Tackling Alzheimer's Disease with Existing Drugs:A Promising Strategy for Bypassing Obstacles

The unmet need for the development of effective drugs to treat Alzheimer's disease has been steadily growing, representing a major challenge in drug discovery. In this con-text, drug repurposing, namely the identification of novel therapeutic indications for approved or investigational compounds, can be seen as an attractive attempt to obtain new medications reducing both the time and the economic burden usually required for research and development programs. In the last years, several classes of drugs have evidenced promising beneficial effects in neurodegenerative diseases, and for some of them, preliminary clinical trials have been started. This review aims to illustrate some of the most recent examples of drugs reprofiled for Alzheimer’s disease, considering not only the finding of new uses for existing drugs but also the new hypotheses on disease pathogenesis that could promote previ-ously unconsidered therapeutic regimens. Moreover, some examples of structural modifica-tions performed on existing drugs in order to obtain multifunctional compounds will also be described

Growth factors for clinical-scale expansion of human articular chondrocytes : Relevance for automated bioreactor systems

The expansion of chondrocytes in automated bioreactors for clinical use requires that a relevant number of cells be generated, starting from variable initial seeding densities in one passage and using autologous serum. We investigated whether the growth factor combination transforming growth factor beta 1/fibroblast growth factor 2/platelet-derived growth factor BB (TFP), recently shown to enhance the proliferation capacity of human articular chondrocytes (HACs), allows the efficiency of chondrocyte use to be increased at different seeding densities and percentages of human serum (HS). HACs were seeded at 1,000, 5,000, and 10,000 celIS/cm(2) in medium containing 10 bovine serum or 10,000 cells/cm(2) with 1 chondrogenic capacity of post-expanded HACs was then assessed in pellet cultures. Expansion with TFP allowed a sufficient number of HACs to be obtained in one passage even at the lowest seeding density and HS percentage and variability in cartilage-forming capacity of HACs expanded under the different conditions to be reduced. Instead, larger variations and insufficient yields were found in the absence of TFP. By allowing large numbers of cells to be obtained, starting from a wide range of initial seeding densities and HS percentages, the use of TFP may represent a viable solution for the efficient expansion of HACs and addresses constraints of automated clinical bioreactor systems

Diagnostic and Therapeutic Approach to Children and Adolescents with Obstructive Sleep Apnea Syndrome (OSA): Recommendations in Emilia-Romagna Region, Italy

Obstructive sleep apnoea syndrome (OSA) in paediatrics is a rather frequent pathology caused by pathophysiological alterations leading to partial and prolonged obstruction (hypoventilation) and/or intermittent partial (hypopnoea) or complete (apnoea) obstruction of the upper airways. Paediatric OSA is characterised by daytime and night-time symptoms. Unfortunately, there are few data on shared diagnostic-therapeutic pathways that address OSA with a multidisciplinary approach in paediatric age. This document summarizes recommendations from the Emilia-Romagna Region, Italy, developed in order to provide the most appropriate tools for a multidisciplinary approach in the diagnosis, treatment and care of paediatric patients with OSA. The multidisciplinary group of experts distinguished two different 'step' pathways, depending on the age group considered (i.e., under or over two years). In most cases, these pathways can be carried out by the primary care paediatrician, who represents the first filter for approaching the problem. For this reason, it is essential that the primary care paediatrician receives adequate training on how to formulate the diagnostic suspicion of OSA and on what criteria to use to select patients to be sent to the hospital centre. The relationship between the paediatrician of the patient and her/his parents must see a synergy of behaviour between the various players in order to avoid uncertainty about the diagnostic and therapeutic decisions as well as the follow-up phase. The definition and evaluation of the organizational process and outcome indicators of the developed flow-chart, and the impact of its implementation will remain fundamental

INTERFERÊNCIA DO ESTADO DE HUMOR NA MELHORA DOS COMPONENTES DA CAPACIDADE FUNCIONAL EM IDOSOS.

Estados de humor são sentimentos autorreguladores que, quando positivos, podem contribuir para um envelhecimento saudável, manter ou melhorar os níveis funcionais. Tal melhora pode ser notada em indivíduos que praticam atividade física sistematizada, como a dança por exemplo. Para verificar se há influência dos estados de humor nos componentes funcionais e a interferência do exercício físico nesses aspectos, o presente estudo foi realizado com 30 idosos, distribuídos igualmente em dois grupos (grupo treinamento e grupo controle). O Grupo de Treinamento participou de um protocolo de dança com duração de 1 hora, três vezes por semana, durante 12 semanas e o Grupo Controle não frequentou qualquer programa de atividade física. Todos os participantes foram avaliados pela Lista de Estados de Ânimo Reduzida e Ilustrada e pela bateria de testes da AAHPERD. Para os estados de humor foi utilizado o Teste binomial com nível de significância de 5% e uma análise comparativa pré e pós. Para os componentes da capacidade funcional foi utilizada a análise de variância para medidas repetidas ANOVA two way adotando-se mesmo nível de significância. Não foram detectadas mudanças estatisticamente significativas para os estados de humor, embora os componentes funcionais tenham apresentado  melhoras na coordenação, agilidade e força com a prática  de dança. Os idosos que apresentaram melhores níveis funcionais tiveram os estados de humor positivos intensificados e os negativos mantidos ou reduzidos. Idosos adeptos ao exercício físico com estados de humor mais positivos apresentaram os melhores níveis funcionais

Stem cell differentiation for muscle regeneration

Physical activity has a positive role on muscle remodelling and vascularization, involv-ing stem cells differentiation processes. Indeed, the skeletal muscle homeostasis and repair are maintained by a subset of muscle stem/progenitor cells called Satellite Cells (SCs), while for heart repair and remodelling the cardiac potential of progenitor cells is otherwise expressed by different stem cell types: bone marrow hematopoietic stem cells (BMHSC), bone marrow mesenchymal stem cells (BMMSC), cardiac stem cells and embryonic stem cells. The ε isoform of the PKC family (PKCε) is a serine-threonine kinase that is expressed in muscle and in a variety of other tissues, regulating their homeostasis acting on cell death and differentiation. We focused on the role of PKCε in skeletal, cardiac and smooth muscle differentiation of adult stem cells. We found that inhibition of PKCε prevents myogenic differentiation of the myoblast cell line C2C12 and of primary SCs. In vivo PKCε inhibition resulted in impaired muscle regeneration, as well [1]. On the contrary, in cardiac and smooth muscle differentia-tion of stem cells we observed a negative role of PKCε both in vitro and in vivo [2,3]. In fact, it impaired cardiac markers expression like NKX2.5 and GATA4 but also vascular differ-entiation markers like SMA and PECAM. PKCε should therefore be considered as a finely tuned modulator of muscle cell differentiation

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, "privileged" synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound1, bearing apara-fluoro phenyl moiety, showed low-micromolar potency against T acute lymphoblastic leukemia cell growth. More in-depth biologic studies demonstrated, for this analog, cell death-inducing properties associated with its capability to simultaneously activate both the receptor and the mitochondrial apoptosis cascades. This peculiar behavior offers promises for achieving an expanded anticancer effect, namely intense cytotoxic response coupled with reduced predisposition of chemoresistance insurgence. Altogether, this study allowed the identification of compound1as a lead compound worth to be progressed as an anticancer drug candidate

PKC epsilon involvement in Th17 in vitro differentiation: implications in psoriasis pathogenesis

Psoriasis is a noncontagious, arytematous-squamose dermatitits affecting both sexes and all races. Although its exact etiology is largely unknown, it is now recognized as one of the most common immune-mediated disorders and several studies demonstrate an impairment of regulatory T-cells (Tregs) function and an up-regulation of IL-17 levels produced by T-helper 17 lymphocytes (Th17)(1,2). Protein kinase C epsilon (PKCε) is a serine/threonine kinase which plays a key role in the proliferation and differentiation of epidermal cells. We have previously demonstrated a role for PKCε in the pathogenesis of the autoimmune disease Hashimoto’s thyroiditis (3). PKCε is over-expressed in CD4+ T lymphocytes isolated from PBMC fraction in patients affected by this pathology and its forced down-modulation primed the TGF-mediated in vitro Treg polarization of human T CD4+ cells. Since it has been demonstrated that PKC-signalling is altered in psoriatic keratinocytes (4), we investigated the involvement of PKCε in Th17 in vitro differentiation and its potentially implication in immune response correlated to psoriasis. Using western blot and real time PCR, we have observed that PKCε protein levels and mRNA increase during Th17-lineage in vitro differentiation from naïve CD4+ T cells with a similar trend of Th17 markers of differentiation STAT3 and RoRyT. Moreover, PKCε overexpression significantly increases STAT3 and phosphorylated STAT3 levels, suggesting that PKCε boosts Th17 polarization. Thereafter, we sought to investigate PKCε expression in CD4+ lymphocytes obtained from peripheral blood of psoriatic patients and we observed that PKCε expression levels are significantly higher compared with healthy donors. Intriguingly, we observed a closely correlation of PKCε expression with PASI index, suggesting an involvement of the kinase with the severity of the disease. Collectively these data suggest that PKCε might be involved in Th17 differentiation, that it could be a key factor to regulate Th17 pathological expansion and therefore a potential psoriatic pharmacological target

Correlation between Protein Kinase Cε expression and thrombotic risk in Primary Myelofibrosis (PMFs)

Myelofibrosis (MF) - either primary (PMF) or arising from a previous PV or ET - is a Philadelphia-negative MPNs characterized by aberrant platelet production and consequent variable platelet count with altered hemostatic function (1). It has already been demonstrated that the risk of thrombotic events is one of the most common co-morbidities associated with PV and ET (2-5). However, risk of thrombotic events in PMF has not been investigated yet. We previously demonstrated that PKCepsilon (PKCε) is over-expressed in platelets from patients with acute myocardial infarction and accounts for their increased reactivity (6). Additionally, we recently showed that PKCε overexpression plays a crucial role in PMF MK impaired differentiation and that its levels correlated with the disease severity (expressed by the IPSS/DIPPS risk category) (7,8). On these bases, we analyzed PKCε expression in platelets from PMF patients, investigating a potential correlation with thrombotic risk and the aggressiveness of the disease. For this study, peripheral blood samples from 6 PMF patients and 3 healthy donors (HD) were collected in Na-citrate tubes. PKCε mRNA and protein levels were determined in platelets purified as described by Carubbi C, 2012. Finally, patients are stratified according to the history of cardio-vascular events and the IPSS/DIPSS risk category. PMF platelets showed significantly higher mRNA levels of PKCε as compared to HD. Protein analysis confirm PKCε over-expression in PMF platelets, almost reaching statistical significance. We then found that platelet from PMF patients who suffered from cardiovascular events display significantly higher levels of PKCε as compared to the one with a negative history. Finally, similarly to what observed in PMF magakaryocytes, we showed a positive correlation between PKCε platelets levels and IPSS/DIPSS risk category, with the lowest levels in low-risk patients and higher levels in high-risk patients. Collectively, our preliminary results indicate that PMF platelets show an aberrant expression of PKCε which correlates with the disease burden and a history of cardiovascular events. This suggests that the over-expression of PKCε may account for PMF platelet altered reactivity and function

Febrile rhabdomyolysis of unknown origin in refugees coming from West Africa through the Mediterranean

Abstract Objectives Cases of undiagnosed severe febrile rhabdomyolysis in refugees coming from West Africa, mainly from Nigeria, has been observed since May 2014. The aim of this study was to describe this phenomenon. Methods This was a multicentre retrospective observational study of cases of febrile rhabdomyolysis reported from May 2014 to December 2016 in 12 Italian centres. Results A total of 48 cases were observed, mainly in young males. The mean time interval between the day of departure from Libya and symptom onset was 26.2 days. An average 8.3 further days elapsed before medical care was sought. All patients were hospitalized with fever and very intense muscle aches. Creatine phosphokinase, aspartate aminotransferase, and lactate dehydrogenase values were abnormal in all cases. The rhabdomyolysis was ascribed to an infective agent in 16 (33.3%) cases. In the remaining cases, the aetiology was undefined. Four out of seven patients tested had sickle cell trait. No alcohol abuse or drug intake was reported, apart from a single reported case of khat ingestion. Conclusions The long incubation period does not support a mechanical cause of rhabdomyolysis. Furthermore, viral infections such as those caused by coxsackievirus are rarely associated with such a severe clinical presentation. It is hypothesized that other predisposing conditions like genetic factors, unknown infections, or unreported non-conventional remedies may be involved. Targeted surveillance of rhabdomyolysis cases is warranted