Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: Potential relevance to prevention of cardiovascular events

Background: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored. Method: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 μM] to assess their effects on SA (100 μM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test. Results: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 μM) significantly reduced SA-induced inflammation (IL1β, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 μM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT. Conclusions: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection

Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat.

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RNA activation of haploinsufficient Foxg1 gene in murine neocortex

More than one hundred distinct gene hemizygosities are specifically linked to epilepsy, mental retardation, autism, schizophrenia and neuro-degeneration. Radical repair of these gene deficits via genome engineering is hardly feasible. The same applies to therapeutic stimulation of the spared allele by artificial transactivators. Small activating RNAs (saRNAs) offer an alternative, appealing approach. As a proof-of-principle, here we tested this approach on the Rett syndrome-linked, haploinsufficient, Foxg1 brain patterning gene. We selected a set of artificial small activating RNAs (saRNAs) upregulating it in neocortical precursors and their derivatives. Expression of these effectors achieved a robust biological outcome. saRNA-driven activation (RNAa) was limited to neural cells which normally express Foxg1 and did not hide endogenous gene tuning. saRNAs recognized target chromatin through a ncRNA stemming from it. Gene upregulation required Ago1 and was associated to RNApolII enrichment throughout the Foxg1 locus. Finally, saRNA delivery to murine neonatal brain replicated Foxg1-RNAa in vivo

Long non-coding RNAs and cancer: a new frontier of translational research?

Author manuscriptTiling array and novel sequencing technologies have made available the transcription profile of the entire human genome. However, the extent of transcription and the function of genetic elements that occur outside of protein-coding genes, particularly those involved in disease, are still a matter of debate. In this review, we focus on long non-coding RNAs (lncRNAs) that are involved in cancer. We define lncRNAs and present a cancer-oriented list of lncRNAs, list some tools (for example, public databases) that classify lncRNAs or that scan genome spans of interest to find whether known lncRNAs reside there, and describe some of the functions of lncRNAs and the possible genetic mechanisms that underlie lncRNA expression changes in cancer, as well as current and potential future applications of lncRNA research in the treatment of cancer.RS is supported as a fellow of the TALENTS Programme (7th R&D Framework Programme, Specific Programme: PEOPLE—Marie Curie Actions—COFUND). MIA is supported as a PhD fellow of the FCT (Fundação para a Ciência e Tecnologia), Portugal. GAC is supported as a fellow by The University of Texas MD Anderson Cancer Center Research Trust, as a research scholar by The University of Texas System Regents, and by the Chronic Lymphocytic Leukemia Global Research Foundation. Work in GAC’s laboratory is supported in part by the NIH/ NCI (CA135444); a Department of Defense Breast Cancer Idea Award; Developmental Research Awards from the Breast Cancer, Ovarian Cancer, Brain Cancer, Multiple Myeloma and Leukemia Specialized Programs of Research Excellence (SPORE) grants from the National Institutes of Health; a 2009 Seena Magowitz–Pancreatic Cancer Action Network AACR Pilot Grant; the Laura and John Arnold Foundation and the RGK Foundation

Vertical handover between WiFi and UMTS networks: experimental performance analysis

In this paper, we analyze the performance of vertical handover (VHO) algorithms for seamless mobility between WiFi and UMTS networks. We focus on a no-coupling scenario, characterized by the lack of any form of cooperation between the involved players (users and network operators). In this “hostile” scenario, the VHO operations are completely operated by the mobile terminal (MT), and the network authentication procedures are unoptimized, leading to typically long handover times. In this context, we first propose a low-complexity Received Signal Strength Indicator (RSSI)-based algorithm and, then, an improved hybrid RSSI/goodput version. We present experimental results based on the implementation of a real testbed with commercial WiFi (Guglielmo) and UMTS (Telecom Italia) Italian deployed networks. Despite the relatively long handover times experienced in our testbed, the proposed RSSI-based VHO algorithm guarantees an effective goodput increase at the MTs. Moreover, this algorithm mitigates the ping-pong phenomenon. Our results show that, by using simple MT-driven VHO mechanisms, the users can benefit from redundant and heterogeneous wireless network infrastructures. This can be done by leveraging on pre-existing commercially deployed networks, without the need for any modification of them

Experimental analysis of VHO-enabled mobile application for data offloading in heterogeneous wireless networks

Recent years have seen the relentless market explosion of mobile devices, whose ever increasing capabilities (in terms of computational power, networking, and sensing) make them attractive to an endless number of connected applications and services (especially in business and infotainment domains) which can be fully experienced in mobility. This huge market growth naturally involves a constant increase of mobile internet accesses with a consequent overload for mobile operators and potentially a reduced performance for mobile users. In this scenario and during last years, the research field of data offloading and Vertical HandOver (VHO) has gained a significant attention by service providers to start offloading mobile data traffic from 3G/4G networks to WiFi networks. The reduction of the load on cellular network is instrumental to allow the user to be Always Best Connected (ABC) with limited costs. In this paper, we present and analyze the performance of a real VHO-enabled ABC mobile application for Android Platform. The application has been tested in a national trial involving several users all over Italy, commercial (Guglielmo Srl) and private WiFi networks and cellular networks of the main Italian mobile operators for more than a month and 150.000 distinct logs collected during the evaluation