1,721,021 research outputs found
“Derivatives of 1-(2-fluorobiphenyl-4-yl)-alkyl carboxylic acid for the therapy of transthyretin amyloidosis”.
No full textThe invention relates to the use of derivatives of 1-(2-fluorobiphenyl-4- yl)-alkyl carboxylic acid as agents capable of stabilising the tetrameric native state of transthyretin for the prophylaxis and treatment of amyloidosis
Can brain network connectivity facilitate the clinical development of disease-modifying anti-Alzheimer drugs?
Full text linkThe preclinical phase of Alzheimer's disease represents a crucial time window for therapeutic intervention but requires the identification of clinically relevant biomarkers that are sensitive to the effects of disease-modifying drugs. Amyloid peptide and tau proteins, the main histological hallmarks of Alzheimer's disease, have been widely used as biomarkers of anti-amyloid and anti-tau drugs. However, these biomarkers do not fully capture the multiple biological pathways of the brain. Indeed, robust amyloid-target engagement by anti-amyloid monoclonal antibodies has recently translated into modest cognitive and clinical benefits in Alzheimer's disease patients, albeit with potentially life-threatening side effects. Moreover, targeting the tau pathway has yet to result in any positive clinical outcomes. Findings from computational neuroscience have demonstrated that brain regions do not work in isolation but are interconnected within complex network structures. Brain connectivity studies suggest that misfolded proteins can spread through these connections, leading to the hypothesis that Alzheimer's disease is a pathology of network disconnectivity. Based on these assumptions, here we discuss how incorporating brain connectivity outcomes could better capture global brain functionality and, in conjunction with traditional Alzheimer's disease biomarkers, could facilitate the clinical development of new disease-modifying anti-Alzheimer's disease drugs.Pin et al. propose a new paradigm in the field of pharmacological research for Alzheimer's disease. According to this new perspective, brain connectivity could play a key role in the search for pharmacological targets, in patient selection for clinical trials, and finally, as an efficacy marker to evaluate pharmaceutical compounds
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin
Full text linkThe inherent amyloidogenic potentialof wild type transthyretin (TTR) is enhanced by a large number of point mutations, which destabilize the TTR tetramer, thereby promoting its disassembly and pathological aggregation responsible for TTR-related amyloidosis. TTR stabilizers are able to interact with the thyroxine-binding sites of TTR, stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on in vitro, ex vivo and X-ray analyses to assess the TTR structural stabilization by analogues of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID). Overall, considering together binding selectivity and protective effects on TTR native structure by flurbiprofen analogues in the presence of plasma proteins, as determined by Western Blot,the aforementioned properties of analyzed compounds appear to be better (CHF5075 and CHF4802) or similar (CHF4795) or worse (CHF5074, also known as CSP-1103) as compared to those of diflunisal, used as a reference TTR stabilizer. Molecular details of the determinants affecting the interactionsof CHF5075, CHF4802 and CHF4795 with wild type TTRand of CHF5074 withtheamyloidogenic A25TTTR variant havebeen elucidated by X-ray analysis. Distinct interactions with TTR appear to characterize flurbiprofen analogues and the NSAID diflunisal and its analogues as TTR stabilizers. Relationships between stabilizing effect on TTR by flurbiprofen analogues determined experimentally and molecular details of their interactions with TTR have been established, providing the rationale for their protective effects on the native protein structure
IN VIVO AND IN VITRO STUDY ON MICROGLIA ACTIVATION OF CHF5074, A NONSTEROIDAL ANTI-INFLAMMATORY DERIVATIVE WITH GAMMA-SECRETASE MODULATORYACTIVITY
No full textBackground: CHF5074, nonsteroidal anti-inflammatory derivative with g
-secretase modulatory activity has been shown to inhibit brain plaque deposition
and to attenuate or reverse memory deficit in different transgenic
mouse models of Alzheimer disease (AD). The recent discovery of modulation
Rho-GTPase-dependent signaling suggests that the range of biological
actions exerted by this drug may be wider than expected. Since neuroinflammation
is considered a major pathogenetic mechanism in AD, we investigated
the possible regulation of microglia activation by CHF5074 in vivo
and in vitro. Methods: The Tg2576 transgenic mouse carrying a transgene
coding for the 695-amino acid isoform of human APP derived from a large
Swedish family with early-onset AD was used for in vivo study. CHF5074
60 mg/kg was administered for 2 months to female transgenic and wild-type
mice of 7 months of age (n 1⁄4 12/group). Activated microglia was measured
by Iba1 immunohistochemistry, area fraction and cell number evaluation. In
vitro experiments were carried out on microglia enriched rat primary
cultures, activated by LPS 0.1mM for 8 h, and CHF5074 pretreatment was
performed at 1, 3 and 10mM one hour before LPS administration. TNFalfa,
IL-6, IL-12 and RANTES were measured by ELISA in the cell culture
medium. Results: In vivo, quantification of immunoreactivity indicated that
compared to transgenic controls, wild-type animals had much lower activated
microglia (cell count and area fraction, P<0.05). Compared to
Tg2576 control mice, activated microglia in the cerebral cortex was significantly
(P < 0.05) reduced by CHF5074 treatment. In vitro experiments indicated
that RANTES up-regulation by LPS was significantly attenuated by
CHF5074 3 and 10 mM. Conclusions: This results of this study showed that
CHF5074 significantly inhibits neuroinflammatory activity mediated by microglia.
RANTES (regulated upon activation, normal T cell expressed and
secreted) regulation could support a specific role in microglia-astrocyte
cross-talk
Type 2 Diabetes Mellitus, Platelet Activation and Alzheimer's Disease: A Possible Connection
Full text link: Type 2 diabetes mellitus DM (T2DM) is associated with a 70% increased risk for dementia, including Alzheimer's disease (AD). Insulin resistance has been proposed to play a pivotal role in both T2DM and AD and the concept of "brain insulin resistance" has been suggested as an interpretation to the growing literature regarding cognitive impairment and T2DM. Subjects with T2DM present an abnormal platelet reactivity that together with insulin resistance, hyperglycaemia and dyslipidaemia effect the vascular wall by a series of events including endothelial dysfunction, oxidative stress and low-grade inflammation. Activated platelets directly contribute to cerebral amyloid angiopathy (CAA) by promoting the formation of β-amyloid (Aβ) aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop suggesting the involvement of platelets in the AD pathogenesis. Moreover, islet amyloid polypeptide deposition, co-localized with Aβ deposits, is a common finding in the brain of patients with T2DM. These observations raise the intriguing prospect that traditional or novel antiplatelet therapeutic strategies may alleviate fibril formation and could be used in the prevention or treatment of AD subjects with diabetes
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Time to test antibacterial therapy in Alzheimer's disease
Full text linkAlzheimer's disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat the disease by reducing brain accumulation of amyloid-β in patients with Alzheimer's disease, with no success. While anti-amyloid-β therapies continue to be tested in prodromal patients with Alzheimer's disease and in subjects at risk of developing Alzheimer's disease, there is an urgent need to provide therapeutic support to patients with established Alzheimer's disease for whom current symptomatic treatment (acetylcholinesterase inhibitors and N-methyl d-aspartate antagonist) provide limited help. The possibility of an infectious aetiology for Alzheimer's disease has been repeatedly postulated over the past three decades. Infiltration of the brain by pathogens may act as a trigger or co-factor for Alzheimer's disease, with Herpes simplex virus type 1, Chlamydia pneumoniae, and Porphyromonas gingivalis being most frequently implicated. These pathogens may directly cross a weakened blood-brain barrier, reach the CNS and cause neurological damage by eliciting neuroinflammation. Alternatively, pathogens may cross a weakened intestinal barrier, reach vascular circulation and then cross blood-brain barrier or cause low grade chronic inflammation and subsequent neuroinflammation from the periphery. The gut microbiota comprises a complex community of microorganisms. Increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may impact Alzheimer's disease pathogenesis. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation and brain amyloid-β deposition in subjects with cognitive impairment. Oral microbiota may also influence Alzheimer's disease risk through circulatory or neural access to the brain. At least two possibilities can be envisaged to explain the association of suspected pathogens and Alzheimer's disease. One is that patients with Alzheimer's disease are particularly prone to microbial infections. The other is that microbial infection is a contributing cause of Alzheimer's disease. Therapeutic trials with antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents are being tested in patients with Alzheimer's disease in double-blind placebo-controlled studies. Although combined antibiotic therapy was found to be effective in animal models of Alzheimer's disease, antibacterial drugs are not being widely investigated in patients with Alzheimer's disease. This is because it is not clear which bacterial populations in the gut of patients with Alzheimer's disease are overexpressed and if safe, selective antibacterials are available for them. On the other hand, a bacterial protease inhibitor targeting P. gingivalis toxins is now being tested in patients with Alzheimer's disease. Clinical studies are needed to test if countering bacterial infection may be beneficial in patients with established Alzheimer's disease
- …
