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PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer.Monday, September 26, 2016
Zhu W, Ye L, Zhang J, Yu P, Wang H, Ye Z, Tian J,
PloS one.
PFKFB3 (6-phosphofructo-2-kinase) synthesizes fructose 2,6-bisphosphate (F2,6P2), which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. Overexpression of the PFKFB3 enzyme leads to high glycolytic metabolism, which is required for cancer cells to survive in the harsh tumor microenvironment. The objective of this study was to investigate the antitumor activity of PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), a small molecule inhibitor of PFKFB3, against gastric cancer and to explore its potential mechanisms. The effects of PFK15 on proliferation, apoptosis and cell cycle progression in gastric cancer cells were evaluated by cytotoxicity and apoptosis assays, flow cytometry, and western blotting. In addition, the invasion inhibition effects of PFK15 were measured by transwell invasion assay and western blot analysis, and a xenograft tumor model was used to verify the therapeutic effect of PFK15 in vivo. Results showed that PFK15 inhibited the proliferation, caused cell cycle arrest in G0/G1 phase by blocking the Cyclin-CDKs/Rb/E2F signaling pathway, and induced apoptosis through mitochondria in gastric cancer cells. Tumor volume and weight were also significantly reduced upon intraperitoneal injection with PFK15 at 25 mg/kg. In addition, PFK15 inhibited the invasion of gastric cancer cells by downregulating focal adhesion kinase (FAK) expression and upregulating E-cadherin expression. Taken together, our findings indicate that PFK15 is a promising anticancer drug for treating gastric cancer.
Sucrose, but not Glucose, Blocks IL1-β-Induced Inflammatory Response in Human Chondrocytes by Inducing Autophagy via AKT/mTOR Pathway.Monday, September 26, 2016
Khan NM, Ansari MY, Haqqi TM,
Journal of cellular biochemistry. 26-Sep-2016
Pathogenesis of osteoarthritis (OA) is multifactorial but interleukin-1β (IL-1β) is known to be an important mediator of cartilage degradation. Autophagy is an essential cellular homeostasis mechanism and has been proposed to protect against cartilage degradation and chondrocyte death under pathological conditions. We investigated the role of autophagy activated by sucrose, a natural disaccharide, in suppressing inflammatory mediator's expression and cell death under pathological conditions in human chondrocytes. Autophagy activation was investigated by Western blotting for LC3 and Beclin-1, immunofluorescence staining for LC3 puncta, and measuring autophagic flux. Activation of mTOR, AKT and P70S6K was evaluated by Western blotting. Chondrocyte apoptosis was evaluated by propidium iodide (PI) staining using flowcytometry, expression of Bax by Western blotting, gene expression by TaqMan assays and caspase 3/7 activity was measured using a luminescence-based assay. We found that sucrose induced active autophagy in OA chondrocytes in vitro dependent on the activation of AKT/mTOR/P70S6K signaling pathways and independent of reactive oxygen species (ROS) production. Sucrose activated autophagy blocked IL-1β-induced apoptosis and mRNA expression of MMP-13, COX-2 and IL-6 in human OA chondrocytes. Glucose or fructose, the two metabolites of sucrose, failed to induce autophagy indicating that autophagy was specifically mediated by sucrose. In conclusion, sucrose attenuate IL-1β induced apoptosis and the expression of catabolic mediators by inducing autophagy, and the autophagy in part was mediated through the activation of AKT/mTOR/P70S6K signaling pathway in human chondrocytes. This article is protected by copyright. All rights reserved.
Rapid Multiplexed Immunoassay for Detection of Antibodies to Kaposi's Sarcoma-Associated Herpesvirus.Monday, September 26, 2016
Logan C, Todorof K, Fiorillo SP, Campbell TB, Elder JH, Borok M, Gudza I, Gwanzura L, Ndemera B, Lochhead MJ, Benson CA, Schooley RT,
PloS one. 26-9-2016
Diagnosis of KSHV-infected individuals remains a challenge. KSHV prevalence is high in several populations with high prevalence of HIV, leading to increased risk of development of Kaposi's sarcoma (KS). While current assays are reliable for detecting antibodies to KSHV, none are routinely utilized to identify individuals with KSHV infection and thus at increased risk for KS due to assay complexity, lack of access to testing, and cost, particularly in resource-limited settings. Here we describe the addition of KSHV proteins LANA and K8.1 to a previously evaluated HIV/co-infection multiplexed fluorescence immunoassay system. This study demonstrates assay performance by measuring antibody reactivity for KSHV and HIV-1 in a collection of clinical specimens from patients with biopsy-proven KS and sourced negative controls. The KSHV assay correctly identified 155 of 164 plasma samples from patients with biopsy-proven KS and 85 of 93 KSHV antibody (Ab)-negative samples for a sensitivity of 95.1% and specificity of 91.4%. Assay performance for HIV-1 detection was also assessed with 100% agreement with independently verified HIV-1 Ab-positive and Ab-negative samples. These results demonstrate good sensitivity and specificity for detection of antibody to KSHV antigens, and demonstrate the potential for multiplexed co-infection testing in resource-limited settings to identify those at increased risk for HIV-1-related complications.
Cyclin A1 expression and paclitaxel resistance in human ovarian cancer cells.Monday, September 26, 2016
Huang KC, Yang J, Ng MC, Ng SK, Welch WR, Muto MG, Berkowitz RS, Ng SW,
European journal of cancer (Oxford, England : 1990). 23-Sep-2016
Our profiling and correlation studies have identified cyclin A1 as one chemoresistance-associated biomarker in ovarian cancer. The results of the characterisation studies suggest that cyclin A1 functions as an oncogene that controls proliferative and survival activities in tumourigenesis and chemoresistance of ovarian cancer.
CD8(+) T cell response to human papillomavirus 16 E7 is able to predict survival outcome in oropharyngeal cancer.Monday, September 26, 2016
Masterson L, Lechner M, Loewenbein S, Mohammed H, Davies-Husband C, Fenton T, Sudhoff H, Jani P, Goon P, Sterling J,
European journal of cancer (Oxford, England : 1990). 23-Sep-2016
This is the first study to provide survival data in OPSCC stratified by cell-mediated immune response to HPV16 peptides. Within the HPV16+ OPSCC cohort, enhanced immunoreactivity to antigen E7 was linked to improved survival. An increase in regulatory T cell frequencies after treatment may suggest that immunosuppression can contribute to a reduced HPV-specific cell-mediated response.
Identification of Genes Potentially Associated with the Fertility Instability of S-Type Cytoplasmic Male Sterility in Maize via Bulked Segregant RNA-Seq.Monday, September 26, 2016
Su A, Song W, Xing J, Zhao Y, Zhang R, Li C, Duan M, Luo M, Shi Z, Zhao J,
PloS one. 23-9-2016
S-type cytoplasmic male sterility (CMS-S) is the largest group among the three major types of CMS in maize. CMS-S exhibits fertility instability as a partial fertility restoration in a specific nuclear genetic background, which impedes its commercial application in hybrid breeding programs. The fertility instability phenomenon of CMS-S is controlled by several minor quantitative trait locus (QTLs), but not the major nuclear fertility restorer (Rf3). However, the gene mapping of these minor QTLs and the molecular mechanism of the genetic modifications are still unclear. Using completely sterile and partially rescued plants of fertility instable line (FIL)-B, we performed bulk segregant RNA-Seq and identified six potential associated genes in minor effect QTLs contributing to fertility instability. Analyses demonstrate that these potential associated genes may be involved in biological processes, such as floral organ differentiation and development regulation, energy metabolism and carbohydrates biosynthesis, which results in a partial anther exsertion and pollen fertility restoration in the partially rescued plants. The single nucleotide polymorphisms (SNPs) identified in two potential associated genes were validated to be related to the fertility restoration phenotype by KASP marker assays. This novel knowledge contributes to the understanding of the molecular mechanism of the partial fertility restoration of CMS-S in maize and thus helps to guide the breeding programs.
Analysis of SOX2-Regulated Transcriptome in Glioma Stem Cells.Monday, September 26, 2016
Acanda de la Rocha AM, López-Bertoni H, Guruceaga E, González-Huarriz M, Martínez-Vélez N, Xipell E, Fueyo J, Gomez-Manzano C, Alonso MM,
PloS one. 26-9-2016
We present a comprehensive analysis of the transcriptome controlled by SOX2 in GSCs, gaining insights in the understanding of the potential roles of SOX2 in glioblastoma.
Utilization of unmodified gold nanoparticles for label-free detection of mercury (II): Insight into rational design of mercury-specific oligonucleotides.Monday, September 26, 2016
Memon AG, Zhou X, Liu J, Wang R, Liu L, Yu B, He M, Shi H,
Journal of hazardous materials. 15-Sep-2016
Colorimetric detection of mercury (II) with the use of DNA oligonucleotides and unmodified gold nanoparticles (AuNPs) as indicators has been extensively studied. This study provides in-depth insights into the rational design of mercury-specific oligonucleotides (MSO) in the biosensing system. The leftover bases of MSO, as a result of the formation of T-Hg(2+)-T base pairs, can adsorb on the AuNPs and hinder their aggregation at concentrations of salt. This phenomenon was directly verified by the changes in particle sizes characterized by dynamic light scattering for the first time. Based on these findings, we proposed a rational design for the MSO with approximately 20-fold improvement in detection sensitivity. The detection limit of the proposed assay decreased to 15nM with a linear working range from 50nM to 300nM for Hg(2+). The cross-reactivity against eight other metal ions was negligible compared with the response to Hg(2+). Considering the diverse applications of AuNPs with oligonucleotides, this study can serve as a good reference and provides important implications in sensing and DNA-directed nanoparticle assembly.
Immunotherapy for Gastroesophageal Cancer.Monday, September 26, 2016
Goode EF, Smyth EC,
Journal of clinical medicine. 15-9-2016
Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1), anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4) trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients.
OSAnalyzer: A Bioinformatics Tool for the Analysis of Gene Polymorphisms Enriched with Clinical Outcomes.Monday, September 26, 2016
Agapito G, Botta C, Guzzi PH, Arbitrio M, Di Martino MT, Tassone P, Tagliaferri P, Cannataro M,
Microarrays (Basel, Switzerland). 22-9-2016
Finally, we present a case study to highlight the usefulness of OSAnalyzer when analyzing a large cohort of patients.
Making Sense of the Tangle: Insights into Chromatin Folding and Gene Regulation.Monday, September 26, 2016
Chung IM, Ketharnathan S, Kim SH, Thiruvengadam M, Rani MK, Rajakumar G,
Genes. 23-9-2016
Proximity ligation assays such as circularized chromosome conformation capture and high-throughput chromosome capture assays have shed light on the structural organization of the interphase genome. Functional topologically associating domains (TADs) that constitute the building blocks of genomic organization are disrupted and reconstructed during the cell cycle. Epigenetic memory, as well as the sequence of chromosomes, regulate TAD reconstitution. Sub-TAD domains that are invariant across cell types have been identified, and contacts between these domains, rather than looping, are speculated to drive chromatin folding. Replication domains are established simultaneously with TADs during the cell cycle and the two correlate well in terms of characteristic features, such as lamin association and histone modifications. CCCTC-binding factor (CTCF) and cohesin cooperate across different cell types to regulate genes and genome organization. CTCF elements that demarcate TAD boundaries are commonly disrupted in cancer and promote oncogene activation. Chromatin looping facilitates interactions between distant promoters and enhancers, and the resulting enhanceosome complex promotes gene expression. Deciphering the chromatin tangle requires comprehensive integrative analyses of DNA- and protein-dependent factors that regulate genomic organization.
Phosphoproteome Analysis Reveals the Molecular Mechanisms Underlying Deoxynivalenol-Induced Intestinal Toxicity in IPEC-J2 Cells.Monday, September 26, 2016
Zhang ZQ, Wang SB, Wang RG, Zhang W, Wang PL, Su XO,
Toxins. 23-9-2016
Deoxynivalenol (DON) is a widespread trichothecene mycotoxin that commonly contaminates cereal crops and has various toxic effects in animals and humans. DON primarily targets the gastrointestinal tract, the first barrier against ingested food contaminants. In this study, an isobaric tag for relative and absolute quantitation (iTRAQ)-based phosphoproteomic approach was employed to elucidate the molecular mechanisms underlying DON-mediated intestinal toxicity in porcine epithelial cells (IPEC-J2) exposed to 20 μM DON for 60 min. There were 4153 unique phosphopeptides, representing 389 phosphorylation sites, detected in 1821 phosphoproteins. We found that 289 phosphopeptides corresponding to 255 phosphoproteins were differentially phosphorylated in response to DON. Comprehensive Gene Ontology (GO) analysis combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that, in addition to previously well-characterized mitogen-activated protein kinase (MAPK) signaling, DON exposure altered phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase/signal transducer, and activator of transcription (JAK/STAT) pathways. These pathways are involved in a wide range of biological processes, including apoptosis, the intestinal barrier, intestinal inflammation, and the intestinal absorption of glucose. DON-induced changes are likely to contribute to the intestinal dysfunction. Overall, identification of relevant signaling pathways yielded new insights into the molecular mechanisms underlying DON-induced intestinal toxicity, and might help in the development of improved mechanism-based risk assessments in animals and humans.
A Novel Zero Velocity Interval Detection Algorithm for Self-Contained Pedestrian Navigation System with Inertial Sensors.Monday, September 26, 2016
Tian X, Chen J, Han Y, Shang J, Li N,
Sensors (Basel, Switzerland). 22-9-2016
Zero velocity update (ZUPT) plays an important role in pedestrian navigation algorithms with the premise that the zero velocity interval (ZVI) should be detected accurately and effectively. A novel adaptive ZVI detection algorithm based on a smoothed pseudo Wigner-Ville distribution to remove multiple frequencies intelligently (SPWVD-RMFI) is proposed in this paper. The novel algorithm adopts the SPWVD-RMFI method to extract the pedestrian gait frequency and to calculate the optimal ZVI detection threshold in real time by establishing the function relationships between the thresholds and the gait frequency; then, the adaptive adjustment of thresholds with gait frequency is realized and improves the ZVI detection precision. To put it into practice, a ZVI detection experiment is carried out; the result shows that compared with the traditional fixed threshold ZVI detection method, the adaptive ZVI detection algorithm can effectively reduce the false and missed detection rate of ZVI; this indicates that the novel algorithm has high detection precision and good robustness. Furthermore, pedestrian trajectory positioning experiments at different walking speeds are carried out to evaluate the influence of the novel algorithm on positioning precision. The results show that the ZVI detected by the adaptive ZVI detection algorithm for pedestrian trajectory calculation can achieve better performance.
A MoS₂ Nanosheet-Based Fluorescence Biosensor for Simple and Quantitative Analysis of DNA Methylation.Monday, September 26, 2016
Xiao L, Xu L, Gao C, Zhang Y, Yao Q, Zhang GJ,
Sensors (Basel, Switzerland). 24-9-2016
MoS₂ nanomaterial has unique properties, including innate affinity with ss-DNA and quenching ability for fluorescence dyes. Here, we present the development of a simple fluorescence biosensor based on water-soluble MoS₂ nanosheets and restriction endonuclease BstUI for methylation analysis of p16 promoter. The biosensing platform exhibited excellent sensitivity in detecting DNA with a linear range of 100 pM~20 nM and a detection limit of 140 pM. More importantly, our method could distinguish as low as 1% difference in methylation level. Compared with previous methylation analysis, our design is both time saving and simple to operate, avoiding the limitations of PCR-based assays without compromising performance.
miR33a/miR33b* and miR122 as Possible Contributors to Hepatic Lipid Metabolism in Obese Women with Nonalcoholic Fatty Liver Disease.Monday, September 26, 2016
Auguet T, Aragonès G, Berlanga A, Guiu-Jurado E, Martí A, Martínez S, Sabench F, Hernández M, Aguilar C, Sirvent JJ, Del Castillo D, Richart C,
International journal of molecular sciences. 22-9-2016
Specific miRNA expression profiles have been shown to be associated with nonalcoholic fatty liver disease (NAFLD). We examined the correlation between the circulating levels and hepatic expression of miR122 and miR33a/b*, the key lipid metabolism-related gene expression and the clinicopathological factors of obese women with NAFLD. We measured miR122 and miR33a/b* expression in liver samples from 62 morbidly obese (MO), 30 moderately obese (ModO), and eight normal-weight controls. MiR122 and miR33a/b* expression was analyzed by qRT-PCR. Additionally, miR122 and miR33b* circulating levels were analyzed in 122 women. Hepatic miR33b* expression was increased in MO compared to ModO and controls, whereas miR122 expression was decreased in the MO group compared to ModO. In obese cohorts, miR33b* expression was increased in nonalcoholic steatohepatitis (NASH). Regarding circulating levels, MO patients with NASH showed higher miR122 levels than MO with simple steatosis (SS). These circulating levels are good predictors of histological features associated with disease severity. MO is associated with altered hepatic miRNA expression. In obese women, higher miR33b* liver expression is associated with NASH. Moreover, multiple correlations between miRNAs and the expression of genes related to lipid metabolism were found, that would suggest a miRNA-host gene circuit. Finally, miR122 circulating levels could be included in a panel of different biomarkers to improve accuracy in the non-invasive diagnosis of NASH.
Keratinocyte Growth Factor Combined with a Sodium Hyaluronate Gel Inhibits Postoperative Intra-Abdominal Adhesions.Monday, September 26, 2016
Wei G, Zhou C, Wang G, Fan L, Wang K, Li X,
International journal of molecular sciences. 24-9-2016
Postoperative intra-abdominal adhesion is a very common complication after abdominal surgery. One clinical problem that remains to be solved is to identify an ideal strategy to prevent abdominal adhesions. Keratinocyte growth factor (KGF) has been proven to improve the proliferation of mesothelial cells, which may enhance fibrinolytic activity to suppress postoperative adhesions. This study investigated whether the combined administration of KGF and a sodium hyaluronate (HA) gel can prevent intra-abdominal adhesions by improving the orderly repair of the peritoneal mesothelial cells. The possible prevention mechanism was also explored. The cecum wall and its opposite parietal peritoneum were abraded after laparotomy to induce intra-abdominal adhesion formation. Animals were randomly allocated to receive topical application of HA, KGF, KGF + HA, or normal saline (Control). On postoperative day 7, the adhesion score was assessed with a visual scoring system. Masson's trichrome staining, picrosirius red staining and hydroxyproline assays were used to assess the magnitude of adhesion and tissue fibrosis. Cytokeratin, a marker of the mesothelial cells, was detected by immunohistochemistry. The levels of tissue plasminogen activator (tPA), interleukin-6 (IL-6), and transforming growth factor β1 (TGF-β1) in the abdominal fluid were determined using enzyme-linked immunosorbent assays (ELISAs). Western blotting was performed to examine the expression of the TGF-β1, fibrinogen and α-smooth muscle actin (α-SMA) proteins in the rat peritoneal adhesion tissue. The combined administration of KGF and HA significantly reduced intra-abdominal adhesion formation and fibrin deposition and improved the orderly repair of the peritoneal mesothelial cells in the rat model. Furthermore, the combined administration of KGF and HA significantly increased the tPA levels but reduced the levels of IL-6, tumor necrosis factor α (TNF-α) and TGF-β1 in the abdominal fluid. The expression levels of TGF-β1, fibrinogen and α-SMA protein and mRNA in the rat peritoneum or adhesion tissues were also down-regulated following the combined administration of KGF and HA. The combined administration of KGF and HA can significantly prevent postoperative intra-abdominal adhesion formation by maintaining the separation of the injured peritoneum and promoting mesothelial cell regeneration. The potential mechanism may be associated with rapid mesothelial cell repair in the injured peritoneum. This study suggests that combined administration of KGF and HA may be a promising pharmacotherapeutic strategy for preventing abdominal adhesions, which is worth further study, and has potential value in clinical applications.
A Novel Tetraenoic Fatty Acid Isolated from Amaranthus spinosus Inhibits Proliferation and Induces Apoptosis of Human Liver Cancer Cells.Monday, September 26, 2016
Mondal A, Guria T, Maity TK, Bishayee A,
International journal of molecular sciences. 22-9-2016
Amaranthus spinosus Linn. (Family: Amaranthaceae) has been shown to be useful in preventing and mitigating adverse pathophysiological conditions and complex diseases. However, only limited information is available on the anticancer potential of this plant. In this study, we examined the antiproliferative and pro-apoptotic effects of a novel fatty acid isolated from A. spinosus-(14E,18E,22E,26E)-methyl nonacosa-14,18,22,26 tetraenoate-against HepG2 human liver cancer cells. We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to determine cell viability, flow cytometry assay for cell cycle analysis, and Western blot analysis to measure protein expression of Cdc2), cyclin B1, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). The MTT assay showed that the fatty acid markedly inhibited the proliferation of HepG2 cells in a dosage-dependent fashion, with a half maximal inhibitory concentration (IC50) value of 25.52 µmol/L. This antiproliferative result was superior to that of another known fatty acid, linoleic acid (IC50 38.65 µmol/L), but comparable to that of standard anticancer drug doxorubicin (IC50 24.68 µmol/L). The novel fatty acid also induced apoptosis mediated by downregulation of cyclin B1, upregulation of Bax, and downregulation of Bcl-2, resulting in the G₂/M transition arrest. Our results provide the first experimental evidence that a novel fatty acid isolated from A. spinosus exhibits significant antiproliferative activity mediated through the induction of apoptosis in HepG2 cells. These encouraging results may facilitate the development of A. spinosus fatty acid for the prevention and intervention of hepatocellular carcinoma.
Characterization of a β-Adrenergic-Like Octopamine Receptor in the Oriental Fruit Fly, Bactrocera dorsalis (Hendel).Monday, September 26, 2016
Li HM, Jiang HB, Gui SH, Liu XQ, Liu H, Lu XP, Smagghe G, Wang JJ,
International journal of molecular sciences. 22-9-2016
The biogenic amine octopamine plays a critical role in the regulation of many physiological processes in insects. Octopamine transmits its action through a set of specific G-protein coupled receptors (GPCRs), namely octopamine receptors. Here, we report on a β-adrenergic-like octopamine receptor gene (BdOctβR1) from the oriental fruit fly, Bactrocera dorsalis (Hendel), a destructive agricultural pest that occurs in North America and the Asia-Pacific region. As indicated by RT-qPCR, BdOctβR1 was highly expressed in the central nervous system (CNS) and Malpighian tubules (MT) in the adult flies, suggesting it may undertake important roles in neural signaling in the CNS as well as physiological functions in the MT of this fly. Furthermore, its ligand specificities were tested in a heterologous expression system where BdOctβR1 was expressed in HEK-293 cells. Based on cyclic AMP response assays, we found that BdOctβR1 could be activated by octopamine in a concentration-dependent manner, confirming that this receptor was functional, while tyramine and dopamine had much less potency than octopamine. Naphazoline possessed the highest agonistic activity among the tested agonists. In antagonistic assays, mianserin had the strongest activity and was followed by phentolamine and chlorpromazine. Furthermore, when the flies were kept under starvation, there was a corresponding increase in the transcript level of BdOctβR1, while high or low temperature stress could not induce significant expression changes. The above results suggest that BdOctβR1 may be involved in the regulation of feeding processes in Bactrocera dorsalis and may provide new potential insecticide leads targeting octopamine receptors.
Cytoproliferative and Cytoprotective Effects of Striatisporolide A Isolated from Rhizomes of Athyrium multidentatum (Doell.) Ching on Human Umbilical Vein Endothelial Cells.Monday, September 26, 2016
Liu DM, Sheng JW, Wang SH, Zhang WF, Zhang W, Zhang DJ,
Molecules (Basel, Switzerland). 22-9-2016
Objectives: The aim of this study was to investigate the proliferative and protective effects of striatisporolide A (SA) obtained from the rhizomes of Athyrium multidentatum (Doell.) Ching on human umbilical vein endothelial cells (HUVECs). Methods: Cell viability was measured by the MTT method. Cell apoptosis was determined by flow cytometry. Intracellular ROS was measured by the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe. Results: The viability rate in cells treated with 100 µM SA alone was increased to 128.72% ± 0.19% and showed a significant difference compared with the control group (p < 0.05). Meanwhile, SA augmented the cell viabilities in H₂O₂-treated HUVECs, and the cell viability was enhanced to 56.94% ± 0.13% (p < 0.01) when pre-incubated with 50 µM SA. The cell apoptosis rates were reduced to 2.17% ± 0.20% (p < 0.05) and 3.1% ± 0.34% (p < 0.01), respectively, after treatment with SA alone or SA/H₂O₂. SA inhibited the overproduction of reactive oxygen species (ROS) in HUVECs induced by H₂O₂ and the fluorescent intensity was abated to 9.47 ± 0.61 after pre-incubated with 100 μM SA. Conclusions: The biological activities of SA were explored for the first time. Our results stated that SA exhibited significant cytoproliferative and minor cytoprotective effects on HUVECs. We presume that the mechanisms of the proliferation and protection actions of SA involve interference with the generation of ROS and the cell apoptosis. These findings provide a new perspective on the biological potential of butenolides.
Anti-Inflammatory Activity of Citrus bergamia Derivatives: Where Do We Stand?Monday, September 26, 2016
Ferlazzo N, Cirmi S, Calapai G, Ventura-Spagnolo E, Gangemi S, Navarra M,
Molecules (Basel, Switzerland). 24-9-2016
Inflammatory diseases affect a large portion of the worldwide population, and chronic inflammation is a major risk factor for several dangerous pathologies. To limit the side effects of both synthetic and biological anti-inflammatory drugs, the use of herbal medicines, nutraceuticals and food supplements has increased tremendously as alternative and/or complementary medicine to treat several pathologies, including inflammation. During the last decades, the biological properties of Citrus bergamia (bergamot) derivatives have obtained important scientific achievements, and it has been suggested their use in a context of a multitarget pharmacological strategy. Here, we present an overview of the anti-inflammatory properties of bergamot extracts that could represent the scientific basis for develop novel and alternative strategies to improve health status and attenuate inflammatory conditions.
Potential of Natural Products in the Inhibition of Adipogenesis through Regulation of PPARγ Expression and/or Its Transcriptional Activity.Monday, September 26, 2016
Feng S, Reuss L, Wang Y,
Molecules (Basel, Switzerland). 23-9-2016
Obesity is a global health problem characterized as an increase in the mass of adipose tissue. Adipogenesis is one of the key pathways that increases the mass of adipose tissue, by which preadipocytes mature into adipocytes through cell differentiation. Peroxisome proliferator-activated receptor γ (PPARγ), the chief regulator of adipogenesis, has been acutely investigated as a molecular target for natural products in the development of anti-obesity treatments. In this review, the regulation of PPARγ expression by natural products through inhibition of CCAAT/enhancer-binding protein β (C/EBPβ) and the farnesoid X receptor (FXR), increased expression of GATA-2 and GATA-3 and activation of the Wnt/β-catenin pathway were analyzed. Furthermore, the regulation of PPARγ transcriptional activity associated with natural products through the antagonism of PPARγ and activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) were discussed. Lastly, regulation of mitogen-activated protein kinase (MAPK) by natural products, which might regulate both PPARγ expression and PPARγ transcriptional activity, was summarized. Understanding the role natural products play, as well as the mechanisms behind their regulation of PPARγ activity is critical for future research into their therapeutic potential for fighting obesity.
Enhanced Cellular Uptake and Pharmacokinetic Characteristics of Doxorubicin-Valine Amide Prodrug.Monday, September 26, 2016
Park Y, Park JH, Park S, Lee SY, Cho KH, Kim DD, Shim WS, Yoon IS, Cho HJ, Maeng HJ,
Molecules (Basel, Switzerland). 23-9-2016
In this study, we synthesized the valine (Val)-conjugated amide prodrug of doxorubicin (DOX) by the formation of amide bonds between DOX and Val. The synthesis of the DOX-Val prodrug was identified by a proton nuclear magnetic resonance (¹H-NMR) assay. In the MCF-7 cells (human breast adenocarcinoma cell; amino acid transporter-positive cell), the cellular accumulation efficiency of DOX-Val was higher than that of DOX according to the flow cytometry analysis data. Using confocal laser scanning microscopy (CLSM) imaging, it was confirmed that DOX-Val as well as DOX was mainly distributed in the nucleus of cancer cells. DOX-Val was intravenously administered to rats at a dose of 4 mg/kg, and the plasma concentrations of DOX-Val (prodrug) and DOX (formed metabolite) were quantitatively determined. Based on the systemic exposure (represented as area under the curve (AUC) values) of DOX-Val (prodrug) and DOX (formed metabolite), approximately half of DOX-Val seemed to be metabolized into DOX. However, it is expected that the remaining DOX-Val may exert improved cellular uptake efficiency in cancer cells after its delivery to the cancer region.
Bioactivity of a Novel Glycolipid Produced by a Halophilic Buttiauxella sp. and Improving Submerged Fermentation Using a Response Surface Method.Monday, September 26, 2016
Marzban A, Ebrahimipour G, Danesh A,
Molecules (Basel, Switzerland). 22-9-2016
An antimicrobial glycolipid biosurfactant (GBS), extracted and identified from a marine bacterium, was studied to inhibit pathogenic microorganisms. Production of the GBS was optimized using a statistical method, a response surface method (RSM) with a central composite design (CCD) for obtaining maximum yields on a cost-effective substrate, molasses. The GBS-producing bacterium was identified as Buttiauxella Species in terms of biochemical and molecular characteristics. This compound showed a desirable antimicrobial activity against some pathogens such as E. coli, Bacillus subtilis, Bacillus cereus, Candida albicans, Aspergilus niger, Salmonella enterica. The rheological studies described the stability of the GBS at high values in a range of pH (7-8), temperature (20-60) and salinity (0%-3%). The statistical optimization of GBS fermentation was found to be pH 7, temperature 33 °C, Peptone 1%, NaCl 1% and molasses 1%. The potency of the GBS as an effective antimicrobial agent provides evidence for its use against food and human pathogens. Moreover, favorable production of the GBS in the presence of molasses as a cheap substrate and the feasibility of pilot scale fermentation using an RSM method could expand its uses in food, pharmaceutical products and oil industries.
Genetic Modifiers of Progression-free Survival in Never-smoking Lung Adenocarcinoma Patients Treated with First-line TKIs.Monday, September 26, 2016
Chang IS, Jiang SS, Yang JC, Su WC, Chien LH, Hsiao CF, Lee JH, Chen CY, Chen CH, Chang GC, Wang Z, Lo FY, Chen KY, Wang WC, Chen YM, Huang MS, Tsai YH, Su YC, Hsieh WS, Shih WC, Shieh SH, Yang TY, Lan Q, Rothman N, Chen CJ, Chanock SJ, Yang PC, Hsiung CA,
American journal of respiratory and critical care medicine. 26-Sep-2016
Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.
A Bayesian integrative approach for multi-platform genomic data: A kidney cancer case study.Monday, September 26, 2016
Chekouo T, Stingo FC, Doecke JD, Do KA,
Biometrics. 26-Sep-2016
Integration of genomic data from multiple platforms has the capability to increase precision, accuracy, and statistical power in the identification of prognostic biomarkers. A fundamental problem faced in many multi-platform studies is unbalanced sample sizes due to the inability to obtain measurements from all the platforms for all the patients in the study. We have developed a novel Bayesian approach that integrates multi-regression models to identify a small set of biomarkers that can accurately predict time-to-event outcomes. This method fully exploits the amount of available information across platforms and does not exclude any of the subjects from the analysis. Through simulations, we demonstrate the utility of our method and compare its performance to that of methods that do not borrow information across regression models. Motivated by The Cancer Genome Atlas kidney renal cell carcinoma dataset, our methodology provides novel insights missed by non-integrative models.
TrpM, a Small Protein Modulating Tryptophan Biosynthesis and Morpho-Physiological Differentiation in Streptomyces coelicolor A3(2).Monday, September 26, 2016
Palazzotto E, Gallo G, Renzone G, Giardina A, Sutera A, Silva J, Vocat C, Botta L, Scaloni A, Puglia AM,
PloS one. 26-9-2016
In the model actinomycete Streptomyces coelicolor A3(2), small open reading frames encoding proteins with unknown functions were identified in several amino acid biosynthetic gene operons, such as SCO2038 (trpX) in the tryptophan trpCXBA locus. In this study, the role of the corresponding protein in tryptophan biosynthesis was investigated by combining phenotypic and molecular analyses. The 2038KO mutant strain was characterized by delayed growth, smaller aerial hyphae and reduced production of spores and actinorhodin antibiotic, with respect to the WT strain. The capability of this mutant to grow on minimal medium was rescued by tryptophan and tryptophan precursor (serine and/or indole) supplementation on minimal medium and by gene complementation, revealing the essential role of this protein, here named TrpM, as modulator of tryptophan biosynthesis. His-tag pull-down and bacterial adenylate cyclase-based two hybrid assays revealed TrpM interaction with a putative leucyl-aminopeptidase (PepA), highly conserved component among various Streptomyces spp. In silico analyses showed that PepA is involved in the metabolism of serine, glycine and cysteine through a network including GlyA, CysK and CysM enzymes. Proteomic experiments suggested a TrpM-dependent regulation of metabolic pathways and cellular processes that includes enzymes such as GlyA, which is required for the biosynthesis of tryptophan precursors and key proteins participating in the morpho-physiological differentiation program. Altogether, these findings reveal that TrpM controls tryptophan biosynthesis at the level of direct precursor availability and, therefore, it is able to exert a crucial effect on the morpho-physiological differentiation program in S. coelicolor A3(2).
Informatics-Based Discovery of Disease-Associated Immune Profiles.Monday, September 26, 2016
Delmas A, Oikonomopoulos A, Lacey PN, Fallahi M, Hommes DW, Sundrud MS,
PloS one. 26-9-2016
Advances in flow and mass cytometry are enabling ultra-high resolution immune profiling in mice and humans on an unprecedented scale. However, the resulting high-content datasets challenge traditional views of cytometry data, which are both limited in scope and biased by pre-existing hypotheses. Computational solutions are now emerging (e.g., Citrus, AutoGate, SPADE) that automate cell gating or enable visualization of relative subset abundance within healthy versus diseased mice or humans. Yet these tools require significant computational fluency and fail to show quantitative relationships between discrete immune phenotypes and continuous disease variables. Here we describe a simple informatics platform that uses hierarchical clustering and nearest neighbor algorithms to associate manually gated immune phenotypes with clinical or pre-clinical disease endpoints of interest in a rapid and unbiased manner. Using this approach, we identify discrete immune profiles that correspond with either weight loss or histologic colitis in a T cell transfer model of inflammatory bowel disease (IBD), and show distinct nodes of immune dysregulation in the IBDs, Crohn's disease and ulcerative colitis. This streamlined informatics approach for cytometry data analysis leverages publicly available software, can be applied to manually or computationally gated cytometry data, is suitable for any clinical or pre-clinical setting, and embraces ultra-high content flow and mass cytometry as a discovery engine.
Functional SNPs of INCENP Affect Semen Quality by Alternative Splicing Mode and Binding Affinity with the Target Bta-miR-378 in Chinese Holstein Bulls.Monday, September 26, 2016
Liu J, Sun Y, Yang C, Zhang Y, Jiang Q, Huang J, Ju Z, Wang X, Zhong J, Wang C,
PloS one. 26-9-2016
Inner centromere protein (INCENP) plays an important role in mitosis and meiosis as the main member of chromosomal passenger protein complex (CPC). To investigate the functional markers of the INCENP gene associated with semen quality, the single nucleotide polymorphisms (SNPs) g.19970 A>G and g.34078 T>G were identified and analyzed. The new splice variant INCENP-TV is characterized by the deletion of exon 12. The g.19970 A>G in the exonic splicing enhancer (ESE) motif region results in an aberrant splice variant by constructing two minigene expression vectors using the pSPL3 exon capturing vector and transfecting vectors into MLTC-1 cells. INCENP-TV was more highly expressed than INCENP-reference in adult bull testes. The g.34078 T>G located in the binding region of bta-miR-378 could affect the expression of INCENP, which was verified by luciferase assay. To analyze comprehensively the correlation of SNPs with sperm quality, haplotype combinations constructed by g.19970 A>G and g.34078 T>G, as well as g.-692 C>T and g.-556 G>T reported in our previous studies, were analyzed. The bulls with H1H12 and H2H2 exhibited a higher ejaculate volume than those with H2H10 and H9H12, respectively (P < 0.05). Bulls with H11H11 and H2H10 exhibited higher initial sperm motility than those with H2H2 (P < 0.05). The expression levels of INCENP in bulls with H1H12 and H11H11 were significantly higher than those in bulls with H9H12 (P < 0.05), as determined by qRT-PCR. Findings suggest that g.19970 A>G and g.34078 T>G in INCENP both of which appear to change the molecular and biological characteristics of the mRNA transcribed from the locus may serve as a biomarkers of male bovine fertility by affecting alternative splicing mode and binding affinity with the target bta-miR-378.
A novel role of bone morphogenetic protein-7 in the regulation of adhesion and migration of human monocytic cells.Monday, September 26, 2016
Sovershaev TA, Unruh D, Sveinbjørnsson B, Fallon JT, Hansen JB, Bogdanov VY, Sovershaev MA,
Thrombosis research. 17-Sep-2016
BMP-7 directly upregulates adhesion and migration of human monocytic cells via activation of β2 integrins, Akt, and FAK. Our findings suggest that BMP-7 may serve as a novel contributor to atherogenesis.
Anti-inflammatory effects of infliximab in mice are independent of TNFα neutralization.Monday, September 26, 2016
Assas BM, Levison S, Little M, England H, Battrick L, Bagnall J, McLaughlin J, Paszek P, Else KJ, Pennock JL,
Clinical and experimental immunology. 26-Sep-2016
Infliximab (IFX) has been used repeatedly in mouse pre-clinical models with associated claims that anti-inflammatory effects are due to inhibition of mouse TNFα. However the mechanism of action in mice remains unclear. In this study, the binding specificity of IFX for mouse TNFα was investigated ex vivo using ELISA, flow cytometry and western blot. IFX did not bind directly to soluble or membrane-bound mouse TNFα nor did it have any effect on TNFα-induced NfKb stimulation in mouse fibroblasts. The efficacy of IFX treatment was then investigated in vivo using a TNFα independent T. muris-induced infection model of chronic colitis. Infection provoked severe transmural colonic inflammation by day 35 post infection. Colonic pathology, macrophage phenotype and cell death were determined. As predicted from the in vitro data, in vivo treatment of T. muris infected mice with IFX had no effect on clinical outcome; neither did it affect macrophage cell phenotype or number. IFX significantly enhanced apoptosis of colonic immune cells, likely to be driven by a direct effect of the humanised antibody itself. We have demonstrated that although IFX does not directly bind to TNFα, observed anti-inflammatory effects in other mouse models may be through host cell apoptosis. We suggest that more careful consideration of xenogeneic responses should be made when utilizing IFX in pre-clinical models. This article is protected by copyright. All rights reserved.
Progression of hypertension and kidney disease in aging fawn-hooded rats is mediated by enhanced influence of renin-angiotensin system and suppression of nitric oxide system and epoxyeicosanoids.Monday, September 26, 2016
Doleželová Š, Jíchová Š, Husková Z, Vojtíšková A, Kujal P, Hošková L, Kautzner J, Sadowski J, Červenka L, Kopkan L,
Clinical and experimental hypertension (New York, N.Y. : 1993). 26-Sep-2016
The fawn-hooded hypertensive (FHH) rat serves as a genetic model of spontaneous hypertension associated with glomerular hyperfiltration and proteinuria. However, the knowledge of the natural course of hypertension and kidney disease in FHH rats remains fragmentary and the underlying pathophysiological mechanisms are unclear. In this study, over the animals' lifetime, we followed the survival rate, blood pressure (telemetry), indices of kidney damage, the activity of renin-angiotensin (RAS) and nitric oxide (NO) systems, and CYP450-epoxygenase products (EETs). Compared to normotensive controls, no elevation of plasma and renal RAS was observed in prehypertensive and hypertensive FHH rats; however, RAS inhibition significantly reduced systolic blood pressure (137 ± 9 to 116 ± 8, and 159 ± 8 to 126 ± 4 mmHg, respectively) and proteinuria (62 ± 2 to 37 ± 3, and 132 ± 8 to 87 ± 5 mg/day, respectively). Moreover, pharmacological RAS inhibition reduced angiotensin (ANG) II and increased ANG 1-7 in the kidney and thereby may have delayed the progression of kidney disease. Furthermore, renal NO and EETs declined in the aging FHH rats but not in the control strain. The present results, especially the demonstration of exaggerated vascular responsiveness to ANG II, indicate that RAS may contribute to the development of hypertension and kidney disease in FHH rats. The activity of factors opposing the development of hypertension and protecting the kidney declined with age in this model. Therefore, therapeutic enhancement of this activity besides RAS inhibition could be attempted in the therapy of human hypertension associated with kidney disease.
Cytokines as Potential Biomarkers of Parkinson Disease.Monday, September 26, 2016
Alcalay RN,
JAMA neurology. 26-Sep-2016
Estimation of Heritability for Nine Common Cancers Using Data from Genome-Wide Association Studies in Chinese Population.Monday, September 26, 2016
Dai J, Shen W, Wen W, Chang J, Wang T, Chen H, Jin G, Ma H, Wu C, Li L, Song F, Zeng Y, Jiang Y, Chen J, Wang C, Zhu M, Zhou W, Du J, Xiang Y, Shu XO, Hu Z, Zhou W, Chen K, Xu J, Jia W, Lin D, Zheng W, Shen H,
International journal of cancer. 26-Sep-2016
The familial aggregation indicated the inheritance of cancer risk. Recent genome-wide association studies (GWAS) have identified a number of common single nucleotide polymorphisms (SNPs). Following heritability analyses have shown that SNPs could explain a moderate amount of variance for different cancer phenotypes among Caucasians. However, little information was available in Chinese population. We performed a genome-wide complex trait analysis (GCTA) for common cancers at nine anatomical sites in Chinese population (14,629 cancer cases vs. 17,554 controls) and estimated the heritability of these cancers based on the common SNPs. We found that common SNPs explained certain amount of heritability with significance for all nine cancer sites: gastric cancer (20.26%), esophageal squamous cell carcinoma (19.86%), colorectal cancer (16.30%), lung cancer (15.17%), and epithelial ovarian cancer (13.31%), and a similar heritability around 10% for Hepatitis B virus (HBV)-related hepatocellular carcinoma, prostate cancer, breast cancer and nasopharyngeal carcinoma. We found that nearly or less than 25% change was shown when removing the regions expanding 250kb or 500kb up and downwards of the GWAS-reported SNPs. We also found strong linear correlations between variance partitioned by each chromosome and chromosomal length only for lung cancer (R(2) =0.641, P=0.001) and esophageal squamous cell cancer (R(2) =0.633, P=0.002), which implied us the complex heterogeneity of cancers. These results indicate polygenic genetic architecture of the nine common cancers in Chinese population. Further efforts should be made to discover the hidden heritability of different cancer types among Chinese. This article is protected by copyright. All rights reserved.
Stability of FeNO and airway hyperresponsiveness to mannitol in untreated asthmatics.Monday, September 26, 2016
Udesen PB, Westergaard CG, Porsbjerg C, Backer V,
The Journal of asthma : official journal of the Association for the Care of Asthma. 26-Sep-2016
In steroid-free non-smoking asthmatics with constant symptom scores and lung function, airway responsiveness to mannitol remained at the same level over a period of months, while a minor change in exhaled FeNO was reported. These results suggest that mannitol is a stable, reliable marker of clinical disease activity.
Water-Soluble and Highly Luminescent Europium(III) Complexes with Favorable Photostability and Sensitive pH Response Behavior.Monday, September 26, 2016
Wei C, Wei H, Yan W, Zhao Z, Cai Z, Sun B, Meng Z, Liu Z, Bian Z, Huang C,
Inorganic chemistry. 26-Sep-2016
Two highly luminescent and water-soluble Eu(III) complexes, Eu1 and Eu2, based on novel carboxyl-functionalized 1,5-naphthyridine derivatives 8-hydroxy-1,5-naphthyridine-2-carboxylic acid (H2L1) and 7-cyano-8-hydroxy-1,5-naphthyridine-2-carboxylic acid (H2L2), respectively, are designed and synthesized. The crystal structure of Eu2 indicates that the central Eu(III) ion is nine-coordinated by three tridentate ligands (O^N^O). Both Eu1 and Eu2 show strong luminescence in aqueous solution with quantum yields (lifetimes) of 28% (1.1 ms) and 14% (0.76 ms), respectively. The chelates display unique UV-light stability in solution and remain highly emissive after 100 min of strong UV irradiation (∼300 W·m(-2) at 345 nm). Moreover, they exhibit reversible luminescence intensity changes with varied pH values, and the response mechanism is investigated. "Turn-on" of the Eu(III) emission upon increasing pH is realized by ligand structure change from keto to enol anion form, resulting in red-shifted absorption band and suppressed quenching from solvents and N-H vibration upon deprotonating. The results show that these novel Eu(III) complexes are quite intriguing for potential application as bioimaging agents and pH probes.
Oxidative Damage of Biomolecules by the Environmental Pollutants NO2(•) and NO3(•).Monday, September 26, 2016
Gamon LF, Wille U,
Accounts of chemical research. 26-Sep-2016
Air pollution is responsible for the premature death of about 7 million people every year. Ozone (O3) and nitrogen dioxide (NO2(•)) are the key gaseous pollutants in the troposphere, which predominantly result from combustion processes. Their inhalation leads to reactions with constituents in the airway surface fluids (ASF) of the respiratory tract and/or lungs. ASF contain small molecular-weight antioxidants, which protect the underlying epithelial cells against oxidative damage. When this defense system is overwhelmed, proteins and lipids present on cell surfaces or within the ASF become vulnerable to attack. The resulting highly reactive protein and lipid oxidation products could subsequently damage the epithelial cells through secondary reactions, thereby causing inflammation. While reactions of NO2(•) with biological molecules are considered to proceed through radical pathways, the biological effect of O3 is attributed to its high reactivity with π systems. Because O3 and NO2(•) always coexist in the polluted ambient atmosphere, synergistic effects resulting from in situ formed strongly oxidizing nitrate radicals (NO3(•)) may also require consideration. For example, in vitro product studies revealed that phenylalanine, which is inert not only to oxidants produced through biochemical processes, but also to NO2(•) or O3 in isolation, is damaged by NO3(•). The reaction is initiated by oxidation of the aromatic ring and, depending on the availability of NO2(•), leads to formation of nitrophenylalanine or β-nitrooxyphenylalanine, which could serve as marker for NO3(•)-induced oxidative damage in peptides. More easily oxidizable aromatic amino acids are directly attacked by NO2(•) and are converted to the same products independent of whether O3 is also present. Remarkably, NO2(•)-induced oxidative damage in peptides occurs not only through the well-established radical oxidation of peptide side chains, but also through an unprecedented fragmentation/rearrangement of the peptide backbone. This process is initiated by a nonradical N-nitrosation of a peptide bond involving the dimer of NO2(•), i.e., N2O4, and contracts the peptide chain in the N → C direction by expelling one amino acid residue with simultaneous fusion of the remaining molecular termini, thereby forming a new peptide bond. This peptide cleavage could potentially be highly relevant for peptide segments with "nonvulnerable" side chains closer to the terminus that are not tied up in complex secondary and tertiary structures and therefore accessible for environmental oxidants. Likewise, NO2(•) reacts with cholesterol at the C═C moiety through an ionic mechanism, which leads to formation of 6-nitrocholesterol in the presence of moisture. Contrary to common belief, this clearly shows that ionic chemistry, in particular nitrosation reactions by intermediately formed NO(+), requires consideration when assessing NO2(•) toxicity. This conclusion is supported by recent work by Colussi et al. (Enami, S.; Hoffmann, M. R.; Colussi, A. J. Absorption of inhaled NO2. J. Phys. Chem. B. 2009, 113, 7977-7981), who showed that anions in the airway surfaces fluids mediate NO2(•) absorption by catalyzing its hydrolytic disproportionation into NO2(-)/HNO2 and NO3(-). These findings could be the key to our understanding why NO2(•), despite its low water solubility, has such pronounced biological effects in vivo.
Latent tuberculosis infection (LTBI): a real host defence or a permanent threat?Monday, September 26, 2016
Sanduzzi A, Ponticiello A, Bocchino M, Perna F, Vatrella A,
Le infezioni in medicina : rivista periodica di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive. 1-Sep-2016
Screening of latent infection by Mycobacterium tuberculosis (LTBI) and treatment of positive subjects is the key point in the prevention of TB; such a strategy should be performed mainly among individuals with risk of progression. Progression from LTBI to active TB is highest both in recent contacts of patients with active TB, and in immunocompromised subjects. Therefore, LTBI could either be considered a permanent host defence or, seen from the opposite point of view, it could represent a long-lasting threat if the efficiency of the immune system declines over a lifetime. Interferon gamma release assays (IGRAs) show better sensitivity and specificity than the Mantoux test.
Tcf7l2/Tcf4 Transcriptional Repressor Function Requires HDAC Activity in the Developing Vertebrate CNS.Monday, September 26, 2016
Wang H, Matise MP,
PloS one. 27-9-2016
The generation of functionally distinct neuronal subtypes within the vertebrate central nervous system (CNS) requires the precise regulation of progenitor gene expression in specific neuronal territories during early embryogenesis. Accumulating evidence has implicated histone deacetylase (HDAC) proteins in cell specification, proliferation, and differentiation in diverse embryonic and adult tissues. However, although HDAC proteins have shown to be expressed in the developing vertebrate neural tube, their specific role in CNS neural progenitor fate specification remains unclear. Prior work from our lab showed that the Tcf7l2/Tcf4 transcription factor plays a key role in ventral progenitor lineage segregation by differential repression of two key specification factors, Nkx2.2 and Olig2. In this study, we found that administration of HDAC inhibitors (Valproic Acid (VPA), Trichostatin-A (TSA), or sodium butyrate) in chick embryos in ovo disrupted normal progenitor gene segregation in the developing neural tube, indicating that HDAC activity is required for this process. Further, using functional and pharmacological approaches in vivo, we found that HDAC activity is required for the differential repression of Nkx2.2 and Olig2 by Tcf7l2/Tcf4. Finally, using dominant-negative functional assays, we provide evidence that Tcf7l2/Tcf4 repression also requires Gro/TLE/Grg co-repressor factors. Together, our data support a model where the transcriptional repressor activity of Tcf7l2/Tcf4 involves functional interactions with both HDAC and Gro/TLE/Grg co-factors at specific target gene regulatory elements in the developing neural tube, and that this activity is required for the proper segregation of the Nkx2.2 (p3) and Olig2 (pMN) expressing cells from a common progenitor pool.
Mapping genetic factors in high-grade glioma patients.Monday, September 26, 2016
Yuan Y, Yunhe M, Xiang W, Yanhui L, Ruofei L, Jiewen L, Qing M,
Clinical neurology and neurosurgery. 20-Sep-2016
Our study demonstrates that different molecular phenotypes are related to specific brain regions. In addition, the structural MRI and genetic profile-based analysis of brain regions associated with survival-associated factors could be used in planning glioma operations and clinical survival predictions.
3,4-Dichloroaniline revisited: A study on the fate of the priority pollutant in a sediment-water system derived from a rice growing region in Italy.Monday, September 26, 2016
Yuan Y, Zhang P, Schäffer A, Schmidt B,
The Science of the total environment. 23-Sep-2016
As ultimate sink for xenobiotics released into the environment, sediments play an important role concerning the evaluation of the fate of foreign compounds. 3,4-Dichloroaniline (3,4-DCA) is a degradation product of herbicide propanil and some urea herbicides. Propanil was extensively used worldwide in rice cultivation. The aim of the study was to examine the fate of (14)C-labeled 3,4-DCA in a sediment-water system; the sediment was derived from a rice field in Northern Italy. After application of (14)C-3,4-DCA, a time-course study was performed using incubation periods from 4h to 56days. Fractions obtained from assays were water phase, sediment phase including methanol and Soxhlet extract as well as non-extractable residues (NER), and mineralized portion ((14)CO2). Soluble fractions were examined by TLC, HPLC and GC-MS. NER found in sediment phases were further fractionated in non-humics, humic acids, fulvic acids and humin. Stability of systems was checked by microbial activity, dissolved oxygen and pH. After 56days of incubation, 23.1% of applied (14)C was mineralized, only 1.30% remained in the water phase, whereas 60.8% was found in the sediment phase, 53.3% of which were NER. Minor metabolites identified were 3,4-dichloroacetanilide (3,4-DCAA) and 3,3',4,4'-tetrachloroazobenzene (TCAB; 2.63% after 56days). According to pH, dissolved oxygen and microbial activity, systems appeared to be stable and not influenced by applied 3,4-DCA. Most striking result was the high mineralization rate as compared to previously published data. This finding suggested an adaptation of the microbial community in the sediment possibly due to decade-long treatment of rice fields with propanil.
OCEAN: Optimized Cross rEActivity estimatioN.Monday, September 26, 2016
Czodrowski P, Bolick WG,
Journal of chemical information and modeling. 26-Sep-2016
The prediction of molecular targets is highly beneficial during the drug discovery process, be it for off-target elucidation or deconvolution of phenotypic screens. Here, we present OCEAN, a target prediction tool exclusively utilizing publically available ChEMBL data. OCEAN uses a heuristics approach based on a validation set containing almost 1000 drug ← → target relationships. New ChEMBL data (ChEMBL20 as well as ChEMBL21) released after the validation was used for a prospective OCEAN performance check. The success rates of OCEAN to predict correctly the targets within the TOP10 ranks are 77% for recently marketed drugs and 62% for all new ChEMBL20 compounds and 51% for all new ChEMBL21 compounds. OCEAN is also capable of identifying polypharmacological compounds; the success rate for molecules simultaneously hitting at least two targets is 64% to be correctly predicted within the TOP10 ranks. The source code of OCEAN can be found at http://www.github.com/rdkit/OCEAN.
Analyses of the Distribution Patterns of Burkholderia pseudomallei and Associated Phages in Soil Samples in Thailand Suggest That Phage Presence Reduces the Frequency of Bacterial Isolation.Monday, September 26, 2016
Withatanung P, Chantratita N, Muangsombut V, Saiprom N, Lertmemongkolchai G, Klumpp J, Clokie MR, Galyov EE, Korbsrisate S,
PLoS neglected tropical diseases. Sep-2016
The presence of podoviruses capable of infecting B. pseudomallei may affect the success of the pathogen isolation from the soil. The currently used culture-based methods of B. pseudomallei isolation appear to under-estimate the bacterial abundance. The detection of phage capable of infecting B. pseudomallei from environmental samples could be a useful preliminary test to indicate the likely presence of B. pseudomallei in environmental samples.
Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing.Monday, September 26, 2016
Jaing CJ, McLoughlin KS, Thissen JB, Zemla A, Gardner SN, Vergez LM, Bourguet F, Mabery S, Fofanov VY, Koshinsky H, Jackson PJ,
PloS one. 26-9-2016
Francisella tularensis is classified as a Class A bioterrorism agent by the U.S. government due to its high virulence and the ease with which it can be spread as an aerosol. It is a facultative intracellular pathogen and the causative agent of tularemia. Ciprofloxacin (Cipro) is a broad spectrum antibiotic effective against Gram-positive and Gram-negative bacteria. Increased Cipro resistance in pathogenic microbes is of serious concern when considering options for medical treatment of bacterial infections. Identification of genes and loci that are associated with Ciprofloxacin resistance will help advance the understanding of resistance mechanisms and may, in the future, provide better treatment options for patients. It may also provide information for development of assays that can rapidly identify Cipro-resistant isolates of this pathogen. In this study, we selected a large number of F. tularensis live vaccine strain (LVS) isolates that survived in progressively higher Ciprofloxacin concentrations, screened the isolates using a whole genome F. tularensis LVS tiling microarray and Illumina sequencing, and identified both known and novel mutations associated with resistance. Genes containing mutations encode DNA gyrase subunit A, a hypothetical protein, an asparagine synthase, a sugar transamine/perosamine synthetase and others. Structural modeling performed on these proteins provides insights into the potential function of these proteins and how they might contribute to Cipro resistance mechanisms.
Fluorescent trimethyl-substituted naphthyridine as a label-free signal reporter for one-step and highly sensitive fluorescent detection of DNA in serum samples.Monday, September 26, 2016
Wang J, Wang X, Wu S, Che R, Luo P, Meng C,
Biosensors & bioelectronics. 20-Sep-2016
A facile label-free sensing method is developed for the one-step and highly sensitive fluorescent detection of DNA, which couples the specific C-C mismatch bonding and fluorescent quenching property of a trimethyl-substituted naphthyridine dye (ATMND) with the exonuclease III (Exo III) assisted cascade target recycling amplification strategy. In the absence of target DNA, the DNA hairpin probe with a C-C mismatch in the stem and more than 4 bases overhung at the 3' terminus could entrap and quench the fluorescence of ATMND and resist the digestion of Exo III, thus showing a low fluorescence background. In the presence of the target, however, the hybridization event between the two protruding segments and the target triggers the digestion reaction of Exo III, recycles the initial target, and simultaneously releases both the secondary target analogue and the ATMND caged in the stem. The released initial and secondary targets take part in another cycle of digestion, thus leading to the release of a huge amount of free ATMND for signal transducing. Based on the fluorescence recovery, the as-proposed label-free fluorescent sensing strategy shows very good analytical performances towards DNA detection, such as a wide linear range from 10pM to 1μM, a low limit of detection of 6pM, good selectivity, and a facile one-step operation at room temperature. Practical sample analysis in serum samples indicates the method has good precision and accuracy, which may thus have application potentials for point-of-care screening of DNA in complex clinical and environmental samples.
Bacterial fatty acid metabolism in modern antibiotic discovery.Monday, September 26, 2016
Yao J, Rock CO,
Biochimica et biophysica acta. 23-Sep-2016
Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isozymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concentrations of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metabolism for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.
Bacteriophages to combat foodborne infections caused by food contamination by bacteria of the Campylobacter genus.Monday, September 26, 2016
Myga-Nowak M, Godela A, Głąb T, Lewańska M, Boratyński J,
Postepy higieny i medycyny doswiadczalnej (Online). 23-9-2016
It is estimated that each year more than 2 million people suffer from diarrheal diseases, resulting from the consumption of contaminated meat. Foodborne infections are most frequently caused by small Gram-negative rods Campylobacter. The hosts of these bacteria are mainly birds wherein they are part of the normal intestinal flora. During the commercial slaughter, there is a likelihood of contamination of carcasses by the bacteria found in the intestinal content. In Europe, up to 90% of poultry flocks can be a reservoir of the pathogen. According to the European Food Safety Authority report from 2015, the number of reported and confirmed cases of human campylobacteriosis exceeds 200 thousands per year, and such trend remains at constant level for several years. The occurrence of growing antibiotic resistance in bacteria forces the limitation of antibiotic use in the animal production. Therefore, the European Union allows only using stringent preventive and hygienic treatment on farms. Achieving Campylobacter free chickens using these methods is possible, but difficult to implement and expensive. Utilization of bacterial viruses - bacteriophages, can be a path to provide the hygienic conditions of poultry production and food processing. Formulations applied in the food protection should contain strictly lytic bacteriophages, be non-pyrogenic and retain long lasting biological activity. Currently, on the market there are available commercial bacteriophage preparations for agricultural use, but neither includes phages against Campylobacter. However, papers on the application of bacteriophages against Campylobacter in chickens and poultry products were published in the last few years. In accordance with the estimates, 2-logarithm reduction of Campylobacter in poultry carcases will contribute to the 30-fold reduction in the incidence of campylobacteriosis in humans. Research on bacteriophages against Campylobacter have cognitive and economic importance. The paper presents current state of research on bacteriophages targeted against Campylobacter.
Isolation of endothelial colony-forming cells from blood samples collected from the jugular and cephalic veins of healthy adult horses.Monday, September 26, 2016
Sharpe AN, Seeto WJ, Winter RL, Zhong Q, Lipke EA, Wooldridge AA,
American journal of veterinary research. Oct-2016
OBJECTIVE To evaluate optimal isolation of endothelial colony-forming cells (ECFCs) from peripheral blood of horses. SAMPLE Jugular and cephalic venous blood samples from 17 adult horses. PROCEDURES Each blood sample was divided; isolation was performed with whole blood adherence (WBA) and density gradient centrifugation (DGC). Isolated cells were characterized by uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-labeled acetylated low-density lipoprotein (DiI-Ac-LDL), vascular tubule formation, and expression of endothelial (CD34, CD105, vascular endothelial growth factor receptor-2, and von Willebrand factor) and hematopoietic (CD14) cell markers by use of indirect immunofluorescence assay (IFA) and flow cytometry. RESULTS Colonies with cobblestone morphology were isolated from 15 of 17 horses. Blood collected from the cephalic vein yielded colonies significantly more often (14/17 horses) than did blood collected from the jugular vein (8/17 horses). Of 14 cephalic blood samples with colonies, 13 were obtained with DGC and 8 with WBA. Of 8 jugular blood samples with colonies, 8 were obtained with DGC and 4 with WBA. Colony frequency (colonies per milliliter of blood) was significantly higher for cephalic blood samples and samples isolated with DGC. Cells formed vascular tubules, had uptake of DiI-Ac-LDL, and expressed endothelial markers by use of IFA and flow cytometry, which confirmed their identity as ECFCs. CONCLUSIONS AND CLINICAL RELEVANCE Maximum yield of ECFCs was obtained for blood samples collected from both the jugular and cephalic veins and use of DGC to isolate cells. Consistent yield of ECFCs from peripheral blood of horses will enable studies to evaluate diagnostic and therapeutic uses.
Expression of T helper cell-associated inflammatory mediator mRNAs in cells of bronchoalveolar lavage fluid samples and oxygen concentration in arterial blood samples from healthy horses exposed to hyperbaric oxygen.Monday, September 26, 2016
Looijen MG, New DJ, Fischer CD, Dardari R, Irwin KM, Berezowski CJ, Bond SL, Léguillette R,
American journal of veterinary research. Oct-2016
OBJECTIVE To evaluate the mRNA expression of T helper (Th)1, Th2, and Th17 cell-associated inflammatory mediators in cells of bronchoalveolar lavage fluid samples collected from healthy horses exposed to hyperbaric oxygen (HBO) and to monitor blood oxygen concentration during and following HBO therapy. ANIMALS 8 healthy horses. PROCEDURES In a randomized controlled crossover design study, each horse was exposed (beginning day 1) to 100% oxygen at a maximum of 3 atmospheres absolute (304 kPa) daily for 10 days or ambient air at atmospheric pressure in the HBO chamber for an equivalent amount of time (control). Bronchoalveolar lavage fluid samples were collected on days 0 and 10. After validation of candidate reference genes, relative mRNA expressions of various innate inflammatory, Th1 cell-derived, Th2 cell-derived (including eotaxin-2), Th17 cell-derived, and regulatory cytokines were measured by quantitative PCR assays. For 3 horses, arterial blood samples were collected for blood gas analysis during a separate HBO session. RESULTS The optimal combination of reference genes was glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine ribosyltransferase, and ribosomal protein L32. Compared with day 0 findings, expression of eotaxin-2 mRNA was significantly lower (0.12-fold reduction) and the percentage of neutrophils in bronchoalveolar lavage fluid samples was significantly lower on day 10 when horses received HBO therapy. Values of Pao2 rapidly increased (> 800 mm Hg) but immediately decreased to pretreatment values when HBO sessions ended. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that HBO therapy does not increase mRNA expression of inflammatory cytokines, but reduces eotaxin-2 mRNA transcription. The Pao2 increase was transient with no cumulative effects of HBO.
Effects of topical ocular application of 1% trifluridine ophthalmic solution in dogs with experimentally induced recurrent ocular canine herpesvirus-1 infection.Monday, September 26, 2016
Spertus CB, Mohammed HO, Ledbetter EC,
American journal of veterinary research. Oct-2016
OBJECTIVE To determine the effects of topical ocular application of 1% trifluridine ophthalmic solution in dogs with experimentally induced recurrent ocular canine herpesvirus-1 (CHV-1) infection. ANIMALS 10 specific pathogen-free Beagles. PROCEDURES 12 months prior to the beginning of the randomized, masked, placebo-controlled 30-day trial, latent ocular CHV-1 infection was experimentally induced in each dog by topical ocular inoculation of both eyes with a field strain of CHV-1. Recurrent ocular CHV-1 infection was induced by oral administration of prednisolone for 7 days (starting day 1). Starting on the fourth day of prednisolone administration, each dog received 1% trifluridine solution or artificial tears (placebo) topically in both eyes 6 times daily for 2 days and then 4 times daily for 12 days. Ophthalmic examinations were performed every 2 days, and ocular disease scores were calculated. Ocular samples for CHV-1 PCR assays and blood samples for clinicopathologic analyses and assessment of CHV-1 serum neutralization antibody titers were collected at predetermined intervals. RESULTS Conjunctivitis was clinically detected in all dogs by day 4. Compared with dogs receiving placebo, mean and total clinical ocular disease scores were significantly lower and median CHV-1 shedding duration was significantly shorter for the trifluridine-treated dogs. Both groups had increasing CHV-1 serum neutralization antibody titers over time, but no significant differences between groups were detected. Clinicopathologic findings were unremarkable throughout the study. CONCLUSIONS AND CLINICAL RELEVANCE Topical ocular application of 1% trifluridine ophthalmic solution was well tolerated and effective at reducing disease scores and viral shedding duration in dogs with experimentally induced ocular CHV-1 infection, but may require frequent administration.
Evaluation of the minimum infectious dose of porcine epidemic diarrhea virus in virus-inoculated feed.Monday, September 26, 2016
Schumacher LL, Woodworth JC, Jones CK, Chen Q, Zhang J, Gauger PC, Stark CR, Main RG, Hesse RA, Tokach MD, Dritz SS,
American journal of veterinary research. Oct-2016
OBJECTIVE To determine the minimum infectious dose of porcine epidemic diarrhea virus (PEDV) in virus-inoculated feed. ANIMALS 30 crossbred 10-day-old pigs. PROCEDURES Tissue culture PEDV was diluted to form 8 serial 10-fold dilutions. An aliquot of stock virus (5.6 × 10(5) TCID50/mL) and each serial PEDV dilution were mixed into 4.5-kg batches of feed to create 9 PEDV-inoculated feed doses; 1 virus-negative dose of culture medium in feed was also created. Pigs were challenge exposed via oral administration of PEDV-inoculated feed, and fecal swab specimens were collected. All pigs were euthanized 7 days after challenge exposure; fresh tissues were collected and used for PCR assay, histologic examination, and immunohistochemical analysis. RESULTS The PCR cycle threshold (Ct) decreased by approximately 10 when PEDV was added to feed, compared with results for equivalent PEDV diluted in tissue culture medium. Pigs became infected with PEDV when challenge exposed with the 4 highest concentrations (lowest concentration to cause infection, 5.6 × 10(1) TCID50/g; Ct = 27 in tissue culture medium and 37 in feed). CONCLUSIONS AND CLINICAL RELEVANCE In this study, PEDV in feed with detectable Ct values of 27 to 37 was infective. The Ct was 37 for the lowest infective PEDV dose in feed, which may be above the limit of detection established for PEDV PCR assays used by some diagnostic laboratories. Overall, results indicated 5.6 × 10(1) TCID50/g was the minimum PEDV dose in feed that can lead to infection in 10-day-old pigs under the conditions of this study.
Increased proportions of Tc17 cells and NK cells may be risk factors for disease progression in Hashimoto's thyroiditis.Monday, September 26, 2016
Liu Y, You R, Yu N, Gong Y, Qu C, Zhang Y, Lu G, Huang Y, Zhang H, Gao Y, Gao Y, Guo X,
International immunopharmacology. 23-Sep-2016
Both cellular and humoral responses play important roles in the pathogenesis of Hashimoto's thyroiditis (HT). However, the immunological differences between euthyroid (mild HT) and hypothyroid (severe HT) patients are unknown. This study aimed to investigate the distribution of lymphocyte subsets and cytokine profiles in HT patients with differences in thyroid function. Peripheral blood was drawn from 18 healthy controls and 54 HT patients (33 patients with mild HT, 21 patients with severe HT). The percentages of B cell subsets, T cell subsets and NK cells were analyzed by flow cytometry. The levels of IL-21 and Bcl-6 mRNA were assessed using real-time PCR. The levels of serum IFN-γ, TNF-α, TGF-β, IL-4, IL-6, IL-10 and a proliferation-inducing ligand (APRIL) were measured by ELISA or cytometric bead array. The percentages of double-negative memory B cells, plasma cells, Tfh cells and Tc17 cells were higher in HT patients than in the healthy controls. The percentages of Tc17 cells and NK cells were higher in the patients with severe HT than in the patients with mild HT. The levels of serum APRIL, IL-6 and IL-10 were higher in the patients with severe HT than in those with mild HT. The percentage of NK cells was positively correlated with TSH levels in the HT patients. Our data indicate that the distribution of lymphocyte subsets and cytokine profiles is aberrant in HT patients, and the increased percentages of Tc17 cells and NK cells and increased cytokine levels might be involved in the progression of HT.
Estimating Generic Drug Use with Electronic Health Records Data from a Health Care Delivery System: Implications for Quality Improvement and Research.Monday, September 26, 2016
Nimbal V, Segal JB, Romanelli RJ,
Journal of managed care & specialty pharmacy. Oct-2016
This study was funded by a grant from the U.S. Food and Drug Administration in cooperative agreement with the Johns Hopkins School of Medicine and the Palo Alto Medical Foundation Research Institute (1U01FD005267-01). Romanelli has received research grant support from Pfizer and Janssen Scientific Affairs. Authors have no other conflicts to disclose. Romanelli and Segal contributed the study concept and design. Nimbal took the lead in data collection, assisted by Romanelli. All authors were involved with data interpretation and revision of the manuscript. The manuscript was written by Romanelli and Nimbal.
Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cells lines.Monday, September 26, 2016
Véras Of Aguiar AC, Of Moura RO, Bezerra Mendonça JF, de Oliveira Rocha HA, Gomes Câmara RB, Dos Santos Carvalho Schiavon M,
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 23-Sep-2016
In spite of great progress in understanding cancer biology, current therapeutic procedures remain unsatisfactory. Chemotherapy is often followed by secondary effects with cellular toxicity negatively affecting the results. The discovery and development of new safe and efficient antitumor agents is necessary. Derivatives of 2-amino thiophene have been a topic of constant investigation due to their versatile synthetic applicability and broad spectrum of biological applications; among which are antifungal and antiproliferative activity shown in prior studies of our group. In the current study, compounds 6CN09, 6CN10, 6CN12, 6CN14, 7CN09 and 7CN11 were analyzed as to antiproliferative effect in human cells of cervical adenocarcinoma (HeLa), human pancreatic adenocarcinoma (PANC-1) and mice fibroblasts (3T3), which were exposed to the compounds in concentrations of 5, 10, 25 and 50μM during 24 and 48h. They were submitted to MTT assay. In order to elucidate the action mechanism of antitumor thiophene derivatives flow cytometry was performed to evaluate cell death and cell cycle analysis. The results showed that thiophene derivatives demonstrated great antiproliferative potential in the HeLa and PANC-1 cell lines when compared with the control, and the percentage of cell proliferation inhibition approximated or was higher than the standard drug used; doxorubicin (Dox). In highlight were the derivatives 6CN14 and 7CN09 that showed greater efficiency in the antiproliferative evaluation. Further, all compounds had a protective effect on the non-tumor 3T3 cell line. The flow cytometry analysis showed few cells in apoptosis in both the HeLa and PANC-1 lines, although the compounds interfered with the progression of the cell cycle, and avoided cell growth and multiplication in the HeLa tumor line. These thiophene derivatives demonstrated cytostatic and antiproliferative effects and may be considered as promising molecular candidates for anticancer drugs.
Small-molecule GSK-3 inhibitor rescued apoptosis and neurodegeneration in anesthetics-injured dorsal root ganglion neurons.Monday, September 26, 2016
Yu T, Lin W,
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 23-Sep-2016
GSK-3 inhibitor SB216763, through PKC, is effective in protecting anesthetics-induced neurotoxicity in DRG.
Neuromodulatory effects of Calyptranthes grandifolia extracts against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells.Monday, September 26, 2016
Kich DM, Bitencourt S, Alves C, Silva J, Pinteus S, Pedrosa R, Laufer S, de Souza CF, Goettert MI,
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 23-Sep-2016
Alzheimer's and Parkinson's diseases are neurodegenerative disorders characterized by progressive neuronal dysfunction. Previous studies revealed that some natural products have neuroprotective properties, including species of the Myrtaceae family. However, the neuromodulatory potential of Calyptranthes grandifolia is not clear. In the present study, we examined the ability of the ethanol and hexane leaf extracts of C. grandifolia to prevent 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Initially, we investigated the potential of the extracts to inhibit the neurodegenerative-related enzymes c-Jun N-terminal kinase 3 (JNK3) and acetylcholinesterase (AChE). In addition, SH-SY5Y cell viability was assessed by MTT assay after 100μM 6-OHDA-induced cell damage. In order to verify the possible effects of both extracts on 6-OHDA-induced cell death, hydrogen peroxide generation, mitochondrial potential and caspases-3 activity were assessed. Our findings revealed that ethanol extract exhibited inhibitory activity against JNK3 and AChE. In addition, when co-treating SH-SY5Y cells with 6-OHDA and the extracts, oxidative stress was inhibited by both extracts through a decrease of mitochondrial depolarization and caspases-3 activity. In summary, ethanol and hexane extracts of C. grandifolia have some suppressive property against neurotoxicity induced by 6-OHDA.
Is ciprofloxacin safe in patients with solitary kidney and upper urinary tract infection?Monday, September 26, 2016
Gluhovschi G, Gadalean F, Gluhovschi C, Velciov S, Petrica L, Bob F, Bozdog G, Kaycsa A,
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 23-Sep-2016
The solitary kidney (SK) undergoes adaptive phenomena of hyperfunction and hyperfiltration. These secondary adaptive phenomena can make it more vulnerable to potentially nephrotoxic therapies. Adverse reactions of the kidneys to ciprofloxacin are rare, but sometimes severe. Therefore, our study sought to assess the reactions to ciprofloxacin of patients with solitary kidney (SK) and urinary tract infection (UTI) by means of urinary biomarkers. We studied 19 patients with SK and urinary tract infection (UTI) who had been administered a 7-day treatment with intravenous ciprofloxacin. Urinary N-acetyl-beta-d-glucosaminidase, alpha 1-microglobulin, and estimated glomerular filtration rate (eGFR) of these patients were measured at the initiation and at the end of treatment. In 47.37% patients NAG diminished under ciprofloxacin treatment. This observation has the significance of favourable evolution of the tubulointerstitial lesions caused by UTI and lack of nephrotoxic effects; 52.63% cases presented an increase of urinary NAG, a fact that suggests a nephrotoxic effect of ciprofloxacin. The evolution of urinary alpha 1-microglobulin was similar to that one of urinary NAG. Only one of three cases with chronic kidney disease (CKD) stage 5 presented acute kidney injury, associated with increase in the tubular markers. In spite of the high variability of the urinary biomarkers, UTI evolved favourably in these cases; eGFR increased in 16 out of 19 patients, a fact which is indicative of a good outcome of renal function, even in patients with elevated levels of the tubular damage biomarkers. This observation supports the hypothesis that eGFR may be dissociated from the biomarkers which assess tubular injury. In SK patients the occurrence of AKI is not frequent, although the urinary biomarkers rise in some patients treated with ciprofloxacin. This is related not only to the nephrotoxic effect of the drug, but probably to the association of other factors (allergy, individual susceptibility). In SK patients, renal tubular biomarkers, especially NAG, allow monitoring of tubular injury and impose caution in prescribing ciprofloxacin treatment, mainly to patients at risk. Ciprofloxacin is relatively safe regarding its nephrotoxicity, while caution is required in vulnerable patients.
Anti-proliferation effects, efficacy of cyasterone in vitro and in vivo and its mechanism.Monday, September 26, 2016
Lu X, Qiu H, Yang L, Zhang J, Ma S, Zhen L,
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 23-Sep-2016
Cyasterone was demonstrated potential inhibition effect in mouse skin carcinoma cells in published report. However, the molecular mechanisms of the cyasterone on cells remain unknown. Herein, we investigated the effects of cyasterone-induced apoptosis in A549 and MGC823 cells in vitro. MTT assay showed that cyasterone caused a significantly decreasing of the proliferation of A549 and MGC823 cells in a time-and dose-dependent manner with IC50 values of 38.50±3.73μg/mL on A549 cells and 32.96±1.24μg/mL on MGC823 cells at 48h, respectively. Hoechst staining and TUNEL staining results indicated the quintessential apoptosis features in immunofluorescence image. Apoptosis and cell cycle were determined by flow cytometry. Cyasterone treatment triggered inhibition of epidermal growth factor receptor- phosphatidylinositol 3 kinase/protein kinase B (EGFR-AKT) signaling pathways and activation of P38 pathways. Furthermore, cyasterone inhibited MGC823 cells xenografted tumor growth in vivo with few changes in body weights. In conclusion, our findings provide the evidence that cyasterone inhibits growth of A549 and MGC823 cells, via regulating EGFR signaling pathway. Our results indicated that cyasterone, a natural EGFR inhibitor, maybe a promising anti-cancer agent.
Spectroscopic Investigation of Interfacial Interaction of Manganese Oxide with Triclosan, Aniline, and Phenol.Monday, September 26, 2016
Shaikh N, Taujale S, Zhang H, Artyushkova K, Ali AS, Cerrato JM,
Environmental science & technology. 26-Sep-2016
We investigated the reaction of manganese oxide [MnOx(s)] with phenol, aniline and triclosan in batch experiments using X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and aqueous chemistry measurements. Analyses of high resolution Mn 3s and Mn 3p XPS spectra suggest that Mn(III) and Mn(II) increase in the surface of reacted MnOx(s), indicating that the oxidation of organic compounds causes the reduction of MnOx(s). The reductive dissolution of MnOx(s) was confirmed by the detection of increasing concentrations of soluble Mn over time. Fitting of C 1s XPS spectra suggests the increase of aromatic and aliphatic bonds for MnOx(s) reacted with organic compounds. Additionally, XPS survey scans of all the reacted samples show an increase in %C and decrease in %Mn on the near surface when compared to unreacted MnOx(s). The increase of Cl in the MnOx(s) surface after reaction with triclosan was detected by XPS survey scans. Raman spectra confirm increased intensity of carbon features in MnOx(s) samples reacted with phenol compared to unreacted MnOx(s). These spectroscopy results indicate that phenol, aniline, triclosan, and related by-products are associated to the surface of MnOx(s) reacted samples. First order kinetic analyses of organic concentrations in solution confirm observations from other studies suggesting that triclosan and phenol react at a similar rate with MnOx(s), while the reaction with aniline is slower. The results from this research contribute to a better understanding of interactions between MnOx(s) and organic compounds that are relevant to natural and engineered environments.
Lrp5/β-catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis.Monday, September 26, 2016
Sennello JA, Misharin AV, Flozak AS, Berdnikovs S, Cheresh P, Varga J, Kamp DW, Budinger GR, Gottardi CJ, Lam AP,
American journal of respiratory cell and molecular biology. 26-Sep-2016
Previous studies established that attenuating Wnt/β-catenin signaling limits lung fibrosis in the bleomycin mouse model of this disease, but the contribution of this pathway to distinct lung cell phenotypes relevant to tissue repair and fibrosis remains incompletely understood. Using microarray analysis, we found that bleomycin-injured lungs from mice that lack the Wnt co-receptor Lrp5 and exhibit reduced fibrosis, showed enrichment for pathways related to extracellular matrix processing, immunity, and lymphocyte proliferation, suggesting the contribution of an immune-matrix remodeling axis relevant to fibrosis. Activation of β-catenin signaling was seen in lung macrophages using the β-catenin reporter mouse, Axin2+/LacZ. Analysis of lung immune cells by flow cytometry post bleomycin administration revealed that Lrp5-/- lungs contained significantly fewer Siglec Flow alveolar macrophages, a cell type previously implicated as positive effectors of fibrosis. Macrophage-specific deletion of β-catenin in CD11ccre;β-cateninflox mice did not prevent development of bleomycin-induced fibrosis but facilitated its resolution by 8 weeks. In a non-resolving model of fibrosis, intratracheal administration of asbestos in Lrp5-/- mice also did not prevent the development of fibrosis but hindered the progression of fibrosis in asbestos-treated Lrp5-/- lungs, phenocopying the findings in bleomycin-treated CD11ccre;β-cateninflox mice. Activation of β-catenin signaling using lithium chloride resulted in worsened fibrosis in wild-type mice, further supporting that the effects of loss of Lrp5 are directly mediated by Wnt/β-catenin signaling. Together these data suggest that lung myeloid cells are responsive to Lrp5/β-catenin signaling, leading to differentiation of an alveolar macrophage subtype that antagonizes the resolution of lung fibrosis.
Purification and characterization of a novel fibrinolytic enzyme from Whitmania pigra Whitman.Monday, September 26, 2016
Chu F, Wang X, Sun Q, Liang H, Wang S, An D, Cui C, Chai Y, Li S, Song S, Ji A,
Clinical and experimental hypertension (New York, N.Y. : 1993). 26-Sep-2016
A fibrinolytic enzyme was purified from the dry body of Whitmania pigra Whitman. The fibrinolytic enzyme was purified to homogeneity with a yield of 0.003% and a purification of 630.7 fold. The molecular weight of the enzyme was estimated to be 26.7 kDa by reduced sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The enzyme was tested by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and it showed that the enzyme was a novel fibrinolytic enzyme. The optimal pH and temperature of the enzyme were 8.5 and 55°C, respectively. Enzyme activity was enhanced by Na(+), Mg(2+,) and K(+). On the contrary, the proteolytic activity was significantly inhibited by Mn(2+), Fe(2+), Fe(3+), ethylenediaminetetraacetic acid (EDTA), and ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA). Fibrinolytic and fibrinogenolytic assays showed that the enzyme preferentially hydrolyzed fibrinogen Aα-chains, followed by Bβ- and γ-chains. The α-, β-, and γ-γ-chains of fibrin were also degraded by the enzyme.
Movement Protein of Cucumber Mosaic Virus Associates with Apoplastic Ascorbate Oxidase.Monday, September 26, 2016
Kumari R, Kumar S, Singh L, Hallan V,
PloS one. 26-9-2016
Plant viral movement proteins facilitate virion movement mainly through interaction with a number of factors from the host. We report the association of a cell wall localized ascorbate oxidase (CsAO4) from Cucumis sativus with the movement protein (MP) of Cucumber mosaic virus (CMV). This was identified first in a yeast two-hybrid screen and validated by in vivo pull down and bimolecular fluorescence complementation (BiFC) assays. The BiFC assay showed localization of the bimolecular complexes of these proteins around the cell wall periphery as punctate spots. The expression of CsAO4 was induced during the initial infection period (up to 72 h) in CMV infected Nicotiana benthamiana plants. To functionally validate its role in viral spread, we analyzed the virus accumulation in CsAO4 overexpressing Arabidopsis thaliana and transiently silenced N. benthamiana plants (through a Tobacco rattle virus vector). Overexpression had no evident effect on virus accumulation in upper non-inoculated leaves of transgenic lines in comparison to WT plants at 7 days post inoculation (dpi). However, knockdown resulted in reduced CMV accumulation in systemic (non-inoculated) leaves of NbΔAO-pTRV2 silenced plants as compared to TRV inoculated control plants at 5 dpi (up to 1.3 fold difference). In addition, functional validation supported the importance of AO in plant development. These findings suggest that AO and viral MP interaction helps in early viral movement; however, it had no major effect on viral accumulation after 7 dpi. This study suggests that initial induction of expression of AO on virus infection and its association with viral MP helps both towards targeting of the MP to the apoplast and disrupting formation of functional AO dimers for spread of virus to nearby cells, reducing the redox defense of the plant during initial stages of infection.
Modulating Behavior in C. elegans Using Electroshock and Antiepileptic Drugs.Monday, September 26, 2016
Risley MG, Kelly SP, Jia K, Grill B, Dawson-Scully K,
PloS one. 26-9-2016
The microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C. elegans, an assay for electroshock/electroconvulsion remains absent. Here, we have developed a quantitative behavioral method to assess the locomotor response following electric shock in C. elegans. Electric shock impairs normal locomotion, and induces paralysis and muscle twitching; after a brief recovery period, shocked animals resume normal locomotion. We tested electric shock responses in loss-of-function mutants for unc-25, which encodes the GABA biosynthetic enzyme GAD, and unc-49, which encodes the GABAA receptor. unc-25 and unc-49 mutants have decreased inhibitory GABAergic transmission to muscles, and take significantly more time to recover normal locomotion following electric shock compared to wild-type. Importantly, increased sensitivity of unc-25 and unc-49 mutants to electric shock is rescued by treatment with antiepileptic drugs, such as retigabine. Additionally, we show that pentylenetetrazol (PTZ), a GABAA receptor antagonist and proconvulsant in mammalian and C. elegans seizure models, increases susceptibility of worms to electric shock.
Complex Mixtures by NMR and Complex NMR for Mixtures: experimental and publication challenges.Monday, September 26, 2016
Wist J,
Magnetic resonance in chemistry : MRC. 26-Sep-2016
Untargeted strategies have changed the rules of the game in complex mixture analysis, introducing an amazing potential for medical and biological applications that is just starting to be tapped. But with great power come great challenges; though untargeted mixture analysis opens the road for many exciting possibilities, the road is still full of perils. On the one hand, this article highlights some of the difficulties that need to be sorted for mixture analysis by NMR to fulfill its potential, along with insight on how they may be managed. Highlighted key points include the need for "computer friendly" solutions for sharing data, experimental design and algorithm to facilitate the steady growth of knowledge and modeling ability in the field, and the need for large-scale studies to improve confidence in newly identified biomarkers. On the other hand, the second part of this article presents some breakthroughs in NMR experiments that, when combined, may modify the landscape of mixture analysis.
Gene expression elucidates functional impact of polygenic risk for schizophrenia.Monday, September 26, 2016
Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, Ruderfer DM, Oh EC, Topol A, Shah HR, Klei LL, Kramer R, Pinto D, Gümüş ZH, Cicek AE, Dang KK, Browne A, Lu C, Xie L, Readhead B, Stahl EA, Xiao J, Parvizi M, Hamamsy T, Fullard JF, Wang YC, Mahajan MC, Derry JM, Dudley JT, Hemby SE, Logsdon BA, Talbot K, Raj T, Bennett DA, De Jager PL, Zhu J, Zhang B, Sullivan PF, Chess A, Purcell SM, Shinobu LA, Mangravite LM, Toyoshiba H, Gur RE, Hahn CG, Lewis DA, Haroutunian V, Peters MA, Lipska BK, Buxbaum JD, Schadt EE, Hirai K, Roeder K, Brennand KJ, Katsanis N, Domenici E, Devlin B, Sklar P,
Nature neuroscience. 26-Sep-2016
Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.
Transport of haloacids across biological membranes.Monday, September 26, 2016
Su X, Li R, Kong KF, Tsang JS,
Biochimica et biophysica acta. 23-Sep-2016
Haloacids are considered to be environmental pollutants, but some of them have also been tested in clinical research. The way that haloacids are transported across biological membranes is important for both biodegradation and drug delivery purposes. In this review, we will first summarize putative haloacids transporters and the information about haloacids transport when studying carboxylates transporters. We will then introduce MCT1 and SLC5A8, which are respective transporter for antitumor agent 3-bromopyruvic acid and dichloroacetic acid, and monochloroacetic acid transporters Deh4p and Dehp2 from a haloacids-degrading bacterium. Phylogenetic analysis of these haloacids transporters and other monocarboxylate transporters reveals their evolutionary relationships. Haloacids transporters are not studied to the extent that they deserve compared with their great application potentials, thus future inter-discipline research are desired to better characterize their transport mechanisms for potential applications in both environmental and clinical fields.
Patterns of youth tobacco and polytobacco usage: The shift to alternative tobacco products.Monday, September 26, 2016
Harrell PT, Naqvi SM, Plunk AD, Ji M, Martins SS,
The American journal of drug and alcohol abuse. 26-Sep-2016
Findings are consistent with other research demonstrating shifts in adolescent tobacco product usage towards non-cigarette tobacco products. Continuous monitoring of these patterns is needed to help predict if this shift will ultimately result in improved public health.
Trefoil factor family 2 expression inhibits gastric cancer cell growth and invasion in vitro via interactions with the transcription factor Sp3.Monday, September 26, 2016
Cai Y, Yi M, Chen D, Liu J, Guleng B, Ren J, Shi H,
International journal of molecular medicine. 19-Sep-2016
The trefoil factor family (TFF) is a group of short secretory peptides of gastric mucous neck cells. The loss of TFF2 protein expression enhances gastric inflammation and occurs in gastric cancer. In this study, we examined the effect of TFF2 on gastric cancer cell lines in vitro and characterized the interaction between TFF2 and Sp3, including the mechanisms that mediate this interaction, using genomics and proteomics approaches, as well as genetics techniques, such as RNA interference and gene knockdown. Assays were performed to examine the role of TFF2 and Sp3 in cancer cell proliferation, invasion and migration. We found that TFF2 expression inhibited the proliferation and invasion capacity of gastric cancer cells, and induced apoptosis. TFF2 interacted with the Sp3 protein, as shown by immunofluorescence staining and immunoprecipitation with western blot analysis. Sp3 knockdown in gastric cancer cells antagonized TFF2 antitumor activity. Additionally, TFF2 upregulated the expression of pro-apoptotic proteins, such as Bid, but downregulated the expression of NF-κB and the anti-apoptotic proteins, Bcl-xL and Mcl‑1. By contrast, Sp3 knockdown significantly blocked TFF2 activity, affecting the expression of these proteins. The data from our study demonstrate that the antitumor activity of TFF2 is mediated by an interaction with the Sp3 protein in gastric cancer cells. Additional in vivo and ex vivo warrned in order to fully characterize this interaction.
INTIMATE PARTNER VIOLENCE IS ASSOCIATED WITH INCREASED CD4(+) T-CELL ACTIVATION AMONG HIV-NEGATIVE HIGH-RISK WOMEN.Monday, September 26, 2016
Kalokhe AS, Ibegbu CC, Kaur SP, Amara RR, Kelley ME, Del Rio C, Stephenson R,
Pathogens & immunity. 2016
Our data is the first to suggest an immune link between IPV and HIV, and may help explain differences at the individual level in HIV susceptibility and response to biological HIV prevention strategies. The association of psychological and physical abuse with CD4 activation independent of sexual abuse further supports the existence of a stress-induced immune pathway.
Data on serologic inflammatory biomarkers assessed using multiplex assays and host characteristics in the Multicenter AIDS Cohort Study (MACS).Monday, September 26, 2016
McKay HS, Bream JH, Margolick JB, Martínez-Maza O, Magpantay LI, Phair JP, Rinaldo CR, Abraham AG, Jacobson LP,
Data in brief. Dec-2016
This article contains data on the associations between fixed and modifiable host characteristics and twenty-three biomarkers of inflammation and immune activation measured longitudinally in a cohort of 250 HIV-uninfected men from the Multicenter AIDS Cohort Study (1984-2009) after adjusting for age, study site, and blood draw time of day using generalized gamma regression. This article also presents associations between each biomarker and each host characteristic in a sample restricted to 2001-2009. These data are supplemental to our original research article entitled "Host factors associated with serologic inflammatory markers assessed using multiplex assays" (McKay, S. Heather, Bream, H. Jay, Margolick, B. Joseph, Martínez-Maza, Otoniel, Phair, P. John, Rinaldo, R. Charles, Abraham, G. Alison, L.P. Jacobson, 2016) [1].
DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer.Monday, September 26, 2016
Kakar SS, Worth CA, Wang Z, Carter K, Ratajczak M, Gunjal P,
Journal of cancer stem cell research. 16-08-2016
Ovarian cancer is a highly aggressive and deadly disease. Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly cisplatin or carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately, after few months of initial treatment, tumor relapse occurs due to platinum-resistance. DOXIL (liposomal preparation of doxorubicin) is a choice of drug for recurrent ovarian cancer. However, its response rate is very low and is accompanied by myocardial toxicity. Resistance to chemotherapy and recurrence of cancer is primarily attributed to the presence of cancer stem cells (CSCs), a small population of cells present in cancer. Effect of DOXIL and withaferin A (WFA), both alone and in combination, was investigated on cell proliferation of ovarian cancer cell line A2780 and tumor growth in SCID mice bearing i.p. ovarian tumors. ALDH1 cells were isolated from A2780 using cell sorter, and effect of DOXIL and WFA both alone and in combination on tumorigenic function of ALDH1 was studied using spheroids formation assays in vitro. Western blots were performed to examine the expression of ALDH1 and Notch 1 genes. In our studies, we showed, for the first time, that DOXIL when combined with withaferin A (WFA) elicits synergistic effect on inhibition of cell proliferation of ovarian cancer cells and inhibits the expression of ALDH1 protein, a marker for ALDH1 positive cancer stem cells (CSCs), and Notch1, a signaling pathway gene required for self-renewal of CSCs. Inhibition of expression of both ALDH1 and Notch1 genes by WFA was found to be dose dependent, whereas DOXIL (200 nM) was found to be ineffective. SCID mice, bearing i.p. ovarian tumors, were treated with a small dose of DOXIL (2 mg/kg) in combination with a sub-optimal dose of WFA (2 mg/kg) which resulted in a highly significant (60% to 70%) reduction in tumor growth, and complete inhibition of metastasis compared to control. In contrast, WFA treatment showed a significant reduction in tumor growth but no change in metastasis compared to control. DOXIL showed non-significant reduction in tumor growth and no change in metastasis compared to control. Isolated ALDH1 positive CSCs treated with the combination of DOXIL and WFA resulted in a significant reduction in spheroids formation (tumorigenic function of CSCs) and expression of ALDH1 protein. WFA when used alone at a concentration of 1.5 μM was found to be highly effective in suppression of ALDH1 expression, whereas DOXIL at a concentration of 200 nM was found to be ineffective. DOXIL in combination with WFA elicits synergistic effects, targets cancer stem cells, and has potential to minimize induction of drug resistance and reoccurrence of cancer. Based on our studies, we conclude that the combination of DOXIL with WFA has the potential to be an effective therapy for ovarian cancer and may ameliorate DOXIL related side effects as well as recurrence of ovarian cancer leading to increase in patients' survival rate.
MIDAS robust trend estimator for accurate GPS station velocities without step detection.Monday, September 26, 2016
Blewitt G, Kreemer C, Hammond WC, Gazeaux J,
Journal of geophysical research. Solid earth. Mar-2016
Automatic estimation of velocities from GPS coordinate time series is becoming required to cope with the exponentially increasing flood of available data, but problems detectable to the human eye are often overlooked. This motivates us to find an automatic and accurate estimator of trend that is resistant to common problems such as step discontinuities, outliers, seasonality, skewness, and heteroscedasticity. Developed here, Median Interannual Difference Adjusted for Skewness (MIDAS) is a variant of the Theil-Sen median trend estimator, for which the ordinary version is the median of slopes vij  = (xj-xi )/(tj-ti ) computed between all data pairs i > j. For normally distributed data, Theil-Sen and least squares trend estimates are statistically identical, but unlike least squares, Theil-Sen is resistant to undetected data problems. To mitigate both seasonality and step discontinuities, MIDAS selects data pairs separated by 1 year. This condition is relaxed for time series with gaps so that all data are used. Slopes from data pairs spanning a step function produce one-sided outliers that can bias the median. To reduce bias, MIDAS removes outliers and recomputes the median. MIDAS also computes a robust and realistic estimate of trend uncertainty. Statistical tests using GPS data in the rigid North American plate interior show ±0.23 mm/yr root-mean-square (RMS) accuracy in horizontal velocity. In blind tests using synthetic data, MIDAS velocities have an RMS accuracy of ±0.33 mm/yr horizontal, ±1.1 mm/yr up, with a 5th percentile range smaller than all 20 automatic estimators tested. Considering its general nature, MIDAS has the potential for broader application in the geosciences.
Properties of Flavonoids Isolated from the Bark of Eysenhardtia polystachya and Their Effect on Oxidative Stress in Streptozotocin-Induced Diabetes Mellitus in Mice.Monday, September 26, 2016
Perez-Gutierrez RM, Garcia-Campoy AH, Muñiz-Ramirez A,
Oxidative medicine and cellular longevity. 04-3-2016
Six new flavonoids 2',4'-dihydroxychalcone-6'-O-β-d-glucopyranoside (1), α,3,2',4'-tetrahydroxy-4-methoxy-dihydrochalcone-3'-C-β-glucopyranosy-6'-O-β-d-glucopyranoside (2), 7-hydroxy-5,8'-dimethoxy-6'α-l-rhamnopyranosyl-8-(3-phenyl-trans-acryloyl)-1-benzopyran-2-one (3), 6'7-dihydroxy-5,8-dimethoxy-8(3-phenyl-trans-acryloyl)-1-benzopyran-2-one (4), 9-hydroxy-3,8-dimethoxy-4-prenylpterocarpan (5), and α,4,4'-trihydroxydihydrochalcone-2'-O-β-d-glucopyranoside (6) were isolated from bark of Eysenhardtia polystachya. Antidiabetic activity of compounds 1-5 in terms of their cellular antioxidant and free radical scavenging and also in streptozotocin- (STZ-) induced diabetic mice was evaluated on liver transaminases, lipid peroxidation, total bilirubin, total protein, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (CSH-Px), and glutathione reductase (GSH). Results indicated that 1-5 scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl ((∙)OH), nitric oxide radicals (NO(∙)), superoxide anion radical (O2 (∙-)), radical cation (ABTS(∙+)), and hydrogen peroxide (H2O2) radical, and protection against H2O2 induced BSA damage was also observed. Furthermore, 1-5 showed ability to decrease the oxidative stress in H9c2 cell. Diabetic mice present high levels of lipid peroxide, total protein, SGPT, SGOT, ALP, and TB. However, treatment of STZ-induced diabetes in mice with 1-5 reduced levels of these enzymes leading to protector effect of liver. In addition, with treatment with 1-5, increases in radical scavenging enzymes of CSH-Px, SOD, GSH, and CAT have also been observed in diabetic mice. The antioxidant properties of compounds 1-5 are a promising strategy for ameliorating therapeutic effects by avoiding disorders in the normal redox reactions in healthy cells which consequently could alleviate complications of diabetes.
A Novel Topical Combination Ointment with Antimicrobial Activity against Methicillin-Resistant Streptococcus aureus, Gram-Negative Superbugs, Yeasts, and Dermatophytic Fungi.Monday, September 26, 2016
Thomson KS, Thomson GK, Biehle J, Deeb A, Crawford J, Herrera R,
Current therapeutic research, clinical and experimental. 2016
The results of this study suggest that this combination ointment has a broad in vitro spectrum of antimicrobial activity against both more common bacterial and fungal pathogens and may be particularly useful for treatment of infections by multidrug-resistant organisms. Additional studies are warranted to investigate the full clinical utility as a therapeutic agent and also for possible infection control interventions.
Bursting dynamics remarkably improve the performance of neural networks on liquid computing.Monday, September 26, 2016
Li X, Chen Q, Xue F,
Cognitive neurodynamics. Oct-2016
Burst firings are functionally important behaviors displayed by neural circuits, which plays a primary role in reliable transmission of electrical signals for neuronal communication. However, with respect to the computational capability of neural networks, most of relevant studies are based on the spiking dynamics of individual neurons, while burst firing is seldom considered. In this paper, we carry out a comprehensive study to compare the performance of spiking and bursting dynamics on the capability of liquid computing, which is an effective approach for intelligent computation of neural networks. The results show that neural networks with bursting dynamic have much better computational performance than those with spiking dynamics, especially for complex computational tasks. Further analysis demonstrate that the fast firing pattern of bursting dynamics can obviously enhance the efficiency of synaptic integration from pre-neurons both temporally and spatially. This indicates that bursting dynamic can significantly enhance the complexity of network activity, implying its high efficiency in information processing.
Operator functional state estimation based on EEG-data-driven fuzzy model.Monday, September 26, 2016
Zhang J, Yin Z, Yang S, Wang R,
Cognitive neurodynamics. Oct-2016
This paper proposed a max-min-entropy-based fuzzy partition method for fuzzy model based estimation of human operator functional state (OFS). The optimal number of fuzzy partitions for each I/O variable of fuzzy model is determined by using the entropy criterion. The fuzzy models were constructed by using Wang-Mendel method. The OFS estimation results showed the practical usefulness of the proposed fuzzy modeling approach.
Stain-free histopathology by programmable supercontinuum pulses.Monday, September 26, 2016
Tu H, Liu Y, Turchinovich D, Marjanovic M, Lyngsø J, Lægsgaard J, Chaney EJ, Zhao Y, You S, Wilson WL, Xu B, Dantus M, Boppart SA,
Nature photonics. Aug-2016
The preparation, staining, visualization, and interpretation of histological images of tissue is well-accepted as the gold standard process for the diagnosis of disease. These methods were developed historically, and are used ubiquitously in pathology, despite being highly time and labor intensive. Here we introduce a unique optical imaging platform and methodology for label-free multimodal multiphoton microscopy that uses a novel photonic crystal fiber source to generate tailored chemical contrast based on programmable supercontinuum pulses. We demonstrate collection of optical signatures of the tumor microenvironment, including evidence of mesoscopic biological organization, tumor cell migration, and (lymph-)angiogenesis collected directly from fresh ex vivo mammary tissue. Acquisition of these optical signatures and other cellular or extracellular features, which are largely absent from histologically processed and stained tissue, combined with an adaptable platform for optical alignment-free programmable-contrast imaging, offers the potential to translate stain-free molecular histopathology into routine clinical use.
Naoxintong/PPARα Signaling Inhibits H9c2 Cell Apoptosis and Autophagy in Response to Oxidative Stress.Monday, September 26, 2016
Xu H, Jin J, Chen L, Li C, Xu Q, Shi J, Zhao B, Hou Y, Wang H,
Evidence-based complementary and alternative medicine : eCAM. 2016
Naoxintong (NXT) is an empirical formula based on the principle of traditional Chinese medicine, which has been approved by China Food and Drug Administration (CFDA) and is widely used for treatment of patients with cerebrovascular and cardiovascular diseases in China. The aim of this study is to investigate the protective mechanism of NXT on H9c2 cells (cardiogenic cell line) in response to H2O2. MTT, Western blot, and flow cytometry (FCM) methods were used to identify the protective effect of NXT extract on H2O2-induced H9c2 cells. Here we found that NXT extract significantly increased H9c2 cell viability and reduced H2O2-induced cell apoptosis and autophagy. More importantly, NXT inhibited H2O2-induced H9c2 cell apoptosis and autophagy by increasing PPARα protein levels. In contrast, silenced PPARα terminated NXT protective effect on H2O2-induced H9c2 cells. These findings suggest that NXT/PPARα signaling suppressed H2O2-induced H9c2 cell apoptosis and autophagy.
Helicobacter pylori Activates HMGB1 Expression and Recruits RAGE into Lipid Rafts to Promote Inflammation in Gastric Epithelial Cells.Monday, September 26, 2016
Lin HJ, Hsu FY, Chen WW, Lee CH, Lin YJ, Chen YY, Chen CJ, Huang MZ, Kao MC, Chen YA, Lai HC, Lai CH,
Frontiers in immunology. 2016
Helicobacter pylori infection is associated with several gastrointestinal disorders in the human population worldwide. High-mobility group box 1 (HMGB1), a ubiquitous nuclear protein, mediates various inflammation functions. The interaction between HMGB1 and receptor for advanced glycation end-products (RAGE) triggers nuclear factor (NF)-κB expression, which in turn stimulates the release of proinflammatory cytokines, such as interleukin (IL)-8, and enhances the inflammatory response. However, how H. pylori activates HMGB1 expression and mobilizes RAGE into cholesterol-rich microdomains in gastric epithelial cells to promote inflammation has not been explored. In this study, we found that HMGB1 and RAGE expression increased significantly in H. pylori-infected cells compared with -uninfected cells. Blocking HMGB1 by neutralizing antibody abrogated H. pylori-elicited RAGE, suggesting that RAGE expression follows HMGB1 production, and silenced RAGE-attenuated H. pylori-mediated NF-κB activation and IL-8 production. Furthermore, significantly more RAGE was present in detergent-resistant membranes extracted from H. pylori-infected cells than in those from -uninfected cells, indicating that H. pylori exploited cholesterol to induce the HMGB1 signaling pathway. These results indicate that HMGB1 plays a crucial role in H. pylori-induced inflammation in gastric epithelial cells, which may be valuable in developing treatments for H. pylori-associated diseases.
Proteomics Analysis of Three Different Strains of Mycobacterium tuberculosis under In vitro Hypoxia and Evaluation of Hypoxia Associated Antigen's Specific Memory T Cells in Healthy Household Contacts.Monday, September 26, 2016
Devasundaram S, Gopalan A, Das SD, Raja A,
Frontiers in microbiology. 2016
In vitro mimicking conditions are thought to reflect the environment experienced by Mycobacterium tuberculosis inside the host granuloma. The majority of in vitro dormancy experimental models use laboratory-adapted strains H37Rv or Erdman instead of prevalent clinical strains involved during disease outbreaks. Thus, we included the most prevalent clinical strains (S7 and S10) of M. tuberculosis from south India in addition to H37Rv for our in vitro oxygen depletion (hypoxia) experimental model. Cytosolic proteins were prepared from hypoxic cultures, resolved by two-dimensional electrophoresis and protein spots were characterized by mass spectrometry. In total, 49 spots were characterized as over-expressed or newly emergent between the three strains. Two antigens (ESAT-6, Lpd) out of the 49 characterized spots were readily available in recombinant form in our lab. Hence, these two genes were overexpressed, purified and used for in vitro stimulation of whole blood collected from healthy household contacts (HHC) and active pulmonary tuberculosis patients (PTB). Multicolor flow cytometry analysis showed high levels of antigen specific CD4(+) central memory T cells in the circulation of HHC compared to PTB (p < 0.005 for ESAT-6 and p < 0.0005 for Lpd). This shows proteins that are predicted to be up regulated during in vitro hypoxia in most prevalent clinical strains would indicate possible potential immunogens. In vitro hypoxia experiments with most prevalent clinical strains would also elucidate the probable true representative antigens involved in adaptive mechanisms.
Proteomic Biomarkers Panel: New Insights in Chronic Kidney Disease.Monday, September 26, 2016
Mihai S, Codrici E, Popescu ID, Enciu AM, Rusu E, Zilisteanu D, Albulescu R, Anton G, Tanase C,
Disease markers. 09-09-2016
Chronic kidney disease, despite being a "silent epidemic" disease, represents one of the main causes of mortality in general population, along with cardiovascular disease, which is the leading cause of poor prognosis for these patients. The specific objective of our study was to characterize the relationship between the inflammatory status, the bone disorders markers, and kidney failure in chronic kidney disease patient stages 2-4, in order to design a novel biomarker panel that improves early disease diagnosis and therapeutic response, thus being further integrated into clinical applications. A panel of proteomic biomarkers, assessed by xMAP array, which includes mediators of inflammation (IL-6, TNF-α) and mineral and bone disorder biomarkers (OPG, OPN, OCN, FGF-23, and Fetuin-A), was found to be more relevant than a single biomarker to detect early CKD stages. The association between inflammatory cytokines and bone disorders markers, IL-6, TNF-α, OPN, OPG, and FGF-23, reflects the severity of vascular changes in CKD and predicts disease progression. Proteomic xMAP analyses shed light on a new approach to clinical evaluation for CKD staging and prognosis.
Identification of Bombyx mori nucleopolyhedrovirus bm58a as an auxiliary gene and its requirement for cell lysis and larval liquefaction.Monday, September 26, 2016
Yang R, Zhang J, Feng M, Wu X,
The Journal of general virology. 22-Sep-2016
Bombyx mori nucleopolyhedrovirus (BmNPV) orf 58a (bm58a) and its homologs are highly conserved in genomes of all sequenced Group I alphabaculoviruses and its function is still unknown. Transcriptional analysis revealed that bm58a is a very late gene initiated from a late transcriptional start motif TAAG. To examine its role in the virus, a bm58a knockout virus(vBmbm-58a-KO-PH-GFP) was generated through homologous recombination in Escherichia coli. Analysis of fluorescence microscopy, titration assays, and electron microscopy examination showed that the deletion of bm58a did not affect viral replication and occlusion bodies formation in vitro, indicating that bm58a is not required for viral propagation. However, vBmbm-58a-KO-PH-GFP did not result in cell lysis when wild type virus infected cells began to lyse, and the vBmbm-58a-KO-PH-GFP infected cells remained intact until two weeks post infection. Quantification of polyhedra release from cells confirmed this observation. Accordingly, though deletion of bm58a did not reduce BmNPV infectivity in vivo in bioassays, it did significantly disrupt the larval liquefaction,reducing the level of polyhedra release from infected host. Immunofluorescence analysis demonstrated that Bm58a was predominantly localized on cellular membrane at the late stage of infection, which may contribute to its function of facilitating cell lysis and larval liquefaction. Our results suggest that although bm58a is not essential for viral propagation as an auxiliary gene, but it is a key factor of virus-induced cell lysis and larval liquefaction in vitro and in vivo.
LAMSA: fast split read alignment with long approximate matches.Monday, September 26, 2016
Liu B, Gao Y, Wang Y,
Bioinformatics (Oxford, England). 25-Sep-2016
LAMSA is available at https://github.com/hitbc/LAMSA CONTACT: ydwang@hit.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
B10 cells play a role in the immune modulation of pro- and anti-inflammatory immune responses in mouse islet allograft rejection.Monday, September 26, 2016
Qin Y, Zhang M, Jiang RM, Wu Q, Xu XY, Chen H, Yang T,
Cellular immunology. 19-Sep-2016
Recently, pancreatic islet transplantation has been shown to be a viable option for the treatment of type 1 diabetes mellitus. However, immune destruction becomes the major impediment to the clinical application of islet transplantation. Here, we evaluated changes affecting multiple types of immune cells and cytokines in allogeneic islet transplantation immunity after the administration of B10 cells alone and explored the regulatory mechanisms of B10 cells in T cell-mediated allograft rejection. In vitro assays, B10 cells significantly decreased the proliferative capacity of CD4(+)CD25(-) T cells (13.75%±0.96% vs. 32.76%±0.81%) while enhancing the proliferation of regulatory T cells (Tregs) (26.60%±1.14% vs. 21.52%±0.81%). Furthermore, after the administration of B10 cells in vivo, the frequencies of IL-10(+) B cells and Tregs of islet transplant recipients were increased by the CD19(+)CD5(+)CD1d(hi) B cells, and the CD4(+)/CD8(+) and IFN-γ(+)/IL-17(+) ratios were decreased. Serum IL-10 levels were up-regulated, while IFN-γ levels were down-regulated. Grafts from 1 to 5×10(6) B10 cell-treated recipients exhibited a reduced level of insulitis compared with the untreated controls, although the differences of graft survival times were not statistically significant. In general, in mouse islet allograft rejection, B10 cells may alleviate T cell-mediated immune responses by promoting Treg-cell development and inhibiting Th1 cells activation, via an IL-10-dependent pathway. Development of B10 cell-targeted therapy may be benefit for modulating immune response and provide insight into the signals involved the induction of islet allograft tolerance.
Sugar-modified poly(propylene imine) dendrimers as drug delivery agents for cytarabine to overcome drug resistance.Monday, September 26, 2016
Szulc A, Pulaski L, Appelhans D, Voit B, Klajnert-Maculewicz B,
International journal of pharmaceutics. 22-Sep-2016
Maltose-modified poly(propylene imine) glycodendrimers (PPI-m OS) of the 4th generation provide a promising strategy for leukemia treatment. Anticancer therapy with nucleoside analog drugs such as cytarabine (Ara-C) frequently has limited efficacy due to drug resistance, inefficient uptake and accumulation of the drug inside cancer cells where it has to be transformed into the active triphosphate congener. The cationic nature of PPI dendrimers makes it possible to form complexes with nucleotide Ara-C triphosphate forms (Ara-CTP). The aim of this work was to test the concept of applying PPI glycodendrimers as drug delivery devices in order to facilitate the delivery of activated cytarabine to cancer cells to overcome metabolic limitations of the drug. The study has been carried out using 1301 and HL-60 leukemic cell lines as well as peripheral blood mononuclear cells. The results of cytotoxicity and apoptosis assays showed enhanced activity of Ara-C triphosphate form (Ara-CTP) complexed with PPI-m dendrimers in relation to free Ara-C and Ara-CTP against 1301 leukemic cells. Secondly, enhanced uptake and cytotoxicity of Ara-CTP-dendrimers complexes toward 1301 cells with blocked human equilibrative nucleoside transporter - hENT1 suggested that this combination might be a versatile candidate for chemotherapy against resistant acute lymphoblastic leukemia cells with lower expression of hENT1.
Fungal cell membrane - promising drug target for antifungal therapy.Monday, September 26, 2016
Sant DG, Tupe SG, Ramana CV, Deshpande MV,
Journal of applied microbiology. 26-Sep-2016
Increase in invasive fungal infections over past few years especially in immunocompromised patients prompted the search for new antifungal agents with improved efficacy. Current antifungal armory includes very few effective drugs like Amphotericin B, new generation azoles including voriconazole and posaconazole, echinocandins like caspofungin, micafungin, to name a few. Azole class of antifungals which target fungal cell membrane are first choice of treatment for many years because of their effectiveness. As fungal cell membrane is predominantly made up of sterols, glycerophospholipids and sphingolipids, the role of lipids in pathogenesis and target identification for improved therapeutics were largely pursued by researchers during last few years. Present review focuses on cell membrane as antifungal target with emphasis on membrane biogenesis, structure and function of cell membrane, cell membrane inhibitors, screening assays, recent advances and future prospects. This article is protected by copyright. All rights reserved.
Carbopalladation Cascades Using Carbon-Carbon Triple Bonds: Recent Advances to Access Complex Scaffolds.Monday, September 26, 2016
Düfert A, Werz DB,
Chemistry (Weinheim an der Bergstrasse, Germany). 26-Sep-2016
Alkynes are one of the most versatile functional groups as synthetic handles. They allow for a direct access to partially or fully substituted alkenes through difunctionalization reactions. A prominently utilized transformation for these sequences is the carbopalladation of alkynes, which can be followed by various termination steps such as aromatizations, dearomatizations, cross-coupling reactions, or pericyclic processes, amongst others. This Minireview provides an overview of the recent literature published in the field of carbopalladation chemistry, both with a focus on methodology as well as its application in the syntheses of complex molecular scaffolds, natural products, and functional molecules.
G9a inhibits MEF2C activity to control sarcomere assembly.Monday, September 26, 2016
Ow JR, Palanichamy Kala M, Rao VK, Choi MH, Bharathy N, Taneja R,
Scientific reports. 26-9-2016
In this study, we demonstrate that the lysine methyltransferase G9a inhibits sarcomere organization through regulation of the MEF2C-HDAC5 regulatory axis. Sarcomeres are essential for muscle contractile function. Presently, skeletal muscle disease and dysfunction at the sarcomere level has been associated with mutations of sarcomere proteins. This study provides evidence that G9a represses expression of several sarcomere genes and its over-expression disrupts sarcomere integrity of skeletal muscle cells. G9a inhibits MEF2C transcriptional activity that is essential for expression of sarcomere genes. Through protein interaction assays, we demonstrate that G9a interacts with MEF2C and its co-repressor HDAC5. In the presence of G9a, calcium signaling-dependent phosphorylation and export of HDAC5 to the cytoplasm is blocked which likely results in enhanced MEF2C-HDAC5 association. Activation of calcium signaling or expression of constitutively active CaMK rescues G9a-mediated repression of HDAC5 shuttling as well as sarcomere gene expression. Our results demonstrate a novel epigenetic control of sarcomere assembly and identifies new therapeutic avenues to treat skeletal and cardiac myopathies arising from compromised muscle function.
A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation.Monday, September 26, 2016
Fay JM, Zhu C, Proctor EA, Tao Y, Cui W, Ke H, Dokholyan NV,
Structure (London, England : 1993). 17-Sep-2016
The majority of amyotrophic lateral sclerosis (ALS)-related mutations in the enzyme Cu,Zn superoxide dismutase (SOD1), as well as a post-translational modification, glutathionylation, destabilize the protein and lead to a misfolded oligomer that is toxic to motor neurons. The biophysical role of another physiological SOD1 modification, T2-phosphorylation, has remained a mystery. Here, we find that a phosphomimetic mutation, T2D, thermodynamically stabilizes SOD1 even in the context of a strongly SOD1-destabilizing mutation, A4V, one of the most prevalent and aggressive ALS-associated mutations in North America. This stabilization protects against formation of toxic SOD oligomers and positively impacts motor neuron survival in cellular assays. We solve the crystal structure of T2D-SOD1 and explain its stabilization effect using discrete molecular dynamics (DMD) simulations. These findings imply that T2-phosphorylation may be a plausible innate cellular protection response against SOD1-induced cytotoxicity, and stabilizing the SOD1 native conformation might offer us viable pharmaceutical strategies against currently incurable ALS.
Potent, Reversible, and Specific Chemical Inhibitors of Eukaryotic Ribosome Biogenesis.Monday, September 26, 2016
Kawashima SA, Chen Z, Aoi Y, Patgiri A, Kobayashi Y, Nurse P, Kapoor TM,
Cell. 21-Sep-2016
All cellular proteins are synthesized by ribosomes, whose biogenesis in eukaryotes is a complex multi-step process completed within minutes. Several chemical inhibitors of ribosome function are available and used as tools or drugs. By contrast, we lack potent validated chemical probes to analyze the dynamics of eukaryotic ribosome assembly. Here, we combine chemical and genetic approaches to discover ribozinoindoles (or Rbins), potent and reversible triazinoindole-based inhibitors of eukaryotic ribosome biogenesis. Analyses of Rbin sensitivity and resistance conferring mutations in fission yeast, along with biochemical assays with recombinant proteins, provide evidence that Rbins' physiological target is Midasin, an essential ∼540-kDa AAA+ (ATPases associated with diverse cellular activities) protein. Using Rbins to acutely inhibit or activate Midasin function, in parallel experiments with inhibitor-sensitive or inhibitor-resistant cells, we uncover Midasin's role in assembling Nsa1 particles, nucleolar precursors of the 60S subunit. Together, our findings demonstrate that Rbins are powerful probes for eukaryotic ribosome assembly.
A Functional Role for Antibodies in Tuberculosis.Monday, September 26, 2016
Lu LL, Chung AW, Rosebrock TR, Ghebremichael M, Yu WH, Grace PS, Schoen MK, Tafesse F, Martin C, Leung V, Mahan AE, Sips M, Kumar MP, Tedesco J, Robinson H, Tkachenko E, Draghi M, Freedberg KJ, Streeck H, Suscovich TJ, Lauffenburger DA, Restrepo BI, Day C, Fortune SM, Alter G,
Cell. 21-Sep-2016
While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.
Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.Monday, September 26, 2016
Doan RN, Bae BI, Cubelos B, Chang C, Hossain AA, Al-Saad S, Mukaddes NM, Oner O, Al-Saffar M, Balkhy S, Gascon GG, Nieto M, Walsh CA,
Cell. 21-Sep-2016
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior.
Impact of micropollutants on the life-history traits of the mosquito Aedes aegypti: On the relevance of transgenerational studies.Monday, September 26, 2016
Prud'homme SM, Chaumot A, Cassar E, David JP, Reynaud S,
Environmental pollution (Barking, Essex : 1987). 22-Sep-2016
Hazard assessment of chemical contaminants often relies on short term or partial life-cycle ecotoxicological tests, while the impact of low dose throughout the entire life cycle of species across multiple generations has been neglected. This study aimed at identifying the individual and population-level consequences of chronic water contamination by environmental concentrations of three organic micropollutants, ibuprofen, bisphenol A and benzo[a]pyrene, on Aedes aegypti mosquito populations in experimental conditions. Life-history assays spanning the full life-cycle of exposed individuals and their progeny associated with population dynamics modelling evidenced life-history traits alterations in unexposed progenies of individuals chronically exposed to 1 μg/L ibuprofen or 0.6 μg/L benzo[a]pyrene. The progeny of individuals exposed to ibuprofen showed an accelerated development while the progeny of individuals exposed to benzo[a]pyrene showed a developmental acceleration associated with an increase in mortality rate during development. These life-history changes due to pollutants exposure resulted in relatively shallow increase of Ae. aegypti asymptotic population growth rate. Multigenerational exposure for six generations revealed an evolution of population response to ibuprofen and benzo[a]pyrene across generations, leading to a loss of previously identified transgenerational effects and to the emergence of a tolerance to the bioinsecticide Bacillus turingiensis israelensis (Bti). This study shed light on the short and long term impact of environmentally relevant doses of ibuprofen and benzo[a]pyrene on Ae. aegypti life-history traits and insecticide tolerance, raising unprecedented perspectives about the influence of surface water pollution on vector-control strategies. Overall, our approach highlights the importance of considering the entire life cycle of organisms, and the necessity to assess the transgenerational effects of pollutants in ecotoxicological studies for ecological risk assessment. Finally, this multi-generational study gives new insight about the influence of surface water pollution on microevolutionary processes.
Antibodies to major histocompatibility complex class II antigens directly prime neutrophils and cause acute lung injury in a two-event in vivo rat model.Monday, September 26, 2016
Kelher MR, Banerjee A, Gamboni F, Anderson C, Silliman CC,
Transfusion. 25-Sep-2016
Proinflammatory first events induce PMN MHC class II surface expression, activation of the pulmonary endothelium, and PMN sequestration such that the infusion of cognate antibodies precipitates TRALI.
Expression pattern of CD55 and CD59 on red blood cells in sickle cell disease.Monday, September 26, 2016
Al-Faris L, Al-Rukhayes M, Al-Humood S,
Hematology (Amsterdam, Netherlands). 25-Sep-2016
There is an altered pattern of CD55 and CD59 expression on RBCs of SCD Patients; however, it does not seem to play a causal role in the pathophysiology of anemia, and is unlikely to be influenced by the level of erythropoietin or other inflammatory mediators.
Design, Synthesis and Evaluation of Novel Isoxazolines/Oxime Sulfonates of 2'(2',6')-(Di)Chloropodophyllotoxins as Insecticidal Agents.Monday, September 26, 2016
Yu M, Liu G, Zhang Y, Feng T, Xu M, Xu H,
Scientific reports. 25-9-2016
A series of 2'(2',6')-(di)halogeno-isoxazolopodophyllic acids-based esters, and oxime sulfonates of 2'(2',6')-(di)halogenopodophyllones were prepared by structural modifications of podophyllotoxin as insecticidal agents against Mythimna separata Walker. It was found that when 2'(2',6')-(di)halogenopodophyllones or 2'(2',6')-(di)chloropicropodophyllones reacted with hydroxylamine hydrochloride, the desired products were related with the configuration of their lactones. Three key single-crystal structures of Ie, IIe and IIIb were determined by X-ray diffraction. Especially compounds IIc and Vc showed the highest insecticidal activity. Moreover, some interesting results of structure-insecticidal activity relationships of tested compounds were also observed.
Inundation of asthma target research: Untangling asthma riddles.Monday, September 26, 2016
Singh J, Shah R, Singh D,
Pulmonary pharmacology & therapeutics. 22-Sep-2016
Asthma is inveterate inflammatory disorder, delineated by airway inflammation, bronchial hyperresponsiveness (BHR) and airway wall remodeling. Although, asthma is a vague term, and is recognized as heterogenous entity encompassing different phenotypes. Targeting single mediator or receptor did not prove much clinical significant, as asthma is complex disease involving myriad inflammatory mediators. Asthma may probably involve a large number of different types of molecular and cellular components interacting through complex pathophysiological pathways. This review covers the past, present, and future therapeutic approaches and pathophysiological mechanisms of asthma. Furthermore, review describe importance of targeting several mediators/modulators and receptor antagonists involved in the physiopathology of asthma. Novel targets for asthma research include Galectins, Immunological targets, K (+) Channels, Kinases and Transcription Factors, Toll-like receptors, Selectins and Transient receptor potential channels. But recent developments in asthma research are very promising, these include Bitter taste receptors (TAS2R) abated airway obstruction in mouse model of asthma and Calcium-sensing receptor obliterate inflammation and in bronchial hyperresponsiveness allergic asthma. All these progresses in asthma targets, and asthma phenotypes exploration are auspicious in untangling of asthma riddles.
Systematic Identification of Pharmacological Targets from Small-Molecule Phenotypic Screens.Monday, September 26, 2016
Liu X, Baarsma HA, Thiam CH, Montrone C, Brauner B, Fobo G, Heier JS, Duscha S, Königshoff M, Angeli V, Ruepp A, Campillos M,
Cell chemical biology. 17-Sep-2016
Phenotypic drug discovery offers some advantages over target-based methods, mainly because it allows drug leads to be tested in systems that more closely model distinct disease states. However, a potential disadvantage is the difficulty of linking the observed phenotype to a specific cellular target. To address this problem, we developed DePick, a computational target de-convolution tool to determine targets specifically linked to small-molecule phenotypic screens. We applied DePick to eight publicly available screens and predicted 59 drug target-phenotype associations. In addition to literature-based evidence for our predictions, we provide experimental support for seven predicted associations. Interestingly, our analysis led to the discovery of a previously unrecognized connection between the Wnt signaling pathway and an aromatase, CYP19A1. These results demonstrate that the DePick approach can not only accelerate target de-convolution but also aid in discovery of new functionally relevant biological relationships.
Blood-brain barrier changes in high altitude.Monday, September 26, 2016
Lafuente JV, Bermudez G, Camargo-Arce L, Bulnes S,
CNS & neurological disorders drug targets. 20-Sep-2016
Cerebral syndromes related to high altitude exposure are becoming more frequent as the number of trips to high altitudes has increased in the last decade. The commonest symptom is headache, followed by acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), which can be fatal. The pathophysiology of these syndromes is not fully comprehended. The classical "tight-fit hypothesis" defends the fact that there are some anatomical variations that would obstruct the sinovenous outflow and worsen the vasogenic edema and intracranial hypertension reactive to hypoxia. This could explain microhemorrhages seen in autopsies. However, recent MR studies have demonstrated some components of cytotoxic edema in HACE absent in AMS, suggesting a dysfunction in the water balance at the cellular level. Currently, the "red-ox theory" stands up for trigemino-vascular system (TVS) activation by free radicals formed after hypoxia and the consecutive oxidative stress cascades. Apart from the TVS activation, free radicals can also provoke membrane destabilisation mediated by lipid peroxidation, inflammation, and local HIF-1a and VEGF activation, resulting in gross blood-brain barrier (BBB) dysfunction. Besides, alterations in endothelial cells, such as increased pinocytotic vesicles and disassemble of the interendothelial tight junctions proteins may also increase capillar permeability with subsequent swelling of the astrocyte end-feet. In conclusion, although the pathophysiology of AMS and HACE is not completely understood, recent evidences propose a multifactorial entity, with brain swelling and a deep compromise at BBB considered to play an important role. A better understanding is crucial to reduce and prevent BBB alterations during high altitude exposure.
Baicalein inhibits TNF-α-induced NF-κB activation and expression of NF-κB-regulated target gene products.Monday, September 26, 2016
Li J, Ma J, Wang KS, Mi C, Wang Z, Piao LX, Xu GH, Li X, Lee JJ, Jin X,
Oncology reports. 19-Sep-2016
The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified baicalein from Scutellaria baicalensis as an inhibitor of NF-κB activation. As examined by the NF-κB luciferase reporter assay, we found that baicalein suppressed TNF-α-induced NF-κB activation in a dose-dependent manner. It also inhibited TNF-α-induced nuclear translocation of p65 through inhibition of phosphorylation and degradation of IκBα. Furthermore, baicalein blocked the TNF-α-induced expression of NF-κB target genes involved in anti-apoptosis (cIAP-1, cIAP-2, FLIP and BCL-2), proliferation (COX-2, cyclin D1 and c-Myc), invasion (MMP‑9), angiogenesis (VEGF) and major inflammatory cytokines (IL-8 and MCP1). The flow cytometric analysis indicated that baicalein potentiated TNF-α-induced apoptosis and induced G1 phase arrest in HeLa cells. Moreover, baicalein significantly blocked activation of p38, extracellular signal-regulated kinase 1/2 (ERK1/2). Our results imply that baicalein could be a lead compound for the modulation of inflammatory diseases as well as certain cancers in which inhibition of NF-κB activity may be desirable.
The Chitin-Binding Domain of a GH-18 Chitinase from Vibrio harveyi is Crucial for Chitin-Chitinase Interactions.Monday, September 26, 2016
Suginta W, Sirimontree P, Sritho N, Ohnuma T, Fukamizo T,
International journal of biological macromolecules. 22-Sep-2016
Vibrio harveyi chitinase A (VhChiA) is a GH-18 glycosyl hydrolase with a structure containing three distinct domains: i) the N-terminal chitin-binding domain; ii) the (α/β)8 TIM barrel catalytic domain; and iii) the α+β insertion domain. In this study, we cloned the gene fragment encoding the chitin-binding domain of VhChiA, termed ChBDVhChiA. The recombinant ChBDVhChiA was heterologously expressed in E. coli BL21 strain Tuner(DE3)pLacI host cells, and purified to homogeneity. CD measurements suggested that ChBDVhChiA contained β-sheets as major structural components and fluorescence spectroscopy showed that the protein domain was folded correctly, and suitable for functional characterization. Chitin binding assays showed that ChBDVhChiA bound to both α- and β-chitins, with the greatest affinity for β-colloidal chitin, but barely bound to polymeric chitosan. These results identified the tandem N-acetamido functionality on chitin chains as the specific sites of enzyme-substrate interactions. The binding affinity of the isolated domain was significantly lower than that of intact VhChiA, suggesting that the catalytic domain works synergistically with the chitin-binding domain to guide the polymeric substrate into the substrate binding cleft. These data confirm the physiological role of the chitin-binding domain of the marine bacterial GH-18 chitinase A in chitin-chitinase interactions.
Source: NCBI - Disclaimer and Copyright notice
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