Strain THG-A13T, a Gram-stain negative, facultative anaerobic, non-motile, rod-shaped bacterium was isolated from Aglaia odorata rhizosphere soil in Gyeonggi-do, Republic of Korea. Based on 16S rRNA gene sequence comparisons, strain THG-A13T had closely similarity with Lysobacter niabensis GH34-4T (98.5 %), Lysobacter oryzae YC6269T (97.9 %) and Lysobacter yangpyeongensis GH19-3T (97.3 %). Chemotaxonomic data revealed that strain THG-A13T possesses ubiquinone-8 (Q-8) as the predominant isoprenoid quinone and iso-C15:0, iso-C16:0 and iso-C17:1 ?9c as the major fatty acids. The major polar lipids were phosphatidylethanolamine (PE), phosphatidylglycerol (PG) and diphosphatidylglycerol (DPG). The G+C content was 66.3 mol%. The DNA-DNA relatedness values between strain THG-A13T and its closest phylogenetically neighbours were below 18.0 %. These data corroborated the affiliation of strain THG-A13T to the genus Lysobacter. Thus, the isolate represents a novel species, for which the name Lysobacter terrae sp. nov. is proposed, with THG-A13T as the type strain (= KACC 17646T = JCM 19613T).
1,3,5-Tri(1H-benzo[d]imidazol-2-yl)benzene derivatives as a new kind of fluorescent chemosensors for the detection of nitroaromatic explosives are designed and synthesized by simple N-hydrocarbylation. Among 16 obtained compounds, compound 4g has the best detection effect for picric acid (PA) with good selectivity and high sensitivity. The detection of PA with 4g solution-coated paper strips at picogram level is developed. A simple, portable and low-cost method for detecting PA in solution and contact mode is provided.
Multiple sclerosis (MS) is a complex disease of neurological disability, affecting more than 300 out of every one million people in the world. The purpose of the study was to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in MS patients. Twenty-three patients were enrolled in this study and 13 of them were given hUC-MSC therapy at the same time as anti-inflammatory treatment, whereas the control patients received the anti-inflammatory treatment only. Treatment schedule included 1,000 mg/kg of methylprednisolone i.v. daily for 3 days and then 500 mg/kg for 2 days, followed by oral prednisone 1mg/kg/day for 10 days. The dosage of prednisone was then reduced by 5mg every two weeks until reaching a 5mg/day maintenance dosage. Intravenous infusion of hUC-MSCs was applied three times in a 6 week period for each patient. The overall symptoms of the hUC-MSC treated patients improved compared to patients in the control group. Both the EDSS scores and relapse occurrence were significantly lower than those of the control patients. Inflammatory cytokines were assessed, and the data demonstrated a shift from Th1 to Th2 immunity in hUC-MSC treated patients. Our data demonstrated a high potential for hUC-MSC treatment of MS. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
Abstract The Rattus norvegicus SILN strain is a common used model for nervous system disorder disease study. We sequenced this R. norvegicus strain SILN mitochondrial genome for the first time (GenBank Accession No. KM114606). Its mitogenome was 16,311?bp and coding 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes.
Human ?-defensin 2 (HBD-2) is an antimicrobial peptide produced by mucosal surfaces in response to microbial exposure or inflammatory cytokines. Although HBD-2 is expressed in the esophagus in response to stress and infectious agents, little is known regarding its expression and functional role in esophageal carcinogenesis. In the current investigation, normal esophagus and N-nitrosomethylbenzylamine (NMBA)-induced precancerous and papillomatous lesions of the rat esophagus were characterized for HBD-2 encoding gene Defb4 and protein. HBD-2 was found to be overexpressed in esophagi of rats treated with NMBA compared to animals in control group. Results of Real-time PCR, Western blot and immunohistochemistry demonstrated a positive correlation between the overexpression of HBD-2 and the progression of rat squamous cell carcinogenesis (SCC) in the esophagus. We also observed that HBD-2 is overexpressed in tumor tissues removed from patients with esophageal SCC. Moreover, Defb4 silencing in vitro suppresses the tumor cell proliferation, mobility and invasion in esophageal SCC cell line KYSE-150. The results from this study provide experimental evidence that HBD-2 may play an oncogenic role in the initiation and progression of esophageal SCC and thus serve as a target for chemopreventive and therapeutic interventions.
A human isoform of Collapsin Response Mediator Protein (CRMP) family proteins, CRMP-1, has been identified as a novel invasion suppressor. The aim of this study was to determine CRMP-1 expression pattern in placentas during normal pregnancy and elucidate the clinical significance of CRMP-1 expression in the placentas of women with early-onset preeclamptic pregnancies. We recruited 66 normal healthy pregnant Chinese women and 60 Chinese patients with preeclampsia [early-onset prereclampsia(ePE), n = 30 and late-onset preeclampsia(lPE) n = 30]. Gestational age-matched normal healthy pregnant women were used as controls of early-onset and late-onset preeclampsia, which were 23-33 + 6weeks, n = 18 and control B: 34-40 weeks, n = 20). Quantitative RT-PCR, Western blot analysis and immunohistochemistry were used to analyze the expressions of CRMP-1 in placentas. Expression of CRMP-1 was detected in syncytio- and cytotrophoblasts of all groups using immunohistochemistry. CRMP-1 was most abundantly expressed in syncytiotrophoblasts, moderately in cytotrophoblasts and the intermediate trophoblasts especially in the first trimester. The placental expression of CRMP-1 is particularly striking in the first trimester and decreases throughout pregnancy. There is a significant increase in CRMP-1 expression in the placenta of ePE but not of lPE, as compared to gestational-matched controls. The aberrant upregulation of CRMP-1 expression may link to the mechanism of developing ePE.
Icariin is effective in the treatment of hyperlipidemia. To understand the effect of icariin on lipid metabolism, effects of icariin on PPAR? and its target genes were investigated. Mice were treated orally with icariin at doses of 0, 100, 200, and 400 mg/kg, or clofibrate (500 mg/kg) for five days. Liver total RNA was isolated and the expressions of PPAR? and lipid metabolism genes were examined. PPAR? and its marker genes Cyp4a10 and Cyp4a14 were induced 2-4 fold by icariin, and 4-8 fold by clofibrate. The fatty acid (FA) binding and co-activator proteins Fabp1, Fabp4 and Acsl1 were increased 2-fold. The mRNAs of mitochondrial FA ?-oxidation enzymes (Cpt1a, Acat1, Acad1 and Hmgcs2) were increased 2-3 fold. The mRNAs of proximal ?-oxidation enzymes (Acox1, Ech1, and Ehhadh) were also increased by icariin and clofibrate. The expression of mRNAs for sterol regulatory element-binding factor-1 (Srebf1) and FA synthetase (Fasn) were unaltered by icariin. The lipid lysis genes Lipe and Pnpla2 were increased by icariin and clofibrate. These results indicate that icariin is a novel PPAR? agonist, activates lipid metabolism gene expressions in liver, which could be a basis for its lipid-lowering effects and its beneficial effects against diabetes.
Cholesterol is an essential component of brain and nerve cells and is essential for maintaining the function of the nervous system. Epidemiological studies showed that patients suffering from anxiety disorders have higher serum cholesterol levels. In this study, we investigated the influence of high cholesterol diet on anxiety-like behavior in elevated plus maze in animal model and explored the relationship between cholesterol and anxiety-like behavior from the aspect of central neurochemical changes.
SMARCA5 partners with RSF-1 to compose the RSF complex, which belongs to the ISWI family of chromatin remodelers. Recent studies referred that SMARCA5 was overexpressed in some malignant tumors. However, expression pattern and biological roles of SMARCA5 in breast cancer have not been examined. In the present study, we found that SMARCA5 was overexpressed in breast cancer specimens by immunohistochemistry. Significant association was observed between SMARCA5 overexpression and TNM stage (p?=?0.0199), tumor size (p?=?0.0066), high proliferation index (p?=?0.0366), and poor overall survival (p?=?0.0141). SMARCA5 overexpression also correlated with Rsf-1 expression levels (p?=?0.0120). Furthermore, colony formation assay and Matrigel invasion assay showed that knockdown of SMARCA5 expression in MDA-MB-231 and MDA-MB-435s cell lines with high endogenous expression decreased cell proliferation and cell invasion. Flow cytometry showed knockdown of SMARCA5-arrested cell cycle. Further analysis of cell cycle and invasion-related molecules showed that SMARCA5 downregulated cyclin A, MMP2 expression and upregulated p21 expression. In conclusion, our study demonstrated that SMARCA5 was overexpressed in human breast cancers and correlated with poor prognosis. SMARCA5 contributes to breast cancer cell proliferation and invasion.
A new kind of supramolecular columnar liquid crystal T-A with a broad mesomorphic range (up to 164.9 °C), good thermal stability, and strong fluorescence is designed and formed by the H-bonding between 1,3,5-tri(1H-benzo[d]imidazol-2-yl)benzene (T) and serial gallic acid derivatives (A). Two components are easily available because of simple routes, common reactions, high yields, commercial starting materials, and inexpensive catalysts. The introduction of the 1,2,3-triazole structure into component A makes the textures different and is slightly disadvantageous for the T-A complexes.
The chemokine receptor CXCR4 and signal transducer and activator of transcription 3 (STAT3) play an important role in breast cancer malignancy and metastasis. However, it remains unknown whether STAT3 can be activated by CXCR4 in human breast cancer. The expression levels of CXCR4, STAT3 and p-STAT3 in 208 breast cancer tissues and 26 tumor-adjacent tissues were examined by immunohistochemistry. Flow cytometry, western blot analysis and immunoprecipitation were used to study activation of STAT3 by CXCL12-CXCR4 signaling in human breast cancer cell lines. The expression levels of CXCR4, STAT3 and p-STAT3 were higher in the breast cancer samples than these levels in the tumor-adjacent samples. The combined expression of CXCR4 and p-STAT3 was correlated with TNM stage, tumor size, lymph node metastasis and histological grade of breast cancer. In the breast cancer cells, CXCL12 treatment increased the expression of p-STAT3. The CXCR4 antagonist AMD3100 and the Janus kinase 2 (JAK2) antagonist AG490 inhibited the CXCL12-induced increase in the phosphorylation of STAT3. Furthermore, CXCL12 promoted direct binding of JAK2 to CXCR4. Our findings suggest that activation of the JAK2/STAT3 pathway via CXCL12-CXCR4 signaling plays an important role in breast cancer malignancy and metastasis. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer.
Japanese-specific alleles are expected to be powerful markers for the differentiation of the Japanese from other people. In this study, three single nucleotide polymorphisms (SNPs) in the GALNT11, H19, and PLA2G12A genes were analyzed in 2396 DNA samples from 25 global populations, and the derived alleles suggested that Japanese-specific alleles exist on autosomes. To identify new Japanese-specific alleles, candidate SNPs obtained from the HapMap database were investigated using 875 DNA samples from nine populations. A total of 67 (nearly) Japanese-specific derived alleles were observed. Of them, 57 showed higher frequencies in the Ryukyuans, living in the southernmost part of the Japanese Archipelago, than in the Wajins living in mainland Japan, and 43 were also present in Koreans at low frequencies. Jomon skeletons excavated from Hokkaido, the northernmost island of Japan, showed higher frequencies of the three derived alleles in the GALNT11, H19, and PLA2G12A genes than the Ryukyuans, suggesting that most of the 57 derived alleles observed at the high frequencies in the Ryukyuans originated from the Jomon lineage. These novel markers will be useful in the field of forensics.
Parkinson's disease (PD) is a neurodegenerative movement disorder that is characterized by the progressive degeneration of the dopaminergic (DA) pathway. Mesenchymal stem cells derived from human umbilical cord (hUC-MSCs) have great potential for developing a therapeutic agent as such. HGF is a multifunctional mediator originally identified in hepatocytes and has recently been reported to possess various neuroprotective properties. This study was designed to investigate the protective effect of hUC-MSCs infected by an adenovirus carrying the HGF gene on the PD cell model induced by MPP+ on human bone marrow neuroblastoma cells. Our results provide evidence that the cultural supernatant from hUC-MSCs expressing HGF could promote regeneration of damaged PD cells at higher efficacy than the supernatant from hUC-MSCs alone. And intracellular free Ca(2+) obviously decreased after treatment with cultural supernatant from hUC-MSCs expressing HGF, while the expression of CaBP-D28k, an intracellular calcium binding protein, increased. Therefore our study clearly demonstrated that cultural supernatant of MSC overexpressing HGF was capable of eliciting regeneration of damaged PD model cells. This effect was probably achieved through the regulation of intracellular Ca(2+) levels by modulating of CaBP-D28k expression.
The aim of this study was to evaluate the efficacy and safety of paclitaxel plus oxaliplatin plus fluorouracil/leucovorin (POF) as salvage chemotherapy in pretreated advanced gastric cancer. Fifty-two pretreated patients with the advanced gastric cancer were eligible for this study. The POF regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m(2)) followed by oxaliplatin (85 mg/m(2)) and leucovorin (400 mg/m(2)), administered simultaneously over a 2-hour infusion period, followed by an infusion of fluorouracil (2400 mg/m(2)) over a 46-hour period, every 14 days. From an intention-to-treat analysis, overall response rate and stable disease rate were 28·8 and 38·5%, respectively. The median time to progression and overall survival were 4·1 and 7·9 months, respectively. Grade 3 or 4 neutropaenia, thrombocytopaenia, fatigue, and neuropathy were 38·5, 15·4, 17·3, and 15·4%, respectively. The POF regimen is active in pretreated advanced gastric cancer as salvage chemotherapy, with a favourable toxicity profile.
The genetic diversity and population structure of citrus tristeza virus (CTV) isolates from China were investigated based on partial sequences spanning the C-terminal end of p61 and the complete sequences of the CPm and CP genes. Phylogenetic analysis revealed five known groups (RB, T30, T36, HA and VT) and one new group (VI) consisting of only Chinese CTV isolates. Incongruent phylogenetic trees coupled with recombination analysis suggested several recombination events in the CPm gene. Positive selection was detected at codon 9 of CPm and codons 31, 41 and 68 of CP. The widespread CTV subpopulation AT-1 found in China has a unique amino acid insertion at the C-terminus of p61, which could increase CTV population complexity with implications for the evolutionary history of the virus. Our results suggest relevant roles for gene flow, purifying selection and recombination in shaping the CTV population in China.
The labellum in orchids shares homology with the inner lateral petals of the flower. The labellum is a modified petal and often distinguished from other petals and sepals due to its large size and irregular shape. Herein, we combined two-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) approaches to identify the differentially expressed proteome between labellum and inner lateral petal in one of Orchid species (C. ensifolium). A total of 30 protein spots were identified, which showed more than a two-fold significant difference (p < 0.05) in their expression. Compared with C. ensifolium transcriptome (sequenced in house), 21 proteins matched the translated nucleotide. The proteins identified were classified into 48 categories according to gene ontology (GO). Additionally, these proteins were involved in 18 pathways and 9 possible protein-protein interactions. Serine carboxypeptidase and beta-glucosidase were involved in the phenylpropanoid pathway, which could regulate biosynthesis of floral scent components. Malate dehydrogenase (maeB) and triosephosphate isomerase (TPI) in carbon fixation pathway could regulate the energy metabolism. Xyloglucan endotransglucosylase/hydrolase (XET/XTH) could promote cell wall formation and aid the petal's morphogenesis. The identification of such differentially expressed proteins provides new targets for future studies; these will assess the proteins' physiological roles and significance in labellum and inner lateral petals.
Inflammatory myofibroblastic tumors (IMTs) are uncommon, mesenchymal lesions, and malignant transformation is extremely rare. The current study presents the case of a 56-year-old female with a rapidly growing mass in the right breast, which was diagnosed as IMT. Immunohistochemically, the mass was positive for smooth muscle actin (SMA) and Ki-67 (positive staining in 30% of the cells), and negative for S-100, cluster of differentiation (CD)34, p63 and cytokeratin. Malignant transformation to metaplastic carcinoma of the spindle-cell type was observed following surgical resection. This metaplastic carcinoma demonstrated positive immunoreactivity for cytokeratin, vimentin, CD34, p63 and Ki-67 (>30%), and was negative for cytokeratin 7, SMA, desmin and S-100. The patient underwent total mastectomy of the right breast, followed by palliative chemotherapy with capecitabine; however, the patient succumbed to the disease after 12 weeks. The unusual case presented in the current study emphasizes the importance of pre-operative examinations to determine the benign or malignant nature of IMTs, which aids in the choice of appropriate surgical procedures.
Limited population-based cancer registry data available in China until now has hampered efforts to inform cancer control policy. Following extensive efforts to improve the systematic cancer surveillance in this country, we report on the largest pooled analysis of cancer survival data in China to date. Of 21 population-based cancer registries, data from 17 registries (n?=?138,852 cancer records) were included in the final analysis. Cases were diagnosed in 2003-2005 and followed until the end of 2010. Age-standardized relative survival was calculated using region-specific life tables for all cancers combined and 26 individual cancers. Estimates were further stratified by sex and geographical area. The age-standardized 5-year relative survival for all cancers was 30.9% (95% confidence intervals: 30.6%-31.2%). Female breast cancer had high survival (73.0%) followed by cancers of the colorectum (47.2%), stomach (27.4%), esophagus (20.9%), with lung and liver cancer having poor survival (16.1% and 10.1%), respectively. Survival for women was generally higher than for men. Survival for rural patients was about half that of their urban counterparts for all cancers combined (21.8% vs. 39.5%); the pattern was similar for individual major cancers except esophageal cancer. The poor population survival rates in China emphasize the urgent need for government policy changes and investment to improve health services. While the causes for the striking urban-rural disparities observed are not fully understood, increasing access of health service in rural areas and providing basic health-care to the disadvantaged populations will be essential for reducing this disparity in the future.
Peroxiredoxin 3 (Prx3) is a mitochondrial member of the antioxidant family of thioredoxin peroxidases that uses mitochondrial thioredoxin 2 as a source of reducing equivalents to scavenge hydrogen peroxide (H2O2). Here, we report that the protein levels of Prx3 are significantly reduced in VHL-deficient clear cell renal cell carcinoma (CCRCC). Furthermore, stabilization of HIF-1? protein, caused either by VHL deficiency under normoxia, or by hypoxia, significantly reduced Prx3 expression. Luciferase-reporter and chromatin-immunoprecipitation assays indicated that HIF-1? binds to the hypoxia-responsive elements of PRDX3 promoter and represses its transcription. Finally, shRNA-based assays suggested that Prx3 downregulation is required for the HIF-1?-dependent proliferation of CCRCC cells. Taken together, our results shed new light onto the mechanism of HIF-1?-dependent proliferation in CCRCC cells.
Effective treatment as well as prognostic biomarker for malignant esophageal squamous cell carcinoma (ESCC) is urgently needed. The present study was aimed at identifying oncogenic genes involving dysregulated intracellular Ca2+ signaling, which is known to function importantly in cellular proliferation and migration. Tumors from patients with ESCC were found to display elevated expression of Orai1, a store-operated Ca2+ entry (SOCE) channel, and the high expression of Orai1 was associated with poor overall and recurrence-free survival. In contrast to the quiescent nature of non-tumorigenic epithelial cells, human ESCC cells exhibited strikingly hyperactive in intracellular Ca2+ oscillations, which were sensitive to treatments with Orai1 channel blockers and to orai1 silencing. Moreover, pharmacologic inhibition of Orai1 activity or reduction of Orai1 expression suppressed proliferation and migration of ESCC in vitro and slowed tumor formation and growth in in vivo xenografted mice. Combined, these findings provide the first evidence to imply Orai1 as a novel biomarker for ESCC prognostic stratification and also highlight Orai1-mediated Ca2+ signaling pathway as a potential target for treatment of this deadly disease.
An efficient method for the synthesis of aminomethyl benzimidazoles is developed by using a one-pot batch reaction between amino acids and o-phenylenediamines. This reaction proceeds smoothly in an unmodified household microwave oven, even though scale-up is to 10 g. A desirable method for the quick synthesis of benzimidazoles, which are used as a kind of important intermediates in drug synthesis, is provided by the scale-up utilization of amino acid resource.
Human serum albumin (HSA) has been developed as a model protein to study drug-protein interaction. In the present work, the interaction between our synthesized flavonoid derivative 3d (possessing potent antitumor activity against HepG2 cells) and HSA was investigated using fluorescence spectroscopy, circular dichroism spectroscopy, UV-vis spectroscopy and molecular modeling approach. Fluorescence spectroscopy showed that the fluorescence of HSA can be quenched remarkably by 3d under physiological condition with a slight shift of maximum fluorescence emission bands from 360nm to 363nm. Calculated results from Stern-Volmer equation and modified Stern-Volmer equation indicated that the fluorescence was quenched by static quenching processing with association constant 5.26±0.04×10(4)L mol(-1) at 298K. After comprehensive consideration of the free energy change ?G, enthalpy change ?H and entropy change ?S, electrostatic interactions were confirmed as the main factor that participate in stabilizing the 3d-HSA complex. Both dichroism spectroscopy and UV-vis spectroscopy indicated conformational change of HSA after binding to 3d. Moreover, the structure of HSA was loosened and the percentage of ?-helix decreased with increasing concentration of 3d. Molecular modeling results demonstrated that 3d could bind to HSA well into subdomain IIA, which is related to its capability of deposition and delivery. Three cation-? interactions and three hydrogen bonds occurred between 3d and amino acid residuals ARG218, ARG222 and LYS199. In conclusion, flavonoid derivative 3d can bind to HSA with noncovalent bond in a relatively stable way, so it can be delivered by HSA in a circulatory system.
ST2, a member of the interleukin (IL)-1receptor family, regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions. However, the role of ST2 signaling in tumor growth and metastasis of breast cancers has not been investigated. This study investigated the possible role of soluble ST2 (sST2) in breast cancer.
The first theoretical exploration of superhalogen properties of polynuclear structures based on pseudohalogen ligand is reported here via a case study on eight triply-bridged [Mg2(CN)5](-) clusters. From our high-level ab initio results, all these clusters are superhalogens due to their high vertical electron detachment energies (VDE), of which the largest value is 8.67 eV at coupled-cluster single double triple (CCSD(T)) level. Although outer valence Green's function results are consistent with CCSD(T) in most cases, it overestimates the VDEs of three anions dramatically by more than 1 eV. Therefore, the combined usage of several theoretical methods is important for the accuracy of purely theoretical prediction of superhalogen properties of new structures. Spatial distribution of the extra electron of high-VDE anions here indicates two features: remarkable aggregation on bridging CN units and non-negligible distribution on every CN unit. These two features lower the potential and kinetic energies of the extra electron respectively and thus lead to high VDE. Besides superhalogen properties, the structures, relative stabilities and thermodynamic stabilities with respect to detachment of CN(-1) were also investigated for these anions. The collection of these results indicates that polynuclear structures based on pseudohalogen ligand are promising candidates for new superhalogens with enhanced properties.
Accumulative evidence suggests that polymorphism in the APE1 gene may have association with the etiology of lung cancer by modulating DNA repair capacity. Many studies have evaluated the association with great discrepancies in the results. The present meta-analysis was undertaken to clarify the effects of this polymorphism on lung cancer. A meta-analysis of 15 studies with 4,932 lung cancer patients and 6,555 cancer-free controls was conducted to evaluate the strength of the association using odds ratios (ORs) with 95 % confidence intervals (CIs). Overall, no significant association was found between APE1 polymorphism and lung cancer risk. We also did not observe any statistical evidence of modified lung cancer risk either in smokes or in nonsmokers. In the stratified analysis by ethnicity, however, it was found that the Glu/Clu genotype carriers had 1.16-fold higher risk of suffering lung cancer compared with the carriers of Arg/Glu + Arg/Arg genotypes in Asian population (OR = 1.16, 95 % CI = 1.01-1.32, P = 0.242). This meta-analysis provides statistical evidence for a potential association between APE1 polymorphism and an increased risk of lung cancer in Asian population.
CXCR4 and its ligand CXCL12 can promote the proliferation, survival, and invasion of cancer cells. They have been shown to play an important role in regulating metastasis of breast cancer to specific organs. High CXCR4 expression was also correlated to poor clinical outcome. Previous study also showed that tumor cells express a high level of CXCR4 and that tumor metastasis target tissues (lung, liver, and bone) express high levels of the ligand CXCL12, allowing tumor cells to directionally migrate to target organs via a CXCL12-CXCR4 chemotactic gradient. However, the exact mechanisms of how CXCR4 and CXCL12 enhance metastasis and/or tumor growth and their full implications on breast cancer progression are unknown. Yet it is likely that chemokine receptor signaling may provide more than just a migrational advantage by also helping the metastasized cells establish and survive in secondary environments. In this study, we investigated CXCR4 and CXCL12 expression in breast cancer and analyzed its association with clinicopathological factors by immunohistochemistry first. Then, we detected the mRNA and protein expression of CXCR4 and CXCL12 in breast cancer cell lines by Western blot and RT-PCR. The MDA-MB-231 has CXCR4 expression and very weak CXCL12 expression. So, we constructed the functional CXCL12 expression in MDA-MB-231 using a gene transfection technique. Further experiments were conducted to evaluate the effect of CXCL12 transfection on the biological behaviors of MDA-MB-231. The cell proliferation of MDA-MB-231-CXCL12 was accessed by MTT assay; the apoptosis was analyzed by an AnnexinV-FITC/propidium iodide double staining of flow cytometry method; and the cell invasive ability was examined by Matrigel invasion assay. Immunohistochemical analysis showed the co-expression of CXCR4 and CXCL12 correlated with lymph node metastasis and TNM stage (p?0.01). It suggested that the chemokine CXCL12 and its sole ligand CXCR4 play important role in the malignance of breast cancer. To gain a deeper insight into it, we picked CXCR4-expressing cells MDA-MB-231 to be transfected with CXCL12 stably. The decreased cellular proliferation, increased apoptosis, and invasive ability were found in MDA-MB-231 with successful CXCL12 transfection (p?0.05). Our findings underlined the CXCL12-CXCR4 axis correlated tightly with breast cancer metastasis. CXCL12-CXCR4 axis can increase the invasion and apoptosis of MDA-MB-231 simultaneously. These data strongly support the hypothesis that CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis. Our findings could have significant implications in terms of breast cancer aggressiveness and the effectiveness of targeting the receptors and downstream signaling pathways for the treatment of breast cancer.
Evidence suggests that the hyperammonemia (HA)-induced neuroinflammation and alterations in the serotonin (5-HT) system may contribute to cognitive decline and anxiety disorder during hepatic encephalopathy (HE). Probiotics that maintain immune system homeostasis and regulate the 5-HT system may be potential treatment for HA-mediated neurological disorders in HE. In this study, we tested the efficacy of probiotic Lactobacillus helveticus strain NS8 in preventing cognitive decline and anxiety-like behavior in HA rats. Chronic HA was induced by intraperitoneal injection of ammonium acetate for four weeks in male Sprague-Dawley rats. HA rats were then given Lactobacillus helveticus strain NS8 (10(9) CFU mL(-1)) in drinking water as a daily supplementation. The Morris water maze task assessed cognitive function, and the elevated plus maze test evaluated anxiety-like behavior. Neuroinflammation was assessed by measuring the inflammatory markers: inducible nitric oxide synthase, prostaglandin E2, and interleukin-1 ? in the brain. 5-HT system activity was evaluated by measuring 5-HT and its metabolite, 5-HIAA, and the 5-HT precursor, tryptophan. Probiotic treatment of HA rats significantly reduced the level of inflammatory markers, decreased 5-HT metabolism, restored cognitive function and improved anxiety-like behavior. These results indicate that probiotic L. helveticus strain NS8 is beneficial for the treatment of cognitive decline and anxiety-like behavior in HA rats.
Phosphodiesterase-5 (PDE5) inhibitors are predominantly used in the treatment of erectile dysfunction, and have been recently shown to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD) through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling by elevating cGMP, which is a secondary messenger involved in processes of neuroplasticity. In the present study, the effects of a PDE5 inhibitor, icarrin (ICA), on learning and memory as well as the pathological features in APP/PS1 transgenic AD mice were investigated. Ten-month-old APP/PS1 transgenic mice overexpressing human amyloid precursor protein (APP695swe) and presenilin 1 (PS1-dE9) were given ICA (30 and 60 mg/kg) or sildenafil (SIL) (2 mg/kg), age-matched wild-type (WT) mice were given ICA (60 mg/kg), and APP/PS1 and WT control groups were given an isovolumic vehicle orally twice a day for four months. Results demonstrated that ICA treatments significantly improved learning and memory of APP/PS1 transgenic mice in Y-maze tasks. The amyloid precursor protein (APP), amyloid-beta (A?1-40/42) and PDE5 mRNA and/or protein levels were increased in the hippocampus and cortex of APP/PS1 mice, and ICA treatments decreased these physiopathological changes. Furthermore, ICA-treated mice showed an increased expression of three nitric oxide synthase (NOS) isoforms at both mRNA and protein levels, together with increased NO and cGMP levels in the hippocampus and cortex of mice. These findings demonstrate that ICA improves learning and memory functions in APP/PS1 transgenic mice possibly through the stimulation of NO/cGMP signalling and co-ordinated induction of NOS isoforms.
A novel multi-layer microfluidic device was developed for characterization of drug metabolism in human liver microsomes (HLMs) and their cytotoxicity on cells. The results demonstrated that this platform is robust for low levels of compounds and shows potential for high-throughput drug screening in drug development.
In an effort to augment the atomic emission spectra of conventional laser-induced breakdown spectroscopy (LIBS) and to provide an increase in selectivity, mid-wave to long-wave infrared (IR), LIBS studies were performed on several organic pharmaceuticals. Laser-induced breakdown spectroscopy signature molecular emissions of target organic compounds are observed for the first time in the IR fingerprint spectral region between 4-12 ?m. The IR emission spectra of select organic pharmaceuticals closely correlate with their respective standard Fourier transform infrared spectra. Intact and/or fragment sample molecular species evidently survive the LIBS event. The combination of atomic emission signatures derived from conventional ultraviolet-visible-near-infrared LIBS with fingerprints of intact molecular entities determined from IR LIBS promises to be a powerful tool for chemical detection.
Inflammatory pseudotumors are rare benign tumors consisting of cellular and stromal elements of a localized reactive process. While inflammatory pseudotumors are commonly detected in the lung and occasionally in other organs, only one case of inflammatory pseudotumor of the thymus has been reported in the literature to date. This report presents a 54-year-old male patient with inflammatory pseudotumor of the thymus accompanied by pulmonary inflammation. The patient presented with chest pain and moderate fever for 12 days. Enhanced computed tomography of the thorax revealed an anterior mediastinal solid and cystic mass, which constricted the left brachiocephalic vein accompanied by bilateral lung inflammation and marginal pleural effusion. The patient underwent a median sternotomy for the surgical removal of the mass. Histologically, the resected mass was composed of necrotic and fibrous tissues and inflammatory infiltrates, and the diagnosis was confirmed as an inflammatory pseudotumor of the thymus. The patient's symptoms were resolved following surgery and the patient remained asymptomatic during the six-month follow-up period. In addition, we reviewed the previous literature and discussed the diagnosis and management of our patient. This report provides further insights into the pathogenesis and underlying mechanisms of inflammatory pseudotumors of the thymus to aid in the diagnosis and development of effective therapies.
A 5-point breast imaging classification modified from the seven-category Breast Imaging-Reporting and Data System has been applied for mammographic and ultrasonographic examinations in patients with palpable breast masses. The aim of this study was to confirm the value of combined imaging assessment. We included 5,296 cases (3,002 benign and 2,294 cancer) from January 2004 to December 2011. Ultrasonography showed a significantly (P < 0.01) higher sensitivity and specificity and lower false-negative rate and false-negative predictive value (false-NPV) than mammography. The sensitivity of combined imaging was significantly (P < 0.01) increased and the false-negative rate and false-NPV were significantly (P < 0.01) reduced compared to mammography or ultrasonography alone. However, the specificity was significantly (P < 0.01) declined for combined imaging versus mammography or ultrasonography alone. Compared with combined imaging assessment, a significant (P < 0.01) improvement was noted with substratified scoring, with increased specificity and false-negative rate and decreased sensitivity. In conclusion, the substratified combined imaging score has the potential to provide additional value in the workup of palpable breast lesions.
Interleukin 27 (IL-27), belonging to the IL-12 family, exerts a critical role in immune regulation of infection, autoimmunity, and tumor. In this study, we aimed to investigate the roles of IL-27 and vascular endothelial growth factor (VEGF) in breast cancer.
Skin wound healing is a critical and complex biological process after trauma. This process is activated by signaling pathways of both epithelial and nonepithelial cells, which release a myriad of different cytokines and growth factors. Hepatocyte growth factor (HGF) is a cytokine known to play multiple roles during the various stages of wound healing. This study evaluated the benefits of HGF on reepithelialization during wound healing and investigated its mechanisms of action. Gross and histological results showed that HGF significantly accelerated reepithelialization in diabetic (DB) rats. HGF increased the expressions of the cell adhesion molecules ?1-integrin and the cytoskeleton remodeling protein integrin-linked kinase (ILK) in epidermal cells in vivo and in vitro. Silencing of ILK gene expression by RNA interference reduced expression of ?1-integrin, ILK, and c-met in epidermal cells, concomitantly decreasing the proliferation and migration ability of epidermal cells. ?1-Integrin can be an important maker of poorly differentiated epidermal cells. Therefore, these data demonstrate that epidermal cells become poorly differentiated state and regained some characteristics of epidermal stem cells under the role of HGF after wound. Taken together, the results provide evidence that HGF can accelerate reepithelialization in skin wound healing by dedifferentiation of epidermal cells in a manner related to the ?1-integrin/ILK pathway.
We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-non-mutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti-tumor drug development.
Fusarium head blight (FHB) is a devastating disease that threatens wheat (Triticum aestivum) production in many areas worldwide. FHB infection results in Fusarium-damaged kernels (FDK) and deoxynivalenol (DON) that dramatically reduce grain yield and quality. More effective and accurate disease evaluation methods are imperative for successful identification of FHB-resistant sources and selection of resistant cultivars. To determine the relationships among different types of resistance, 363 (74 soft and 289 hard) U.S. winter wheat accessions were repeatedly evaluated for FDK and DON concentration in greenhouse and field experiments. Single-kernel near-infrared (SKNIR)-estimated FDK and DON were compared with visually estimated FDK and gas chromatography-mass spectroscopy-estimated DON. Significant correlations were detected between percentage of symptomatic spikelets and visual FDK in the greenhouse and field, although correlations were slightly lower in the field. High correlation coefficients also were observed between visually scored FDK and SKNIR-estimated FDK (0.72, P < 0.001) and SKNIR-estimated DON (0.68, P < 0.001); therefore, both visual scoring and SKNIR methods are useful for estimating FDK and DON in breeding programs.
The incidence of breast cancer in developing countries still increasing, to identify novel molecular markers associated with carcinogenesis and prognosis of breast cancer still being implemented. The largest subunit of Remodeling and spacing factor (RSF), Rsf-1, mediates ATPase-dependent chromatin remodeling. Its oncogenic properties have been demonstrated in certain carcinomas. The aim of this study was to examine the prognostic value of Rsf-1 in patients with primary breast carcinoma.
The ginsenoside Rg2(S), which is one of the pharmaceutical components of ginseng, is known to have neuroprotective, anti-inflammation, and anti-diabetic effects. However, the usage of ginsenoside Rg2(S) is restricted owing to the small amounts found in white and red ginseng. To enhance the production of ginsenoside Rg2(S) as a 100 gram unit with high specificity, yield, and purity, an enzymatic bioconversion method was developed to adopt the recombinant glycoside hydrolase (BglPC28), which is a ginsenoside-transforming recombinant ?-glucosidase from Pseudonocardia sp. strain Gsoil 1536. The gene, termed bglPC28, encoding ?-glucosidase (BglPC28) belonging to the glycoside hydrolase family 3 was cloned. bglPC28 consists of 2,232 bp (743 amino acid residues) with a predicted molecular mass of 78,975 Da. This enzyme was overexpressed in Escherichia coli BL21(DE3) using a GST-fused pGEX 4T-1 vector system. The optimum conditions of the recombinant BglPC28 were pH 7.0 and 37 °C. BglPC28 can effectively transform the ginsenoside Re to Rg2(S); the Km values of PNPG and Re were 6.36 ± 1.10 and 1.42 ± 0.13 mM, respectively, and the Vmax values were 40.0 ± 2.55 and 5.62 ± 0.21 µmol min-1 mg-1 of protein, respectively. A scaled-up biotransformation reaction was performed in a 10 L jar fermenter at pH 7.0 and 30°C for 12 hours with a concentration of 20 mg/ml of ginsenoside Re from American ginseng roots. Finally, 113 g of Rg2(S) was produced from 150 g of Re with 84.0 ± 1.1% chromatographic purity. These results suggest that this enzymatic method could be usefully exploited in the preparation of ginsenoside Rg2(S) in the cosmetics, functional food, and pharmaceutical industries.
Diversin was recently reported to play roles in Wnt and JNK pathways. However, the expression pattern and biological roles of diversin in human breast cancer have not been reported. In the present study, we found that diversin was overexpressed in breast cancer specimens by immunohistochemistry and western blot. Significant association was observed between diversin overexpression and TNM stage (p?=?0.0036), nodal metastasis (p?=?0.0033), negative estrogen receptor expression (p?=?0.0012) and triple-negative status (p?=?0.0017). Furthermore, colony formation assay and matrigel invasion assay showed that knockdown of diversin expression in MDA-MB-231 cell line with high endogenous expression decreased cell proliferation and cell invasion. Transfection of diversin plasmid in MCF-7 cell line increased cell proliferation and invasion. Further analysis showed that diversin depletion downregulated JNK phosphorylation while its overexpression upregulated JNK phosphorylation. In conclusion, our study demonstrated that diversin was overexpressed in human breast cancers. Diversin could contribute to breast cancer cell proliferation and invasion.
Feature detection and matching are crucial for robust and reliable image registration. Although many methods have been developed, they commonly focus on only one class of image features. The methods that combine two or more classes of features are still novel and significant. In this work, methods for feature detection and matching are proposed. A Mexican hat function-based operator is used for image feature detection, including the local area detection and the feature point detection. For the local area detection, we use the Mexican hat operator for image filtering, and then the zero-crossing points are extracted and merged into the area borders. For the feature point detection, the Mexican hat operator is performed in scale space to get the key points. After the feature detection, an image registration is achieved by using the two classes of image features. The feature points are grouped according to a standardized region that contains correspondence to the local area, precise registration is achieved eventually by the grouped points. An image transformation matrix is estimated by the feature points in a region and then the best one is chosen through competition of a set of the transformation matrices. This strategy has been named the Grouped Sample Consensus (GCS). The GCS has also ability for removing the outliers effectively. The experimental results show that the proposed algorithm has high registration accuracy and small computational volume.
Purpose: Obesity has been recognized as a significant risk factor for postmenopausal breast cancer. The aim of this study is to investigate the prognostic significance of body mass index (BMI) in hormone receptor-positive, operable breast cancer. Methods: In this retrospective cohort study, 1,192 consecutive patients with curative resection of primary breast cancer were enrolled. Patients were assigned to two groups according to BMI: normal or underweight (BMI < 23.0 kg/m2) and overweight or obese (BMI ?23.0 kg/m2). Associations among BMI and clinicopathological characteristics and prognosis of patients were assessed. Results: A high BMI was significantly (P < 0.01) correlated with age, nodal stage, ALNR, ER positivity, PR positivity and menopausal status at diagnosis. Univariate analysis revealed that BMI, pathologic T stage, nodal stage, axillary lymph node ratio (ALNR) and adjuvant radiotherapy history were significantly (P < 0.05) associated with disease-free survival and overall survival, irrespective of tumour hormone receptor status. Multivariate analysis revealed BMI as an independent prognostic factor in all cases and in hormone receptor-positive cases. Conclusion: A high BMI (?23.0 kg/m^2) is independently associated with poor prognosis in hormone receptor-positive breast cancer.
Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1s expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole-dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.
By self-assembly of (E)-2-(3-(4-(1H-imidazol-1-yl)styryl)-5,5-dimethylcyclohex-2-enylidene)malononitrile (L(1)) and (E)-2-(3-(4-(1H-1,2,4-triazol-1-yl)styryl)-5,5-dimethylcyclohex-2-enylidene)malononitrile (L(2)) with silver(i) salts, eight new complexes, namely AgL(1)2ClO4 (1), AgL(1)2NO3 (2), [AgL(1)2NO3]·C6H6 (3), [AgL(1)2OOCCF3]·C6H6 (4), [AgL(1)2PF6]·C6H6 (5), AgL(2)2NO3 (6), [AgL(2)OOCCF3]2 (7) and AgL(2)2PF6 (8), are presented along with an analysis of their structural features. The structures are built up through the combination of coordination bonds, Ag?, AgF (or O), hydrogen bonding, and ?? stacking interactions to generate new supramolecular architectures. We observed the formation of two-dimensional coordination polymers for complex 7. Solvent benzene molecules and anions are dispersed in the supramolecular structure and play a vital role in building the supramolecular structures of the complexes. The nonlinear optical (NLO) properties of the complexes were investigated using the Z-scan technique and complexes 1, 2, 3, 4 and 7 show obviously nonlinear absorption compared with ligands (L(1) and L(2)).
Vitamin D plays a central role in cellular proliferation, apoptosis induction, and tumor growth suppression. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of vitamin D. A series of epidemiological studies have examined the association between the VDR FokI polymorphism and breast cancer risk, but the findings remain inconclusive. Fifteen eligible case-control studies involving 15,681 cancer cases and 20,632 control subjects were identified through searching PubMed, Embase, and Web of Science. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the association. Heterogeneity across studies was examined with the chi-square-based Q test and the I (2) index. Beggs and Eggers test were also performed to determine publication bias. All statistical data were analyzed by STATA software. The combined estimates did not show significant risks correlated with the FokI polymorphism. However, we found an increased risk in the subgroup analysis by source of control (OR?=?1.11, 95 % CI?=?1.01-1.22; heterogeneity test: P?=?0.116, I (2)?=?0.0 % for ff vs FF; OR?=?1.10, 95 % CI?=?1.01-1.21; heterogeneity test: P?=?0.832, I (2)?=?0.0 % for ff vs Ff?+?FF). This meta-analysis suggests that the presence of FokI polymorphism may contribute to the risk of breast cancer in Caucasians.
Constitutive photomorphogenesis 9 subunit 6, as one subunit of the constitutive photomorphogenesis 9, plays an important role in tumor development. The aim of the study was to investigate the clinical and prognostic implications of constitutive photomorphogenesis 9 subunit 6 protein in breast cancer.
We propose a new structure for piezoelectric energy harvesters. It consists of an elastic beam with two pairs of piezoelectric films operating with the fundamental flexural modes in perpendicular directions. A one-dimensional model is developed and used to analyze the proposed structure. The output power density is calculated and examined. Results show that, with simultaneous flexural motions in two perpendicular directions, the output power has two peaks close to each other resulting from the two fundamental flexural resonances. The distance between the two peaks can be adjusted through design to make the two peaks merge into one wide peak. Hence, the frequency bandwidth through which energy can be harvested is roughly doubled when compared with conventional beam bimorph energy harvesters operating with flexural motion in one direction and one resonance only.
Human and animals studies support the idea that there is a gender-related co-morbidity of pain-related and inflammatory gastrointestinal (GI) diseases with psychological disorders. This co-morbidity is the evidence for the existence of GI-brain axis which consists of immune (cytokines), neural (vagus nerve) and neuroendocrine (HPA axis) pathways. Psychological stress causes disturbances in GI physiology, such as altered GI barrier function, changes in motility and secretion, development of visceral hypersensitivity, and dysfunction of inflammatory responses. Whether GI inflammation would exert impact on psychological behavior is not well established. We examined the effect of experimental gastritis on anxiety- and depression-like behaviors in male and female Sprague-Dawley rats, and evaluated potential mechanisms of action. Gastritis was induced by adding 0.1% (w/v) iodoacetamide (IAA) to the sterile drinking water for 7 days. Sucrose preference test assessed the depression-like behavior, open field test and elevated plus maze evaluated the anxiety-like behavior. IAA treatment induced gastric inflammation in rats of either gender. No behavioral abnormality or dysfunction of GI-brain axis was observed in male rats with IAA-induced gastritis. Anxiety- and depression-like behaviors were apparent and the HPA axis was hyperactive in female rats with IAA-induced gastritis. Our results show that gastric inflammation leads to anxiety- and depression-like behaviors in female but not male rats via the neuroendocrine (HPA axis) pathway, suggesting that the GI inflammation can impair normal brain function and induce changes in psychological behavior in a gender-related manner through the GI-to-brain signaling.
Hexavalent chromium [Cr(VI)] and its compounds, which have the extensive application in diverse industries including metallurgy, textile and electroplating, are known to be genotoxic and mutagenic to humans. Although it is supported by a large body of literatures that p53 and caspase-3 played key roles in Cr(VI)-induced cytotoxicity, it is clear that Cr(VI) could induce apoptosis either without activating caspase, or in a p53- independent manner.
A novel flavonid derivate, 1-(3-chloro-4-(6-ethyl-4-oxo-4H-chromen-2-yl)phenyl)-3-(4-chlorophenyl)urea (3d) synthesized in our lab possesses potent antitumor activity against HepG2 cells. Our previous studies on pharmacological mechanism of 3d mostly focused on cell and gene levels, little is about its metabolomics study. Herein, an ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) based metabolomics approach was established to investigate the antitumor effect of 3d on HepG2 cells and its action mechanism. Q-TOF MS was used to identify metabolites, and tandem mass spectrometry was used to confirm their identity. Comparing 3d-treated HepG2 cells with vehicle control (dimethyl sulfoxide), 32 distinct metabolites involved in glutathione metabolism, glycerophospholipid metabolism, cysteine and methionine metabolism, fatty acid metabolism, and phenylalanine metabolism. The reduced level of glutathione (GSH) and decreased ratio of reduced/oxidized glutathione (GSH/GSSG) in 3d-treated cells indicated the increased oxidative stress after 3d treatment. The significant decrease of phosphatidylcholine (PC) levels and increase of lysophosphatidylcholine (LPC) levels suggested alterations in lipid composition which were causally related to decline in mitochondrial function. Depletion of carnitine and increase of long chain carnitines and fatty acids reflected decline in fatty acid metabolism. The further biological experiments including ROS and MMP measurements confirmed the above probabilities presumed from metabolomic results. Our findings suggested that 3d caused the perturbation of multiple cellular pathways. The increased oxidative stress and the resulting mitochondrial dysfunction resulted in the antiproliferative effect of 3d. The UPLC/Q-TOF MS based metabolomics approach provides new insights into the mechanistic studies of new compounds that distinct from traditional biological studies.
The difference in the removal efficiencies of polycyclic aromatic hydrocarbons (PAHs) in planted and unplanted sludge drying bed was investigated. Pilot-scale sludge drying bed and reed bed had the same size of 3.0 m x 1.0 m x 1.3 m (L x W x H), and the bed height consisted of a 65 cm media layer and a 65 cm super height. Both beds had a ventilation pipe which was mounted on the drainage pipes. The experiment lasted for three years, and the first two years was the sludge loading period, and the third year was the natural stabilization period. In the first two years, a total thickness of 8.4 m of sludge was loaded and the average sludge loading rate was 41.3 kg x (m2 x a)(-1). After the three-year stabilization, the contents of the sixteen PAHs decreased with time in both the sludge drying bed and the reed bed. The total PAHs contents in the surface, middle and bottom sludge layers in the sludge drying bed were 4.161, 3.543 and 3.118 mg x kg(-1) (DW), corresponding to 26.91%, 37.77% and 45.23% of removal; and the values in the reed bed were 2.722, 1.648 and 1.218 mg x kg(-1) (DW), corresponding to 52.18%, 71.05% and 78.60% of removal. The average PAHs removal in the reed bed was 29.86% higher than that in the sludge drying bed. In the stabilized sludge, the removal of low-molecular-weight PAHs predominated. The results suggested that reed played a positive role in the removal of PAHs.
Esophageal duplication cyst (EDC) is a congenital malformation of the posterior primitive foregut, which mainly occurs in the thoracic esophagus. Here, we describe a 3-year-old Han Chinese boy afflicted with intermittent fever of acute onset and dry cough. Thoracic computed tomography revealed an 10 cm × 5.4 cm × 5.8 cm oval-shaped, cyst-like tumor located in the extrapleural space, extending along the right paravertebral gutter and compressing the trachea forward. An additional small-sized, oval-shaped cyst was identified in the posterior mediastinum, between the esophagus and the spinal column, at the T1 level. During open thoracotomy, under general anesthesia, an opaque, thick-walled, esophageal cyst was revealed not to be in communication with the esophageal lumen or the trachea. This cyst was subsequently resected in an en bloc manner. The small (1-cm) esophageal cyst was left untreated based on a "wait-and-see" policy. Histological analysis showed that the resected cyst was walled by hyperplastic, fibrous tissues and locally lined with gastric mucosa inherent glands. This finding was consistent with a diagnosis of EDC, with ectopic gastric mucosa. The respiratory tract symptoms resolved immediately after the operation. Computed tomography obtained at the 6-month follow-up showed that no disease, residual or recurrence, was present after the resection of the large-sized cyst, and the small-sized cyst remained unchanged in size.
VEGFR, ERK and Abl had been respectively identified as good drug targets, and their crosstalk also had been well elaborated. Multitarget drugs were more advantageous for cancer treatment, however, no inhibitors simultaneously acting on the three proteins were developed due to their structural diversities. Herein, N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6-(trifluoromethyl)nicotinamide (NEPT, 6a) was discovered as an active scaffold against VEGFR-2, ERK-2 and Abl-1 kinases through the combination of support vector machine, similarity searching and molecular docking. NEPT and its derivatives were synthesized by convenient routine, their in vitro anti-proliferative abilities against human liver cancer cell line HepG2 were preliminarily evaluated. A representative compound 6b showed an IC50 value of 11.3 ?M and induced significant HepG2 cells apoptosis. Besides, these compounds displayed better anti-proliferative abilities against K562 cells (a cell line with typical hyperactivity of the above multikinases), for example compound 6b exhibited an IC50 value of 4.5 ?M. Based on hepatotoxicity case reports of Abl inhibitors, cytotoxicity of synthetic compounds against normal liver cell lines (QSG7701 and HL7702) was studied, 6b had a similar toxic effect with positive control imatinib, and most compounds showed less than 35% inhibition activities at 100 ?M. Molecular docking study disclosed interactions of 6b with VEGFR-2, ERK-2 and Abl-1 kinases, respectively. Our data suggested the biological activities of 6b may derived from collaborative effects of VEGFR-2, ERK-2 and Abl-1 inhibition.
The objectives of this study are to investigate the expressions of matrix metalloproteinase inducing factor (CD147), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) in laryngeal tumor tissues and its significant correlation with tumor infiltration, metastasis and prognosis. Laryngeal tumor tissue from 48 laryngeal cancer patients with complete clinical information was collected. The laryngitis tissue from 15 patients were collected as control group. Immunohistochemical analysis for CD147, MMP-2 and MMP-9 was performed for all the tissue. The results showed the expression rates of CD147, MMP-2 and MMP-9 in laryngeal carcinoma were 87.5 %, 75.0 % and 79.2 % respectively, significantly higher than those (26.7 %, 6.7 %, and 33.3 % respectively) in the control group are (P?0.01). High expression of CD147, MMP-2 and MMP-9 related to the clinical stages and lymphatic metastasis of laryngeal carcinoma. Univariate survival analysis showed that the 5-year survival of laryngeal carcinoma patients with low expression of CD147, MMP-2 and MMP-9was 83.3 %, 83.3 % and 90 % respectively, while the patients with high expression had 5-year survival at 25 %, 7.7 % and 18.2 % respectively (P?0.05). Multiple regression analysis showed that high expression of MMP-9 was independently associated with poor prognosis (P?0.05). High expression of CD147, MMP-2 and MMP-9 were related with laryngeal carcinoma invasion and metastasis. High expressions of CD147, MMP-2 and MMP-9 were all predictive factors of poor prognosis of laryngeal carcinoma.
Breast cancer is a complex disease; the molecular mechanisms involved in sporadic breast carcinogenesis remain to be elucidated. The present study aimed to explore the deficiency of breast cancer susceptibility gene 1 (BRCA1), including protein loss expression, promoter hypermethylation and gene copy deletion, its correlationship with other tumor markers expression (TP53, MYC, etc.), and clinical significance in sporadic breast cancer. BRCA1 protein expression was negative in 226 of 374 (60.4 %) cases of this study. Cases negative for BRCA1 protein were more often with pathological tumor-node-metastasis stage III, positive for lymph node metastasis and MYC overexpression than BRCA1-positive tumors. BRCA1 hypermethylation was detected in 16.4 % (31 of 189) breast cancers, which correlated with BRCA1 negative, ER negative, MYC overexpression, and triple-negative phenotype. In addition, the percentage of cells with BRCA1 gene copy deletion was significantly increased in BRCA1-methylated tumors. Kaplan-Meier survival analysis showed that patients with BRCA1-negative expression showed a worse overall survival (OS) than those with BRCA1-positive expression, and patients with BRCA1-methylated tumors had a significantly worse disease-free survival than did patients with unmethylated tumors. Furthermore, BRCA1 hypermethylation showed an inverse association with OS in LN-positive or p53-negative subgroup patients. Importantly, uni- and multivariate Cox regression analyses revealed that BRCA1 was an independent prognostic indicator of OS in sporadic breast cancer. Thus, we found MYC overexpression and poor prognosis in sporadic breast cancer with BRCA1 deficiency. The targeting of BRCA1 deficiency in combination with MYC-pathways inhibitors may provide a promising strategy for sporadic breast cancer care, the triple-negative subtype in particular.
Nowadays, treatments for cholestasis remain largely nonspecific and often ineffective. Recent studies showed that inflammatory injuries and oxidative stress occur in the liver with cholestasis. In this study, we would use corilagin to treat the animal model of acute cholestasis in order to define the activity to interfere with inflammation-related and oxidative stress pathway in cholestatic pathogenesis.
To investigate the effects of the major component of high-density lipoprotein apolipoprotein A-I (apoA-I) on the development of atherosclerosis in LPS-challenged ApoE(-/-) mice and the underlying mechanisms.
Elevated serum cholesterol level is generally considered to be a risk factor for the development of cardiovascular diseases which seriously threaten human health. The cholesterol-lowering effects of lactic acid bacteria have recently become an area of great interest and controversy for many researchers. In this study, we investigated the effects of two NS lactobacillus strains, Lactobacillus plantarum NS5 and Lactobacillus delbrueckii subsp. bulgaricus NS12, on lipid metabolism of rats fed a high cholesterol diet.
MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.
A Gram-negative, strictly aerobic, non-motile, non-spore-forming and rod-shaped bacterial strain designated KHI67(T) was isolated from sediment of the Gapcheon River in South Korea and its taxonomic position was investigated by using a polyphasic approach. Strain KHI67(T) was observed to grow optimally at 25-30 °C and at pH 7.0 on nutrient and R2A agar. On the basis of 16S rRNA gene sequence similarity, strain KHI67(T) was shown to belong to the family Sphingomonadaceae and was related to Sphingomonas faeni MA-olki(T) (97.6 % sequence similarity), Sphingomonas aerolata NW12(T) (97.5 %) and Sphingomonas aurantiaca MA101b(T) (97.3 %). The G + C content of the genomic DNA was determined to be 65.6 %. The major ubiquinone was found to be Q-10, the major polyamine was identified as homospermidine and the major fatty acids identified were summed feature 8 (comprising C18:1 ?7c/?6c; 37.0 %), C16:0 (13.0 %), summed feature 3 (comprising C16:1 ?7c/C16:1 ?6c; 12.8 %) and C14:0 2OH (9.3 %). DNA and chemotaxonomic data supported the affiliation of strain KHI67(T) to the genus Sphingomonas. The DNA-DNA relatedness values between strain KHI67(T) and its closest phylogenetic neighbours were below 15 %. Strain KHI67(T) could be differentiated genotypically and phenotypically from the recognised species of the genus Sphingomonas. The isolate therefore represents a novel species, for which the name Sphingomonas ginsenosidivorax sp. nov. is proposed, with the type strain KHI67(T) (=KACC 14951(T) = JCM 17076(T) = LMG 25801(T)).
A series of new isophorone derivatives (1-5), incorporating the heterocyclic ring or aza-crown-ether group, with large Stokes shifts (>140 nm), have been synthesized and characterized. 1-4 display aggregation-induced emission behaviors, while dye 5 is highly emissive in solution but quenched in the solid state. It was found that the tuning of emission color of the isophorone-based compounds in the solid state could be conveniently accomplished by changing the terminal substituent group. The photophysical properties in solution, aqueous suspension, and crystalline state, along with their relationships, are comparatively investigated. Crystallographic data of 1-4 indicate that the existence of multiple intermolecular hydrogen bonding interactions between the adjacent molecules restricts the intramolecular vibration and rotation and enables compounds 1-4 to emit intensely in the solid state. The size and growth processes of particles with different water fractions were studied using a scanning electron microscope, indicating that smaller globular nanoparticles in aqueous suspension are in favor of fluorescence emissions. The above results suggest that substituent groups have a great influence on their molecular packing, electronic structure, and aggregation-induced emission properties. In addition, fluorescence cell imaging experiment proved the potential application of 5.
The aim of this study was to investigate the correlation between Girdin and PI3K in breast cancer stem cells and the clinical implications of the co-expression of these two proteins in breast cancer patients. CD44(+)/CD24(-) tumor cells from the MD-231 cell line were sorted by flow cytometry. The expression status of Girdin and PI3K proteins was detected using western blotting and immunohistochemical staining. The relationship between Girdin and PI3K proteins and clinicopathological parameters was analyzed in 820 breast cancer patients. Girdin and PI3K proteins were more highly expressed in CD44(+)/CD24(-) tumor stem cells compared to the control group and Girdin and PI3K proteins were co-immunoprecipitated in the MD-231 cell line. Of the 820 enrolled breast cancer patients, Girdin and PI3K proteins were expressed in 295 (35.98%) and 492 (60.00%) cases, respectively. There were 162 (19.76%) cases which co-expressed Girdin and PI3K proteins. Univariate and multivariate analyses indicated that the co-expression of Girdin and PI3K proteins correlated with histological type, metastatic nodes and distant metastasis (P=0.01, 0.001 and 0.001, respectively). After analyzing survival rates, cases with Girdin and PI3K co-expression were shown to attain a significantly increased distant metastasis rate and poorer postoperative, disease-specific survival compared to those with Girdin and PI3K co-expression (P=0.001). In the Cox regression test, Girdin and PI3K co-expression was detected as an independent prognostic factor (P=0.001). Girdin may regulate the biological behavior of breast cancer via the PI3K/Akt/mTOR pathway, and thus, serve as a potential new target for breast cancer treatment.
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