From human Megakaryocytes to platelets: Effects of aspirin on high-mobility group Box 1/receptor for advanced glycation end products axis

Platelets (PLTs) are the major source of high-mobility group box 1 (HMGB1), a protein that is involved in sterile inflammation of blood vessels and thrombosis. Megakaryocytes (MKs) synthesize HMGB1 and transfer both protein and mRNA into PLTs and PLT-derived microvesicles (MV). Free HMGB1 found in supernatants of in vitro differentiated MKs and in a megakaryoblastic cell line (DAMI cells). Aspirin “in vivo” and “in vitro” not only reduces HMGB1 and receptor for advanced glycation end products expression on MKs and PLTs but also drives the movement of HMGB1 from MKs into PLTs and PLT-derived MV. These findings suggest that consumption of low doses of aspirin reduces the risk of atherosclerosis complications as well as reducing PLT aggregation by the inhibition of COX-1

Hypoxia, inflammation and necrosis as determinants of glioblastoma cancer stem cells progression

Tumor hypoxic microenvironment causes hypoxia inducible factor 1 alpha (HIF-1ff) activation and necrosis with alarmins release. Importantly, HIF-1ff also controls the expression of alarmin receptors in tumor cells that can bind to and be activated by alarmins. Human tumor tissues possess 1-2% of cancer stem cells (CSCs) residing in hypoxic niches and responsible for the metastatic potential of tumors. Our hypothesis is that hypoxic CSCs express alarmin receptors that can bind alarmins released during necrosis, an event favoring CSCs migration. To investigate this aspect, glioblastoma stem-like cell (GSC) lines were kept under hypoxia to determine the expression of hypoxic markers as well as receptor for advanced glycation end products (RAGE). The presence of necrotic extracts increased migration, invasion and cellular adhesion. Importantly, HIF-1ff inhibition by digoxin or acriflavine prevented the response of GSCs to hypoxia alone or plus necrotic extracts. In vivo, GSCs injected in one brain hemisphere of NOD/SCID mice were induced to migrate to the other one in which a necrotic extract was previously injected. In conclusion, our results show that hypoxia is important not only for GSCs maintenance but also for guiding their response to external necrosis. Inhibition of hypoxic pathway may therefore represent a target for preventing brain invasion by glioblastoma stem cells (GSCs)

Hypoxia and inflammation as a consequence of β-fibril accumulation. A perspective view for new potential therapeutic targets

Amyloidoses are heterogeneous diseases that result from the deposition of toxic insoluble β-sheet fibrillar protein aggregates in different tissues. The cascade of molecular events leading to amyloidoses and to the related clinical manifestations is not completely understood. Nevertheless, it is known that tissue damage associated to this disease involves alteration of tissue architecture, interaction with cell surface receptors, inflammation elicited by the amyloid protein deposition, oxidative stress, and apoptosis. However, another important aspect to consider is that systemic protein massive deposition not only subverts tissue architecture but also determines a progressive cellular hypertrophy and dilation of the extracellular space enlarging the volume of the organ. Such an alteration increases the distance between cells and vessels with a drop in pO2 that, in turn, causes both necrotic cell death and activation of the hypoxia transcription factor HIF-1α. Herewith, we propose the hypothesis that both cell death and hypoxia represent two important events for the pathogenesis of damage and progression of amyloidoses. In fact, molecules released by necrotic cells activate inflammatory cells from one side while binding to HIF-1α-dependent membrane receptors expressed on hypoxic parenchymal cells on the other side. This latter event generates a signaling cascade triggering NFκB activation and chronic inflammation. Finally, we also suggest that this scenario, once proved and detailed, might suggest important targets for new therapeutic interventions

The modulation of sirtuins and apoptotic proteins in rats after exhaustive exercise

A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circu- lating human lymphocytes leading to lipid peroxide- tion, DNA damage, mitochondrial perturbations, and protein oxidation. In a training experiment, Wistar rats were divided into control group (CG) and exer- cise group (EG). After a running level exercise until exhaustion, we observed an increase in the mRNA content and protein expression of SIRT1 and SIRT7 in the EG compared to the CG. Moreover, such train- ing exercise did not change mRNA transcripts and protein expression of FOXO3A and GADD45. We also observed an increase of pro-apoptotic protein bax and a decrease of the anti-apoptotic protein bcl-2 in the EG. Accordingly, we observed a caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage only in EG rats. Statistical analysis of the data showed a significant correlation between SIRT1 and SIRT7 expression and apoptotic proteins such as bax, bcl-2 in both tissues. We conclude that, in both muscle, such exercise activates both a damaging apoptotic mecha- nism with bax increase and bcl-2 decrease and a counterbalancing protective mechanism with SIRT1 and SIRT7 increase

The Protective Effect of a Unique Mix of Polyphenols and Micronutrients against Neurodegeneration Induced by an In Vitro Model of Parkinson’s Disease

: Parkinson's disease (PD) is second-most common disabling neurological disorder worldwide, and unfortunately, there is not yet a definitive way to prevent it. Polyphenols have been widely shown protective efficacy against various PD symptoms. However, data on their effect on physio-pathological mechanisms underlying this disease are still lacking. In the present work, we evaluated the activity of a mixture of polyphenols and micronutrients, named A5+, in the murine neuroblastoma cell line N1E115 treated with 6-Hydroxydopamine (6-OHDA), an established neurotoxic stimulus used to induce an in vitro PD model. We demonstrate that a pretreatment of these cells with A5+ causes significant reduction of inflammation, resulting in a decrease in pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α, and CXCL1), a reduction in ROS production and activation of extracellular signal-regulated kinases (ERK)1/2, and a decrease in apoptotic mechanisms with the related increase in cell viability. Intriguingly, A5+ treatment promoted cellular differentiation into dopaminergic neurons, as evident by the enhancement in the expression of tyrosine hydroxylase, a well-established dopaminergic neuronal marker. Overall, these results demonstrate the synergic and innovative efficacy of A5+ mixture against PD cellular pathological processes, although further studies are needed to clarify the mechanisms underlying its beneficial effect

An integrative multi-platform analysis for discovering biomarkers of osteosarcoma

<p>Abstract</p> <p>Background</p> <p>SELDI-TOF-MS (Surface Enhanced Laser Desorption/Ionization-Time of Flight-Mass Spectrometry) has become an attractive approach for cancer biomarker discovery due to its ability to resolve low mass proteins and high-throughput capability. However, the analytes from mass spectrometry are described only by their mass-to-charge ratio (<it>m</it>/<it>z</it>) values without further identification and annotation. To discover potential biomarkers for early diagnosis of osteosarcoma, we designed an integrative workflow combining data sets from both SELDI-TOF-MS and gene microarray analysis.</p> <p>Methods</p> <p>After extracting the information for potential biomarkers from SELDI data and microarray analysis, their associations were further inferred by link-test to identify biomarkers that could likely be used for diagnosis. Immuno-blot analysis was then performed to examine whether the expression of the putative biomarkers were indeed altered in serum from patients with osteosarcoma.</p> <p>Results</p> <p>Six differentially expressed protein peaks with strong statistical significances were detected by SELDI-TOF-MS. Four of the proteins were up-regulated and two of them were down-regulated. Microarray analysis showed that, compared with an osteoblastic cell line, the expression of 653 genes was changed more than 2 folds in three osteosarcoma cell lines. While expression of 310 genes was increased, expression of the other 343 genes was decreased. The two sets of biomarkers candidates were combined by the link-test statistics, indicating that 13 genes were potential biomarkers for early diagnosis of osteosarcoma. Among these genes, cytochrome c1 (CYC-1) was selected for further experimental validation.</p> <p>Conclusion</p> <p>Link-test on datasets from both SELDI-TOF-MS and microarray high-throughput analysis can accelerate the identification of tumor biomarkers. The result confirmed that CYC-1 may be a promising biomarker for early diagnosis of osteosarcoma.</p

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Factors associated with maternal mortality in Sub-Saharan Africa: an ecological study

<p>Abstract</p> <p>Background</p> <p>Maternal health is one of the major worldwide health challenges. Currently, the unacceptably high levels of maternal mortality are a common subject in global health and development discussions. Although some countries have made remarkable progress, half of the maternal deaths in the world still take place in Sub-Saharan Africa where little or no progress has been made. There is no single simple, straightforward intervention that will significantly decrease maternal mortality alone; however, there is a consensus on the importance of a strong health system, skilled delivery attendants, and women's rights for maternal health. Our objective was to describe and determine different factors associated with the maternal mortality ratio in Sub-Saharan countries.</p> <p>Methods</p> <p>An ecological multi-group study compared variables between many countries in Sub-Saharan Africa using data collected between 1997 and 2006. The dependent variable was the maternal mortality ratio, and Health care system-related, educational and economic indicators were the independent variables. Information sources included the WHO, World Bank, UNICEF and UNDP.</p> <p>Results</p> <p>Maternal mortality ratio values in Sub-Saharan Africa were demonstrated to be high and vary enormously among countries. A relationship between the maternal mortality ratio and some educational, sanitary and economic factors was observed. There was an inverse and significant correlation of the maternal mortality ratio with prenatal care coverage, births assisted by skilled health personnel, access to an improved water source, adult literacy rate, primary female enrolment rate, education index, the Gross National Income per capita and the per-capita government expenditure on health.</p> <p>Conclusions</p> <p>Education and an effective and efficient health system, especially during pregnancy and delivery, are strongly related to maternal death. Also, macro-economic factors are related and could be influencing the others.</p

An Integrated Bioinformatics Approach Identifies Elevated Cyclin E2 Expression and E2F Activity as Distinct Features of Tamoxifen Resistant Breast Tumors

Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers