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This paper examined the relationship among countermovement jump (CMJ), football category, chronological age, relative age, and pubertal development status to investigate which parameter could be better associated with jumping performance. We tested 259 young male football players (14.9 ± 1.8 yrs; 169.7 ± 9.8 cm; 60.6 ± 11.3 kg; 20.9 ± 2.6 kg m -2 ) belonging to elite football academies. One-sample chi-square tests were used to test the uniformity of distributions of the proportions of players in each year quarter (relative age effect, RAE) for the whole sample and stratified for each football age category (U14, U15, U17, and U19). One-way ANOVAs were used to test the associations among a) categories, RAE, and CMJ, and b) the pubertal status category and CMJ. Pearson's correlation assessed the relationship among variables. The birth distribution among the year's quarters significantly differed from the expected proportion of 25 % of participants each quarter ( χ 2  = 41.74; p  < 0.001), highlighting the presence of a relative age effect. Results indicate that age significantly influences CMJ ( F (6,231)  = 8.85, p  < 0.001, η 2 p  = 0.187), and a significant interaction effect (age × birth quarter) was found. Coaches, strength and conditioning trainers, and scouts should be aware of physical and biological players' maturation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Type 2 inflammation is a heterogeneous condition due to the complex activation of different immunological pathways. Rapid progress in research to evaluate the efficacy of biologics for chronic rhinosinusitis with nasal polyps and asthma has led to the availability of effective therapeutic options. These drugs are safe, but temporary iatrogenic hypereosinophilia may sometimes be associated with clinical symptoms or organ damage. Here, we describe a case of severe hypereosinophilia in a patient with chronic rhinosinusitis with nasal polyps and asthma treated with dupilumab and a subsequent therapeutic shift to mepolizumab that led to maintenance of symptom control and concomitant normalization of blood eosinophil count., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2024/05/dic.2024-3-5-COI.pdf, (Copyright © 2024 Munari S, Ciotti G, Cestaro W, Corsi L, Tonin S, Ballarin A, Floriani A, Dartora C, Bosi A, Tacconi M, Gialdini F, Gottardi M, Menzella F.)

The influence of biological maturity status on talent identification and development in youth soccer has been debated extensively. Alternative methods have thus recently emerged to estimate maturity status, such as the Pubertal Development Scale (PDS), but their relationship with physical capabilities of young soccer players still needs to be determined. The present study investigated the relationships of different PDS-derived pubertal status measures, chronological age, and relative age with selected performance variables in youth soccer. Sixty-one male soccer players were assessed for physical capabilities using field tests for sprinting, vertical jumps (countermovement jump, CMJ), intermittent high-intensity endurance, and repeated sprint ability. Chronological age was defined as the number of days since birth, and relative age was defined in terms of age quarters. PDS-derived measures of puberal status, otherwise, were determined as an average PDS score, a PDS category score, and a pubertal category. Chronological age, relative age, and measures of pubertal status were scarcely related (p > 0.05) to selected measures of soccer performance. Significant correlations were only found between different measures of pubertal status and the variable "work" in the CMJ test (range r = 0.33-0.36; p < 0.01) and between chronological age and CMJ height (r = -0.297; p = 0.02). The present results suggest that physical performance of young soccer players is poorly related to chronological age, relative age, and pubertal status. Potential effects of biological maturity status on physical capabilities may not be easily identifiable in a group of young soccer players narrowed in terms of chronological age and training status., Competing Interests: The authors declare no conflict of interest., (Copyright: © Academy of Physical Education in Katowice.)

Policosanols (PCs) are bioactive compounds extracted from different natural waxes. In this work, the purification, characterization and assessment of the antioxidant and anti-inflammatory activity was carried out on PCs from an innovative source, i.e. a waxy material from supercritical-fluid extraction (SFE) of non-psychoactive Cannabis sativa L. (hemp) inflorescences. Starting from this material, PCs were obtained by microwave-assisted trans -esterification and hydrolysis, followed by preparative liquid chromatography under normal phase conditions. The purified product was characterized using high-performance liquid chromatography (HPLC) with an evaporative light scattering detector (ELSD). In vitro cell-free and cell-based antioxidant and anti-inflammatory assays were then performed to assess their bioactivity. HPLC-ELSED analysis of the purified mixture from hemp wax revealed C 26 OH and C 28 OH as the main compounds. In vitro assays indicated an inhibition of intracellular reactive oxygen species (ROS) production, a reduction of nuclear factor kappa B (NF-κB) activation and of the activity of the neutrophil elastase. Immunoblotting assays allowed us to hypothesize the mechanism of action of the compounds of interest, given the higher levels of MAPK-activated protein kinase 2 (MK2) and heme oxygenase-1 (HO-1) protein expression in the PC pretreated HaCaT cells. In conclusion, even if more research is needed to unveil other molecular mechanisms involved in hemp PC activity, the results of this work suggest that these compounds may have potential for use in oxinflammation processes., Competing Interests: Federica Pellati reports financial support was provided by University of Modena and Reggio Emilia, Department of Life Sciences (FAR2023). The other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Asthma is a disease characterised by heterogeneous and multifaceted airway inflammation. Despite the availability of effective treatments, a substantial percentage of patients with the type 2 (T2)-high, but mainly the T2-low, phenotype complain of persistent symptoms, airflow limitation, and poor response to treatments. Currently available biologicals target T2 cytokines, but no monoclonal antibodies or other specific therapeutic options are available for non-T2 asthma. However, targeted therapy against alarmins is radically changing this perspective. The development of alarmin-targeted therapies, of which tezepelumab (TZP) is the first example, may offer broad action on inflammatory pathways as well as an enhanced therapeutic effect on epithelial dysfunction. In this regard, TZP demonstrated positive results not only in patients with severe T2 asthma but also those with non-allergic, non-eosinophilic disease. Therefore, it is necessary to identify clinical features of patients who can benefit from an upstream targeted therapy such as anti-thymic stromal lymphopoietin. The aims of this narrative review are to understand the role of alarmins in asthma pathogenesis and epithelial dysfunction, examine the rationale underlying the indication of TZP treatment in severe asthma, summarise the results of clinical studies, and recognise the specific characteristics of patients potentially eligible for TZP treatment., Competing Interests: Declaration of conflicting interestsThe authors declare that there is no conflict of interest.

Hermetia illucens is a promising insect due to its ability to convert low-value substrates as food chain by-products into highly nutritious feed. Its feeding and nutrition are important issues. The aim of this work was to investigate the effect of different substrates consisting of coffee silverskin, a by-product of the roasting process, enriched with different inclusions of microalgae (5%, 10%, 20%, and 25%), Schizochytrium limacinum, and Isochrysis galbana , combined with the assessment of environmental sustainability by LCA. In general, the addition of microalgae led to an increase in larval growth performance due to the higher content of protein and lipids, although S. limacinum showed the best results with respect to larvae fed with coffee silverskin enriched with I. galbana . A higher prepupal weight was observed in larvae fed with 10%, 20%, and 25% S. limacinum ; shorter development times in larvae fed with 25% of both S. limacinum and I. galbana ; and a higher growth rate in larvae fed with 25% S. limacinum . The 10% S. limacinum inclusion was only slightly different from the higher inclusions. Furthermore, 10% of S. limacinum achieved the best waste reduction index. The greater the inclusion of microalgae, the greater the environmental impact of larval production. Therefore, the addition of 10% S. limacinum appears to be the best compromise for larval rearing, especially considering that a higher inclusion of microalgae did not yield additional benefits in terms of the nutritional value of H. illucens prepupae.

The discovery of the interactome of cannabidiol (CBD), a non-psychoactive cannabinoid from Cannabis sativa L., has been here performed on chronic myelogenous leukemia cancer cells, using an optimized chemo-proteomic stage, which links Drug Affinity Responsive Target Stability with Limited Proteolysis Multiple Reaction Monitoring approaches. The obtained results showed the ability of CBD to target simultaneously some potential protein partners, corroborating its well-known poly-pharmacology activity. In human chronic myelogenous leukemia K562 cancer cells, the most fascinating protein partner was identified as the 116 kDa U5 small nuclear ribonucleoprotein element called EFTUD2, which fits with the spliceosome complex. The binding mode of this oncogenic protein with CBD was clarified using mass spectrometry-based and in silico analysis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Approximately 3-10% of people with asthma have severe asthma (SA). Patients with SA have greater impairment in daily life and much higher costs. Even if asthma affects the entire bronchial tree, small airways have been recognized as the major site of airflow limitation. There are several tools for studying small airway dysfunction (SAD), but certainly the most interesting is oscillometry. Despite several studies, the clinical usefulness of oscillometry in asthma is still in question. This paper aims to provide evidence supporting the use of oscillometry to improve the management of SA in clinical practice., Areas Covered: In the ATLANTIS study, SAD was strongly evident across all severity. Various tools are available for evaluation of SAD, and certainly an integrated use of these can provide complete and detailed information. However, the most suitable method is oscillometry, implemented for clinical routine by using either small pressure impulses or small pressure sinusoidal waves., Expert Opinion: Oscillometry, despite its different technological implementations is the best tool for determining the impact of SAD on asthma and its control. Oscillometry will also be increasingly useful for choosing the appropriate drug, and there is ample room for a more widespread diffusion in clinical practice.

Neuropathic pain (NP) is a chronic disease that affects the normal quality of life of patients. To date, the therapies available are only symptomatic and they are unable to reduce the progression of the disease. Many studies reported the efficacy of Cannabis sativa L. (C. sativa) on NP, but no Δ 9 -tetrahydrocannabinol (Δ 9 -THC)-free extracts have been investigated in detail for this activity so far. The principal aim of this work is to investigate the potential pain-relieving effect of innovative cannabidiol-rich non-psychotropic C. sativa oils, with a high content of terpenes (K2), compared to the same extract devoid of terpenes (K1). Oral administration of K2 (25 mg kg -1 ) induced a rapid and long-lasting relief of pain hypersensitivity in a mice model of peripheral neuropathy. In spinal cord samples, K2 reduced mitogen-activated protein kinase (MAPKs) levels and neuroinflammatory factors. These effects were reverted by the administration of a CB2 antagonist (AM630), but not by a CB1 antagonist (AM251). Conversely, K1 showed a lower efficacy in the absence of CB1/CB2-mediated mechanisms. In LPS-stimulated murine microglial cells (BV2), K2 reduced microglia pro-inflammatory phenotype through the downregulation of histone deacetylase 1 (HDAC-1) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IKBα) and increased interleukin-10 (IL-10) expression, an important antiinflammatory cytokine. In conclusion, these results suggested that K2 oral administration attenuated NP symptoms by reducing spinal neuroinflammation and underline the important role of the synergism between cannabinoids and terpenes., (© 2022 John Wiley & Sons Ltd.)

The present research reports the results of a long-term study (70 days) of the dynamics of Staphylococcus aureus artificially inoculated in a Tenebrio molitor rearing chain for human consumption. To this end, a rearing substrate consisting of organic wheat middlings was spiked with S. aureus to obtain three initial contamination levels, namely 1 (low level), 5 (medium level) and 7 (high level) Log colony forming unit per gram. Microbial viable counting coupled with metataxonomic analysis were performed to evaluate: i) the persistence and growth of S. aureus in the rearing substrate; ii) the colonization and growth of S. aureus in the insect larvae; iii) the occurrence and load of S. aureus in the frass (excrement from larvae mixed with substrate residues); iv) the presence of S. aureus enterotoxins in the rearing substrate, frass, and larvae. The results of the present study highlighted that wheat middlings contaminated with S. aureus do not represent a suitable environment for the multiplication of the pathogen, irrespective of the initial contamination level. Of note, frass originated from the larvae reared on contaminated wheat middlings might potentially represent a source of S. aureus, with cell loads depending on the initial contamination level. A complex resident microbiota was revealed by metataxonomic analysis. Interestingly, co-occurrence/co-exclusions analysis did not reveal associations between the target microorganism and the microbiota of wheat middlings, larvae, or frass. Considering safety aspects of larvae, the results overall collected suggested that, under the applied conditions, T. molitor represents an inhospitable or even hostile environment for S. aureus, with this latter showing counts below the detection limit in the larvae at the end of the 70-day rearing trial, irrespective of the initial contamination level. The results also suggested that a combination of bactericidal factors, including unfavorable environmental conditions (such as low a w of wheat middlings and frass), might have established in the rearing chain. Finally, the absence of staphylococcal toxins suggests that, even when S. aureus is present at high contamination levels, it is not able to produce toxins in wheat middlings, larvae, or frass., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In recent years, the more widespread availability of biological drugs with specific mechanisms of action has led to significant breakthroughs in the management of severe asthma. Over time, numerous randomised clinical trials have been conducted to evaluate the efficacy and safety of these biologics and define the eligibility criteria of patients suitable for various therapeutic options. These studies were conducted under controlled conditions not always applicable to real life. For this and other reasons, real-world evidence and pragmatic studies are required to provide useful information on the effectiveness of biological drugs and their safety, even in the long term. Because differences in outcomes have sometimes emerged between clinical trials and real-life studies, it is important to clarify the causes of these discrepancies and define the significance of the results of studies conducted in the course of daily clinical practice. Thus, a scientific debate is ongoing, and no consensus has been reached. The purpose of this narrative review is to analyse the differences between randomised trials and real-world evidence studies, focusing on their roles in guiding clinicians among different therapeutic options and understanding the reasons for the large discrepancies often found in the results obtained.

In the last few years, several efforts have been made to identify original strategies against glioblastoma multiforme (GBM): this requires a more detailed investigation of the molecular mechanism of GBM so that novel targets can be identified for new possible therapeutic agents. Here, using a combined biochemical and proteomic approach, we evaluated the ability of a blood-brain barrier-permeable 2,3-benzodiazepin-4-one, called 1g, to interfere with the activity and the expression of brain glycogen phosphorylase (PYGB) on U87MG cell line in parallel with the capability of this compound to inhibit the cell growth and cycle. Thus, our results highlighted PYGB as a potential therapeutic target in GBM prompting 1g as a capable anticancer drug thanks to its ability to negatively modulate the uptake and metabolism of glucose, the so-called "Warburg effect", whose increase is considered a common feature of cancer cells in respect of their normal counterparts.

The edible insect food chain represents a relatively novel food-producing system; hence, associated biological risks still need to be exhaustively evaluated. In the present study, the dynamics of Escherichia coli during the whole living period of Tenebrio molitor larvae (from eggs to pupae) were studied. To this end, a rearing substrate consisting of organic wheat middlings was spiked with E. coli cells at two initial contamination levels: 1 log cfu g -1 (low) and 6 log cfu g -1 (high). Microbial viability counting coupled with metataxonomic analyses was used to assess i) the persistence and growth of E. coli in the rearing substrate (wheat middlings); ii) the colonization and growth of E. coli in the insect larvae; and iii) the occurrence and load of E. coli in the frass (excrement from larvae mixed with substrate residues). The results highlighted a very limited persistence of the pathogen in all analyzed samples. In more detail, the results suggested that when E. coli was present at very low levels in the eggs of the insect, the pathogen was not able to reach concerning levels in the larvae. Moreover, when E. coli was present in the wheat middlings used for rearing, the environmental conditions of the substrate (low a w values) were not favorable for its survival and multiplication, irrespective of the presence of the larvae and their frass. Surprisingly, under the conditions applied in the present study, the larvae fed wheat middlings contaminated with E. coli seemed to be inhospitable or even hostile environments for microbial survival or multiplication. To explain the low levels of E. coli cells in the larvae reared in the present study, many factors can be considered, including the immune response of the host, microbial composition and interactions established in the gut of larvae, and insect species. Of note, part of the major fraction of the microbiota of larvae at the end of rearing was represented by Lactococcus, thus suggesting a possible effect of this lactic acid bacterium on E. coli decay. Further research is needed to better clarify the interactions between E. coli and the insect gut, as well as the interactions established among the target microorganism and those naturally harbored by the insect gut., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We characterize poly(3-hydroxybutyrate- co -3-hydroxyhexanoate) (PHBH) scaffolds for tissue repair and regeneration, manufactured by three-dimensional fused filament fabrication (FFF). PHBH belongs to the class of polyhydroxyalkanoates with interesting biodegradable and biocompatible capabilities, especially attractive for tissue engineering. Equally, FFF stands as a promising manufacturing technology for the production of custom-designed scaffolds. We address thermal, rheological and cytotoxicity properties of PHBH, placing special emphasis on the mechanical response of the printed material in a wide deformation range. Indeed, effective mechanical properties are assessed in both the linear and nonlinear regime. To warrant uniqueness of the material parameters, these are measured directly through digital image correlation, both in tension and compression, while experimental data fitting of finite-element analyses is only adopted for the determination of the second invariant coefficient in the nonlinear regime. Mechanical data are clearly porosity dependent, and they are given for both the cubic and the honeycomb infill pattern. Local strain spikes due to the presence of defects are observed and measured: those falling in the range 70-100% lead to macro-crack development and, ultimately, to failure. Results suggest the significant potential attached to FFF printing of PHBH for customizable medical devices which are biocompatible and mechanically resilient., Competing Interests: We declare we have no competing interests., (© 2022 The Authors.)

Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium; to counteract it, specific vaccines have been launched in record time under emergency use authorization or conditional marketing authorization by virtue of a favorable risk/benefit balance. Among the various technological platforms, there is that exploiting a nucleoside-modified messenger RNA (modRNA), such as Comirnaty ® , and that which is adenoviral vector-based. In the ongoing pharmacovigilance, the product information of the latter has been updated about the risk of thrombotic thrombocytopenia, venous thromboembolism without thrombocytopenia and immune thrombocytopenia without thrombosis. However, from an in-depth literature review, the same adverse events can rarely occur with modRNA vaccines too. In support of this, we here report a three-case series of thrombotic deaths in patients over 50 with comorbidities temporally after Comirnaty ® , investigated by means of post-mortem histopathology and immunohistochemistry. In two out of three cases, the cause of death is traced back to pulmonary microthromboses rich in activated platelets, quite similar morphologically to those described in patients who died from severe COVID-19. Even if remote in the face of millions of administered doses, clinicians should be aware of the possible thrombotic risk also after Comirnaty ® , in order to avoid a misdiagnosis with potentially lethal consequences. Since COVID-19 vaccines are inoculated in subjects to be protected, maximum attention must be paid to their safety, and prophylactic measures to increase it are always welcome. In light of the evidence, the product information of modRNA COVID-19 vaccines should be updated about the thrombotic risk, as happened for adenoviral vector-based vaccines.

In this study, extracts from non-psychoactive Cannabis sativa L. varieties were characterized by means of ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) and their antiproliferative activity was assessed in vitro. The human chronic myelogenous leukaemia cell line K562 was chosen to investigate the mechanism of cell death. The effect on the cell cycle and cell death was analysed by flow cytometry. Proteins related to apoptosis were studied by western blotting. Mechanical properties of cells were assessed using the Micropipette Aspiration Technique (MAT). The results indicated that the cannabidiol (CBD)-rich extract inhibited cell proliferation of K562 cell line in a dose-dependent manner and induced apoptosis via caspase 3 and 7 activation. A significant decrease in the mitochondrial membrane potential was detected, together with the release of cytochrome c into the cytosol. The main apoptotic markers were not involved in the mechanism of cell death. The extract was also able to modify the mechanical properties of cells. Thus, this hemp extract and its pure component CBD deserve further investigation for a possible application against myeloproliferative diseases, also in association with other anticancer drugs., (© 2022 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Micro-computed tomography (micro-CT) imaging is an emerging technology with many applications in small animals, for example, the study of pulmonary diseases, although clear guidelines and critical mass of evidence are still missing in the preclinical literature. The neonatal rabbit is a valuable model for studying pulmonary development. However, the longitudinal monitoring of lung function by micro-CT can be challenging. Distinctive datasets corresponding to the end-inspiration and end-expiration phases need to be generated and analyzed to derive lung-functional parameters. The quality of CT scans and the reliability of parameters obtained remain highly dependent on the anesthesia protocol used. Three different anesthetic protocols were tested. The combination of dexmedetomidine 0.25 mg/kg injected intraperitoneally followed by 1% isoflurane was found to facilitate CT imaging at 4 and 11 days after birth. Contrarily, isoflurane and ketamine-xylazine were found unsuitable and thus not investigated further. Total lung volumes significantly increased at day 11 compared with baseline in both respiratory phases, whereas lung tissue remained constant. As expected, functional residual capacity, air-to-tissue ratio, and minute ventilation were significantly increased at day 11 in each animal. Those parameters were correlated with inspiratory capacity, compliance, elastance, and resistance of both respiratory system and tissue component, as measured by flexiVent. Lung development was also evaluated by histomorphometric analyses. In conclusion, we have identified a safe and suitable anesthesia protocol for micro-CT imaging in neonatal rabbits. Moreover, the possibility to longitudinally measure lung function in the same subject dramatically reduced the intraexperimental variability.

Background: Coronavirus disease 2019 (COVID-19) is a complex disease with many clinicopathological aspects, including abnormal immunothrombosis, and the full comprehension of its pathogenetic mechanisms is urgently required., Methods/results: By means of a multidisciplinary approach, we here report a catastrophic COVID-19 in a 44-year-old Philippine male patient, discovered lupus anticoagulant (LAC)-positive shortly before death, occurred 8 days after hospitalization in a clinical scenario refractory to standard high acuity care recalling Asherson's syndrome (catastrophic antiphospholipid syndrome)., Conclusion: A parallelism between this severe form of COVID-19 and Asherson's syndrome can be so drawn. Both the diseases in fact exhibit hypercytokinemia, thrombotic microangiopathy, disseminated intravascular coagulation and multiple organ failure, they show a relationship with viral infections, and they are burdened by a high mortality rate. A genetic predisposition to develop these two overlapping conditions may be supposed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver failure and by an impaired neurotransmission and neurological function caused by hyperammonemia (HA). HE, in turn, decreases the phosphorylation of protein kinase C epsilon (PKCε), contributing to the impairment of neuronal functions. Dehydroepiandrosterone (DHEA) exerts a neuroprotective effect by increasing the GABAergic tone through GABA A receptor stimulation. Therefore, we investigated the protective effect of DHEA in an animal model of HE, and the possible modulation of PKCε expression in different brain area. Methods: Fulminant hepatic failure was induced in 18 male, Sprague-Dawley rats by i.p. administration of 3 g/kg D-galactosamine, and after 30 min, a group of animals received a subcutaneous injection of 25 mg/kg (DHEA) repeated twice a day (3 days). Exploratory behavior and general activity were evaluated 24 h and 48 h after the treatments by the open field test. Then, brain cortex and cerebellum were used for immunoblotting analysis of PKCε level. Results: DHEA administration showed a significant improvement of locomotor activity both 24 and 48 h after D-galactosamine treatment ( **** p < 0.0001) but did not ameliorate liver parenchymal degeneration. Western blot analysis revealed a reduced immunoreactivity of PKCε ( * p < 0.05) following D-galactosamine treatment in rat cortex and cerebellum. After the addition of DHEA, PKCε increased in the cortex in comparison with the D-galactosamine-treated ( *** p < 0.001) and control group ( * p < 0.05), but decreased in the cerebellum ( * p < 0.05) with respect to the control group. PKCε decreased after treatment with NH 4 Cl alone and in combination with DHEA in both cerebellum and cortex ( **** p < 0.0001). MTS assay demonstrated the synergistic neurotoxic action of NH 4 Cl and glutamate pretreatment in cerebellum and cortex along with an increased cell survival after DHEA pretreatment, which was significant only in the cerebellum ( * p < 0.05). Conclusion: An association between the DHEA-mediated increase of PKCε expression and the improvement of comatose symptoms was observed. PKCε activation and expression in the brain could inhibit GABA-ergic tone counteracting HE symptoms. In addition, DHEA seemed to ameliorate the symptoms of HE and to increase the expression of PKCε in cortex and cerebellum., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Di Cerbo, Roncati, Marini, Carnevale, Zavatti, Avallone and Corsi.)

Mechanobiology has nowadays acquired the status of a topic of fundamental importance in a degree in Biological Sciences. It is inherently a multidisciplinary topic where biology, physics and engineering competences are required. A course in mechanobiology should include lab experiences where students can appreciate how mechanical stimuli from outside affect living cell behaviour. Here we describe all the steps to build a cell stretcher inside an on-stage cell incubator. This device allows exposing living cells to a periodic mechanical stimulus similar to what happens in physiological conditions such as, for example, in the vascular system or in the lungs. The reaction of the cells to the periodic mechanical stretching represents a prototype of a mechanobiological signal integrated by living cells. We also provide the theoretical and experimental aspects related to the calibration of the stretcher apparatus at a level accessible to researchers not used to dealing with topics like continuum mechanics and analysis of deformations. We tested our device by stretching cells of two different lines, U87-MG and Balb-3T3 cells, and we analysed and discussed the effect of the periodic stimulus on both cell reorientation and migration. We also discuss the basic aspects related to the quantitative analysis of the reorientation process and of cell migration. We think that the device we propose can be easily reproduced at low-cost within a project-oriented course in the fields of biology, biotechnology and medical engineering., (© 2021. Biomedical Engineering Society.)

On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic; from that date, the vaccine race has begun, and many technology platforms to develop a specific and effective COVID-19 vaccine have been launched in several clinical trials (protein subunit, RNA-based, DNA-based, replicating viral vector, nonreplicating viral vector, inactivated virus, live attenuated virus, and virus-like particle). Among the next-generation strategies, nucleoside-modified messenger RNA vaccines appear the most attractive, not only to counteract emerging pathogens but also for the possible applications in regenerative medicine and cancer therapy. However, exactly as all innovative drugs, they deserve careful pharmacovigilance in the short and long term., (© 2021 Wiley Periodicals LLC.)

Coronavirus Disease 2019 (COVID-19) is upsetting the world and innovative therapeutic solutions are needed in an attempt to counter this new pandemic. Great hope lies in vaccines, but drugs to cure the infected patient are just as necessary. In the most severe forms of the disease, a cytokine storm with neuroinflammation occurs, putting the patient's life at serious risk, with sometimes long-lasting sequelae. Palmitoylethanolamide (PEA) is known to possess anti-inflammatory and neuroprotective properties, which make it an ideal candidate to be assumed in the earliest stage of the disease. Here, we provide a mini-review on the topic, pointing out phospholipids consumption in COVID-19, the possible development of an antiphospholipid syndrome secondary to SARS-CoV-2 infection, and reporting our preliminary single-case experience concerning to a 45-year-old COVID-19 female patient recently treated with success by micronized / ultramicronized PEA., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hermetia illucens larvae are among the most promising insects for use as food or feed ingredients due to their ability to convert organic waste into biomass with high-quality proteins. In this novel food or feed source, the absence of antibiotic-resistant bacteria and their antibiotic resistance (AR) genes, which could be horizontally transferred to animal or human pathogens through the food chain, must be guaranteed. This study was conducted to enhance the extremely scarce knowledge on the occurrence of AR genes conferring resistance to the main classes of antibiotics in a rearing chain of H. illucens larvae and how they were affected by rearing substrates based on coffee silverskin supplemented with increasing percentages of Schizochytrium limacinum or Isochrysis galbana microalgae. Overall, the PCR and nested PCR assays showed a high prevalence of tetracycline resistance genes. No significant effect of rearing substrates on the distribution of the AR genes in the H. illucens larvae was observed. In contrast, the frass samples were characterized by a significant accumulation of AR genes, and this phenomenon was particularly evident for the samples collected after rearing H. illucens larvae on substrates supplemented with high percentages (>20%) of I. galbana. The latter finding indicates potential safety concerns in reusing frass in agriculture.

Micro-CT imaging could be considered a powerful non-invasive tool for accessing pulmonary fibrosis in mice. However, the choice of the anesthesia protocol plays a fundamental role to obtain robust and reproducible data, avoiding misinterpretations of the results. Inhaled anesthesia is commonly used for micro-CT lung imaging, but sometimes the standardization of the protocol may be challenging for routine activities in drug discovery. In this study we used micro-CT to evaluate the effects of two anesthetic protocols, consisting in Alfaxalone and Dexmedetomidine mixture, as injectable agents, and gaseous isoflurane, on vehicle and bleomycin-treated mice. No significant differences were highlighted between the protocols either for lung aeration degrees by micro-CT or histologic analyses in both the controls and bleomycin-treated groups. Our results support Alfaxalone and Dexmedetomidine mixture as a suitable and safe alternative compared to isoflurane for lung imaging. We also concluded that this injectable mixture may be applied for several imaging technologies and on different mice models., (Copyright © 2020 Ferrini, Mecozzi, Corsi, Ragionieri, Donofrio and Stellari.)

Stress is a typical body's natural defense to a generic physical or psychic change. A specific linking mechanism between ulcer onset and psycho-physical stress prolonged exposure has been reported. We decided to investigate the possible effects of Borago officinalis L. (Borago) in preventing physical (stress)-induced gastric ulcers in a rat model. Eighty male Sprague-Dawley rats were randomly divided into 16 groups, pretreated with a control solution, omeprazole (20 mg/kg), Borago methanolic extract (25, 50, 100, 250, and 500 mg/kg), Borago organic extract (50, 100, 250, and 500 mg/kg), Borago aqueous extract (5, 10, 20, 30, and 40 mg/kg), and D(-)-2-Amino-5-phosphonovaleric acid (AP5) (25 mg/kg) and kept in stressful conditions such as water immersion and restraint-induced stress ulcers. The animals were sacrificed and their stomach scored for the severity and the number of gastric ulcers. Methanolic extract (500 mg/kg) significantly reduced both ulcer parameters ( *** p < 0.001 and ** p < 0.01, respectively). Aqueous and organic extract significantly decreased severity score at 5 and 10 mg/kg ( ** p < 0.01 and *** p < 0.001, respectively), and at 250 and 500 mg/kg ( *** p < 0.001), respectively, while gastric ulcers' resulted number significantly reduced only at 10 mg/kg ( * p < 0.05) and at 500 mg/kg ( ** p < 0.01), respectively. On the other hand, aqueous extract significantly increased the mucosal gastric content of cAMP ( * p < 0.05) and NR2A and NR2B subunits ( * p < 0.05 and ** p < 0.01, respectively) at 5 mg/kg. Organic extract showed also a significant cytotoxic effect at 500 and 1,000 mg/kg with a 3T3 cell viability reduction of 43.6% ( ** p < 0.01) and 92.1% ( *** p < 0.001), respectively. Borago aqueous extract at 10 mg/kg could be considered as a potential protective agent against stress-induced ulcers, and it is reasonable to possibly ascribe such protective activity to a modulation of the NR2A and NR2B subunit expression., (Copyright © 2020 Di Cerbo, Carnevale, Avallone, Zavatti and Corsi.)

A novel 2,3-benzodiazepine-4 derivative, named 1 g , has recently been shown to function as an anti-proliferative compound. We now show that it perturbs the formation of a functional mitotic spindle, inducing a spindle assembly checkpoint (SAC)-dependent arrest in human cells. Live analysis of individual microtubules indicates that 1 g promotes a rapid and reversible reduction in microtubule growth. Unlike most anti-mitotic compounds, we found that 1 g does not interfere directly with tubulin or perturb microtubule assembly in vitro The observation that 1 g also triggers a SAC-dependent mitotic delay associated with chromosome segregation in Drosophila neural stem cells, suggests that it targets a conserved microtubule regulation module in humans and flies. Altogether, our results indicate that 1 g is a novel promising anti-mitotic drug with the unique properties of altering microtubule growth and mitotic spindle organization., Competing Interests: Competing interestsThe content of this paper is included in a current patent application., (© 2020. Published by The Company of Biologists Ltd.)

Dystrophin deficiency is associated with alterations in cell physiology. The functional consequences of dystrophin deficiency are particularly severe for muscle physiology, as observed in Duchenne muscle dystrophy (DMD). DMD is caused by the absence of a 427 kDa isoform of dystrophin. However, in addition to muscular dystrophy symptoms, DMD is frequently associated with memory and attention deficits and epilepsy. While this may be associated with a role for dystrophin in neuronal physiology, it is not clear what neuronal alterations are linked with DMD. Our work shows that CA1 pyramidal neurons from DBA/2J-mdx mice have increased afterhyperpolarization compared to WT controls. All the other electrotonic and electrogenic membrane properties were unaffected by this genotype. Finally, basal synaptic transmission, short-term and long-term synaptic plasticity at Schaffer collateral to CA1 glutamatergic synapses were unchanged between mdx and WT controls. These data show that the excitatory component of hippocampal activity is largely preserved in DBA/2J-mdx mice. Further studies, extending the investigation to the inhibitory GABAergic function, may provide a more complete picture of the functional, network alterations underlying impaired cognition in DMD. In addition, the investigation of changes in neuronal single conductance biophysical properties associated with this genotype, is required to identify the functional alterations associated with dystrophin deficiency and clarify its role in neuronal function., Competing Interests: Declaration of competing interest No competing interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Rhodiola rosea L. (Crassulaceae) has been used for years in the traditional medicine of several countries as an adaptogen drug, able to preserve homeostasis in response to stress stimuli. Currently R. rosea roots and rhizome are classified as a traditional herbal medicinal product for temporary relief of symptoms of stress, such as fatigue and sensation of weakness by the European Medicines Agency., Hypothesis/purpose: Increasing evidences suggest the involvement of neuroinflammation in response to stress. However, whether the modulation of neuroinflammatory parameters could be involved in the anti-stress effect of R. rosea has been barely studied. Thus, the aim of this work is to investigate the possible modulation of molecular inflammatory processes elicited by a R. rosea roots and rhizome ethanolic extract in an in vitro model of corticotropin releasing hormone (CRH)-stimulated BV2 microglial cells., Methods: BV2 cells were stimulated with CRH 100 nM and changes in cell viability, cytokines production and heat shock protein 70 (HSP70) levels were evaluated. Intracellular pathways related to inflammation, such as nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) nuclear translocation and mitogen-activated protein kinases (MAPK) activation were also analyzed., Results: We found that R. rosea extract (2.7% m/m rosavin and 1% m/m salidroside) 20 µg/ml was able to counteract the neuroinflammatory effect of CRH by inhibiting NF-κB nuclear translocation with a mechanism of action involving the modulation of mitogen-activated protein kinase-activated protein kinase 2 (MKK2), extracellular signal-regulated kinase 1/2 (ERK 1/2) and c-Jun n-terminal kinase (JNK), resulting in a reduction of HSP70 expression., Conclusion: This work expands the knowledge of the intracellular mechanisms involved in R. rosea anti-stress activity and may be useful for the study of other adaptogen drugs., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: Pasta is a refined carbohydrate with a low glycemic index. Whether pasta shares the metabolic advantages of other low glycemic index foods has not really been investigated. The aim of this study is to document, in people with type-2 diabetes, the consumption of pasta, the connected dietary habits, and the association with glucose control, measures of adiposity, and major cardiovascular risk factors., Methods: We studied 2562 participants. The dietary habits were assessed with the European Prospective Investigation into Cancer and Nutrition (EPIC) questionnaire. Sex-specific quartiles of pasta consumption were created in order to explore the study aims., Results: A higher pasta consumption was associated with a lower intake of proteins, total and saturated fat, cholesterol, added sugar, and fiber. Glucose control, body mass index, prevalence of obesity, and visceral obesity were not significantly different across the quartiles of pasta intake. No relation was found with LDL cholesterol and triglycerides, but there was an inverse relation with HDL-cholesterol. Systolic blood pressure increased with pasta consumption; but this relation was not confirmed after correction for confounders., Conclusions: In people with type-2 diabetes, the consumption of pasta, within the limits recommended for total carbohydrates intake, is not associated with worsening of glucose control, measures of adiposity, and major cardiovascular risk factors.

Glioblastoma multiforme (GBM) is the most aggressive malignant tumor of the central nervous system, with poor survival in both treated and untreated patients. Recent studies began to explain the molecular pathway, comprising the dynamic structural and mechanical changes involved in GBM. In this context, some studies showed that the human glioblastoma cells release high levels of glutamate, which regulates the proliferation and survival of neuronal progenitor cells. Considering that cancer cells possess properties in common with neural progenitor cells, it is likely that the functions of glutamate receptors may affect the growth of cancer cells and, therefore, open the road to new and more targeted therapies.

In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB 1 and CB 2 . CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ 9 -THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa , since it contains only few levels of Δ 9 -THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ 9 -THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ 9 -THC deprived hemp.

In the last decades, adverse food reactions have increased considerably in dogs and cats. In this study we report on the possible onset of food intolerances symptoms, including otitis, diarrhoea, generalised anxiety, and dermatitis in a cohort of 8 dogs consuming commercial diets. All dogs received an organic chicken-based diet for 15 days. We performed analysis of blood biochemical parameters, kibble composition, and oxytetracycline (OTC) serum concentration before and after 15 days of organic chicken-based diet supplementation. We hypothesised that a chronic intake of contaminated food enhanced by the presence of nanoparticle aggregates might be at the base of the onset of pharmacologic or idiopathic food intolerances. At the end of the evaluation period, an overall significant reduction of otitis, diarrhoea, generalised anxiety, and dermatitis was observed. Biochemical analyses indicate a significant increase in the alkaline phosphatase, from 41 to 52.5 U/L, after 15 days (••p <0.01), while a significant decrease in Gamma-glutamyl transferase and urea, from 9.37 to 6.25 U/L and from 32.13 ± 8.72 to 22.13 ± 7.8 mg/dL, respectively, was observed (•p <0.05). A significant decrease, from 0.22 to 0.02 μg/mL, in mean OTC serum concentration was also observed (••p <0.01). Composition analysis revealed the presence of OTC, calcium, aluminium, silicon, and phosphorous nanoparticle aggregates. Further research on a wider sample size would help to confirm the hypothesis proposed here.

Background: The role of polyphenol intake on cardiovascular risk factors is little explored, particularly in people with diabetes., Aim: To evaluate the association between the intake of total polyphenols and polyphenol classes with the major cardiovascular risk factors in a population with type 2 diabetes., Methods: Dietary habits were investigated in 2573 males and females participants of the TOSCA.IT study. The European Prospective Investigation on Cancer and Nutrition (EPIC) questionnaire was used to assess dietary habits. In all participants, among others, we assessed anthropometry, plasma lipids, blood pressure, C-reactive protein and HbA1c following a standard protocol. The USDA and Phenol-Explorer databases were used to estimate the polyphenol content of the habitual diet., Results: Average intake of polyphenols was 683.3 ± 5.8 mg/day. Flavonoids and phenolic acids were the predominant classes (47.5% and 47.4%, respectively). After adjusting for potential confounders, people with the highest intake of energy-adjusted polyphenols (upper tertile) had a more favorable cardiovascular risk factors profile as compared to people with the lowest intake (lower tertile) (BMI was 30.7 vs 29.9 kg/m 2 , HDL-cholesterol was 45.1 vs 46.9 mg/dl, LDL-cholesterol was 103.2 vs 102.1 mg/dl, triglycerides were 153.4 vs 148.0 mg/dl, systolic and diastolic blood pressure were respectively 135.3 vs 134.3 and 80.5 vs 79.6 mm/Hg, HbA1c was 7.70 vs 7.67%, and C-reactive Protein was 1.29 vs 1.25 mg/dl, p < .001 for all). The findings were very similar when the analysis was conducted separately for flavonoids or phenolic acids, the two main classes of polyphenols consumed in this population., Conclusions: Polyphenol intake is associated with a more favorable cardiovascular risk factors profile, independent of major confounders. These findings support the consumption of foods and beverages rich in different classes of polyphenols particularly in people with diabetes., Clinical Trial: http://www.clinicaltrials.gov; Study ID number: NCT00700856., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes., Methods: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856., Findings: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups., Interpretation: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events., Funding: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: We compared a bundle of interventions including wound infiltration and continuous infusion with local anesthetics plus a single morphine bolus (CWI-M) with continuous epidural infusion (CEI) as postoperative analgesia., Methods: Fifty-one adults undergoing open abdominal aortic aneurysm repair were randomized in this non-inferiority open-label trial. In the CEI group, patients received thoracic epidural levobupivacaine 0.12% plus sufentanil 0.4 µg/mL infusion for 48 hours. In the CWI-M group, the wound was infiltrated with 10 mL levobupivacaine 0.5%, patients received a morphine bolus before the end of anesthesia and levobupivacaine 0.25% infusion through two multi-holed pre-peritoneal catheters for 48 hours. Systemic morphine was administered as rescue in both groups. The primary endpoint was the mean Numeric Rating Scale score in the first 48 hours after surgery., Results: Mean NRS was 1.7 (95% CI: from 1.2 to 2.2) in the CEI and 2.2 (95% CI: from 1.7 to 2.7) in the CWI-M group, the 90% CI of difference was from -0.1 to 1.1, not including the non-inferiority margin of 1.3. The cumulative rescue morphine dose per patient was higher in CWI-M than in CEI group (3.7±4.4 vs. 0.8±2.4 mg, P=0.006); moreover, NRS at arousal was higher in CWI-M (P=0.003). No differences were observed in postoperative hemodynamic parameters, recovery-related outcomes, length of stay nor complications., Conclusions: CWI-M was comparable to CEI in in postoperative pain control, but it was associated with higher need of rescue systemic opiates and with a worse early pain control.

Background and Aims: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes., Methods and Results: We studied 2573 people, aged 50-75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire. Women had a more adverse plasma lipid profile than men. Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 ± 2.4 vs 11.5 ± 2.5 and 3.4 ± 3.2 vs 2.3 ± 3.2, P < 0.04), and a higher intake of fiber (11.2 ± 2.8 vs 10.4 ± 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women., Conclusions: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose: The optimal macronutrient composition of the diet for the management of type 2 diabetes is debated, particularly with regard to the ideal proportion of fat and carbohydrates. The aim of the study was to explore the association of different proportions of fat and carbohydrates of the diet-within the ranges recommended by different guidelines-with metabolic risk factors., Methods: We studied 1785 people with type 2 diabetes, aged 50-75, enrolled in the TOSCA.IT Study. Dietary habits were assessed using a validated food-frequency questionnaire (EPIC). Anthropometry, fasting lipids, HbA1c and C-reactive protein (CRP) were measured., Results: Increasing fat intake from <25 to ≥35 % is associated with a significant increase in LDL-cholesterol, triglycerides, HbA1c and CRP (p < 0.05). Increasing carbohydrates intake from <45 to ≥60 % is associated with significantly lower triglycerides, HbA1c and CRP (p < 0.05). A fiber intake ≥15 g/1000 kcal is associated with a better plasma lipids profile and lower HbA1c and CRP than lower fiber consumption. A consumption of added sugars of ≥10 % of the energy intake is associated with a more adverse plasma lipids profile and higher CRP than lower intake., Conclusions: In people with type 2 diabetes, variations in the proportion of fat and carbohydrates of the diet, within the relatively narrow ranges recommended by different nutritional guidelines, significantly impact on the metabolic profile and markers of low-grade inflammation. The data support the potential for reducing the intake of fat and added sugars, preferring complex, slowly absorbable, carbohydrates.

It has been shown that the antagonism of glutamate receptors activity was able inhibit proliferation and induce apoptosis in several neuronal and non-neuronal cancer cell lines. In addition, it has been shown that glutamate might facilitate the spread and growth of leukemia T cells through interactions with AMPA receptors. The aim of the present study was to investigate the modulation of cell cycle elicited by a novel 2,3-benzodiazepine-4-one non-competitive AMPA antagonist derivative in the human leukemia Jurkat T cells. Our results indicated that the 1-(4-amino-3,5-dimethylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4h-2,3-benzodiazepin-4-one, named 1g, exerted a significant growth inhibition of leukemia Jurkat T cells in a time and dose dependent manner, arresting the transition of G2/M phase through activation of Myt-1. The molecule also induced apoptosis through the enhanced expression of the pro-apoptotic p53, and the inhibition of Bcl-2, and Bcl-xl, followed by the activation of caspase-3. The results suggested that compound 1g might act mostly as a cytostatic rather than cytotoxic compound. Although further studies are necessary, in order to identify others specific pathways involved in the activity of the present molecule, the presented results identified a novel molecule acting on specific G2/M checkpoint regulation pathway. Finally, our data suggest that compound 1g might be a good molecule for future development in the cancer research., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Metal-based nanoparticles (NPs), are currently used in many application fields including consumer products, pharmaceuticals, and biomedical treatments. In spite to their wide applications, an in-depth study of their potential toxic effects is still lacking. The aim of the present research was to investigate the potential initiator or promoter-like activity of different metallic NPs such as gold, iron, cobalt, and cerium using the Balb/3T3 two-stage transformation assay. The results indicated that all the selected metallic NPs, except for cobalt, when used as initiators did not induce any transformation in Balb/3T3 cell line. Moreover, Au and Fe3 O4 NPs, when used in place of the tumor promoter treatment TPA, increased significantly the number of Foci/dish as compared to the MCA treatment alone. The number of Foci/dish was 2.6 for Au NPs and 2.13 for Fe3 O4 ones, similar to those obtained by the positive control treatment (MCA + TPA), whereas 1.27 for MCA treatment alone. On the contrary, CeO2 NPs did not show any difference in the number of Foci/dish, as compared to MCA alone, but it decreased the number of foci by 65% in comparison to the positive control (MCA + TPA). As expected, cobalt NPs showed an increased cytotoxicity and only a few surviving cells were found at the time of analysis showing a number of Foci/dish of 0.13. For the first time, our data clearly showed that Au and Fe3 O4 NPs act as promoters in the two stage transformational assay, suggesting the importance to fully investigate the NPs carcinogenic potential with different models., (© 2014 Wiley Periodicals, Inc.)

Many reports have shown promising beneficial effects of long-chain polyunsaturated fatty acids (L-PUFAs) of the omega 3 series in several brain diseases. In the present study, we tested the hypothesis that omega 3 fatty acids supplement reduced pro-inflammatory functions in vitro and in vivo. We demonstrated that a supplement rich in PUFAs (SRP) increased cell viability in a dose-dependent manner suggesting its protective role against lipopolysaccharide (LPS)-induced cell death in BV2 microglial cell line. In the same cultures, the supplement rich in PUFAs reduced the reactive oxygen species (ROS) and nitric oxide (NO) production. A most prominent target for ROS management is the family of peroxisome proliferator-activated receptors (PPARs). The co-treatment with SRP and LPS increased significantly the nuclear immunoreactivity of PPAR-γwhen compared the LPS treatment alone. Moreover, the chronic administration of the SRP in rats, increased the immunoreactivity of the PPAR-γ1 protein confirming its potential neuroprotective effect.

This research on "America's Cup" grinders investigated the effects of a specific eight-week long-arm cranking ergometer (ACE) training on upper body (UB) aerobic fitness (ventilatory threshold - Tvent, respiratory compensation point- RCP, -oxygen uptake peak - VO₂peak) and high intensity working capacity. The training consisted of sessions carried out for 20-30 mins, three times per week, at an intensity between the UB-Tvent and UB-RCP, and replaced part of a typical lower limb aerobic training whilst maintaining the usual weekly schedule of callisthenics, resistance training and sailing. Seven sailors, including four grinders and three mastmen (age 30 ± 5.5 years, height 1.9 ± 0.04 m, body mass 102 ± 3.6 kg), were evaluated through both an ACE cardiopulmonary maximal exercise test (CPET) and an ACE all-out up to exhaustion exercise test, before and after the ACE training. UB aerobic fitness improved significantly: UB-VO₂peak increased from 4.29 ± 0.442 to 4.52 ± 0.522 l·min(-1) (6.4 ± 3.66%), VO₂ at UB-Tvent from 2.42 ± 0.282 to 2.97 ± 0.328 l·min(-1) (22.8 ± 5.09%) and VO₂ at UB-RCP from 3.25 ± 0.402 to 3.75 ± 0.352 l·min(-1) (16.1 ± 10.83%). Peak power at the ACE CPET increased from 351 ± 27.5 to 387 ± 33.5 W (10.5 ± 6.93%). The all-out test total mechanical work increased from 28.9 ± 2.35 to 40.1 ± 3.76 kJ (72.1 ± 4.67%). In conclusion, a high intensity aerobic ACE training can be effective in improving grinding performance by increasing UB aerobic fitness and all-out working capacity.

Aims: The aim of this study is to investigate the effect of hemin in colonic epithelial cells (Caco-2) cell proliferation and if this effect was due to a direct modulation of 18-kDa translocator protein (TSPO) and/or heme oxygenase type 1 (HO-1)., Main Methods: The main methods are as follow: cell proliferation and cell cytotoxic assays on Caco-2 cell lines treated with hemin in the presence or not of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195) and Sn-protoporphyrin IX (Sn-PPIX), and immunoblotting for TSPO and HO-1 protein analysis, siRNA directed against TSPO., Key Findings: Hemin was shown to be toxic for the Caco-2 cell line in a concentration and time dependent manner. Although hemin was able to induce HO-1 in a dose dependent manner, a specific HO-1 inhibitor, Sn-PPIX, was unable to interfere with the effect of hemin on Caco-2 cells. Instead, PK 11195, a specific TSPO ligand, was able to counteract the effect of hemin, suggesting an important role of TSPO in the hemin activity. Cell viability assay further confirms the high cytotoxic effects exerted by hemin on Caco-2 cells expressing TSPO compared to the siRNA-TSPO targeted cells. In addition, hemin was able to decrease significantly the TSPO protein density in a dose dependent manner after 24h of incubation., Significance: The interaction and the consecutive down regulation of TSPO by hemin played an important role in the control of Caco-2 cell viability. The presented data suggest that TSPO might contribute to protect cells from potential toxic compounds such as free tetrapyrroles, candidating this receptor as a survival receptor protein., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose:   Models of temporal lobe epilepsy are commonly utilized to study focal epileptogenesis and ictogenesis. The criteria that define animal models representative of human mesial temporal lobe may vary in different laboratories. We describe herein a focal epilepsy model of mesial temporal (hippocampal) origin that relies on the analysis of interictal and ictal electroencephalography (EEG) patterns and on their correlation with seizure symptoms and neuropathologic findings. The study is based on guinea pigs, a species seldom utilized to develop chronic epilepsy models., Methods:   Young adult guinea pigs were bilaterally implanted under isoflurane anesthesia with epidural electrodes over somatosensory cortex and depth electrodes in CA1 hippocampal region. A stainless steel guide cannula was positioned unilaterally in the right dorsal hippocampus to inject 1 μl of 0.9% NaCl solution containing 1 μg kainic acid (KA). One week after surgery, continuous 24 h/day video-EEG monitoring was performed 48 h before and every other week after KA injection, for no <1 month. EEG data were recorded wide-band at 2 kHz. After video-EEG monitoring, brains were analyzed for thionine and Timm staining and glial fibrillary acid protein (GFAP) immunostaining., Key Findings:   Unilateral injection of KA in dorsal hippocampus of guinea pigs induces an acute nonconvulsive status epilepticus (SE) that terminates within 24 h (n = 22). Chronic seizures with very mild motor signs (undetectable without EEG monitoring) and highly variable recurrence patterns appear in 45.5% (10 of 22) KA-treated animals, with variable delays from the initial SE. In these animals interictal events, CA1 cell loss, gliosis, and altered Timm staining pattern were observed. The induction of a chronic condition did not correlate with the duration of the nonconvulsive acute SE, but correlated with the extension and quality of neuropathologic damage., Significance:   We demonstrate that a model of hippocampal (mesial temporal lobe) epilepsy can be developed in the guinea pig by intrahippocampal injection of KA. Seizure events in this model show little behavioral signs and may be overlooked without extensive video-EEG monitoring. The establishment of a chronic epileptic condition correlates with the extension of the hippocampal damage (mainly cell loss and gliosis) and not with the intensity of the initial SE., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Background/aims: The surveillance of cardiovascular risk factors has been recommended worldwide. The current study is aimed to estimate the prevalence of cardiovascular risk factors among first-year students from a public university in the city of Sao Paulo, Brazil., Methods: A cross-sectional study of 56 first-year students, of both genders, was performed. Information about demographic characteristics, family history of chronic diseases, smoking, and physical activity was obtained by means of a standardised questionnaire. Anthropometrical parameters (BMI, waist circumference, body fat percentage), metabolic parameters (glycaemia, serum lipid profile), and dietary data (total energy intake, percentage of total energy from macronutrients, cholesterol and dietary fiber) were assessed., Results: The risk of cardiovascular diseases was characterised by family history of cardiovascular diseases (44.6%), smoking (10.7%), physical inactivity (35.7%), borderline high total cholesterol and LDL-c levels (16.1% and 5.4, respectively), decreased HDL-c levels (8.9%), increased triglyceride levels (8.9%), and overweight and obesity (17.8% and 7.1%, respectively). The diet of the students was inadequate: it was high in fat and protein, and low in carbohydrate and dietary fibre., Conclusions: The prevalence of risk factors for cardiovascular diseases in young adults draws attention to the need to adopt preventive plans in the university setting.

Objective: In this research we investigated the anti-inflammatory activity of a non-peptidyl low molecular weight radical scavenger (IAC) in an acute and chronic animal model of inflammation., Methods: For this purpose the effect of IAC (10, 25, 50 mg/kg) was tested in rats on the associated behavioral responses to subsequent inflammatory and noxious challenges, such as hind paw oedema induced by intra-plantar injection of carrageenan and granuloma induced by subcutaneous implant of a cotton pellet, using indometacin (2.5 mg/kg) as reference drug. Moreover, the serum level of several cytokines was tested in the animal treated (or not) with IAC (50 mg/kg) both in the absence and presence of carrageenan-induced inflammation., Key Findings: IAC showed a significant anti-inflammatory activity in both in acute and chronic models of inflammation. In addition IAC down regulated significantly the serum levels of interleukin (IL) 2 and IL6 whereas it increased the serum concentration of IL1α and glutathione., Conclusion: Although it remains to be elucidated whether or not the antioxidant property of IAC is directly responsible for the modulation of the tested cytokines, these results suggest IAC to be a possible candidate for a novel anti-inflammatory compound., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate called IAC, is a new non-peptidyl low molecular weight radical scavenger able to give a fast reaction with the majority of radical species involved in the oxidative stress. This intrinsic property might be of particular interest in all the processes where it presents an over production of reactive oxygen/nitrogen species (ROS/RNS) such as inflammation. Indeed, it is well known that systemic inflammatory response is associated with the production of ROS, nitric oxide (NO), which in turn deplete the endogenous GSH, mediating cytotoxicity. It has been shown that IAC through its antioxidant activity, exerted a protective effect in vitro in islets isolated from type-2 diabetic patients, and in vivo in a non-obese diabetic mouse model and in DNBS-induced colitis in rats. The ability of IAC to protect brain from ischemia, suggests a possible use of the compound in broad range of inflammatory- related diseases. It is well known that the use of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of untoward side-effects such as gastrointestinal ulceration. The major pathogenetic element in the development of these effects is the depletion of prostaglandins (PGs) through inhibition of cyclooxygenase. The evidence that IAC protects gastric mucosa in an animal model of indomethacin-induced ulcer, through local increase of PGE2 levels and antioxidant activity, candidates this compound as a novel, promising, anti-inflammatory compound avoiding the major common untoward side-effects elicited by NSAID's.

This study was designed to assess the effect of the phytoestrogenic compound ferutinin, chronically administered in ovariectomized progesterone primed rats, alone or in combination with estradiol benzoate. After 2, 3 and 4 weeks of treatments, female rats were tested for receptive (lordosis) and proceptive behaviors (hops, darts and ear wigglings). Ferutinin given alone markedly increased the intensity of the lordotic response in ovariectomized rats but failed to significantly affect proceptivity. On the other hand estradiol benzoate significantly increased both receptive and proceptive behaviors. When administered in combination with estradiol, ferutinin reduced the increase in receptivity and proceptivity due to estrogen effects, acting as an antiestrogen. At the end of the behavioral experiments, animals were sacrificed and Western blot analysis of estrogen receptor alpha (ERalpha) levels was performed in the dissected hypothalami. Ferutinin increased ERalpha expression when administered alone, as estradiol did, but decreased the response to estradiol when administered in combination. These results suggest that ferutinin displays estrogenic or antiestrogenic activity through ERalpha in the hypothalamus, depending on the absence or the presence of estrogen priming.

Objectives: We investigated the ability of a novel low-molecular-weight free-radical scavenger, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), to protect the gastric mucosa from indometacin-induced ulceration., Methods: The pharmacological effects of IAC, administered orally or by intraperitoneal injection, on the gastric mucosa were assessed in a rat model of gastric ulceration induced by indometacin. The effect of IAC on the level of prostaglandin PGE2 in the gastric mucosa was also investigated., Results: IAC, which has no ulcerative activity per se, had a preventive and protective activity against indometacin-induced gastric ulceration. This effect could be only partially attributed to a modulatory effect of IAC on PGE2 levels; it is more likely to be due to the antioxidant activity of the compound., Conclusions: Taking into account the properties of IAC and the mechanisms underlying gastric inflammation elicited by non-steroidal anti-inflammatory drugs, IAC may represent a novel anti-ulcer agent.

Benzodiazepines of natural origin (NBZDs) have been found in human blood and brains as well as in medicinal plants and foods. In plasma and brain tissue there are i.e. diazepam and nordiazepam equal to commercial drugs but there are also other benzodiazepine-like compounds termed "endozepines", which act as agonists at the benzodiazepine receptors of central type (CBR). A synthetic pathway for the production of NBZDs has not yet been found, but it has been suggested that micro-organisms may synthesize molecules with benzodiazepine-like structures. Hence NBZDs could be of both endogenous and exogenous source and be considered as natural anxyolitic and sedative. Interestingly there are also natural compounds, such as the polypeptide Diazepam Binding Inhibitor (DBI) acting as an "inversive agonist" implicated in fair and panic disorders. It has been suggested that NBZDs may play a role in the pathogenesis of hepatic encephalopathy (HE). Multidirectional studies evaluated NBZDs levels (1) in the blood of normal subjects, of cirrhotic with or without HE and in commercial benzodiazepine consumers; (2) in the blood of cirrhotic treated or not with a non-absorbable antibiotic; (3) in several constituents of our diet. In conclusion, NBZDs increase sometime in cirrhotics with or without HE but they reach concentrations not higher than those found in commercial benzodiazepines consumers. Hence NBZDs must be considered as occasional precipitating factor of HE and benzodiazepine antagonists only symptomatic drugs. The finding that NBZDs may be in part synthesized by intestinal bacterial flora and in part constituent of our diet underlines the importance to feed cirrhotic patients with selected food.

The peripheral benzodiazepine receptor (PBR), is an 18 kDa protein of the mammalian mitochondrial membrane and is a highly conserved protein among the mammalian. PBR is involved in numerous biological functions, including steroid biosynthesis, mitochondrial oxidative phosporylation and cell proliferation. The presence of PBR at the nuclear subcellular level has been demonstrated in aggressive breast cancer cell line and human glioma cells, where it seems to be involved in cell proliferation. In our previous studies we investigated the presence of nuclear PBR in different hepatic tumour cell lines with regard to binding to [3H] PK 11,195 and protein analysis. The results obtained by saturation binding experiments and Scatchard analysis of nuclear PBR density in parallel with the results on the growth curves of the cell lines tested, indicate that the nuclear PBR density correlates inversely with cell doubling time. Moreover, the cell line with high nuclear PBR proliferates in response to PBR ligands, whereas that with low nuclear PBR does not. All these findings support the idea that PBR could play a pivotal role in cell proliferation and this receptor protein could be potentially important either in early diagnosis or chemopreventive strategies against degenerative disease.