SOAT1 deficiency attenuates atherosclerosis by regulating inflammation and cholesterol transportation via HO-1 pathway.

Sterol O-acyltransferase 1 (SOAT1) is a key enzyme for cholesteryl ester biosynthesis. The objective of the present study is to investigate the role and underlying molecular mechanisms of SOAT1 in atherosclerosis. Our results indicated that SOAT1 was highly expressed in endothelial cells of atherosclerotic lesions in human patients with atherosclerosis and in apolipoprotein E deficient (ApoE-/-) mice fed with high fat diet (HFD). We established a model of atherosclerosis using ApoE and SOAT1 gene double knockout (ApoE-/-SOAT1-/-) mice. SOAT1-/- alleviated HFD-induced and spontaneously developed atherosclerotic lesions in ApoE-/- mice, accompanied with the reduced triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C), while the enhanced high-density lipoprotein-cholesterol (HDL-C) in serum of ApoE-/- mice. SOAT1-/- decreased collagen accumulation in the lesions. SOAT1-/- reduced macrophage infiltration and suppressed inflammation in ApoE-/- mice fed with HFD, as evidenced by the decreased expressions of pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6 and tumor necrosis factor α (TNF-α). Of importance, SOAT1-/--attenuated inflammation was along with the inactivation of ß-catenin and nuclear factor kappa B (NF-κB) ApoE-/- mice. Moreover, oxidative stress observed in ApoE-/- mice was inactivated by SOAT1 double knockout. In addition, expression levels of fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), protein convertase subtilisin/kexin type 9 (PCSK 9) and sterol regulatory element-binding protein-1c (SREBP-1c) were decreased in liver, peritoneal macrophages and abdominal aortas of SOAT1-knockout ApoE-/- mice. In contrast, SOAT1-/- displayed improved expressions of peroxisome proliferator-activated receptor-γ (PPAR-γ) and lipoxygenase (LOX)-α in liver, peritoneal macrophages and abdominal aortas of ApoE-/- mice. Of note, the in vitro study, oxidized low-density lipoprotein (ox-LDL) incubation reduced heme oxygenase (HO-1) expressions in human umbilical vein endothelial cells (HUVECs), which was improved by SOAT1 knockdown. Pre-treatment of sn-protoporphyrin (SnPP), an important HO-1 inhibitor, abolished the role of SOAT1 inhibition in suppressing inflammation and abnormal cholesterol transportation. These results indicated that SOAT1 deficiency protected against atherosclerosis progression via inhibiting cholesterol transportation in ApoE-/- mice, which was, at least partly, dependent on HO-1 expressions.

Central nervous system progression in advanced non-small cell lung cancer patients with EGFR mutations in response to first-line treatment with two EGFR-TKIs, gefitinib and erlotinib: a comparative study.

BACKGROUND: Central nervous system (CNS) brain metastasis of advanced non-small cell lung cancer (NSCLC) patients confers a worse quality of life and prognosis. The efficacy comparison of two first-generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib as first-line treatment for CNS metastasis NSCLC patients with EGFR-sensitizing mutations is yet to be elucidated. METHODS: A retrospective analysis was done on cerebral metastasis rate after erlotinib or gefitinib as first-line treatment for advanced NSCLC patients with EGFR-sensitizing mutations. Time to neurological progression (nTTP) and median progression-free survival (mPFS) were calculated. RESULTS: The study involved 279 patients (erlotinib group: 108, gefitinib group: 171). After a median follow-up of 22 months, 27 patients (25%) in the erlotinib group and 60 patients (35.1%) in the gefitinib group showed CNS progression. The HR of CNS progression for erlotinib versus gefitinib was 0.695 [95% confidence interval (CI), 0.406-1.190], suggesting a risk reduction of 30.5% although not achieving statistical significance. The 6-, 12- and 18-month cumulative CNS progression rates were 0.9, 3.7 and 12% for erlotinib compared with corresponding rates of 5.8, 9.4 and 17% for gefitinib (P = 0.181). However, for those patients with preexisting brain metastases prior to EGFR-TKI treatment, erlotinib as first line treatment significantly extended the median nTTP in comparison to gefitinib (30 months vs 15.8 months, p = 0.024). CONCLUSIONS: Our data show that nTTP can be effectively extended in preexisting brain metastases patients with EGFR-sensitizing mutations initially treated with erlotinib compared with gefitinib. If confirmed, our results indicate that erlotinib may play an important role in controlling CNS progression from EGFR mutation-positive NSCLC.

Antitumor activity of the pachymic acid in nasopharyngeal carcinoma cells.

OBJECTIVE: To investigate the antitumour efficacy of pachymic acid (PA), which is a fungal extract component, on nasopharyngeal carcinoma (NPC) cells CNE-1, CNE-2. METHODS: We have chosen NPC cell line CNE-2 for the study, and the cells were treated with PA before the detection. CCK-8 assay was used to detect the proliferative ability, and Annexin V-PI double staining was used for the detection of apoptosis rate; and the nucleus damage was detected by transmission electron microscope, the protein expression of the DNA damage pathway were detected by Western blot. RESULTS: PA can significantly inhibited proliferation of CNE-1, CNE-2 cells. The proportion of apoptotic cells of all cell lines gradually increased in a dose-dependent manner induced by PA, P < 0.05. Meanwhile, the nucleus could be caused morphological changes and the expression of DNA damage-related proteins was upregulated by PA in CNE-2. CONCLUSIONS: PA can significantly inhibit cell proliferation and increase the apoptosis rates and may induce the apoptosis of the human NPC cells.

The long-term survival of the doublet regimen of concurrent chemoradiation therapy for locoregionally advanced nasopharyngeal carcinoma: a retrospective study.

OBJECTIVE: This study introduces innovative strategies, the doublet regimen of concurrent chemoradiotherapy, to ensure longer survival for locoregionally advanced nasopharyngeal carcinoma. METHODS: We retrospectively reviewed 104 locoregionally advanced nasopharyngeal carcinoma patients who underwent taxane combined platinum-based concurrent chemoradiotherapy in our center between January 2013 and December 2018. All statistical analyses were performed using the Kaplan-Meier method (SPSS 23.0). Different groups were compared with the Wilcoxon rank-sum test. RESULTS: Ultimately, 104 patients were selected for this study, including 18 and 86 who received either concurrent chemoradiation therapy alone or concurrent chemoradiation therapy plus adjuvant chemotherapy, respectively. The median follow-up time for progression free survival was 53.0 months (IQR 48.5-57.5). The 3-years progression-free survival (PFS), overall survival (OS), local-regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) rates of the doublet regimen of concurrent chemotherapy for locoregionally advanced nasopharyngeal carcinoma were 85.9%, 96.0%, 96.0% and 90.8%, respectively. Additionally, we analyzed the subgroups and found that the 3-years PFS, OS, LRRFS and DMFS rates for stage III versus stage IVa were 97.8% versus 75.5% (P = 0.000), 100% versus 92.5% (P = 0.004), 100% versus 92.4% (P = 0.015) and 97.8% versus 82.8% (P = 0.002), respectively. During concurrent chemotherapy, acute chemotherapy adverse events of grade 3 or 4 was only 18.3%. Leukopenia was the most common acute chemotherapy adverse event (in 10 patients [9.6%]), followed by neutropenia (in 8 patients [7.6%]). CONCLUSION: The doublet regimen of taxane plus platinum concurrent chemoradiotherapy resulted in improved long-term survival of locoregionally advanced nasopharyngeal carcinoma patients, especially for local control rate and warrants further prospective evaluation.

Synthesis, crystal structure and quantum chemical study on 3-phenylamino-4-phenyl-1,2,4-triazole-5-thione.

3-Phenylamino-4-phenyl-1,2,4-triazole-5-thione was synthesized and characterized by elemental analysis, IR and X-ray single crystal diffraction. Density functional theory calculations of the structure, natural bond orbitals, atomic charge distributions and thermodynamic functions of the title compound were performed at B3LYP/ 6-311G** and PBE1PBE/6-311G**levels of theory, respectively. NPA atomic charge distributions indicate that the title compound can be used as a potential multi-dentate ligand to coordinate with various metallic ions. Calculation of the second order optical nonlinearity was also carried out. The thermodynamic properties of C(0)(p,m), S(0)(m) and H(0)(m) were calculated and correlative equations between the thermodynamic properties and temperatures were also obtained.

Diaqua-bis{[1-hydr-oxy-2-(1H-imidazol-3-ium-1-yl)ethane-1,1-di-yl]bis-(hydrogen phospho-nato)}manganese(II).

In the title compound, [Mn(C(5)H(9)N(2)O(7)P(2))(2)(H(2)O)(2)], the Mn(II) atom (site symmetry ) is coordinated by four phos-pho-n-ate O atoms from a pair of partially deprotonated 1-hydr-oxy-2-(imidazol-3-yl)ethane-1,1-bis-phophonic acid ligands (imhedpH(3) (-)) and two water mol-ecules, resulting in a slightly distorted trans-MnO(6) octa-hedral geometry for the metal ion. In the ligands, the imidazole units are protonated and two of the hydr-oxy O atoms of the phospho-nate groups are deprotonated and chelate the Mn(II), thus forming the neutral mol-ecule of the title compound. The two protonated O atoms within the phospho-nate groups of one imhedpH(3) (-) ligand act as hydrogen-bond acceptors for a bifurcated hydrogen bond originating from the coordinated water mol-ecule. The phospho-nate units of neigboring mol-ecules are connected with their equivalents in neighboring mol-ecules via two types of inversion-symmetric hydrogen-bonding arrangements with four and two strong O-H⋯O hydrogen bonds, respectively. The two inter-actions connect mol-ecules into infinite chains along [111] and [110], in combination forming a tightly hydrogen-bonded three-dimensional supra-molecular network. This network is further stabilized by additional hydrogen bonds between the protonated imidazole units and one of the coordinated P-O O atoms and by additional O-H⋯O hydrogen bonds between the water mol-ecules and the P=O O atoms of neigboring mol-ecules.

Electrical stimulation boosts seed germination, seedling growth, and thermotolerance improvement in maize (Zea mays L.).

Electrical signaling, similar to chemical signalings such as calcium (Ca2+), reactive oxygen species (ROS, mainly hydrogen peroxide: H2O2), nitric oxide (NO), and hydrogen sulfide (H2S), regulates many physiological processes. However, the effect of electrical stimulation on seed germination, seedling growth, and thermotolerance improvement in maize was little known. In this study, using maize as materials, the effect of electrical stimulation on seed germination, seedling growth, and thermotolerance improvement in maize was explored. The results suggested that electrical stimulation with optimal intensity boosted germination rate and seedling growth (as indicated in the increase in the length of shoots and roots, as well as fresh weight) under normal germination conditions. In addition, electrical stimulation augmented the survival rate of maize seedlings, mitigated the decrease in the tissue vitality, and reduced the peroxidation of membrane lipids under heat stress. These data suggested that electrical stimulation could boost seed germination, seedling growth, and thermotolerance improvement in maize.

RAS mutations in acute myeloid leukaemia patients: A review and meta-analysis.

RAS oncogene mutations frequently occur in acute myeloid leukaemia (AML), but the prognostic significance of RAS mutations in AML is inconclusive. We searched the databases of PubMed, Web of Science, EMBASE, and Cochrane from 1990 to 2018. In this study, 24 eligible studies were included, and the meta-analysis was conducted with the Comprehensive Meta-Analysis Version 2 software program. The row hazard ratio (HR) was adjusted and re-evaluated when publication bias existed after detecting all the heterogeneities. A combined analysis showed that RAS mutations were not associated with a poor prognosis in general AML patients (HR: 0.96, 95% CI: 0.78-1.19, p = 0.70). To further verify the results, a subgroup analysis was conducted. Interestingly, in the analysis of age bracket, children with RAS mutations had an unfavourable survival (HR: 1.35, 95% CI: 1.05-1.75, p = 0.02) of AML, but the adults did not (HR: 0.87, 95% CI: 0.70-1.09, p = 0.21). Further analysis of the subgroup of children indicated that patients with NRAS mutations had an adverse prognosis (HR: 1.55, 95% CI: 1.13-2.12, p = 0.007), but not those with KRAS mutations (HR: 1.51, 95% CI: 0.34-6.73, p = 0.59). In conclusion, this study revealed that RAS mutations did not influence the over survival for adults with AML. However, NRAS mutations may be a key prognostic marker related with poor survival for children with AML.

[Study on the fluorescence characteristic and mechanism of ether-water solution].

The fluorescence spectra of low concentration diethyl ether-water solution excited by different UV light, and the variation rule of the fluorescence characteristic along with the incidence light wavelength and the solution concentration were studied. Also the emission mechanism together with the spectral characteristic were analyzed. The result shows that the ether solution exhibits an obvious fluorescence peak nearby 306 nm, for which the best excitation wavelength is 245 nm, moreover, there is an inferior peak at 292 nm. The shape of the fluorescence spectrum is invariable ultimately along with the change in excitation light wavelength, and the peak value assumes the Gaussian distribution with the stimulation light wavelength. Meanwhile the emission intensity of the inferior peak and that of the prominent peak are in competition with each other. With increasing the concentration, the fluorescence intensity at 306 nm strengthens linearly, and after increasing the concentration to 7%, concentration-quenching occurs, so the intensity linearly weakens. The findings can provide the reference for detecting concentration and purity of the virulent and anesthetic matter-diethyl ether and so on.

Effects of motor imagery on walking function and balance in patients after stroke: A quantitative synthesis of randomized controlled trials.

OBJECTIVE: This study aimed to evaluate the effects of motor imagery (MI) on walking function and balance in patients after stroke. METHODS: Related randomized controlled trials (RCTs) were searched in 12 electronic databases (Cochrane Central Register of Controlled Trials, PubMed, Science Direct, Web of Science, Allied and Complementary Medicine, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, WanFang, and VIP) from inception to November 30, 2016, and Review Manager 5.3 was used for meta-analysis. References listed in included papers and other related systematic reviews on MI were also screened for further consideration. RESULTS: A total of 17 studies were included. When compared with "routine methods of treatment or training", meta-analyses showed that MI was more effective in improving walking abilities (standardized mean difference [SMD] = 0.69, random effect model, 95% confidence interval [CI] = 0.38 to 1.00, P < 0.0001) and motor function in stroke patients (SMD = 0.84, random effect model, 95% CI = 0.45 to 1.22, P < 0.0001), but no statistical difference was noted in balance (SMD = 0.81, random effect model, 95% CI = -0.03 to 1.65, P = 0.06). Statistically significant improvement in walking abilities was noted at short-term (0 to < six weeks) (SMD = 0.83, fixed effect model, 95% CI = 0.24 to 1.42, P = 0.006) and long-term (≥six weeks) assessments (SMD = 0.45, fixed effect model, 95% CI = 0.25 to 0.64, P < 0.00001). Subgroup analyses suggested that MI had a positive effect on balance with short-term duration (0 to < six weeks) (SMD = 4.67, fixed effect model, 95% CI = 2.89 to 6.46, P < 0.00001), but failed to improve balance (SMD = 0.82, random effect model, 95% CI = -0.27 to 1.90, P = 0.14) with long-term (≥six weeks) duration. CONCLUSION: MI appears to be a beneficial intervention for stroke rehabilitation. Nonetheless, existing evidence regarding the effects of MI in patients after stroke remains inconclusive because of significantly statistical heterogeneity and methodological flaws identified in the included studies. More large-scale and rigorously designed RCTs in future research with sufficient follow-up periods are needed to provide more reliable evidence on the effects of MI in post-stroke patients.

Structural, spectral and magnetic studies of two Co(II)-N-heterocyclic diphosphonates based on multinuclear units.

Two examples of Co(II)-N-heterocyclic coordination polymers based on 1-hydroxyethylidenediphosphonic acid (H5L=CH3C(OH)(PO3H2)2), namely 0.5(H3NCH2CH2NH3)·[Co6(Cl2)(H3L)2(H2L)(HL)(2,2'-bipy)6] 1 and 2(NH4)·[Co3(HL)2(H2O)2(phen)2]·2(H2O) 2, have been solvothermally obtained by introducing the second ligands 2,2'-bipyridine/1,10-phenanthroline (2,2'-bipy/phen) and characterized by powder X-ray diffraction (PXRD), elemental analysis, IR, TG-DSC. The single-crystal X-ray diffractions show that compound 1 possesses a 0-D structure with hexa-nuclear cluster [Co6(O-P-O)8] built through single/double O-P-O bridges and compound 2 displays a 1-D ladder-like chain structure with magnetic topology building blocks [Co4(O-P-O)4]n. Then H-bonding and π-π stacking interactions further expand the two low-dimensional structures into three-dimensional supramolecular frameworks. Fluorescent measurements reveal that both the maximum emission peaks of 1-2 are centered at 423nm, mainly deriving from intraligand π*-π transition state of N-heterocyclic ligand 2,2'-bipy/phen, respectively. Magnetism data indicate that 1 exhibits antiferromagnetic behavior within hexa-nuclear Co(II) clusters, while 2 shows weak ferromagnetic interactions in 1-D topology Co(II)-chain, showing promising potential as magnetic materials.

Tet methylcytosine dioxygenase 2 inhibits atherosclerosis via upregulation of autophagy in ApoE-/- mice.

Tet methylcytosine dioxygenase 2 (TET2) mediates the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The loss of TET2 is associated with advanced atherosclerotic lesions. Our previous study showed that TET2 improves endothelial cell function by enhancing endothelial cell autophagy. Accordingly, this study determined the role of TET2 in atherosclerosis and potential mechanisms. In ApoE-/- mice fed high-fat diet, TET2 overexpression markedly decreased atherosclerotic lesions with uniformly increased level of 5hmC and decreased level of 5mC in genomic DNA. TET2 overexpression also promoted autophagy and downregulated inflammation factors, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, monocyte chemotactic protein 1, and interleukin-1. Consistently, TET2 knockdown with small hairpin RNA (shRNA) in ApoE-/- mice decreased 5hmC and increased 5mC levels in atherosclerotic lesions. Meanwhile, autophagy was inhibited and atherosclerotic lesions progressed with an unstable lesion phenotype characterized by large lipid core, macrophage accumulation, and upregulated inflammation factor expression. Experiments with the cultured endothelial cells revealed that oxidized low-density lipoprotein (ox-LDL) inhibited endothelial cell autophagy. TET2 shRNA strengthened impaired autophagy and autophagic flux in the ox-LDL-treated endothelial cells. TET2 overexpression reversed these effects by decreasing the methylation level of the Beclin 1 promoter, which contributed to the downregulation of inflammation factors. Overall, we identified that TET2 was downregulated during the pathogenesis of atherosclerosis. The downregulation of TET2 promotes the methylation of the Beclin 1 promoter, leading to endothelial cell autophagy, impaired autophagic flux, and inflammatory factor upregulation. Upregulation of TET2 may be a novel therapeutic strategy for treating atherosclerosis.

Down-regulation of PTEN by HCV core protein through activating nuclear factor-κB.

The hepatitis C virus (HCV) core protein is an important causative agent in HCV related hepatocellular carcinoma (HCC). Tumor suppressor gene PTEN appears to act in the liver at the crossroad of processes controlling cell proliferation. In this study we investigated the effect of the HCV core protein on the PTEN pathway in hepatocarcinogenesis. The HCV core was transfected stably into HepG2 cell. The effect of HCV core on cell proliferation and viability were detected by 3-(4, 5)-dimethylthiahiazo-(-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) assay, clonogenic survival assay and Fluorescence Activating Cell Sorter (FACS) analysis. The expressions of PTEN were detected by real time RT-PCR and/or Western blot analysis, also the mechanism of down-regulation of PTEN was explored by western blot, luciferase assay and RNA interference. We found the HCV core promoted cell proliferation, survival and G2/M phase accumulation. It downregulated PTEN at mRNA and protein level and activated PTEN downstream gene Akt accompanied with NF-κB activation. Furthermore, the inhibition of HCV core by its specific shRNAs decreased the effect of growth promotion and G2/M phase arrest, inhibited the expression of nuclear p65 and increased PTEN expression. The activity of PTEN was restored when treated with NF-κB inhibitor PDTC. By luciferase assay we found that NF-κB inhibited PTEN promoter transcription activity directly in HCV core cells, while PDTC was contrary. Our study suggests that HCV proteins could modulate PTEN by activating NF-κB. Furthermore strategies designed to restore the expression of PTEN may be promising therapies for preventing HCV dependent hepatocarcinogenesis.

Synthesis, characteristic and theoretical investigation of the structure, electronic properties and second-order nonlinearity of salicylaldehyde Schiff base and their derivatives.

A series of asymmetric donor-acceptor substituted salen-type Schiff-bases have been synthesized and their structures, electronic properties and second order nonlinearities were investigated by DFT methods. In order to verify the stable of these Schiff-base derivates, the IR spectrum of these Schiff-base derivates were calculated, the result showed that these compounds are stable. The results of TD-DFT calculation indicate that the derivatives with the electron-donating group (CH3, OCH3 or N(C2H5)2) have a red shift absorption compared to derivatives with the electron-withdrawing group (NO2). The analysis of MOS indicates that the CN group has contribution to the LUMO orbital while the groups of OCH3, N(C2H5)2 and NO2 have contribution to the HOMO orbital. OCH3, N(C2H5)2 as electron rich groups, made the derivates have a larger first static hyperpolarizability. However, the compound (II) with a NO2 substituent, also has a large first static hyperpolarizability. This is probably because of the special transition model, namely the values of two oscillator strength f (fHOMO-1-LUMO=0.405, fHOMO-LUMO=0.321) are almost equal. In order to understand the influence of the energy gap (ΔE) between the HOMO and the LUMO orbitals on the first static hyperpolarizability, we calculated the energy gap (ΔE) of all Schiff-base compounds. The results show that the smaller the HOMO-LUMO energy gap is, the larger the first static hyperpolarizability is.

DFT studies on nonlinear optical properties of neutral nest-shaped heterothiometallic [MOS3Py5Cu3X] (M=Mo, W; X=F, Cl, Br, I) clusters.

Theoretical calculations were carried out on some neutral nest-shaped heterothiometallic cluster compounds [MOS(3)Py(5)Cu(3)X] (M=Mo, W; X=F, Cl, Br, I) with the high first static hyperpolarizabilities beta values. The geometries of these cluster compounds were optimized by the restricted DFT method at B3LYP level with LanL2DZ base set without any constrains. In order to understand the relationship between the first static hyperpolarizabilities and the compositions of these clusters, the frontier orbital compositions and energy gaps between the HOMO and LUMO orbitals were calculated and analysed. In these clusters the HOMO orbitals are mainly composed of halogen atoms and the first static hyperpolarizability increases from F to I atom. The LUMO orbitals of clusters [MoOS(3)Py(5)Cu(3)X] are comprised of Mo, O and S atoms while the LUMO orbitals of clusters [WOS(3)Py(5)Cu(3)X] composed of W atom and pyridine ring. The energy gaps between the HOMO and LUMO orbitals of the clusters [MoOS(3)Py(5)Cu(3)X] are smaller than those of the clusters [WOS(3)Py(5)Cu(3)X]. As a result the first static hyperpolarizability values of the clusters [MoOS(3)Py(5)Cu(3)X] are higher than those of the clusters [WOS(3)Py(5)Cu(3)X].