Targeting the Oxytocinergic System: A Possible Pharmacological Strategy for the Treatment of Inflammation Occurring in Different Chronic Diseases

Unresolved inflammation represents a central feature of different human pathologies including neuropsychiatric, cardiovascular, and metabolic diseases. The epidemiologic relevance of such disorders justifies the increasing interest in further understanding the mechanisms underpinning the inflammatory process occurring in such chronic diseases to provide potential novel pharmacological approaches. The most common and effective therapies for controlling inflammation are glucocorticoids; however, a variety of other molecules have been demonstrated to have an anti-inflammatory potential, including neuropeptides. In recent years, the oxytocinergic system has seen an explosion of scientific studies, demonstrating its potential to contribute to a variety of physiological processes including inflammation. Therefore, the aim of the present review was to understand the role of oxytocin in the modulation of inflammation occurring in different chronic diseases. The criterion we used to select the diseases was based on the emerging literature showing a putative involvement of the oxytocinergic system in inflammatory processes in a variety of pathologies including neurological, gastrointestinal and cardiovascular disorders, diabetes and obesity. The evidence reviewed here supports a beneficial role of oxytocin in the control of both peripheral and central inflammatory response happening in the aforementioned pathologies. Although future studies are necessary to elucidate the mechanistic details underlying such regulation, this review supports the idea that the modulation of the endogenous oxytocinergic system might represent a new potential pharmacological approach for the treatment of inflammation

Quantitative comparison of the protein corona of nanoparticles with different matrices

: Nanoparticles (NPs) are paving the way for improved treatments for difficult to treat diseases diseases; however, much is unknown about their fate in the body. One important factor is the interaction between NPs and blood proteins leading to the formation known as the "protein corona" (PC). The PC, consisting of the Hard (HC) and Soft Corona (SC), varies greatly based on the NP composition, size, and surface properties. This highlights the need for specific studies to differentiate the PC formation for each individual NP system. This work focused on comparing the HC and SC of three NPs with different matrix compositions: a) polymeric NPs based on poly(lactic-co-glycolic) acid (PLGA), b) hybrid NPs consisting of PLGA and Cholesterol, and c) lipidic NPs made only of Cholesterol. NPs were formulated and characterized for their physico-chemical characteristics and composition, and then were incubated in human plasma. In-depth purification, identification, and statistical analysis were then performed to identify the HC and SC components. Finally, similar investigations demonstrated whether the presence of a targeting ligand on the NP surface would affect the PC makeup. These results highlighted the different PC fingerprints of these NPs, which will be critical to better understand the biological influences of the PC and improve future NP designs

Barriers and applied activity, quality of life and self‑efficacy in prostate cancer survivors 1 year after completing radiotherapy

Purpose The aims of the study were to assess self-reported physical activity (PA) levels, barriers to PA, quality of life and self-efficacy to manage chronic disease of prostate cancer survivor 1 year after radiotherapy treatment. Methods A cross-sectional case–control study was performed. Prostate cancer survivor patients treated with radiotherapy were recruited from the Radiation Oncology Service of the “Complejo Hospitalario Universitario” (Granada) and compared with age-matched healthy men. Outcomes included were perception of benefits for physical activity and potential barriers (Exercise Benefits/Barriers Scale), physical activity levels assessed by the International Physical Activity Questionnaire (IPAQ), quality of life (EuroQol five-dimension three-levels) and self-efficacy (Self-Efficacy to Manage Chronic Disease). Results A total of 120 patients were included in our study. Significant differences were found between groups with worse results for the prostate cancer patient group in the variable perception of the benefit of physical activity, potential barriers, and physical activity. Regarding quality of life and self-efficacy, significant differences were also observed between groups with a greater score in the control group. Conclusion In conclusion, the results of this study reveal that self-reported PA levels, as measured using the IPAQ, were low in prostate cancer survivors after treatment. Results also showed worse perception of benefits for PA and potential barriers by the cancer survivors. Similarly, the quality of life and self-efficacy to manage chronic disease of prostate cancer survivors was lower.Universidad de Granada/ CBUAThe Spanish Ministry of Education (Grant numbers FPU:20/ 01670, FPU:19/02609, FPU:17/00408)

Prevalence of endotoxemia after surgery and its association with ICU length of stay

INTRODUCTION: The aim of this observational study was to investigate the prevalence of endotoxemia after surgery and its association with ICU length of stay. METHODS: 102 patients admitted to a university ICU after surgery were recruited. Within four hours of admission, functional data were collected and APACHE II severity score calculated. Arterial blood samples were taken and endotoxemia was measured by chemiluminescence (Endotoxin Activity (EA)). Patients were stratified according to their endotoxin levels (low, intermediate and high) and according to their surgical procedures. Differences between endotoxin levels were assessed by ANOVA, accepting P < 0.05 as significant. Data are expressed as mean +/- SD. RESULTS: EA levels were low in 68 (66%) patients, intermediate in 17 (17%) and high in 17 (17%). Age (61 +/- 17 years) and APACHE II score 8.3 +/- 3.7 (P = 0.542) were not significantly different in the three EA groups. Functional parameters on admission were similar between EA groups: white blood cells 11093 +/- 4605 cells/mm3 (P = 0.385), heart rate 76 +/- 16 bpm (P = 0.898), mean arterial pressure 88.8 +/- 13.6 mmHg (P = 0.576), lactate 1.18 +/- 0.77 mmol/L (P = 0.370), PaO2/FiO2 383 +/- 109 mmHg (P = 0.474). Patients with high levels of EA were characterized by longer length of stay in the ICU: 1.9 +/- 3.0 days in the low EA group, 1.8 +/- 1.4 days in intermediate and 5.2 +/- 7.8 days in high group (P = 0.038). CONCLUSIONS: 17% of our patients were characterized by high levels of endotoxemia as assessed by EA assay, despite their low level of complexity on admission. High levels of endotoxin were associated with a longer ICU length of stay

Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice

Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain

Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease

: Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors

Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-α

<p>Abstract</p> <p>Background</p> <p>In addition to cytotoxic mechanisms directly impacting neurons, β-amyloid (Aβ)-induced glial activation also promotes release of proinflammatory molecules that may self-perpetuate reactive gliosis and damage neighbouring neurons, thus amplifying neuropathological lesions occurring in Alzheimer's disease (AD). Palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory, analgesic, antiepileptic and neuroprotective effects. PEA is a lipid messenger isolated from mammalian and vegetable tissues that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. Some of its pharmacological properties are considered to be dependent on the expression of peroxisome proliferator-activated receptors-α (PPARα).</p> <p>Findings</p> <p>In the present study, we evaluated the effect of PEA on astrocyte activation and neuronal loss in models of Aβ neurotoxicity. To this purpose, primary rat mixed neuroglial co-cultures and organotypic hippocampal slices were challenged with Aβ_1-42and treated with PEA in the presence or absence of MK886 or GW9662, which are selective PPARα and PPARγ antagonists, respectively. The results indicate that PEA is able to blunt Aβ-induced astrocyte activation and, subsequently, to improve neuronal survival through selective PPARα activation. The data from organotypic cultures confirm that PEA anti-inflammatory properties implicate PPARα mediation and reveal that the reduction of reactive gliosis subsequently induces a marked rebound neuroprotective effect on neurons.</p> <p>Conclusions</p> <p>In line with our previous observations, the results of this study show that PEA treatment results in decreased numbers of infiltrating astrocytes during Aβ challenge, resulting in significant neuroprotection. PEA could thus represent a promising pharmacological tool because it is able to reduce Aβ-evoked neuroinflammation and attenuate its neurodegenerative consequences.</p

Relations de la philosophie avec son histoire

It is a great honor to present one of the proceedings of the Institut In- ternational de Philosophie in the \uablessico Intellettuale Europeo\ubb series. Both have longstanding traditions. the Institut International de Philosophie (IIP) was founded during the momentous ann\ue9e Descartes of 1937 and its meet- ings have taken place on a yearly basis (with the exception of 1939 to 1946 because of World War two). Its first president was l\ue9on Robin. Past pres- idents during the last four decades were Georg Henrik von Wright, Max Black, Paul Ricoeur, Jerzy Pelc, David Pears, Ruth Barcan Marcus, Evan- dro agazzi, tomonobu Imamichi, Jaakko Hintikka, anne Fagot-largeault, Hans lenk, tom\ue1s Calvo Mart\uednez and Enrico Berti. Ioanna Ku\ue7uradi is currently the president and Bernard Bourgeois the secretary general. to date, its membership lists 102 philosophers from forty-four countries. Its several committees are concerned with international communication and coopera- tion in philosophy from the point of view of reason and tolerance. a con- stant focus is placed on the mutual opening of philosophical cultures, tra- ditions and approaches.1 the Istituto per il lessico Intellettuale Europeo of the National Research Council of Italy (lIE and since 2001 IlIESI) was founded in 1964 and has been hosting its own international meetings every three years. We are count- ing fifty-five Entretiens de l\u2019Institut International de Philosophie and fifteen Colloqui Internazionali del Lessico Intellettuale Europeo. the IlIESI is ded- icated to the history of cultural and scientific terminology. It focuses on the phenomenon of cultural migration, which accompanies the whole history of civilizations while involving continuous relations and reciprocal exchanges among diverse cultures, and thus translations (in their widest sense) of texts and modules from one to another context, be it linguistic, economic, politi- cal, or cultural. Its researchers investigate several epochs under the assump- tion that at the root of the history of philosophy and of the sciences and more generally of the history of ideas lie textual corpora that have been de- veloped in the context of each discipline over the centuries.2 today, the \uablessico Intellettuale Europeo\ubb series, which was started in 1967, boasts 124 volumes. and we find it extremely inspiring that volume 125 of the series hosts the sixty-third IIP meeting, which is its sixth meeting in Italy, after Venice in 1958 (in coincidence with the twelfth World Con- gress of Philosophy), l\u2019aquila in 1964, Bellagio in 1982, Palermo in 1985 and Santa Margherita/Genova in 1989. all presentations but one that were given at the Entretiens de Rome of the Institut International de Philosophie on 24-28 September 2014 have found their way to this volume. appropriate funding was provided by the Italian Ministry for Education, university and Research within the PRIN2012 \u201cuniversalism and its limits\u201d, unit coordinator Riccardo Pozzo and national coordinator loris Sturlese. the four papers contributed by Giovanni Pugli- si, Hans Poser, Evandro agazzi and Enrico Berti were read at the meeting of the Committee on the History of Philosophy of the F\ue9d\ue9ration Interna- tionale des Soci\ue9t\ue9s de Philosophie (FISP) dedicated to the textual basis of the intercultural history of philosophy \u2013 Migrating Alphabets, which took place in Rome in the aula Marconi at the main seat of the National Re- search Council of Italy on 11 January 2011

Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported