Targeting dementias through cancer kinases inhibition

The failures in Alzheimer's disease (AD) therapy strongly suggest the importance of reconsidering the research strategies analyzing other mechanisms that may take place in AD as well as, in general, in other neurodegenerative dementias. Taking into account that in AD a variety of defects result in neurotransmitter activity and signaling efficiency imbalance, neuronal cell degeneration and defects in damage/repair systems, aberrant and abortive cell cycle, glial dysfunction, and neuroinflammation, a target may be represented by the intracellular signaling machinery provided by the kinome. In particular, based on the observations of a relationship between cancer and AD, we focused on cancer kinases for targeting neurodegeneration, highlighting the importance of targeting the intracellular pathways at the intersection between cell metabolism control/duplication, the inhibition of which may stop a progression in neurodegeneration

Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link?

p53 transcriptional activity depends mainly on posttranslational modifications and protein/protein interaction. Another important mechanism that controls p53 function is its conformational stability since p53 is an intrinsically unstable protein. An altered conformational state of p53, independent from point mutations, has been reported in tissues from patients with Alzheimer's disease (AD), leading to an impaired and dysfunctional response to stressors. Recent evidence shows that one of the activators that induces p53 posttranslational modification and wild-type conformational stability is homeodomain interacting protein kinase 2 (HIPK2). Hence, conditions that induce HIPK2 deregulation would result in a dysfunctional response to stressors by affecting p53 activity. Discovering the mechanisms of HIPK2 activation/inhibition and the ways to manipulate HIPK2 activity are an interesting option to affect several biological pathways, including those underlying AD. Soluble beta-amyloid peptides have recently been involved in HIPK2 degradation, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus, before triggering the amyloidogenic cascade. Here we discuss about these findings and the potential relevance of HIPK2 as a target for AD and highlight the existence of a novel amyloid-based mechanism in AD potentially leading to the survival of injured dysfunctional cells

Role of hormones in the regulation of RACK1 expression as a signaling checkpoint in immunosenescence

Immunosenescence defines the decline in immune function that occurs with aging. This has been associated, at least in part, with defective cellular signaling via protein kinase C (PKC) signal transduction pathways. Our data suggest reduced PKC activation and consequently reduced response to lipopolysaccharide (LPS) stimulation and cytokine release. The lack of PKC activation seems to be dependent on the reduced expression of the receptor for activated C kinase 1 (RACK1), a scaffolding protein involved in multiple signal transduction cascades. The defective expression of RACK1 may be dependent on age-related alteration of the balance between the adrenal hormones cortisol and dehydroepiandrosterone (DHEA). DHEA levels reduce with aging, while cortisol levels remain substantially unchanged, resulting in an overall increase in the cortisol:DHEA ratio. These hormonal changes are significant in the context of RACK1 expression and signaling function because DHEA administration in vivo and in vitro can restore the levels of RACK1 and the function of the PKC signaling cascade in aged animals and in human cells. In contrast, there is evidence that cortisol can act as a negative transcriptional regulator of RACK1 expression. The rack1 gene promoter contains a glucocorticoid responsive element that is also involved in androgen signaling. Furthermore DHEA may have an indirect influence on the post-transcriptional regulation of the functions of the glucocorticoid receptor. In this review, we will examine the role of the hormonal regulation of rack1 gene transcriptional regulation and the consequences on signaling and function in immune cells and immunosenescence

Shoulder function after breast reconstruction with the latissimus dorsi flap: A prospective cohort study - Combining DASH score and objective evaluation.

Abstract Objectives The latissimus dorsi (LD) flap is well-known in breast reconstruction especially in previously-irradiated patients, in order to have a low capsular contraction rate whenever an implant is associated. The aim of this study is to closely evaluate the effect of LD flap harvesting on shoulder function as well as specific movements related to the LD, both objectively and subjectively. Materials and methods We retrospectively collected data on 86 patients who underwent pedicled LD muscle flap for breast reconstruction at the European Institute of Oncology between September 1995 until March 2011. Results The majority of patients showed a joint recovery superior to 80% in all joint movements examined. Disabilities of the Arm, Shoulder and Hand questionnaire revealed minimal disability similar to normal range and furthermore it appears to decrease in all sports and in particular in those who practice with LD involvement. Conclusion Focusing this data, a growing, "disability-free" percentage changes depending on whether or not the patients have practiced sport could be appreciate

Nuclear Factor \u3baB-Dependent Neurite Remodeling Is Mediated by Notch Pathway

In this study, we evaluated whether a cross talk between nuclear factor \u3baB (NF-\u3baB) and Notch may take place and contribute to regulate cell morphology and/or neuronal network in primary cortical neurons. We found that lack of p50, either induced acutely by inhibiting p50 nuclear translocation or genetically in p50(-/-) mice, results in cortical neurons characterized by reduced neurite branching, loss of varicosities, and Notch1 signaling hyperactivation. The neuronal morphological effects found in p50(-/-) cortical cells were reversed after treatment with the \u3b3-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-1-alanyl 1]-S-phenylglycine t-butyl ester) or Notch RNA interference. Together, these data suggested that morphological abnormalities in p50(-/-) cortical neurons were dependent on Notch pathway hyperactivation, with Notch ligand Jagged1 being a major player in mediating such effect. In this line, we demonstrated that the p50 subunit acts as transcriptional repressor of Jagged1. We also found altered distribution of Notch1 and Jagged1 immunoreactivity in the cortex of p50(-/-) mice compared with wild-type littermates at postnatal day 1. These data suggest the relevance of future studies on the role of Notch/NF-\u3baB cross talk in regulating cortex structural plasticity in physiological and pathological conditions

Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival

BACKGROUND: Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whose activity is fundamental in maintaining wild-type p53 function, thereby controlling the destiny of cells when exposed to DNA damaging agents. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer's Disease (AD) that led to an impaired and dysfunctional response to stressors. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the molecular mechanisms underlying the impairment of p53 activity in two cellular models, HEK-293 cells overexpressing the amyloid precursor protein and fibroblasts from AD patients, starting from recent findings showing that p53 conformation may be regulated by HIPK2. We demonstrated that beta-amyloid 1-40 induces HIPK2 degradation and alters HIPK2 binding activity to DNA, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus. Expression of HIPK2 was analysed by western blot experiments, whereas HIPK2 DNA binding was examined by chromatin immunoprecipitation analysis. In particular, we evaluated the recruitment of HIPK2 onto some target promoters, including hypoxia inducible factor-1alpha and metallothionein 2A. CONCLUSIONS/SIGNIFICANCE: These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells

Разработка способов ремонта трубопроводов, проложенных способов ННБ

Секция IV. ОБЕСПЕЧЕНИЕ НАДЕЖНОСТИ И БЕЗОПАСНОСТИ ПРИ СООРУЖЕНИИ, РЕКОНСТРУКЦИИ, МОДЕРНИЗАЦИИ И РЕМОНТЕ ОБЪЕКТОВ МАГИСТРАЛЬНОГО ТРУБОПРОВОДНОГО ТРАНСПОРТ

PRENYLATED CURCUMIN ANALOGUES AS MULTIPOTENT TOOLS TO TACKLE ALZHEIMER'S DISEASE

Alzheimer's disease is likely to be caused by copathogenic factors including aggregation of A\u3b2 peptides into oligomers and fibrils, neuroinflammation and oxidative stress. To date, no effective treatments are available and because of the multifactorial nature of the disease, it emerges the need to act on different and simultaneous fronts. Despite the multiple biological activities ascribed to curcumin as neuroprotector, its poor bioavailability and toxicity limit the success in clinical outcomes. To tackle Alzheimer's disease on these aspects, the curcumin template was suitably modified and a small set of analogues was attained. In particular, derivative 1 turned out to be less toxic than curcumin. As evidenced by capillary electrophoresis and transmission electron microscopy studies, 1 proved to inhibit the formation of large toxic A\u3b2 oligomers, by shifting the equilibrium towards smaller non-toxic assemblies and to limit the formation of insoluble fibrils. These findings were supported by molecular docking and steered molecular dynamics simulations which confirmed the superior capacity of 1 to bind A\u3b2 structures of different complexity. Remarkably, 1 also showed in vitro anti-inflammatory and anti-oxidant properties. In summary, the curcumin-based analogue 1 emerged as multipotent compound worth to be further investigated and exploited in the Alzheimer's disease multi-target context

Conformational altered p53 as an early marker of oxidative stress in Alzheimer\u27s disease

In order to study oxidative stress in peripheral cells of Alzheimer\u27s disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named unfolded p53 , was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients