Potential biomarkers and novel pharmacological targets in protein aggregation-related neurodegenerative diseases

The aggregation of specific proteins plays a pivotal role in the etiopathogenesis of several neurodegenerative diseases (NDs). β-Amyloid (Aβ) peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated protein tau are the two main neuropathological lesions in Alzheimer's disease. Meanwhile, Parkinson's disease is defined by the presence of intraneuronal inclusions (Lewy bodies), in which α-synuclein (α-syn) has been identified as a major protein component. The current literature provides considerable insights into the mechanisms underlying oligomeric-related neurodegeneration, as well as the relationship between protein aggregation and ND, thus facilitating the development of novel putative biomarkers and/or pharmacological targets. Recently, α-syn, tau and Aβ have been shown to interact each other or with other "pathological proteins" to form toxic heteroaggregates. These latest findings are overcoming the concept that each neurodegenerative disease is related to the misfolding of a single specific protein. In this review, potential opportunities and pharmacological approaches targeting α-syn, tau and Aβ and their oligomeric forms are highlighted with examples from recent studies. Protein aggregation as a biomarker of NDs, in both the brain and peripheral fluids, is deeply explored. Finally, the relationship between biomarker establishment and assessment and their use as diagnostics or therapeutic targets are discussed

Isolated olecranon fractures in children affected by osteogenesis imperfecta type I treated with single screw or tension band wiring system: outcomes and pitfalls in relation to bone mineral density

The purpose of this study is to compare the results of 2 techniques, tension band wiring (TBW) and fixation with screws, in olecranon fractures in children affected with osteogenesis imperfecta (OI) type I. Between 2010 and 2014, 21 olecranon fractures in 18 children with OI (average age: 12 years old) were treated surgically. Ten patients were treated with the screw fixation and 11 with TBW. A total of 65% of olecranon fractures occurred as a result of a spontaneous avulsion of the olecranon during the contraction of the triceps muscle. The average follow-up was 36 months. Among the children treated with 1 screw, 5 patients needed a surgical revision with TBW due to a mobilization of the screw. In this group, the satisfactory results were 50%. In patients treated with TBW, the satisfactory results were 100% of the cases. The average Z-score, the last one recorded in the patients before the trauma, was -2.53 in patients treated with screw fixation and -2.04 in those treated with TBW. TBW represents the safest surgical treatment for patients suffering from OI type I, as it helps to prevent the rigidity of the elbow through an earlier recovery of the range of motion, and there was no loosening of the implant. In analyzing the average Z-score before any fracture, the fixation with screws has an increased risk of failure in combination with low bone mineral density

Cytokine secretion responsiveness of lymphomonocytes following cortisol cell exposure: Sex differences

The stress hormone cortisol has been recognized as a coordinator of immune response. However, its different ability to modulate the release of inflammatory mediators in males and females has not been clarified yet. Indeed, the dissection of cortisol specific actions may be difficult due to the complex hormonal and physio-pathological individual status. Herein, the release of inflammatory mediators following increasing cortisol concentrations was investigated in an in vitro model of primary human male and female lymphomonocytes. The use of a defined cellular model to assess sex differences in inflammatory cytokine secretion could be useful to exclude the effects of divergent and fluctuating sex hormone levels occurring in vivo. Herein, the cells were challenged with cortisol concentrations resembling the plasma levels achieving in physiological and stressful conditions. The production of cytokines and other molecules involved in inflammatory process was determined. In basal conditions, male cells presented higher levels of some pro-inflammatory molecules (NF-kB and IDO-1 mRNAs, IL-6 and kynurenine) than female cells. Following cortisol exposure, the levels of the pro-inflammatory cytokines, IL-6 and IL-8, were increased in male cells. Conversely, in female cells IL-6 release was unchanged and IL-8 levels were decreased. Anti-inflammatory cytokines, IL-4 and IL-10, did not change in male cells and increased in female cells. Interestingly, kynurenine levels were higher in female cells than in male cells following cortisol stimulus. These results highlighted that cortisol differently affects male and female lymphomonocytes, shifting the cytokine release in favour of a pro-inflammatory pattern in male cells and an anti-inflammatory secretion profile in female cells, opening the way to study the influences of other stressful factors involved in the neurohumoral changes occurring in the response to stress conditions

Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-κB, p38 and JNK

Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α), which efficiently mimic the stress-related changes in neurotrophic and pro-inflammatory genes.Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-γ) in neuronal-like cells.In contrast, neuronal cell treatment with LPS and TNF-α decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-κB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (. i.e., interleukin-6 and IFN-γ) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-α. In addition, the production of inflammatory mediators was inhibited, and the release of interleukin-10 was restored to control levels.Furthermore, the intracellular signalling mechanism regulating TDZ-elicited effects was specifically investigated. TDZ induced extracellular signal-regulated kinase (ERK) phosphorylation and inhibited constitutive p38 activation. Moreover, TDZ counteracted the activation of p38 and c-Jun NH2-terminal kinase (JNK) elicited by LPS-TNF-α, suggesting that the neuro-protective role of TDZ could be mediated by p38 and JNK.Overall, our results demonstrated that the protective effects of TDZ under inflammation in neuronal-like cells function by decreasing pro-inflammatory signalling and by enhancing anti-inflammatory signalling

Fattening system influences fatty acids composition in organic Maremmana bullocks

Organic UE Regulation No 889/2008 states that, in the choice of breeds or strains, account shall be taken of the capacity of animals to adapt to local conditions, their vitality and their resistance to disease. Preference is to be given to indigenous breeds and strains. Maremmana is a very rustic and long-lived Italian cattle breed, which seems to be the direct descendant of Italian aurochs (Bos primigenius) (Giorgetti et al., 2009). Selection has always been directed towards disease resistance and adaptation to the harsh environment, where Maremmana cattle live, and generally these cattle never are treated against parasites (Martini, 2001). Maremmana cattle can graze all the year, utilizing, in the summer and winter periods, the Mediterranean scrub as source of food and refuge. Rearing system, quality of the pasture and possible concentrate integrations can influence the quality of meat and its fatty acid composition. The aim of this research is to compare the fatty acid muscle composition of Maremmana bullocks reared in different fattening systems

TUMOR NECROSIS FACTOR ALPHA TRIGGERS OSTEOGENESIS THROUGH THE INVOVLVEMENT OF Gs-COUPLED RECEPTOR SIGNALS

Tumor Necrosis Factor alpha (TNF-α) plays a role in several chronic immune and inflammatory diseases, where inhibition of TNF has led to significant clinical improvement. Actually, this cytokine is involved in bone healing by affecting mesenchymal stem cell (MSC) behaviour in a dose- and time-dependent manner1,2. Indeed, in the early inflammatory phase after fracture, low doses of TNF-α are required to favour MSC migration, survival and differentiation, thus initiating bone repair. At high dose, in the chronic uncontrolled phase of inflammation, the same cytokine has destructive effects on bone and contribute to bone loss1,2. As other soluble factors released in cell microenvironment, the cytokine modulates expression and functioning of different G protein coupled receptors (GPCRs) and of their regulatory proteins (GPCR regulated kinases, GRKs)3, thus dictating the final biological outcome of these receptor proteins in controlling bone anabolic processes. Herein, we investigated the effects of TNF-α low doses on the expression and functional responsiveness of A2B adenosine receptor (A2B AR), a Gs-coupled puringergic receptor that controls mesenchymal stem cell (MSC) differentiation to osteoblasts4,5. In our hands, TNF-α exerted a pro-differentiating action on MSCs, pushing towards an osteoblast phenotype, and without any effects on cell proliferation. The cytokine increased the A2B AR-mediated pro-osteogenic effects, through the A2B AR desensitization impairment mediated by GRK2 inhibition. These data i) support the anabolic effect of sub-massimal concentration of TNF-α in bone reparative processes and ii) demonstrate that the cytokine regulates GPCR responses by interfering with desensitization machinery and potentiating in turn the anabolic responses evoked by Gs-GPCRs. Overall these results indicated that manipulating MSC local environment by lregulates membrane receptors favouring bone remodelling