Neuroprotection by Drugs, Nutraceuticals and Physical Activity

Acute and chronic neural injuries, including stroke, brain trauma and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD) are associated with high morbidity and mortality rates [...]

Compressive strength of heterogeneous masonry walls containing blends of brick types

The study presents a systematic approach for the evaluation of the compression strength of masonry walls composed of heterogeneous mixes of different types of blocks. First of all, the mechanics of a compressed heterogeneous masonry stack is investigated through a series of experimental tests and Finite Element models, then it is reviewed and discussed. Then, the problem of deriving the necessary material parameters entering the Hilsdorf formula is addressed. Solutions for the correct evaluation of the lacking data are presented based on the existing literature data. Finally, the well-known Hilsdorf formula is extended to the field of block blends with different mechanical properties. A deep experimental investigation on stacks and wallets made with fired clay, limestone and sandstone blocks is introduced for the first time. The comparison of the experimental data with the proposed theory points out the very good predictive capability of the extended Hilsdorf formula derived herein

Evaluation of the residual carrying capacity of a large-scale model bridge through frequency shifts

Structural systems are often subjected to degradation processes due to different kinds of phenomena like unexpected loadings, ageing of the materials, and fatigue cycles. This is true, especially for bridges, in which their safety evaluation is crucial for planning maintenance activities. This paper discusses the experimental evaluation of the residual carrying capacity from frequency changes due to distributed damage scenarios. For this purpose, in the laboratory of the University of Bologna, an experimental reinforced concrete model bridge was built and loaded. The applied forces produced bending moments causing up to three increasing levels of damage severity, namely early and diffused concrete cracking, and finally rebar yielding. By processing the acceleration signals recorded during the dynamic tests on the model bridge, the main natural frequencies of the bridge were obtained and the remaining bearing capacity was estimated based on the damage state. The opening and closure of cracks during a dynamic excitation produced a biased estimation of natural frequencies related to each damaged condition. The frequency decay predicted by the theory of breathing cracks applied to the performed experiments properly estimated the losses in the carrying capacity

P-glycoprotein (ABCB1) and oxidative stress: Focus on Alzheimer's disease

ATP-binding cassette (ABC) transporters, in particular P-glycoprotein (encoded by ABCB1), are important and selective elements of the blood-brain barrier (BBB), and they actively contribute to brain homeostasis. Changes in ABCB1 expression and/or function at the BBB may not only alter the expression and function of other molecules at the BBB but also affect brain environment. Over the last decade, a number of reports have shown that ABCB1 actively mediates the transport of beta amyloid (A\u3b2) peptide. This finding has opened up an entirely new line of research in the field of Alzheimer's disease (AD). Indeed, despite intense research efforts, AD remains an unsolved pathology and effective therapies are still unavailable. Here, we review the crucial role of ABCB1 in the A\u3b2 transport and how oxidative stress may interfere with this process. A detailed understanding of ABCB1 regulation can provide the basis for improved neuroprotection in AD and also enhanced therapeutic drug delivery to the brain

Esculetin provides neuroprotection against mutant huntingtin-induced toxicity in huntington’s disease models

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we investigated the neuroprotective effects of esculetin (ESC), a bioactive phenolic compound, in an inducible PC12 model and a transgenic Drosophila melanogaster model of HD, both of which express mHTT fragments. ESC partially inhibited the progression of mHTT aggregation and reduced neuronal death through its ability to counteract the oxidative stress and mitochondria impairment elicited by mHTT in the PC12 model. The ability of ESC to counteract neuronal death was also confirmed in the transgenic Drosophila model. Although ESC did not modify the lifespan of the transgenic Drosophila, it still seemed to have a positive impact on the HD phenotype of this model. Based on our findings, ESC may be further studied as a potential neuroprotective agent in a rodent transgenic model of HD

Oxidative Stress: How Has It Been Considered in the Design of New Drug Candidates for Neurodegenerative Diseases?

Editorial on the Research Topi

From the dual function lead AP2238 to AP2469, a multi-target-directed ligand for the treatment of Alzheimer\u2019s disease

The development of drugs with different pharmacological properties appears to be an innovative therapeutic approach for Alzheimer\u2019s disease. In this article, we describe a simple structural modification of AP2238, a first dual function lead, in particular the introduction of the catechol moiety performed in order to search for multi-target ligands. The new compound AP2469 retains antiacetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme (BACE)1 activities compared to the reference, and is also able to inhibit Ab42 self aggregation, Ab42 oligomer-binding to cell membrane and subsequently reactive oxygen species formation in both neuronal and microglial cells. The ability of AP2469 to interfere with Ab42 oligomer-binding to neuron and microglial cell membrane gives this molecule both neuroprotective and antiinflammatory properties. These findings, together with its strong chain-breaking antioxidant performance, make AP2469 a potential drug able to modify the course of the diseas

Identification of recurrent genetic patterns from targeted sequencing panels with advanced data science: a case-study on sporadic and genetic neurodegenerative diseases

open8noThis work is funded by the University of Bologna, the IRCCS Institute of Neurological sciences of Bologna, and by the European Grants H2020 GenoMed4All [AM1] (Grant N. 101017549) and H2020 MSCA-ITN IMforFUTURE (Grant N. 721815).Background Targeted Next Generation Sequencing is a common and powerful approach used in both clinical and research settings. However, at present, a large fraction of the acquired genetic information is not used since pathogenicity cannot be assessed for most variants. Further complicating this scenario is the increasingly frequent description of a poli/oligogenic pattern of inheritance showing the contribution of multiple variants in increasing disease risk. We present an approach in which the entire genetic information provided by target sequencing is transformed into binary data on which we performed statistical, machine learning, and network analyses to extract all valuable information from the entire genetic profile. To test this approach and unbiasedly explore the presence of recurrent genetic patterns, we studied a cohort of 112 patients affected either by genetic Creutzfeldt–Jakob (CJD) disease caused by two mutations in the PRNP gene (p.E200K and p.V210I) with different penetrance or by sporadic Alzheimer disease (sAD). Results Unsupervised methods can identify functionally relevant sources of variation in the data, like haplogroups and polymorphisms that do not follow Hardy–Weinberg equilibrium, such as the NOTCH3 rs11670823 (c.3837 + 21 T > A). Supervised classifiers can recognize clinical phenotypes with high accuracy based on the mutational profile of patients. In addition, we found a similar alteration of allele frequencies compared the European population in sporadic patients and in V210I-CJD, a poorly penetrant PRNP mutation, and sAD, suggesting shared oligogenic patterns in different types of dementia. Pathway enrichment and protein–protein interaction network revealed different altered pathways between the two PRNP mutations. Conclusions We propose this workflow as a possible approach to gain deeper insights into the genetic information derived from target sequencing, to identify recurrent genetic patterns and improve the understanding of complex diseases. This work could also represent a possible starting point of a predictive tool for personalized medicine and advanced diagnostic applications.openTarozzi, M.; Bartoletti-Stella, A.; Dall’Olio, D.; Matteuzzi, T.; Baiardi, S.; Parchi, P.; Castellani, G.; Capellari, S.Tarozzi, M.; Bartoletti-Stella, A.; Dall’Olio, D.; Matteuzzi, T.; Baiardi, S.; Parchi, P.; Castellani, G.; Capellari, S