2-Amino-nicotinamide induces apoptosis of prostate cancer cells via inhibition of PI3K/AKT and phosphorylation of STA3/JAK2

Purpose: To study the cytotoxicity of 2-amino-nicotinamide against prostate cancer (PCa) cells, and the underlying molecular mechanism.Methods: The effect of 2-amino-nicotinamide on cell viability and apoptosis was determined by 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) and flow cytometry, respectively, while its effect on cellular production of fluorescent-oxidized product from DCFH-DA was measured using flow cytometry. Apoptosis-related protein expressions were evaluated by western blot assay.Results: 2-Amino-nicotinamide produced cytotoxicity against MCF-7, SGC7901, PCa 22Rv1 and LNCaP cancer cell lines (p < 0.05). Mechanistic data revealed that 2-amino-nicotinamide activated apoptosis, and enhanced cleavage of PARP and caspase-3 in PCa 22Rv1 and LNCaP cells. In PCa 22Rv1 and LNCaP cell lines, cytochrome C and Bax levels were enhanced by treatment with 2-aminonicotinamide, while Bcl-2 protein level was suppressed (p < 0.05). Activated expressions of PI3K, Akt and ERK in PCa 22Rv1 and LNCaP cells were down-regulated, while p38 expression was increased.Moreover, 2-amino-nicotinamide suppressed the activation of JAK2 and STAT3, but did not alter total JAK2 and STAT3 levels in PCa 22Rv1 and LNCaP cells (p < 0.05).Conclusion: 2-Amino-nicotinamide exerts cytotoxic effects on prostate carcinoma cells via activation of apoptosis and down-regulation of PI3K/AKT and STA3/JAK2. Thus, 2-amino nicotinamide is a potential bioactive agent for prostate cancer management. Keywords: 2-Amino-nicotinamide, Apoptosis, Fluorescent-oxidized, Cytotoxicit

Understanding Haemophilus parasuis infection in porcine spleen through a transcriptomics approach

<p>Abstract</p> <p>Background</p> <p><it>Haemophilus parasuis </it>(HPS) is an important swine pathogen that causes Glässer's disease, which is characterized by fibrinous polyserositis, meningitis and arthritis. The molecular mechanisms that underlie the pathogenesis of the disease remain poorly understood, particularly the resistance of porcine immune system to HPS invasion. In this study, we investigated the global changes in gene expression in the spleen following HPS infection using the Affymetrix Porcine Genechip™.</p> <p>Results</p> <p>A total of 931 differentially expressed (DE) transcripts were identified in the porcine spleen 7 days after HPS infection; of these, 92 unique genes showed differential expression patterns based on analysis using BLASTX and Gene Ontology. The DE genes involved in the immune response included genes for inflammasomes (<it>RETN</it>, <it>S100A8</it>, <it>S100A9</it>, <it>S100A12</it>), adhesion molecules (<it>CLDN3</it>, <it>CSPG2</it>, <it>CD44</it>, <it>LGALS8</it>), transcription factors (<it>ZBTB16</it>, <it>SLC39A14</it>, <it>CEBPD</it>, <it>CEBPB</it>), acute-phase proteins and complement (<it>SAA1</it>, <it>LTF</it>, <it>HP</it>, <it>C3</it>), differentiation genes for epithelial cells and keratinocytes (<it>TGM1</it>, <it>MS4A8B</it>, <it>CSTA</it>), and genes related to antigen processing and presentation (<it>HLA-B</it>, <it>HLA-DRB1</it>). Further immunostimulation analyses indicated that mRNA levels of <it>S100A8</it>, <it>S100A9</it>, and <it>S100A12 </it>in porcine PK-15 cells increased within 48 h and were sustained after administration of lipopolysaccharide (LPS) and Poly(I:C) respectively. In addition, mapping of DE genes to porcine health traits QTL regions showed that 70 genes were distributed in 7 different known porcine QTL regions. Finally, 10 DE genes were validated by quantitative PCR.</p> <p>Conclusion</p> <p>Our findings demonstrate previously unrecognized changes in gene transcription that are associated with HPS infection <it>in vivo</it>, and many potential cascades identified in the study clearly merit further investigation. Our data provide new clues to the nature of the immune response in mammals, and we have identified candidate genes that are related to resistance to HPS.</p

Scaffold Structural Microenvironmental Cues to Guide Tissue Regeneration in Bone Tissue Applications

In the process of bone regeneration, new bone formation is largely affected by physico-chemical cues in the surrounding microenvironment. Tissue cells reside in a complex scaffold physiological microenvironment. The scaffold should provide certain circumstance full of structural cues to enhance multipotent mesenchymal stem cell (MSC) differentiation, osteoblast growth, extracellular matrix (ECM) deposition, and subsequent new bone formation. This article reviewed advances in fabrication technology that enable the creation of biomaterials with well-defined pore structure and surface topography, which can be sensed by host tissue cells (esp., stem cells) and subsequently determine cell fates during differentiation. Three important cues, including scaffold pore structure (i.e., porosity and pore size), grain size, and surface topography were studied. These findings improve our understanding of how the mechanism scaffold microenvironmental cues guide bone tissue regeneration

Risk factors of CVD mortality among the elderly in Beijing, 1992 - 2009: An 18-year cohort study

Few researchers have examined the effects of multiple risk factors of cardiovascular disease (CVD) mortality simultaneously. This study was to determine the associations of combined lifestyle and other factors with CVD mortality among the elderly (n = 3,257), in Beijing, China, through data mining of the Beijing Longitudinal Study of Aging (BLSA). BLSA is a representative cohort study from 1992 to 2009, hosted by Xuan Wu Hospital. Competing risk survival analysis was conducted to explore the association between risk factors and CVD mortality. The factors focused mainly on lifestyle, physical condition, and the model was adjusted for age and gender. There were 273 of the 1,068 recorded deaths caused by CVD among the 2010 participants. Living in a suburban area (HR = 0.614, 95% CI: 0.410-0.921) was associated with lower CVD mortality. Increasing age (66-75: HR = 1.511, 95% CI: 1.111-2.055; ≥76: HR = 1.847, 95% CI: 1.256-2.717), high blood pressure (HR = 1.407, 95% CI: 1.031-1.920), frequent consumption of meat (HR = 1.559, 95% CI: 1.079-2.254) and physical inactivity (p = 0.046) were associated with higher CVD mortality. The study provides an instructional foundation for the control and prevention of CVD in Beijing, China

A study of multinucleated giant cells in esophageal cancer

Objectives: To evaluate the occurrence, abundance, distribution, nature and clinical significance of multi-nucleated giant cell (MGC) in esophageal cancer. Materials and methods: MGCs were examined with conventional pathology, immunohistochemistry and immunofluorescence in 107 esophageal cancer tissues. The findings were correlated to pathological diagnosis and clinical behavior of the cancers. Results: MGCs were identified in 31.7% (34/107) of the cases. MGCs were positive for CD11c, CD11b, CD32, CD16, HLA-DR and MMP9, and negative for CD163, CD206 and CD64 giving a molecular profile of proinflammatory M1 but not immunosuppressive M2. MGCs were significantly related to decreased lymph node metastasis (p = 0.011), low pTNM stage (p = 0.044), favorable survival (p = 0.04), squamous cell cancer type rather than other histopathological subtypes (p = 0.020) and associated to better differentiation (p = 0.063). Conclusions: MGCs belong to M1 macrophage and perform phagocytosis and scavenging of cancer cells that would benefit patients' survival and could serve as a prognostic marker

Risk factors for cerebrovascular disease mortality among the elderly in Beijing: A competing risk analysis

Objective: To examine the associations of combined lifestyle factors and physical conditions with cerebrovascular diseases (CBVD) mortality, after accounting for competing risk events, including death from cardiovascular diseases, cancers and other diseases. Methods: Data on 2010 subjects aged over 55 years were finally analyzed using competing risk models. All the subjects were interviewed by the Beijing Longitudinal Study of Aging (BLSA), in China, between 1 January 1992 and 30 August 2009. Results: Elderly females were at a lower risk of death from CBVD than elderly males (HR = 0.639, 95% CI = 0.457-0.895). Increasing age (HR = 1.543, 95% CI = 1.013-2.349), poor self-rated health (HR = 1.652, 95% CI = 1.198-2.277), hypertension (HR = 2.201, 95% CI = 1.524-3.178) and overweight (HR = 1.473, 95% CI = 1.013-2.142) or obesity (HR = 1.711, 95% CI = 1.1754-2.490) was associated with higher CBVD mortality risk. Normal cognition function (HR = 0.650, 95% CI = 0.434-0.973) and living in urban (HR = 0.456, 95% CI = 0.286-0.727) was associated with lower CBVD mortality risk. Gray\u27s test also confirmed the cumulative incidence (CIF) of CBVD was lower in the \u27married\u27 group than those without spouse, and the mortality was lowest in the \u27nutrition sufficient\u27 group among the \u27frequent consumption of meat group\u27 and the \u27medial type group\u27 (P valu

Single-cell transcriptome sequencing reveals tumor heterogeneity in family neuroblastoma

Neuroblastoma(NB) is the most common extracranial solid tumor in childhood, and it is now believed that some patients with NB have an underlying genetic susceptibility, which may be one of the reasons for the multiplicity of NB patients within a family line. Even within the same family, the samples show great variation and can present as ganglioneuroblastoma or even benign ganglioneuroma. The genomics of NB is still unclear and more in-depth studies are needed to reveal its key components. We first performed single-cell RNA sequencing(sc-RNAseq) analysis on clinical specimens of two family neuroblastoma(FNB) and four sporadic NB cases. A complete transcriptional profile of FNB was constructed from 18,394 cells from FNB, and we found that SDHD may be genetically associated with FNB and identified a prognostic related CAF subtype in FNB: Fib-4. Single-cell flux estimation analysis (scFEA) results showed that malignant cells were associated with arginine spermine, oxaloacetate and hypoxanthine, and that malignant cells metabolize lactate at lower levels than T cells. Our study provides new resources and ideas for the development of the genomics of family NB, and the mechanisms of cell-to-cell interactions and communication and the metabolic landscape will provide new therapeutic targets

Anthropogenic modification of phosphorus sequestration in lake sediments during the Holocene: A global perspective

Human activity has fundamentally altered the global phosphorus (P) cycle. Yet our understanding of when and how humans influenced the P cycle has been limited by the scarcity of long-term P sequestration records, particularly outside Europe and North America. Lake sediments provide a unique archive of past P burial rates and allow the human-mediated disruption of the global P cycle to be examined. We compiled the first global-scale and continentally resolved reconstruction of lake-wide Holocene P burial rates using 108 lakes from around the world. In Europe, lake P burial rates started to increase noticeably after ∼4000 calendar years before 1950 CE (cal BP), whereas the increase occurred later in China (∼2000 cal BP) and in North America (∼550 cal BP), which is most likely related to different histories of population growth, land-use and associated soil erosion intensities. Anthropogenic soil erosion explains ∼86% of the observed changes in global lake P burial rates in pre-industrial times. We also provide the first long-term estimates of the global lake P sink over the Holocene (∼2686 Tg P). We estimate that the global mean lake sediment P sequestration since 1850 CE (100 cal BP) is ∼1.54 Tg P yr−1, representing approximately a six-fold increase above the mean pre-industrial value (∼0.24 Tg P yr−1; 11,500 to 100 cal BP) and around a ten-fold increase above the Early-Middle Holocene low-disturbance baseline of 0.16 Tg P yr−1. This study suggests that human activities have been affecting the global P cycle for millennia, with substantial alteration after industrial times (1850 CE)

Differential sensitivity of target genes to translational repression by miR-17~92

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genesCX is a Pew Scholar in Biomedical Sciences. This study is supported by the PEW Charitable Trusts, Cancer Research Institute, National Institute of Health (R01AI087634, R01AI089854, RC1CA146299, R56AI110403, and R01AI121155 to CX), National Natural Science Foundation of China (31570882 to WHL, 31570883 to NX, 31570911 to GF, 91429301 to JH, 31671428 and 31500665 to YZ), 1000 Young Talents Program of China (K08008 to NX), 100 Talents Program of The Chinese Academy of Sciences (YZ), National Program on Key Basic Research Project of China (2016YFA0501900 to YZ), the Fundamental Research Funds for the Central Universities of China (20720150065 to NX and GF), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A1A01052387 to SGK, NRF-2016R1A4A1010115 to SGK and PHK), and 2016 Research Grant from Kangwon National University (SGK)