Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy

Tauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have investigated whether dimethyl fumarate (DMF), an inducer of the transcription factor NRF2, could mitigate tauopathy in a mouse model. The signaling pathways modulated by DMF were also studied in mouse embryonic fibroblast (MEFs) from wild type or KEAP1-deficient mice. The effect of DMF on neurodegeneration, astrocyte and microglial activation was examined in Nrf2+/+ and Nrf2−/− mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with DMF (100 mg/kg, i.g) during three weeks. DMF induces the NRF2 transcriptional through a mechanism that involves KEAP1 but also PI3K/AKT/GSK-3-dependent pathways. DMF modulates GSK-3β activity in mouse hippocampi. Furthermore, DMF modulates TAU phosphorylation, neuronal impairment measured by calbindin-D28K and BDNF expression, and inflammatory processes involved in astrogliosis, microgliosis and pro-inflammatory cytokines production. This study reveals neuroprotective effects of DMF beyond disruption of the KEAP1/NRF2 axis by inhibiting GSK3 in a mouse model of tauopathy. Our results support repurposing of this drug for treatment of these diseasesThis work was supported by a Spanish Ministerio de Ciencia e Innovación Grant SAF2016-76520-

Pros and cons of NRF2 activation as adjunctive therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease with an important inflammatory component accompanied by deregulated redox-dependent signaling pathways that are feeding back into inflammation. In this context, we bring into focus the transcription factor NRF2, a master redox regulator that exerts exquisite antioxidant and anti-inflammatory effects. The review does not intend to be exhaustive, but to point out arguments sustaining the rationale for applying an NRF2-directed co-treatment in RA as well as its potential limitations. The involvement of NRF2 in RA is emphasized through an analysis of publicly available transcriptomic data on NRF2 target genes and the findings from NRF2-knockout mice. The impact of NRF2 on concurrent pathologic mechanisms in RA is explained by its crosstalk with major redox-sensitive inflammatory and cell death-related pathways, in the context of the increased survival of pathologic cells in RA. The proposed adjunctive therapy targeted to NRF2 is further sustained by the existence of promising NRF2 activators that are in various stages of drug development. The interference of NRF2 with conventional anti-rheumatic therapies is discussed, including the cytoprotective effects of NRF2 for alleviating drug toxicity. From another perspective, the review presents how NRF2 activation would be decreasing the efficacy of synthetic anti-rheumatic drugs by increasing drug efflux. Future perspectives regarding pharmacologic NRF2 activation in RA are finally proposed.The collaboration of the authors was supported by European COST Action CA20121: Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar). Webpage: https://benbedphar.org/about-benbedphar/. GM, EM, CMN, IVN, EMD and AC were supported by the Romanian Ministry of Research, Innovation and Digitization through the European Regional Development Fund, Competitiveness Operational Program 2014–2020 [the REDBRAIN project, ID: P_37_732

Hardware design of a small UAS helicopter for remote sensing operations

This paper presents the hardware design and integration process employed to develop an Unmanned Aircraft System (UAS) helicopter. The design process evolves from the bare airframe (without any electronics), to become a complete and advanced UAS platform for remote sensing applications. The improvements, design decisions and justifications are described throughout the paper. Two airframes have been used during the design and integration process: the AF25B model and the more advanced AF30 model, from the Copterworks company. The airframe engine reliability and fuel economy have been improved by adding an Electronic Fuel Injection (EFI) and Capacitor Discharge Ignition (CDI), both managed by an Engine Control Unit (ECU). On-board power supply generation and regulation have also been designed and validated. Finally, the integration process incorporates on-board mission computation to improve the concept of operation in remote sensing applications. Several flight tests have been performed to verify the reliability of the whole system. The flight test results demonstrate the correct process of integration and the feasibility of the UAS.Peer ReviewedPostprint (published version

Overall Cdk activity modulates the DNA damage response in mammalian cells

It's the degree of activation, not a specific cyclin-dependent kinase, that is important for genome maintenance in postreplicative cells

Development of a small UAS helicopter for remote sensing operations

This paper describes the integration process developing a UAS helicopter from single airframe to become a complete UAS platform for remote sensing applications. The airframe selected was the model AF30 from the Copterworks company. The airframe engine reliability and fuel economy have been improved adding an Electronic Fuel Injection (EFI) and Capacitor Discharge Ignition (CDI) both managed by an Engine Control Unit (ECU). Finally, the integration process incorporate on-board mission computation to improve the concept of operation. The integration process and the preliminary test are also described in the paper.Peer ReviewedPostprint (published version

Hardware design of a small UAS helicopter for remote sensing operations

This paper presents the hardware design and integration process employed to develop an Unmanned Aircraft System (UAS) helicopter. The design process evolves from the bare airframe (without any electronics), to become a complete and advanced UAS platform for remote sensing applications. The improvements, design decisions and justifications are described throughout the paper. Two airframes have been used during the design and integration process: the AF25B model and the more advanced AF30 model, from the Copterworks company. The airframe engine reliability and fuel economy have been improved by adding an Electronic Fuel Injection (EFI) and Capacitor Discharge Ignition (CDI), both managed by an Engine Control Unit (ECU). On-board power supply generation and regulation have also been designed and validated. Finally, the integration process incorporates on-board mission computation to improve the concept of operation in remote sensing applications. Several flight tests have been performed to verify the reliability of the whole system. The flight test results demonstrate the correct process of integration and the feasibility of the UAS.Peer Reviewe

Development of a small UAS helicopter for remote sensing operations

This paper describes the integration process developing a UAS helicopter from single airframe to become a complete UAS platform for remote sensing applications. The airframe selected was the model AF30 from the Copterworks company. The airframe engine reliability and fuel economy have been improved adding an Electronic Fuel Injection (EFI) and Capacitor Discharge Ignition (CDI) both managed by an Engine Control Unit (ECU). Finally, the integration process incorporate on-board mission computation to improve the concept of operation. The integration process and the preliminary test are also described in the paper.Peer Reviewe