than 90%. Furthermore, aptamer-mediated in vivo delivery of luciferase mRNA showed that Apt-1-luciferase mRNA could be targeted to the liver and hepatic luciferase expression was significantly increased. These results demonstrate that the aptamer paves the way for clinical application, evidencing  significant potential to offer reference information for early diagnosis.

A Domino Protocol toward High-performance Unsymmetrical Dibenzo[d,d']thieno[2,3-b;4,5-b']dithiophenes Semiconductors.

Unsymmetric organic semiconductors have many advantages such as good solubility, rich intermolecular interactions for potential various optoelectronic applications. However, their synthesis is more challenging due to intricate structures thus normally suffering tedious synthesis. Herein, we report a trisulfur radical anion (S3⋅-) triggered domino thienannulation strategy for the synthesis of dibenzo[d,d']thieno[2,3-b;4,5-b']dithiophenes (DBTDTs) using readily available 1-halo-2-ethynylbenzenes as starting materials. This domino protocol features no metal catalyst and the formation of six C-S and one C-C bonds in a one-pot reaction. Mechanistic study revealed a unique domino radical anion pathway. Single crystal structure analysis of unsymmetric DBTDT shows that its unique unsymmetric structure endows rich and multiple weak S⋅⋅⋅S interactions between molecules, which enables the large intermolecular transfer integrals of 86 meV and efficient charge transport performance with a carrier mobility of 1.52 cm2 V-1 s-1. This study provides a facile and highly efficient synthetic strategy for more high-performance unsymmetric organic semiconductors.

A facile and light-controllable drug combination for enhanced photopharmacology.

We investigated the feasibility of creating cyclic azobenzene/azobenzene-based photo-switchable drugs that can fine-tune antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with light dependence. Furthermore, a "light-controlled drug combination" of these obtained drugs could be reversibly controlled to efficiently improve the antibiotic effect so as to reduce the minimum inhibitory concentrations (MICs) with different wavelength light illumination. Importantly, their antimicrobial activity could be easily manipulated by using light in bacterial patterning studies with high spatiotemporal precision, which might allow for localized activation of drugs and provide an alternative solution for practical clinical application in photopharmacology.

Analysis of carotid vulnerable plaque MRI high-risk features and clinical risk factors associated with concomitant acute cerebral infarction.

BACKGROUND: This study aimed to investigate the correlation between the high-risk characteristics of high-resolution MRI carotid vulnerable plaques and the clinical risk factors and concomitant acute cerebral infarction (ACI). METHODS: Forty-five patients diagnosed with a single vulnerable carotid plaque by MRI were divided into two groups based on whether they had ipsilateral ACI. The clinical risk factors and the observation values or frequency of occurrence of high-risk MRI phenotypes of plaque volume, LRNC, IPH and ulcer were statistically compared between the two groups. RESULTS: A total of 45 vulnerable carotid artery plaques were found in 45 patients, 23 patients with ACI and 22 patients without ACI. There were no significant differences in age, sex, smoking, serum TC, TG and LDL between the two groups (all P > 0.05), but the ACI group had significantly more patients with hypertension (P < 0.05) and the without ACI group coronary heart disease (P < 0.05). The volume of vulnerable carotid plaque in the group with ACI (1004.19 ± 663.57 mm3) was significantly larger than that in the group without ACI (487.21 ± 238.64 mm3) (P < 0.05). The phenotype of vulnerable carotid artery plaque was 13 cases of LRNC, 8 cases of LRNC + IPH, 5 cases of LRNC + Ulcer, and 19 cases of LRNC + IPH + Ulcer. There was no significant difference in this distribution between the two groups (all P > 0.05) with the exception of LRNC + IPH + Ulcer. The 14 cases of LRNC + IPH + LRNC + IPH + Ulcer (60.87%) in the group with ACI and was significantly greater than the 5 (22.73%) in patients without ACI (P < 0.05). CONCLUSION: It is preliminarily thought that hypertension is the main clinical risk factor for vulnerable carotid plaques with ACI and the combination of plaque volume with vulnerable carotid plaque and LRNC + IPH + Ulcer is a high-risk factor for complicated ACI. It has high clinical therapeutic value due to the accurate diagnosis of responsible vessels and plaques with high-resolution MRI.

Greater habitual resveratrol intakes were associated with lower risk of hip fracture- a 1:1 matched case-control study in Chinese elderly.

The aim of the study was to testify the association of dietary resveratrol (RSV) intakes with hip fracture risk in Chinese elderly. This was a 1:1 age- and gender- matched case-control study. Eligible cases were newly diagnosed patients of hip fracture. Dietary assessment was made by a 79-item validated food frequency questionnaire. Habitual RSV intakes were estimated as the sum of trans- and cis- isomers of resveratrol and piceid according to the available database. Multivariable conditional logistic regression was applied to examine the relationship of dietary RSV and RSV-rich foods with hip fracture risk. A total of 1,070 pairs of hip fracture incident cases and controls were recruited and 1,065 were included for analysis. Compared with the lowest group, total RSV in the highest quartile group had significantly reduced hip fracture risk by 66.3% (OR: 0.337, 0.222 ~ 0.571, ptrend < 0.001). Similar findings were observed for cis- and trans-RSV, cis- and trans-Piceid, as well as RSV-rich foods (grapes, apples and nuts) respectively. Subgroup analysis suggested more evident findings among female and less obese participants. Our findings demonstrated that higher habitual RSV intakes and RSV-rich foods, even in a relatively low amount, were associated with reduced risk of hip fracture in Chinese elderly.

Multi-aptamer-mediated hairpin allosteric and aptamer-assisted CRISPR system for detection of S. pneumoniae and S. aureus.

A novel nucleic acid aptamer nanoprobes-mediated hairpin allosteric and aptamer-assisted CRISPR system for detection of Streptococcus pneumoniae and Staphylococcus aureus is presented. In this fluorescence assay system, utilizing the hairpin allosteric effect caused by the aptamer binding to the target bacteria, the detection of S. pneumoniae is first achieved through changes in fluorescence due to FRET. Subsequently, a Cas12a protein mixture is added to detect S. aureus. The amplified output signal is triggered by two methods to ensure the sensitivity of the method: the synergistic FRET effect is achieved by the assembly of multi-aptamer through the conjugation of streptavidin-biotin, and the trans-cleavage function of CRISPR/Cas 12a. Under the optimized conditions, the proposed hairpin allosteric aptasensor could achieve high sensitivity (a detection limit of 135 cfu/mL) and broad-concentration quantification (dynamic range of 103-107 cfu/mL) of S. pneumoniae. The aptamer-assisted CRISPR system for S. aureus detection showed good linearity (R2 = 0.996) in the concentration range 102-108 cfu/mL, with a detection limit of 39 cfu/mL. No cross-reactivity with other foodborne pathogenic bacteria was observed in both systems. Taking only 55 min, this method of multiple pathogen detection proved to be promising.

Compositing Benzothieno[3,2-b]Benzofuran Derivatives with Single-Walled Carbon Nanotubes for Enhanced Thermoelectric Performance.

Although numerous thermoelectric (TE) composites of organic materials and single-walled carbon nanotubes (SWCNTs) have been developed in the past decade, most of the research has been related to polymers without much on organic small molecules (OSMs). In this work, benzothieno[3,2-b]benzofuran (BTBF) and its derivatives (BTBF-Br and BTBF-2Br) were synthesized and their TE composites with SWCNTs were prepared. It is found that the highest molecular orbital level and band gap (Eg) of BTBF, BTBF-Br, and BTBF-2Br gradually decrease upon the introduction of electron-withdrawing Br group on BTBF. These changes significantly improve the Seebeck coefficient and power factor (PF) of OSM/SWCNT composites. An appropriate energy barrier between BTBF-2Br and SWCNTs promotes the energy filtering effect, which further contributes to the enhancement of composites' thermoelectric properties. The composites of SWCNTs and BTBF-2Br with the smallest Eg (4.192 eV) afford the best thermoelectric performance with the room temperature power factor of 169.70 ± 3.46 µW m-1 K-2 in addition to good mechanical flexibility and thermal stability. This study provides a feasible strategy for the preparation of OSM/SWCNT composites with improved thermoelectric properties.

The protective effects of simvastatin in Cadmium-Induced preosteoblast injury through Nox4.

Cadmium (Cd) has a direct toxic effect on bones. Statins such as simvastatin have protective effects on various diseases, including on tissue injury. The current study revealed the efficacy of simvastatin on Cd-induced preosteoblast injury. Preosteoblast MC3T3-E1 cells were incubated with various doses of CdCl2 for 12 h, 24 h and 48 h, and then the cell cytotoxicity was assessed using MTT assay and flow cytometry, respectively. The expression level of Nox4 was assessed by Western blot and qRT-PCR. The morphological appearance of MC3T3-E1 cells was observed under a microscope. Cells exposed to CdCl2 (5 µM) were further treated by simvastatin at various doses, subsequently cell viability, apoptosis and the expression of Nox4 were measured. Furthermore, to confirm the protective effects of simvastatin on Cd-induced pre-osteoblast injury, functional rescue assays were performed after corresponding cell treatment by simvastatin (10-8 M), CdCl2 (5 µM), and overexpression of Nox4. Expressions of cell apoptosis-related markers were measured by Western blot and qRT-PCR. The results revealed that CdCl2 caused MC3T3-E1 cell injury because the cell viability was decreased and the apoptosis was increased. Nox4 expression was up-regulated with the increase of CdCl2 concentrations. Simvastatin increased the cell viability, relieved the cell apoptosis and Nox4 expression previously increased by CdCl2. The effects of CdCl2 on MC3T3-E1 cells and Nox4 expression could be attenuated by simvastatin, and promoted by Nox4 overexpression. The current study found that simvastatin protects Cd-induced preosteoblast injury via Nox4, thus, it can be used as a potential drug for treating cadmium-induced bone injury.

Single nucleotide polymorphism genotyping of ALDH2 gene based on asymmetric PCR and fluorescent probe-mediated melting curves.

Detection of single nucleotide polymorphisms (SNPs) is of great value in precision medicine. The polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene is caused by a G1510A transition, resulting in the substitution of glutamic acid by lysine at position 487. People of different ALDH2 genotypes show different susceptibility to cancer, metabolic diseases, etc. SNP analysis based on fluorescent probe-mediated melting curves is a relatively efficient and cost-effective method. Genomic DNA extracted from 100 whole blood samples was subjected to polymorphisms mutational analysis using asymmetric PCR and probe-mediated melting curves. Then a certain number of samples from each genotype were randomly selected for direct sequencing verification. The new assay can be performed in 2 h without post-PCR processing such as gel electrophoresis and validated by direct sequencing in a blind study with 100% concordance. Moreover, comparing the detection of polymorphisms of ALDH2 with the clinics, and an overall agreement of 100% (100/100) was demonstrated. Our study has shown a high level of concordance between DNA sequencing, which is suitable for the detection of clinical specimens. Based on the concept of probe-mediated melting curves, we further developed this platform as a universal strategy for the detection of polymorphisms related to folate metabolism.

Characterization of transit rates in the large intestine of mice following treatment with a CGRP antibody, CGRP receptor antibody, and small molecule CGRP receptor antagonists.

OBJECTIVE: To characterize the effects of blocking calcitonin gene-related peptide (CGRP) activity in a mouse model of gastrointestinal transport. BACKGROUND: Migraine management using CGRP modulating therapies can cause constipation of varying frequency and severity. This variation might be due to the different mechanisms through which therapies block CGRP activity (e.g., blocking CGRP, or the CGRP receptor) with antibodies or receptor antagonists. The charcoal meal gastrointestinal transit assay was used to characterize constipation produced by these modes of therapy in transgenic mice expressing the human receptor activity-modifying protein 1 (hRAMP1) subunit of the CGRP receptor complex. METHODS: Male and female hRAMP1 mice were dosed with compound or vehicle and challenged with a charcoal meal suspension via oral gavage. The mice were then humanely euthanized and the proportion of the length of the large intestine that the charcoal meal had traveled indicated gastrointestinal transit. RESULTS: Antibody to the CGRP receptor produced % distance traveled (mean ± standard deviation) of 31.8 ± 8.2 (4 mg/kg; p = 0.001) and 33.2 ± 6.0 (30 mg/kg; p < 0.001) compared to 49.7 ± 8.3 (control) in female mice (n = 6-8), and 35.6 ± 13.5 (30 mg/kg, p = 0.019) compared to 50.2 ± 14.0 (control) in male mice (n = 10). Telcagepant (5 mg/kg, n = 8) resulted in % travel of 30.6 ± 14.7 versus 41.2 ± 8.3 (vehicle; p = 0.013) in male mice. Atogepant (3 mg/kg, n = 9) resulted in % travel of 30.6 ± 12.0, versus 41.2 ± 3.7 (control; p = 0.030) in female mice. The CGRP antibody galcanezumab (n = 7-10; p = 0.958 and p = 0.929) did not have a statistically significant effect. CONCLUSIONS: These results are consistent with reported clinical data. Selectively blocking the CGRP receptor may have a greater impact on gastrointestinal transit than attenuating the activity of the ligand CGRP. This differential effect may be related to physiologically opposing mechanisms between the CGRP and AMY1 receptors, as the CGRP ligand antibody could inhibit the effects of CGRP at both the CGRP and AMY1 receptors.

Comprehensive characterization and identification of chemical constituents in Yangwei decoction using ultra high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry.

Yangwei decoction, a classical traditional Chinese medicine prescription, has been widely used to treat exogenous cold and internal injury with damp stagnation for many centuries. However, its systematic chemical profiling remains ambiguous, which has hampered the interpretation of pharmacology and the mechanism of its formula. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry method was successfully established for the first time to separate and identify the complicated components of Yangwei decoction. The accurate mass data of the protonated molecules, deprotonated molecules, and fragment ions were detected in positive and negative ion modes. A total of 226 compounds in Yangwei decoction were tentatively identified and unambiguously characterized by comparing their retention times and mass spectrometry data with those of reference standards and literature, including 24 lignans, 18 alkaloids, 9 phenylpropanoid glycosides, 76 flavonoids, 59 triterpenoids, 17 organic acids, 7 gingerols, 8 lactones, and 8 other compounds. The present study provides a novel method of constituents characterization for well-known Chinese medicine prescriptions. The study aims to lay a robust foundation for future research, providing the holistic quality control and pharmacology of Yangwei decoction.

Quality evaluation of the classical prescription, Danggui Jianzhong decoction, using ultra-high-performance liquid chromatography fingerprint, chemical pattern recognition, and network pharmacology.

Danggui Jianzhong decoction is a classical prescription that has been widely used for thousands of years. However, the quality of this formula is difficult to control owing to its complex chemical component system. In this study, a simple and efficient method comprising ultra-high-performance liquid chromatography fingerprint, chemical pattern recognition, and network pharmacology was established to evaluate the quality of this decoction. A total of 20 common peaks were obtained by fingerprint analysis and 19 chemicals were identified. The fingerprint similarity of 15 batch samples ranged from 0.963 to 0.991. Chemical pattern recognition analysis could clearly classify 15 batches of Danggui Jianzhong decoction into three groups. Further, seven chemical markers were screened out. A herbs-active components-targets-disease network was constructed and enrichment analyses were performed, which indicated that these 19 chemical components are the medicinal substances of Danggui Jianzhong decoction. Further, the mechanism employed by this formula to treat primary dysmenorrhea may be related to the regulation of inflammatory response. In conclusion, this combination approach enables accurate evaluation and prediction of the quality of Danggui Jianzhong decoction, and lays the foundation for studies on the material basis and exploration of the mechanism of Danggui Jianzhong decoction in the treatment of primary dysmenorrhea.

Assembly and optical properties of 1D helical bundles induced by triphenylamine, side chains and solvents in crystals.

Two novel helical aromatic foldamer derivatives TPA-Q6(n-He) and TPA-Q6(i-Bu) were synthesized and characterized by introducing n-hexyloxy and isobutoxy side chains, respectively, and modifying quinoline amide foldamers with the triphenylamine (TPA) moiety at the N-terminus. X-ray single crystal diffraction analyses and theoretical calculations showed that the quinoline amide hexamer derivative TPA-Q6(i-Bu) enabled one-dimensional (1D) helical self-assembly in solids due to the synergistic interaction of the flexible π units of TPA, the steric hindrance of the alkyl groups, and methanol molecules. The chemical modification of the TPA end group significantly enhanced the fluorescence due to the intramolecular charge transfer. Steady-state fluorescence spectra and transient decay curves showed that TPA-Q6(i-Bu) forming a 1D helical assembly obviously exhibited a redshift of the emission wavelength and an increase of phosphorescence lifetimes in crystals compared with TPA-Q6(n-He) adopting the alternating insertion arrangement induced by the long alkyl chains. The results offered a new way to explore the intrinsic relationship among molecular structures, packing modes and optical properties for foldamers.

Retracted: The Effects of Ludartin on Cell Proliferation, Cell Migration, Cell Cycle Arrest and Apoptosis Are Associated with Upregulation of p21WAF1 in Saos-2 Osteosarcoma Cells In Vitro.

The authors repeated experiments and found that the results shown in figure 2 were not reproducible. Reference: Shuang-li Zhang, Bao-lin Li, Wei Li, Ming Lu, Lin-ying Ni, Hui-li Ma, Qing-gang Meng. The Effects of Ludartin on Cell Proliferation, Cell Migration, Cell Cycle Arrest and Apoptosis Are Associated with Upregulation of p21WAF1 in Saos-2 Osteosarcoma Cells In Vitro. Med Sci Monit 2018; 24: LBR4926-4933. 10.12659/MSM.909193.

NAF1 rs4691896 Is Significantly Associated with Coal Workers' Pneumoconiosis in a Chinese Han Population: A Case-Control Study.

BACKGROUND Previous studies have demonstrated the important role of genetic predisposition in coal workers' pneumoconiosis (CWP) in addition to environmental factors. The pathogenesis of pulmonary fibrosis disease is related to telomere activity. We performed this study to assess the association between genetic variants of telomere-related genes and the risk of CWP. MATERIAL AND METHODS We enrolled 652 CWP Chinese Han patients and 648 dust-exposed controls in this case-control design study, genotyping 8 single-nucleotide polymorphisms (SNPs) including TERT (rs2736100), TERC (rs10936599 and rs12696304), and NAF1 (rs7675998, rs3822304, rs12331717, rs936562 and rs4691896) using the Sequenom MassARRAY system. RESULTS We identified a significant allele association between NAF1 rs4691896 and CWP by comparing patients with controls (22.0% vs. 13.0%, odds ratio [OR]: 1.89, 95% confidence interval [CI]: 1.54-2.33, Pc=1.14×10⁻8). The genotype frequency of rs4691896 differed significantly between the patients and controls (Pc=1.49×10⁻8). In addition, rs4691896 was correlated with CWP in an additive genetic model (OR: 1.96, 95% CI: 1.58-2.44, Pc=8.96×10⁻9) and a dominant model (OR: 2.15, 95% CI: 1.70-2.73, Pc=2.39×10⁻9). CONCLUSIONS Our study for the first time demonstrates an association between a telomere-related gene (NAF1) and CWP in a Chinese Han population, and provides valuable insight to further understand the possible pathogenetic mechanism of fibrosis in CWP.

Synthesis and Antiproliferative Activities of Novel Substituted 5-Anilino-α-Glucofuranose Derivatives.

In order to find novel antitumor candidate agents with high efficiency and low toxicity, 14 novel substituted 5-anilino-α-glucofuranose derivatives have been designed, synthesized and evaluated for antiproliferative activities in vitro. Their structures were characterized by NMR (1 H and 13 C) and HR-MS, and configuration (R/S) at C(5) was identified by two-dimensional 1 H,1 H-NOESY-NMR spectrum. Their antiproliferative activities against human tumor cells were investigated by MTT assay. The results demonstrated that most of the synthesized compounds had antiproliferative effects comparable to the reference drugs gefitinib and lapatinib. In particular, (5R)-5-O-(3-chloro-4-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}anilino)-5-deoxy-1,2-O-(1-methylethylidene)-α-glucofuranose (9da) showed the most potent antiproliferative effects against SW480, A431 and A549 cells, with IC50 values of 8.57, 5.15 and 15.24 µm, respectively. This work suggested 5-anilino-α-glucofuranose as an antitumor core structure that may open a new way to develop more potent anti-cancer agents.

Novel 4-arylaminoquinazolines bearing N,N-diethyl(aminoethyl)amino moiety with antitumour activity as EGFRwt-TK inhibitor.

Herein, four novel 4-arylaminoquinazoline derivatives with N,N-diethyl(aminoethyl)amino moiety were designed, synthesised and evaluated on biological activities in vitro. All synthesised compounds have inhibitory effects against tumour cells (SW480, A549, A431 and NCI-H1975). In particular, 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((N,N-diethyl(aminoethyl))aminomethyl)furan-2-yl)quinazoline (6a) and 6-(5-((N,N-diethylethyl)aminomethyl)furan-2-yl)-4-(4-(E)-(propen-1-yl)phenylamino)quinazoline (6d) were potent antitumour agents which showed high antiproliferative activities against tumour cells in vitro. Moreover, compound 6a could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G0/G1 phase at tested concentrations. Also, compound 6a could inhibit the activity of wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) with IC50 value of 15.60 nM. Molecular docking showed that compound 6a formed three hydrogen bonds with EGFRwt-TK, while lapatinib formed only two hydrogen bonds with the receptor protein. It is believed that this work would be giving a reference for developing anti-cancer drugs targeted EGFR-TK.