Insights into the Structural Conformations of the Tau Protein in Different Aggregation Status

Tau is a protein characterized by large structural portions displaying extended conformational changes. Unfortunately, the accumulation of this protein into toxic aggregates in neuronal cells leads to a number of severe pathologies, collectively named tauopathies. In the last decade, significant research advancements were achieved, including a better understanding of Tau structures and their implication in different tauopathies. Interestingly, Tau is characterized by a high structural variability depending on the type of disease, the crystallization conditions, and the formation of pathologic aggregates obtained from in vitro versus ex vivo samples. In this review, we reported an up-to-date and comprehensive overview of Tau structures reported in the Protein Data Bank, with a special focus on discussing the connections between structural features, different tauopathies, different crystallization conditions, and the use of in vitro or ex vivo samples. The information reported in this article highlights very interesting links between all these aspects, which we believe may be of particular relevance for a more informed structure-based design of compounds able to modulate Tau aggregation

Exhaustive CoMFA and CoMSIA analyses around different chemical entities: a ligand-based study exploring the affinity and selectivity profiles of 5-HT1A ligands

The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands

Constrained 1,4-dialkylpiperazines as monoamine transporters inhibitors for cocaine-related abuse

Cocaine abuse and addiction remain grave health and societal problems with nearly 11,000 overdose deaths in 2015. Despite the high prevalence of cocaine use, no FDA-approved therapeutic for treating cocaine addiction has been achieved. The primary target for cocaine is dopamine transporter (DAT) and the rewarding and reinforcing effects of cocaine are mediated predominantly by its inhibition, with a consequent ‘reverse agonist’ effect. Several DAT inhibitors have been proposed as potential drugs for cocaine abuse.[1-2] One of the most studied DAT inhibitors, GBR12909 (Ki DAT = 3.7 nM), is able to slightly increase DA level and to blunt the cocaine-induced elevation of extracellular DA in vivo without exerting the central exciting effects of cocaine and addiction. Unfortunately, the phase I clinical trials failed, due to its cardiotoxicity.[3-4] In a lead optimisation program focused to identify novel and safe GBR12909 analogues, nine constrained derivatives were design and synthesized in a ligand based approach. Maintaining unaltered the fluoro-phenyl and phenylpropylpiperazine moiety, the rigidification of the ethylene ether, by means of tetrahydrofuran, dioxolane, dioxane, oxathiolane and dithiolane ring, was investigated in a focused SAR study (Fig. 1). All the compounds were assayed for the determination of the binding affinity for DAT, NET and SERT. In particular, two dioxolane derivatives displayed a binding affinity comparable to that of GBR12909, with Ki of 21.2 and 13.9 nM for DAT, and a selectivity ratio SERT/DAT > 30. Since the cyclization introduces one chiral centre, the two enantiomers of one racemic mixture were prepared following enantioselective synthetic procedures. The (R)- and (S)-forms showed a binding affinity comparable to the one determined for the racemate (Ki DAT of 16 and 46 nM, respectively), suggesting that the configuration of the stereocenters slightly affect the binding to the DAT transporter. For the most interesting derivatives, uptake inhibition assays were conducted in rat brain synaptosomes. It was observed that the potency trend parallel the affinity values

The geometrical nature of optical resonances : from a sphere to fused dimer nanoparticles

We study the electromagnetic response of smooth gold nanoparticles with shapes varying from a single sphere to two ellipsoids joined smoothly at their vertices. We show that the plasmonic resonance visible in the extinction and absorption cross sections shifts to longer wavelengths and eventually disappears as the mid-plane waist of the composite particle becomes narrower. This process corresponds to an increase of the numbers of internal and scattering modes that are mainly confined to the surface and coupled to the incident field. These modes strongly affect the near field, and therefore are of great importance in surface spectroscopy, but are almost undetectable in the far field

BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting

: The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer

Team players against headache: multidisciplinary treatment of primary headaches and medication overuse headache

Multidisciplinary approaches are gaining acceptance in headache treatment. However, there is a lack of scientific data about the efficacy of various strategies and their combinations offered by physiotherapists, physicians, psychologists and headache nurses. Therefore, an international platform for more intense collaboration between these professions and between headache centers is needed. Our aims were to establish closer collaboration and an interchange of knowledge between headache care providers and different disciplines. A scientific session focusing on multidisciplinary headache management was organised at The European Headache and Migraine Trust International Congress (EHMTIC) 2010 in Nice. A summary of the contributions and the discussion is presented. It was concluded that effective multidisciplinary headache treatment can reduce headache frequency and burden of disease, as well as the risk for medication overuse headache. The significant value of physiotherapy, education in headache schools, and implementation of strategies of cognitive behavioural therapy was highlighted and the way paved for future studies and international collaboration

Cardiometabolic risk is unraveled by color Doppler ultrasound of the clitoral and uterine arteries in women consulting for sexual symptoms

Female sexual dysfunction (FSD) may be a mirror of a poor cardiometabolic state. In a small pilot study enrolling 71 women with FSD, we previously demonstrated that clitoral Pulsatility Index (PI) evaluated by using color Doppler ultrasound (CDU), reflecting vascular resistance, was associated with cardiometabolic risk factors. Data on uterine CDU in this context are lacking. First, to confirm previously reported data on the direct association between clitoral PI and cardiometabolic risk factors on a larger study population of women consulting for sexual symptoms; second, to investigate eventual similar correlations between cardiometabolic risk factors and CDU parameters of the uterine artery. We also ascertained whether uterine artery PI, similarly to what had previously been observed for clitoral artery PI, was directly related to body image uneasiness and psychopathological symptoms, assessed by validated questionnaires. N = 230 women consulting our clinic for sexual symptoms were examined with clitoral CDU and blood sampling and were asked to fill out the Female Sexual Function Index, the Middlesex Hospital Questionnaire (MHQ) and the Body Uneasiness Test (BUT). In a subgroup of women (n = 164), we also performed transvaginal CDU with measurement of uterine artery parameters. At multivariate analysis, we found a direct association between clitoral PI and body mass index (BMI) (p = 0.004), waist circumference (WC) (p = 0.004), triglycerides (p = 0.006), insulin (p = 0.029) and HOMA-IR (p = 0.009). Furthermore, a correlation between obesity and Metabolic Syndrome (MetS) and a higher clitoral PI was observed (p = 0.003 and p = 0.012, respectively). Clitoral PI was also correlated with MHQ-S (p = 0.010), a scale exploring somatized anxiety symptoms, and BUT-B Positive Symptom Distress Index (p = 0.010), a measure of body image concerns. Similarly, when investigating the uterine artery, we were able to demonstrate an association between its PI and BMI (p < 0.0001), WC (p = 0.001), insulin (p = 0.006), glycated haemoglobin (p =  < 0.0001), and HOMA-IR (p = 0.009). Women diagnosed with obesity and MetS showed significantly higher uterine PI values vs. those without obesity or MetS (p = 0.001 and p = 0.004, respectively). Finally, uterine PI was associated with BUT-A Global Severity Index (p < 0.0001) and with several other BUT-A subdomains. Vascular resistance of clitoral and uterine arteries is associated with cardiometabolic risk factors and body image concerns in women consulting for sexual symptoms. If further confirmed in different populations, our data could suggest CDU, a common examination method, as a useful tool for an identification—and possible correction—of cardiometabolic risk factors