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Age-related macular degeneration (AMD) is a common retinal pathology characterized by degeneration of macula's retinal pigment epithelium (RPE) and photoreceptors, visual impairment, or loss. Compared to wet AMD, dry AMD is more common, but lacks cures; therefore, identification of new potential therapeutic targets and treatments is urgent. Increased oxidative stress and declining antioxidant, detoxifying systems contribute to the pathophysiologic mechanisms underlying AMD. The present work shows that the Embryonic Lethal Abnormal Vision-Like 1/Human antigen R (ELAVL1/HuR) and the Vascular Endothelial Growth Factor (VEGF) protein levels are higher in the RPE of both dry and wet AMD patients compared to healthy subjects. Moreover, increased HuR protein levels are detected in the retina, and especially in the RPE layer, of a dry AMD model, the nuclear factor erythroid 2-related factor 2 (Nrf2) / peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) double knock-out mouse. The crosstalk among Nrf2, HuR and VEGF has been also studied in ARPE-19 cells in basal and stressful conditions related to the AMD context (i.e., oxidative stress, autophagy impairment, Nrf2 deficit), offering new evidence of the mutual influence between Nrf2 and HuR, of the dependence of VEGF expression and secretion by these two factors, and of the increased susceptibility of cells to stressful conditions in Nrf2- or HuR-impaired contexts. Overall, this study shows evidence of the interplay among Nrf2, HuR and VEGF, essential factors for RPE homeostasis, and represents an additional piece in the understanding of the complex pathophysiologic mechanisms underlying AMD., Competing Interests: Declaration of Competing Interest I declare that potential competing interests do not exist and there is no financial/personal interest, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Among the tumors with the highest lethality, gliomas are primary brain tumors associated with common recurrence inclined to metastasize along the neuraxis and occasionally out of the central nervous system. Even though metastasis is the main responsible for death in oncological patients, few dedicated treatments are approved. Therefore, the establishment of effective anti-metastasis agents is the final frontier in cancer research. Interestingly, some copper complexes have demonstrated promising efficacy as antimetastatic agents, but they may cause off-site effects such as the alteration of copper homeostasis in healthy tissues. Thus, the incorporation of copper-based antimetastatic agents in rationally designed nano-architectures can increase the treatment localization reducing the side effects. Here, copper complex loaded hybrid nano-architectures (CuLNAs) are presented and employed to assess the impact of an intracellular copper source on glioma cell invasiveness. The novel CuLNAs are fully characterized and exploited for cell migration modulation in a glioma cell line. The results demonstrate that CuLNAs significantly reduce cell migration without impairing cell proliferation compared to standard gold and copper NAs. A concomitant antimigratory-like regulation of the epithelial-to-mesenchymal transition genes confirmed these results, as the gene encoding for the epithelial protein E-cadherin was upregulated and the other explored mesenchymal genes were downregulated. These findings, together with the intrinsic behaviors of NAs, demonstrate that the inclusion of metal complexes in the nano-architectures is a promising approach for the composition of a family of agents with antimetastatic activity., Competing Interests: Declaration of Competing Interest The Authors declare no competing financial interests that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In the synthesis of metal-organic frameworks (MOFs), the choice of the metal precursor plays a key role because of the influence that it can exert on the crystallization kinetics. The present work explores the use of metal-carbamato complexes for the synthesis of benchmark MOFs, namely HKUST-1 and UiO-66. Cu 2 (O 2 CNEt 2 ) 4 ·2NHEt 2 and Zr(O 2 CNEt 2 ) 4 , prepared using straightforward CO 2 fixation reactions starting from the corresponding metal chlorides and diethylamine, were employed as metal precursors for MOF formation. The synthesis conditions, including the solvent, temperature, and ligand protonation degree, were systematically investigated, revealing metal carbamates as highly reactive precursors due to their prompt release of CO 2 and amine upon reaction with protic species, i.e. , the polycarboxylic linkers. This property of metal carbamates allowed us to identify room temperature protocols to achieve MOFs with comparable properties to those obtained using traditional metal precursors. Subsequent optimization of the reaction conditions led to the design of a one-pot synthetic strategy for HKUST-1, starting directly from copper(II) chloride and diethylamine under a CO 2 atmosphere. The MOFs were characterized using various techniques, including powder X-ray diffraction, N 2 sorption analysis, 1 H nuclear magnetic resonance spectroscopy, and CHN elemental analysis, and compared to reference samples prepared according to literature procedures.

Primary cilia are sensory organelles that extend from the cellular membrane and are found in a wide range of cell types. Cilia possess a plethora of vital components that enable the detection and transmission of several signaling pathways, including Wnt and Shh. In turn, the regulation of ciliogenesis and cilium length is influenced by various factors, including autophagy, organization of the actin cytoskeleton, and signaling inside the cilium. Irregularities in the development, maintenance, and function of this cellular component lead to a range of clinical manifestations known as ciliopathies. The majority of people with ciliopathies have a high prevalence of retinal degeneration. The most common theory is that retinal degeneration is primarily caused by functional and developmental problems within retinal photoreceptors. The contribution of other ciliated retinal cell types to retinal degeneration has not been explored to date. In this review, we examine the occurrence of primary cilia in various retinal cell types and their significance in pathology. Additionally, we explore potential therapeutic approaches targeting ciliopathies. By engaging in this endeavor, we present new ideas that elucidate innovative concepts for the future investigation and treatment of retinal ciliopathies., (© 2024. The Author(s).)

Parents and caregivers may seek help with different questions or concerns on how to handle the diverse gender expressions of their children. Sometimes the issue may be evident while seeking medical advice for other concerns. Because of the many uncertainties around this topic, clinicians need to know what to say and what can be done to provide the best possible care for gender-diverse children., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a new synthetic strategy for obtaining mixed-valence triiron complexes where the metal centers are bridged by a novel, highly functionalized hydrocarbyl ligand. The alkynyl-vinyliminium complexes [Fe 2 Cp 2 (CO)(μ-CO){μ-η 1 :η 3 -C(X-CCH)CHCNMe 2 }]CF 3 SO 3 (X = 4-C 6 H 4 , [2a1]CF3SO3; X = (CH 2 ) 3 , [2a2]CF3SO3) were synthesized in almost quantitative yields from the aminocarbyne precursor [Fe 2 Cp 2 (CO) 2 (μ-CO){μ-CNMe 2 }]CF 3 SO 3 , [1a]CF3SO3, and the di-alkynes HCC-X-CCH. Then, the ferracycle [Fe(Cp)(CO){C(NMe 2 )CHC(4-C 6 H 4 CCH)C(O)}], 4a1, was produced in 47% yield from the cleavage of [2a1]CF3SO3 promoted by pyrrolidine. Subsequent reactions of the acetonitrile adducts [Fe 2 Cp 2 (CO)(μ-CO)(NCMe){μ-CNMe(R)}]CF 3 SO 3 (R = Me, [1aACN]CF3SO3; R = Xyl, [1bACN]CF3SO3) ([Fe I Fe I ]) with 4a1 ([Fe II ]) at room temperature resulted in the formation of [Fe I Fe I Fe II ] complexes [Fe 2 Cp 2 (CO)(μ-CO){μ-η 1 :η 3 -C(X-CCHC(NMe 2 )FeCp(CO)CO)CHCNMe(R)}]CF 3 SO 3 (R = Me, [5a1]CF3SO3; R = Xyl, [5b1]CF3SO3) in yields ranging from 56% to 64%. The new products were characterized by IR and multinuclear NMR spectroscopy, and the structures of [2a2]CF3SO3 and 4a1 were confirmed by single crystal X-ray diffraction. Cyclic voltammetry and spectroelectrochemical studies on [5a1]+ have revealed that reduction and oxidation events occur almost independently at the [Fe I Fe I ] and [Fe II ] units, respectively. This observation underscores a minimal electronic interaction between the two fragments within the triiron complex. Accordingly, DFT studies pointed out that the HOMO and LUMO orbitals are predominantly localized in the two distinct compartments of [5a1]+.

Objectives: This study aimed to investigate the dynamic patterns of perception and expectations among COPD patients. Methods: Conducted at the Heart-Respiratory Rehabilitation Unit, IRCCS Fondazione Don Carlo Gnocchi, in Milan, Italy, the research involved 28 participants (16 males; mean age 72.8 ± 9.9) in face-to-face interviews. Utilizing a Grounded Theory approach, complemented by clinical data, recorded, and transcribed interviews underwent enhancement through the integration of two pictorial tools. Results: The central theme that emerged was a profound sense of responsibility toward their condition, perceived as a significant threat to life. Key symptoms, such as shortness of breath, coupled with negative expectations about their condition, contributed to depressive mood and avoidance behaviors. A notable proportion ( N = 17; 60.71%) of participants struggled to envision a positive future, expressing a pervasive sense of hopelessness, which significantly influenced their health behaviors and adherence to medical recommendations. Conversely, individuals who felt supported and optimistic about treatment efficacy exhibited more positive expectations and adopted proactive coping strategies. Discussion: Recognizing the dynamic nature of patients' perceptions and negative illness expectations is essential to create personalized therapeutic interventions and meet the specific needs of COPD patients, ultimately improving the overall effectiveness of their care journey., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The indole scaffold has been established as a key organic moiety for developing new drugs; on the other hand, a range of diiron bis-cyclopentadienyl complexes have recently emerged for their promising anticancer potential. Here, we report the synthesis of novel diiron complexes with an indole-functionalized vinyliminium ligand (2-5) and an indole-lacking analogue for comparative purposes (6), which were characterized by analytical and spectroscopic techniques. Complexes 2-6 are substantially stable in DMSO‑d 6 and DMEM-d solutions at 37 °C (8% average degradation after 48 h) and display a balanced hydrophilic/lipophilic behaviour (LogP ow values in the range -0.32 to 0.47), associated with appreciable water solubility. The complexes display selective antiproliferative potency towards several cancer cells in monolayer cultures, mainly in the low micromolar range, with reduced toxicity towards noncancerous epithelial cells. Thus, the cytotoxicity of the complexes is comparable to or better than clinically used metallopharmaceutical cisplatin. Comparing the antiproliferative activity obtained for complexes containing different ligands, we confirmed the importance of the indolyl group in the mechanism of antiproliferative activity of these complexes. Cell-based mechanistic studies suggest that the investigated diiron vinyliminium complexes (DVCs) show cytostatic rather than cytotoxic effects and subsequently induce a population of cells to undergo apoptosis. Furthermore, the molecular mechanism of action involves interactions with mitochondrial DNA and proteins, the reactive oxygen species (ROS)-scavenging properties and antioxidant activity of these complexes in cancer cells. This study highlights the importance of DVCs to their cancer cell activity and reinforces their prospective therapeutic potential as anticancer agents., 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 © 2023 Elsevier B.V. All rights reserved.)

Diruthenacyclopentenone complexes of the general composition [Ru 2 Cp 2 (CO) 2 {μ-η 1 :η 3 -CH═C(C(OH)(R))C(═O)}] ( 2a - c ; Cp = η 5 -C 5 H 5 ) were synthesized in 94-96% yields from the reactions of [Ru 2 Cp 2 (CO) 2 {μ-η 1 :η 3 -C(Ph)═C(Ph)C(═O)}] ( 1 ) with 1-ethynylcyclopentanol, 17α-ethynylestradiol, and 17-ethynyltestosterone, respectively, in toluene at reflux. Protonation of 2a - c by HBF 4 afforded the corresponding allenyl derivatives [Ru 2 Cp 2 (CO) 3 {μ-η 1 :η 2 -CH═C═R}]BF 4 ( 3a - c ) in 85-93% yields. All products were thoroughly characterized by elemental analysis, mass spectrometry, and IR, UV-vis, and nuclear magnetic resonance spectroscopy. Additionally, 2a and 3a were investigated by cyclic voltammetry, and the single-crystal diffraction method was employed to establish the X-ray structures of 2b and 3a . The cytotoxicity in vitro of 2b and 3a - c was evaluated against nine human cancer cell lines (A2780, A2780R, MCF-7, HOS, A549, PANC-1, Caco-2, PC-3, and HeLa), while the selectivity was assessed on normal human lung fibroblast (MRC-5). Overall, complexes exert stronger cytotoxicity than cisplatin, and 3b (comprising 17α-estradiol derived ligand) emerged as the best-performing complex. Inductively coupled plasma mass spectrometry cellular uptake studies in A2780 cells revealed a higher level of internalization for 3b and 3c compared to 2b , 3a, and the reference compound RAPTA-C. Experiments conducted on A2780 cells demonstrated a noteworthy impact of 3a and 3b on the cell cycle, leading to the majority of the cells being arrested in the G0/G1 phase. Moreover, 3a moderately induced apoptosis and oxidative stress, while 3b triggered autophagy and mitochondrial membrane potential depletion.

Dimethyl fumarate (DMF) is an FDA-approved drug for the treatment of psoriasis and multiple sclerosis. DMF is known to stabilize the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. It has also been shown that DMF influences autophagy and participates in the transcriptional control of inflammatory factors by inhibiting NF-κB and its downstream targets. DMF is receiving increasing attention for its potential to be repurposed for several diseases. This versatile molecule is indeed able to exert beneficial effects on different medical conditions through a pleiotropic mechanism, in virtue of its antioxidant, immunomodulatory, neuroprotective, anti-inflammatory, and anti-proliferative effects. A growing number of preclinical and clinical studies show that DMF may have important therapeutic implications for chronic diseases, such as cardiovascular and respiratory pathologies, cancer, eye disorders, neurodegenerative conditions, and systemic or organ specific inflammatory and immune-mediated diseases. This comprehensive review summarizes and highlights the plethora of DMF's beneficial effects and underlines its repurposing opportunities in a variety of clinical conditions., 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 © 2023 Bresciani, Manai, Davinelli, Tucci, Saso and Amadio.)

We report the synthesis and the assessment of the anticancer potential of two series of diruthenium biscyclopentadienyl carbonyl complexes. Novel dimetallacyclopentenone compounds ( 2 - 4 ) were obtained (45-92% yields) from the thermal reaction (PhCCPh exchange) of [Ru 2 Cp 2 (CO)(μ-CO){μ-η 1 :η 3 -C(Ph)═C(Ph)C(═O)}], 1 , with alkynes HCCR [R = C 5 H 4 FeCp (Fc), 3-C 6 H 4 (Asp), 2-naphthyl; Cp = η 5 -C 5 H 5 , Asp = OC(O)-2-C 6 H 4 C(O)Me]. Protonation of 1 - 3 by HBF 4 afforded the corresponding μ-alkenyl derivatives 5 - 7 , in 40-86% yields. All products were characterized by IR and NMR spectroscopy; moreover, cyclic voltammetry ( 1 , 2 , 5 , 7 ) and single-crystal X-ray diffraction ( 5 , 7 ) analyses were performed on representative compounds. Complexes 5 - 7 revealed a cytotoxic activity comparable to that of cisplatin in A549 (lung adenocarcinoma), SW480 (colon adenocarcinoma), and ovarian (A2780) cancer cell lines, and 2 , 5 , 6 , and 7 overcame cisplatin resistance in A2780cis cells. Complexes 2 , 5 , and 7 (but not the aspirin derivative 6 ) induced an increase in intracellular ROS levels. Otherwise, 6 strongly stabilizes and elongates natural DNA (from calf thymus, CT-DNA), suggesting a possible intercalation binding mode, whereas 5 is less effective in binding CT-DNA, and 7 is ineffective. This trend is reversed concerning RNA, and in particular, 7 is able to bind poly(rA)poly(rU) showing selectivity for this nucleic acid. Complexes 5 - 7 can interact with the albumin protein with a thermodynamic signature dominated by hydrophobic interactions. Overall, we show that organometallic species based on the Ru 2 Cp 2 (CO) x scaffold ( x = 2, 3) are active against cancer cells, with different incorporated fragments influencing the interactions with nucleic acids and the production of ROS.

Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function after stimulation. During cardiothoracic surgeries ( n = 21), supramaximal, unilateral phrenic nerve stimulation was performed every 30 min for 1 min. Diaphragm biopsies were collected after the last stimulation and analyzed for mitochondrial respiration in permeabilized fibers and protein expression and enzymatic activity of biomarkers of oxidative stress and mitophagy. Patients received, on average, 6.2 ± 1.9 stimulation bouts. Stimulated hemidiaphragms showed lower leak respiration, maximum electron transport system (ETS) capacities, oxidative phosphorylation (OXPHOS), and spare capacity compared with unstimulated sides. There were no significant differences between mitochondrial enzyme activities and oxidative stress and mitophagy protein expression levels. Intraoperative phrenic nerve electrical stimulation led to an acute decrease of mitochondrial respiration in the stimulated hemidiaphragm, without differences in biomarkers of mitophagy or oxidative stress. Future studies warrant investigating optimal stimulation doses and testing post-operative chronic stimulation effects on weaning from the ventilator and rehabilitation outcomes.

The COVID-19 pandemic caused a temporary lockdown period in Italy, during which the delivery of in-person treatment for children with autism spectrum disorder (ASD) in public health services was discontinued. This occurrence represented a crucial challenge for both families and professionals. We assessed the short-term outcomes of a sample of 18 children who received an early intervention with the Early Start Denver Model (ESDM), delivered at low intensity over one year in the pre-pandemic period, after six months of interruption of in-presence treatment due to lockdown restrictions. Children who received the ESDM treatment maintained their gains in sociocommunicative skills and did not exhibit any developmental regression. Additionally, there was evidence of a decrease in the restrictive and repetitive behavior (RRB) domain. The parents, who were already familiar with the principles of the ESDM, only received telehealth support from therapists that aimed to sustain the gains already achieved. We believe that it is always helpful to support parents in their daily lives by implementing interactional and play skills with their children to integrate and consolidate the results obtained in the individual interventions conducted by experienced therapists.

Diiron μ-aminocarbyne complexes [Fe 2 Cp 2 (NCMe)(CO)(μ-CO){μ-CN(Me)(R)}]CF 3 SO 3 (R = Xyl, [1a NCMe ]CF 3 SO 3 ; R = Me, [1b NCMe ]CF 3 SO 3 ; R = Cy, [1c NCMe ]CF 3 SO 3 ; R = CH 2 Ph, [1d NCMe ]CF 3 SO 3 ), freshly prepared from tricarbonyl precursors [1a-d]CF 3 SO 3 , reacted with NaOCN (in acetone) and NBu 4 SCN (in dichloromethane) to give [Fe 2 Cp 2 (k N -NCO)(CO)(μ-CO){μ-CN(Me)(R)}] (R = Xyl, 2a ; Me, 2b ; Cy, 2c ) and [Fe 2 Cp 2 (k N -NCS)(CO)(μ-CO){μ-CN(Me)(CH 2 Ph)}], 3 in 67-81% yields via substitution of the acetonitrile ligand. The reaction of [1a NCMe -1c NCMe ]CF 3 SO 3 with KSeCN in THF at reflux temperature led to the cyanide complexes [Fe 2 Cp 2 (CN)(CO)(μ-CO){μ-CNMe(R)}], 6a - c (45-67%). When the reaction of [1a NCMe ]CF 3 SO 3 with KSeCN was performed in acetone at room temperature, subsequent careful chromatography allowed the separation of moderate amounts of [Fe 2 Cp 2 (k Se -SeCN)(CO)(μ-CO){μ-CN(Me)(Xyl)}], 4a , and [Fe 2 Cp 2 (k N -NCSe)(CO)(μ-CO){μ-CN(Me)(Xyl)}], 5a . All products were fully characterized by elemental analysis, IR, and multinuclear NMR spectroscopy; moreover, the molecular structure of trans -6b was ascertained by single crystal X-ray diffraction. DFT calculations were carried out to shed light on the coordination mode and stability of the {NC Se -} fragment.

The aim of this study was to evaluate the interaction between gastrointestinal (GI) disorders, sleep problems, and challenging behaviors in children with a diagnosis of Autism Spectrum Disorder (ASD) and their effect on parental stress. The secondary objective was to assess the frequency and type of GI and feeding disorders in a sample of children with ASD through a multidisciplinary assessment and, finally, to investigate families' perceptions and satisfaction with the proposed multidisciplinary approach. All children underwent a comprehensive gastroenterological and neuropsychiatric evaluation supported by standardized questionnaires. Pediatric gastroenterologists, specifically trained in Applied Behavior Analysis (ABA), provided advice for parent-delivered behavioral intervention for food selectivity. Thirty-six children with an autism diagnosis (29 males, age 4.5 +/-2.2 years, mean +/- SD) were enrolled. A positive correlation between sleep problems and aggressive behavior was found, and this association was stronger in children experiencing more problematic mealtime behaviors (b = 0.788, p = 0.014). Sleep difficulties were associated with stereotyped behaviors and parent-perceived stress. Parents interviewed about the gastroenterology visit perceived this multidisciplinary approach as helpful in addressing food selectivity. This study shows that sleep and mealtime issues can have a synergistic negative impact on ASD symptoms. A multidisciplinary approach and an integrated assessment of GI, feeding problems, and sleep disorders could be helpful in diagnosing comorbidities and to provide targeted advice to parents.

Diiron vinyliminium complexes constitute a large family of organometallics displaying a promising anticancer potential. The complexes [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(R3)C(R4)CN(R1)(R2)}]CF3SO3 (2a-c, 4a-d) were synthesized, assessed for their behavior in aqueous solutions (D2O solubility, Log Pow, stability in D2O/Me2SO-d6 mixture at 37°C over 48 h) and investigated for their antiproliferative activity against A2780 and A2780cisR ovarian cancer cell lines and the nontumoral one Balb/3T3 clone A31. Cytotoxicity data collected for 50 vinyliminium complexes were correlated with the structural properties (i.e. the different R1-R4 substituents) using the partial least squares methodology. A clear positive correlation emerged between the octanol-water partition coefficient and the relative antiproliferative activity on ovarian cancer cell lines, both of which appear as uncorrelated to the cancer cell selectivity. However, the different effects played by the R1-R4 substituents allow tracing guidelines for the development of novel, more effective compounds. Based on these results, three additional complexes (4p-r) were designed, synthesized and biologically investigated, revealing their ability to hamper thioredoxin reductase enzyme and to induce cancer cell production of reactive oxygen species., (© The Author(s) 2022. Published by Oxford University Press.)

Objective: To analyze the clinical management, the outcomes, and the trend in hysterectomy rates (HR) in patients who underwent this procedure for cervical intraepithelial neoplasia (CIN)., Methods: Multicentric retrospective observational study conducted on 242 patients who underwent hysterectomy for CIN between 2010 and 2020 in nine Italian institutions. Hysterectomy for invasive or micro-invasive neoplasia, sub-total hysterectomy, or trachelectomy were excluded., Results: A significant increase in the trend of HR for CIN was recorded (P = 0.002, r = 0.81; C.I. 95%: 0.415-0.949); HR increased from 0.46% in the year 2010 to 3.32% in 2020. The mortality rate was 0.4%, and 5% had operative complications. On definitive histopathology examination, a CIN of any grade was recorded in 71.5% of cases, and an occult invasive cancer in 1.24%. No pathology or CIN1 was found in 26.8% of cases, suggesting over treatment. During follow-up, a vaginal lesion was recorded in 5% of cases., Conclusion: A significant increase in the number of hysterectomies performed for CIN in the last 10 years was recorded. Hysterectomy for CIN can lead to complications, risk of the onset of vaginal lesions, and risk of overtreatment, and remains, in the first instance, an unacceptable treatment, to be proposed only after adequate counseling., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Dimetallic complexes are suitable platforms for the assembly of small molecular units, and the reactivity of bridging alkenyl ligands has been widely investigated to model C-C bond forming processes. Here, we report the unusual coupling of an alkenyl ligand, bridging coordinated on a diruthenium scaffold, with a series of alkynes, revealing two possible outcomes. The diruthenium complex [Ru 2 Cp 2 (Cl)(CO)(μ-CO){μ-η 1 :η 2 -C(Ph)CH(Ph)}], 2, was prepared in two steps from [Ru 2 Cp 2 (CO) 2 (μ-CO){μ-η 1 :η 2 -C(Ph)CH(Ph)}]BF 4 , [1]BF4, in 69% yield. Then, the reaction of 2 with C 2 (CO 2 Me) 2 , promoted by AgCF 3 SO 3 in dichloromethane, afforded in 51% yield the complex [Ru 2 Cp 2 (CO) 2 {μ-η 3 :η 2 -C(Ph)CH(Ph)C(CO 2 Me)C(CO 2 Me)}]CF 3 SO 3 , [3]CF 3 SO 3 , containing a ruthenacyclopentene-based hydrocarbyl ligand. On the other hand, 2 reacted with other alkynes and AgX salts to give the butadienyl complexes [Ru 2 Cp 2 (CO) 2 {μ-η 3 :η 2 -C(R)CH(R')C(Ph)C(Ph)}]X (R = R' = H, [4]BF 4 ; R = R' = Me, [5]CF 3 SO 3 ; R = R' = Ph, [6]CF 3 SO 3 ; R = Ph, R' = H, [7]CF 3 SO 3 ), in 42-56% yields. All products were characterized by IR and NMR spectroscopy, and by single crystal X-ray diffraction in the cases of 2, [3]CF 3 SO 3 and [6]BF 4 . DFT calculations highlighted the higher stability of [4-7] + -like structures with respect to the corresponding [3] + -like isomers. It is presumable that [3] + -like isomers initially form as kinetic intermediates, then undergo H-migration which is disfavoured in the presence of carboxylato substituents on the alkyne. Such hypothesis was supported by the computational optimization of the transition states for H-migration in the cases of R = R' = H and R = R' = CO 2 Me.

Photodynamic therapy (PDT) is a promising anticancer strategy based on the light energy stimulation of photosensitizers (PS) molecules within a malignant cell. Among a multitude of recently challenged PS, Rose bengal (RB) has been already reported as an inducer of cytotoxicity in different tumor cells. However, RB displays a low penetration capability across cell membranes. We have therefore developed a short-term amino acids starvation protocol that significantly increases RB uptake in human astrocytoma cells compared to normal rat astrocytes. Following induced starvation uptake, RB is released outside cells by the exocytosis of extracellular vesicles (EVs). Thus, we have introduced a specific pharmacological treatment, based on the GW4869 exosomes inhibitor, to interfere with RB extracellular release. These combined treatments allow significantly reduced nanomolar amounts of administered RB and a decrease in the time interval required for PDT stimulation. The overall conditions affected astrocytoma viability through the activation of apoptotic pathways. In conclusion, we have developed for the first time a combined scheme to simultaneously increase the RB uptake in human astrocytoma cells, reduce the extracellular release of the drug by EVs, and improve the effectiveness of PDT-based treatments. Importantly, this strategy might be a valuable approach to efficiently deliver other PS or chemotherapeutic drugs in tumor cells.

The room temperature reactions with internal alkynes, RCCR, of the μ-allenyl acetonitrile complex [Ru 2 Cp 2 (CO) 2 (NCMe){μ-η 1 :η 2 -C 1 HC 2 C 3 Me 2 }]BF 4 (1-NCMe), freshly prepared from the tricarbonyl precursor [Ru 2 Cp 2 (CO) 3 {μ-η 1 :η 2 -C 1 HC 2 C 3 Me 2 }]BF 4 , 1, proceeded with alkyne insertion into ruthenium-allenyl bond and allenyl-CO coupling, affording compounds [Ru 2 Cp 2 (CO) 2 {μ-η 2 :η 5 -C(R)C(R)C 1 HC 2 (C 3 MeCH 2 )C(OH)}]BF 4 (R = Ph, 2; R = CO 2 Me, 3; R = CO 2 Et, 4) in 83-94% yields. Deprotonation of 2-4 by triethylamine gave [Ru 2 Cp 2 (CO) 2 {μ-η 2 :η 5 -C(R)C(R)CHC(CMeCH 2 )C(O)}] (R = Ph, 5; R = CO 2 Me, 6; R = CO 2 Et, 7) in 75-88% yields, and 2-4 could be recovered upon HBF 4 ·Et 2 O addition to 5-7. All the products, 2-7, were fully characterized by elemental analysis, IR and multinuclear NMR spectroscopy. The structure of 2 was ascertained by single crystal X-ray diffraction and investigated by DFT calculations, revealing a six-membered ruthenacycle with Shannon aromaticity index in line with related compounds. The formation of ruthenium-coordinated ruthenabenzenes from a preexistent diruthenium scaffold is a versatile but underdeveloped approach exploiting cooperative effects typical of a dimetallic core.

We report a screening study aimed to assess for the first time the air- and water-stability and the biological potential of simple metal-carbamates. These molecular metallic species are based on elements belonging to the groups 4-5, 7-9 and 11, and tin, and are easily available from inexpensive reagents. Complexes [Ag(O 2 CNEt 2 )] (13-Ag) and [Au(O 2 CNMe 2 )(PPh 3 )] (14-Au) resulted substantially stable in aqueous media and exhibited a potent in vitro cytotoxicity. Especially 13-Ag revealed a significant selectivity against the A549 lung adenocarcinoma and the A2780 ovarian cancer cell lines with respect to the noncancerous HEK293 cell line. Generation of ROS (reactive oxygen species) and mitochondrial membrane depolarization were recognized for 13-Ag and 14-Au; notwithstanding, the cell death mechanism is different in the two cases: apoptosis and cell cycle arrest in G0/G1 phase for 13-Ag; necroptosis and cell cycle arrest in S phase for 14-Au. Both 13-Ag and 14-Au are endowed with antibacterial activity, which is relatively stronger for 13-Ag towards Gram negative and for 14-Au towards Gram positive strains, respectively., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The μ-(amino)alkylidyne complex [Fe 2 Cp 2 (CO) 2 (μ-CO){μ-CNMe(CH 2 CHCH 2 )}]CF 3 SO 3 , [1]CF 3 SO 3 , reacted with NBu 4 CN in dichloromethane affording the μ-(cyano)(amino)alkylidene [Fe 2 Cp 2 (CO) 2 (μ-CO){μ-C(CN)N(Me)(CH 2 CHCH 2 )}], 2, in 91% yield. Decarbonylation of 2 by using Me 3 NO in acetone at room temperature yielded [Fe 2 Cp 2 (CO)(μ-CO){μ-κ 3 C -C(CN)N(Me)(CH 2 CHCH 2 )}], 3, containing a multidentate alkylidene-alkene ligand occupying both a bridging site and a terminal site, in admixture with the μ-(amino)alkylidyne cyanide product [Fe 2 Cp 2 (CN)(CO)(μ-CO){μ-CN(Me)(CH 2 CHCH 2 )}], 4. The reaction of the μ-(amino)alkylidyne imine complex [Fe 2 Cp 2 (CO)(μ-CO)(NHCPh 2 ){μ-CN(Me)(CH 2 CHCH 2 )}]CF 3 SO 3 , [7]CF 3 SO 3 , with NBu 4 CN gave 3 with an optimized yield of 75% via imine elimination. According to DFT calculations, 3 is less stable than its geometric isomer 4 by 13.4 kcal mol -1 and quantitative conversion to 4 was achieved by refluxing a THF solution of 3 for 2 hours. No replacement of alkene coordination occurred upon treating 3 with CO or PPh 3 . The previously unknown compounds 2, 3, 4 and [7]CF 3 SO 3 were fully characterized by analytical and spectroscopic techniques and the structure of 3 was elucidated by single crystal X-ray diffraction.

Coronavirus disease 2019 (COVID-19) is transmitted person-to-person mainly by close contact or droplets from respiratory tract. However, the actual time of viral shedding is still uncertain as well as the different routes of transmission. We aimed to characterize RNA shedding from nasopharyngeal and rectal samples in prolonged cases of mild COVID-19 in young male soldiers. Seventy patients from three different military locations were monitored after recommending to follow more strict isolation measures to prevent the spread of the virus. Then, nasopharyngeal, rectal, and blood samples were taken. SARS-CoV-2 RNA was detected by RT-PCR and specific antibodies by chemiluminescent immunoassays. The median nucleic acid conversion time (NACT) was 60 days (IQR: 7-85 days). Rectal swabs were taken in 60 % of patients. Seven patients (10 %) were positive in nasopharyngeal and rectal swabs, and five (7.14 %) remained positive in rectal swabs, but negative in nasopharyngeal samples. Four patients (5.71 %) that had been discharged, were positive again after 15 days. No significant difference was found in nucleic acid conversion time between age groups nor clinical classification. Maintaining distancing among different positive patients is essential as a possible re-exposure to the virus could cause a longer nucleic acid conversion time in SARS-COV-2 infections.

Nitriles (N≡CR) are ubiquitous in coordination chemistry, yet literature studies on metal-nitrile bonding based on a multi-technique approach are rare. We selected an easily-available di-organoiron framework, containing both π-acceptor (CO, aminocarbyne) and donor (Cp = η 5 -C 5 H 5 ) ligands, as a suitable system to provide a comprehensive description of the iron-nitrile bond. Thus, the new nitrile (2-12)CF 3 SO 3 and the related imine/amine complexes (8-9)CF 3 SO 3 were synthesized in 58-83% yields from the respective tris-carbonyl precursors (1a-d)CF 3 SO 3 , using the TMNO strategy (TMNO = trimethylamine-N-oxide). The products were fully characterized by elemental analysis, IR (solution and solid state) and multinuclear NMR spectroscopy. In addition, the structures of (2)CF 3 SO 3 , (3)CF 3 SO 3 , (5)CF 3 SO 3 and (11)CF 3 SO 3 were ascertained by single crystal X-ray diffraction. Salient spectroscopic data of the nitrile complexes are coherent with the scale of electron-donor power of the R substituents; otherwise, this scale does not match the degree of Fe → N π-back-donation and the Fe-N bond energies, which were elucidated in (2-7)CF 3 SO 3 by DFT calculations.

The Early Start Denver Model (ESDM) is an evidence-based early intervention model for young children with autism spectrum disorder (ASD). It is crucial to investigate the feasibility of the ESDM in community settings in contexts that are culturally different from American universities in which the model was originally developed. The aim was to further evaluate the effectiveness of the ESDM delivered within the Italian community setting at low intensity. We compared a group aged 19 to 43 months receiving the ESDM for 2 h per week over the course of 1 year with a concurrent, comparable, non-randomized control group receiving treatment as usual (TAU). Children were evaluated at baseline (T0) and after 6 months (T1) and 12 months (T2) of intervention. Feasibility was evaluated by parent and therapist questionnaires, retention rate, and therapist treatment fidelity. Both groups made similar gains in cognition and language abilities. The ESDM group made larger improvement in domains measured by the ESDM Curriculum Checklist, including communication, social skills, and maladaptive behaviors. Feasibility seemed well supported by retentions, therapists and parent satisfaction, and treatment fidelity. Our study further supports the feasibility of the ESDM implemented within the Italian public health system and suggests a better response in the ESDM-treated group than in the control group.

The catalytic potential of ammonium halide salts was explored in the coupling reaction of a model aziridine with carbon dioxide, highlighting the superior activity of [NH2Et2]I. Then, working at room temperature, atmospheric CO2 pressure and in the absence of solvent, the [NH2Et2]I-catalyzed synthesis of a series of 5-aryl-2-oxazolidinones was accomplished in good to high yields and excellent selectivity, from 2-aryl-aziridines with N-methyl or N-ethyl groups. NMR studies and DFT calculations outlined the pivotal role of both the diethylammonium cation and the iodide anion. The proposed method represents a convenient choice for obtaining a limited number of valuable molecules for which more complex and more expensive catalytic systems have been reported even in recent years.

The catalytic potential of a large series of easily available metal carbamates (based on thirteen different non-precious metal elements) was explored for the first time in the coupling reaction between 2-aryl-aziridines and carbon dioxide, working under solventless and ambient conditions and using tetraalkylammonium halides as co-catalysts. The straightforward synthesis of novel [NbCl3(O2CNEt2)2], NbCl, and [NbBr3(O2CNEt2)2], NbBr, is reported. The niobium complex NbCl, in combination with NBu4I, emerged as the best catalyst of the overall series to convert aziridines with small N-alkyl substituents into the corresponding 5-aryl-oxazolidin-2-ones.

The development of sustainable synthetic routes to access valuable oxazolidinones via CO 2 fixation is an active research area, and the aziridine/carbon dioxide coupling has aroused a considerable interest. This reaction features a high activation barrier and thus requires a catalytic system, and may present some other critical issues. Here, the straightforward gram-scale synthesis of a series of 5-aryl-2-oxazolidinones was developed at ambient temperature and atmospheric CO 2 pressure, in the absence of any catalyst/co-catalyst. The key to this innovative procedure consists in the direct transfer of the pre-formed amine/CO 2 adduct (carbamate) to common aziridine precursors (dimethylsulfonium salts), replacing the classical sequential addition of amine (intermediate isolation of aziridine) and then CO 2 . The reaction mechanism was investigated by NMR spectroscopy and DFT calculations applied to model cases., (© 2020 Wiley-VCH GmbH.)

Following a related review dating back to 2003, the present review discusses in detail the various synthetic, structural and reactivity aspects of metal species containing one or more carbamato ligands, representing a large family of compounds across all the periodic table. A preliminary overview is provided on the reactivity of carbon dioxide with amines, and emphasis is given to recent findings concerning applications in various fields.

Caffeine, a xanthine alkaloid compound, is consumed widely and daily by humans, as it is present in several regular beverages such as tea, coffee, soda beverages, and some drugs. Its consumption triggers arousal and alertness, improves mood, and causes the release of catecholamines, which induce beneficial effects on human behavior. Nonetheless, caffeine has been related to other beneficial effects such as antioxidant and anti-inflammatory actions that are extremely important to human health, altering the cellular redox and inflammatory status in a dose-dependent manner. Caffeine intake has also shown ergogenic effects, which are attributed to different factors, such as enhanced substrate utilization, fatigue delay, and alertness. As such, caffeine has been consumed by athletes from different sports modalities, with positive and negative effects declared. Although peripheral tissues such as the heart, skeletal muscle, and adipocytes are also impacted, there is a deficit of recognized mechanisms in systemic metabolism when compared to caffeine action in the central nervous system. This review summarizes the most relevant classical and current literature available regarding the use of caffeine in different metabolic situations, such as oxidative and inflammatory status, as well as anaerobic and aerobic physical exercises. Here, we identified the non-central nervous system caffeine mechanisms modulation, as most are still unknown or controversial, highlighting its influence in the peripheral system and its essential and crucial impacts on the human's organism adaptation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs) are considered as promising nanoparticle theranostic tools in many pathological contexts. The increasing clinical employment of therapeutic nanoparticles is contributing to the development of a new research area related to the design of artificial EVs. To this aim, different approaches have been described to develop mimetic biologically functional nanovescicles. In this paper, we suggest a simplified procedure to generate plasma membrane-derived nanovesicles with the possibility to efficiently encapsulate different drugs during their spontaneously assembly. After physical and molecular characterization by Tunable Resistive Pulse Sensing (TRPS) technology, transmission electron microscopy, and flow cytometry, as a proof of principle, we have loaded into mimetic EVs the isoquinoline alkaloid Berberine chloride and the chemotherapy compounds Temozolomide or Givinostat. We demonstrated the fully functionality of these nanoparticles in drug encapsulation and cell delivery, showing, in particular, a similar cytotoxic effect of direct cell culture administration of the anticancer drugs. In conclusion, we have documented the possibility to easily generate scalable nanovesicles with specific therapeutic cargo modifications useful in different drug delivery contexts., Competing Interests: The authors declare no conflict of interest.

As there is growing evidence for the tumor microenvironment's role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple-negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of cancer progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was barely detectable in breast cancer (BC) cell lines. Genetic and pharmacological gain- and loss-of-function experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cδ confers its protumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, that led to upregulation of NR4A1 in TNBC cells, where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, along with a decrease in tumor metastasis, emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA data sets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease-free survival, highlighting it as a therapeutic target for TNBC.

Standardized screening programs ensure that children are monitored for early signs of autism spectrum disorder (ASD) in order to promote earlier diagnosis and intervention. The aim of this study is to identify early signs of atypical development consistent with ASD or other developmental disorders in a population of 224 low-risk toddlers through a two-stage screening approach applied at 12 and 18 months of age. We adopted two screening tools combined: 1. the Communication and Symbolic Behavior Scales Developmental Profile (CSBS DP) Infant-Toddler Checklist (I-TC) and 2. The Quantitative Checklist for Autism in Toddlers (Q-CHAT). We assessed their sensitivity and specificity related to the diagnostic outcome at 36 months. The results showed that autistic signs can be detected as early as the first year even through a few questions extrapolated from both screeners and that our model could be used as a screening procedure in the Italian public health system.

Background: The use of NSAIDs has become a common practice to counteract the pro-inflammatory acute effects of exercise, in order to improve sports performance. The liver, due to its central role in energy metabolism, may be involved primarily in the process of ROS generation and consequently inflammation after exhaustive exercise., Objective: To analyze the influence of diclofenac on the liver TLR4 pathway and time to exhaustion in rats submitted to repeated exhaustive swimming., Methods: An exhaustive test was performed in order to mimic athletes' routine, and inflammatory status and oxidative stress markers were evaluated in the liver. Animals were divided into sedentary and exhaustion groups, with this last performing three exhaustive swimming bouts. At the same time, diclofenac or saline was pre-administered once a day for nine days., Results: Data showed significantly increased COX-2, TLR4, and MyD88 protein content in the liver after exhaustive swimming bouts. The levels of pro-inflammatory cytokines also increased after exhaustive exercise, while these effects were attenuated in the group treated with diclofenac plus exhaustive swimming bouts. The anti-inflammatory modulation provoked by diclofenac treatment was associated with an increased time to exhaustion in the exercise bouts. The exhaustive exercise increased TBARS formation, but diclofenac treatment blunted this elevation, while GSH/GSSG ratios in both exhaustion-saline and exhaustion-diclofenac-treated groups were lower than in the sedentary-saline group., Conclusions: Our findings suggest that diclofenac may improve exercise performance and represent an effective tool to ameliorate the pro-inflammatory status in liver when associated with exhaustive exercise, and the liver may be a possible therapeutic target., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pancreatic Neuroendocrine Neoplasms (pNEN) are rare tumors which treatment still represent an important clinical problem, due to the paucity of medical treatments. Due to tumor complexity, techniques as 3D cultures are important to study drug activity in a more realistic model. This study aims to compare three different 3D culture methods in order to understand which one can be considered the best option in terms of experimental easiness and reproducibility in studying the efficacy of a target drug on pNEN. The BON1 cell line was used as a pNEN model and the well-known Receptor Tyrosine Kinase inhibitor Sunitinib was used in order to better investigate the different features of each method. The investigated methods are: (1) 96-well hanging drop plates (HD plates), (2) 24-well plates with a cell-repellent surface, and (3) ultra-low attachment 96-well plates with clear round bottom (ULA plates). The evaluated parameters during the study were: cell seeding, easiness in spheroids formation, morphology, culture maintenance, medium change, spheroids monitoring, picture quality, spheroid perimeter measurement reproducibility error, possibility to perform assays into the seeding plate, overall time of the experiment. Moreover, we investigated how culture methods can influence experimental outcomes evaluating perimeter changes, cell viability and immunohistochemistry of spheroids treated with different Sunitinib concentrations. Results showed that each method has weak and strong points but, considering the easiness of spheroids maintenance and reproducibility results, ULA plates method appears to be the best approach to culture BON1 spheroids and, therefore, to study pNEN., (Copyright © 2019 Bresciani, Hofland, Dogan, Giamas, Gagliano and Zatelli.)

Broncho-pulmonary neuroendocrine neoplasms (BP-NENs) are neoplasms orphan of an efficient therapy. Available medical treatments derived from clinical trials are not specific for the management of this malignancy. Sunitinib is a multi-receptor tyrosine-kinases (RTKs) inhibitor that has already shown its efficacy in NENs, but there are no available data about its action in BP-NENs. Therefore, our aim was to understand the effects of RTKs inhibition promoted by sunitinib in order to evaluate new putative targets useful in malignancy treatment. Since our results underlined a role for EGFR and IGF1R in modulating sunitinib antiproliferative action, we investigated the effects of erlotinib, an EGFR inhibitor, and linsitinib, an IGF1R inhibitor, in order to understand their function in regulating cells behaviour. Cell viability and caspase activation were evaluated on two immortalised human BP-NEN cell lines and primary cultures. Our results showed that after treatment with sunitinib and/or IGF1, EGF and VEGF, the antiproliferative effect of sunitinib was counteracted by EGF and IGF1 but not by VEGF. Therefore, we evaluated with AlphaScreen technology the phosphorylated EGFR and IGF1R levels in primary cultures treated with sunitinib and/or EGF and IGF1. Results showed a decrease of p-IGF1R after treatment with sunitinib and an increase after co-treatment with IGF1. Then, we assessed cell viability and caspase activation on BP-NEN cell lines after treatment with linsitinib and/or erlotinib. Results demonstrate that these two agents have a stronger antiproliferative effect compared to sunitinib. In conclusion, our results suggest that IGF1R and EGF1R could represent putative molecular targets in BP-NENs treatment.

This study investigate the effects of high-intensity interval training (HIIT) on systemic levels of inflammatory and hormonal markers in postmenopausal women with metabolic syndrome (MS). Fifteen postmenopausal women with MS completed the training on treadmills. Functional, body composition parameters, maximal oxygen uptake (VO 2 max), and lipid profile were assessed before and after HIIT. Serum or plasma levels of cytokines and hormonal markers were measured along the intervention. The analysis of messenger RNA (mRNA) expression of these cytokines was performed in peripheral blood mononuclear cells (PBMC). VO 2 max and some anthropometric parameters were improved after HIIT, while decreased levels of proinflammatory markers and increased levels of interleukin-10 (IL-10) were also found. Adipokines were also modulated after 12 weeks or training. The mRNA expression of the studied genes was unchanged after HIIT. In conclusion, HIIT benefits inflammatory and hormonal axis on serum or plasma samples, without changes on PBMC of postmenopausal MS patients.

Aging is characterised by a gradual loss of the functional reserve. This, along with the fostering of sedentary habits and the increase in risk factors, causes a deterioration of antioxidant defences and an increase of the circulatory levels of inflammatory and oxidative markers, boosting a low-rate chronic inflammation, defined as inflamm-aging. This phenomenon is present in the aetiopathology of chronic diseases, as well as in cognitive deterioration cases associated with aging. The objective of this review is to describe the modulation of antioxidant and anti-inflammatory effects of physical exercise of moderate intensity and volume in the elderly. Evidence of its effectiveness as a non-pharmacological resource is presented, which decreases some deleterious effects of aging. This is mainly due to its neuroprotective action, the increase in circulating anti-inflammatory markers, and the improvement of antioxidant defence derived from its practice., (Copyright © 2018 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.)

Easily available and inexpensive Fe III carbamates were employed in the solvent-free synthesis of a series of cyclic carbonates from epoxides and CO 2 at room temperature and atmospheric pressure, in the presence of a cocatalyst. Different experimental conditions (type and concentration of catalyst and cocatalyst, as well as reaction time) were investigated: Fe(O 2 CNEt 2 ) 3 and NBu 4 Br acted as the best catalyst/cocatalyst combination, allowing the formation of propylene carbonate and 1,2-butylene carbonate with quantitative yield and selectivity in 24 h. According to NMR and DFT studies, the reaction proceeds with the dynamic trapping of carbon dioxide as a carbamato ligand., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Donation of returned medicines is a debated health policy issue as it is discouraged by WHO, but accepted in some countries., Methods: Lessons learned from a donation programme of returned medicines carried out in Europe were documented., Results: The donation programme we reviewed followed a strict protocol for collection, sorting and distribution of returned drugs, in order to avoid the major limitations associated with unused medicine donations. Over a period of 3 years, 23 145 boxes of medicines were donated to 14 organizations operating in Europe, Africa and Latin America., Conclusions: The donations covered about one-third of the volume of medicines used by beneficiary organizations. The programme helped to decrease expenditure by both patients and health facilities.

The authors report the first modification of ionic liquids with metal carbamates. A selection of homoleptic N,N-dialkylcarbamates of group 4 and 5 metals, M(O 2 CNR 2 ) n , were dissolved in bis(trifluoromethylsulfonyl)imide-based ionic liquids, i.e. [bmim][Tf 2 N] and [P(oct) 4 ][Tf 2 N], at 293 K. The resulting solutions were characterized by means of IR, UV and NMR spectroscopy, and the data were compared to those of the respective metal compounds. Notably, the dissolution process did not proceed with the release of any of the original carbamato ligands, thus preserving the intact coordination frame around the metal centre. The solvation process of Ti(O 2 CN i Pr 2 ) 4 , as a model species, in [bmim][Tf 2 N] was rationalized by DFT calculations. As a comparative study, solutions of NbF 5 and MCl 5 (M = Nb, Ta) in [bmim][Tf 2 N] were also investigated, revealing the possible occurrence of solvent anion coordination to the metal centres.

Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Key Points: An early inflammatory response and oxidative stress are implicated in the signal transduction that alters both hepatic redox status and mitochondrial function after traumatic brain injury (TBI). Peripheral oxidative/inflammatory responses contribute to neuronal dysfunction after TBI Exercise training alters the profile of oxidative-inflammatory status in liver and protects against acute hyperglycaemia and a cerebral inflammatory response after TBI. Approaches such as exercise training, which attenuates neuronal damage after TBI, may have therapeutic potential through modulation of responses by metabolic organs. The vulnerability of the body to oxidative/inflammatory in TBI is significantly enhanced in sedentary compared to physically active counterparts., Abstract: Although systemic responses have been described after traumatic brain injury (TBI), little is known regarding potential interactions between brain and peripheral organs after neuronal injury. Accordingly, we aimed to investigate whether a peripheral oxidative/inflammatory response contributes to neuronal dysfunction after TBI, as well as the prophylactic role of exercise training. Animals were submitted to fluid percussion injury after 6 weeks of swimming training. Previous exercise training increased mRNA expression of X receptor alpha and ATP-binding cassette transporter, and decreased inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α and interleukin (IL)-6 expression per se in liver. Interestingly, exercise training protected against hepatic inflammation (COX-2, iNOS, TNF-α and IL-6), oxidative stress (decreases in non-protein sulfhydryl and glutathione, as well as increases in 2',7'-dichlorofluorescein diacetate oxidation and protein carbonyl), which altered hepatic redox status (increases in myeloperoxidase and superoxide dismutase activity, as well as inhibition of catalase activity) mitochondrial function (decreases in methyl-tetrazolium and Δψ, as well as inhibition of citrate synthase activity) and ion gradient homeostasis (inhibition of Na + ,K + -ATPase activity inhibition) when analysed 24 h after TBI. Previous exercise training also protected against dysglycaemia, impaired hepatic signalling (increase in phosphorylated c-Jun NH2-terminal kinase, phosphorylated decreases in insulin receptor substrate and phosphorylated AKT expression), high levels of circulating and neuronal cytokines, the opening of the blood-brain barrier, neutrophil infiltration and Na + ,K + -ATPase activity inhibition in the ipsilateral cortex after TBI. Moreover, the impairment of protein function, neurobehavioural (neuromotor dysfunction and spatial learning) disability and hippocampal cell damage in sedentary rats suggests that exercise training also modulates peripheral oxidative/inflammatory pathways in TBI, which corroborates the ever increasing evidence regarding health-related outcomes with respect to a physically active lifestyle., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Background: High-intensity interval training (HIIT) improves cardiometabolic markers, but its effects on the quality of life of patients with type 2 diabetes (T2D) is not well known., Aim: To determine the effects of a 12-week HIIT exercise program on cardiometabolic and quality of life variables of T2D patients., Material and Methods: Nine T2D women were assigned to a HIIT + nutritional education (GE) and 10, to a nutritional education alone group (GC). At baseline and after each intervention, anthropometric and body composition parameters using bio-impedance were assessed, and a blood sample was obtained to measure serum lipid levels, blood glucose and glycated hemoglobin. Quality of life was assessed using the SF-12 questionnaire adapted for the Chilean population., Results: There were no significant changes on the lipid profile variables in the GE group, although HDL cholesterol was increased significantly (p < 0.05) in the GC group. Total fat mass was decreased in the GE group from 43.5 ± 1.5 to 41.9 ± 1.5%, p < 0.01. Fasting glucose and glycated hemoglobin decreased in the GE group. There was a significant correlation between the decrease in total fat mass and that of glycated hemoglobin. There were significant increases in quality of life parameters; physical function, physical role, pain, general health, vitality, emotional role, mental health, and social function in the GE but not in the GC group., Conclusions: A 12-week program of HIIT plus nutritional education improves cardiometabolic and quality of life parameters on type 2 diabetics.

Nonsteroidal anti-inflammatory drugs, such as diclofenac, are widely used to treat inflammation and pain in several conditions, including sports injuries. This study analyzes the influence of diclofenac on the toll-like receptor-nuclear factor kappa B (TLR-NF-κB) pathway in skeletal muscle of rats submitted to acute eccentric exercise. Twenty male Wistar rats were divided into 4 groups: control-saline, control-diclofenac, exercise-saline, and exercise-diclofenac. Diclofenac or saline were administered for 7 days prior to an acute eccentric exercise bout. The inflammatory status was evaluated through mRNA levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNF-α), and protein content of COX-2, IL-6, and TNF-α in vastus lateralis muscle. Data obtained showed that a single bout of eccentric exercise significantly increased COX-2 gene expression. Similarly, mRNA expression and protein content of other inflammation-related genes also increased after the acute exercise. However, these effects were attenuated in the exercise + diclofenac group. TLR4, myeloid differentiation primary response gene 88 (MyD88), and p65 were also upregulated after the acute eccentric bout and the effect was blunted by the anti-inflammatory drug. These findings suggest that pretreatment with diclofenac may represent an effective tool to ameliorate the pro-inflammatory status induced by acute exercise in rat skeletal muscle possibly through an attenuation of the TLR4-NF-κB signaling pathway.

The liver is remarkably important during exercise outcomes due to its contribution to detoxification, synthesis, and release of biomolecules, and energy supply to the exercising muscles. Recently, liver has been also shown to play an important role in redox status and inflammatory modulation during exercise. However, while several studies have described the adaptations of skeletal muscles to acute and chronic exercise, hepatic changes are still scarcely investigated. Indeed, acute intense exercise challenges the liver with increased reactive oxygen species (ROS) and inflammation onset, whereas regular training induces hepatic antioxidant and anti-inflammatory improvements. Acute and regular exercise protocols in combination with antioxidant and anti-inflammatory supplementation have been also tested to verify hepatic adaptations to exercise. Although positive results have been reported in some acute models, several studies have shown an increased exercise-related stress upon liver. A similar trend has been observed during training: while synergistic effects of training and antioxidant/anti-inflammatory supplementations have been occasionally found, others reported a blunting of relevant adaptations to exercise, following the patterns described in skeletal muscles. This review discusses current data regarding liver responses and adaptation to acute and regular exercise protocols alone or combined with antioxidant and anti-inflammatory supplementation. The understanding of the mechanisms behind these modulations is of interest for both exercise-related health and performance outcomes.

Background and Objective: Although hard training is mandatory in elite level futsal training, few studies have proposed a biochemical follow up in futsal players during a whole season. Therefore, the aim of this study was to compare functional and biochemical markers in Brazilian elite level futsal players throughout a competition season., Materials and Methods: Eight players aged 25.5±5.4 years were evaluated at three time points: preseason (T1), immediately before the FIFA ® -Intercontinental-Futsal-Cup (T2), and at the end of the season (T3), with a tapering period of 1 week before T2. Functional parameters (weight, height, body fat, VO 2 max, heart rate, and distance ran) and blood sampling for cell count and lipid profile (cholesterol, HDL-C, LDL-C, triglycerides) were assessed at each time point. After, a Yo-Yo R2 test was carried out in each time point (T1, T2 and T3) and blood samples to assess skeletal muscle damage (creatine kinase [CK], lactate dehydrogenase [LDH]), inflammation (C-reactive protein [CRP]) and oxidative stress markers (ischemia modified albumin [IMA], and advanced oxidation protein products [AOPP]) were obtained before and after the tests., Results: Although functional parameters did not change throughout the season, greater total number of erythrocytes (P≤0.05), and hemoglobin (P≤0.05) were found at T2 compared to T1. Similarly, lower LDH (P≤0.05) and CK (P≤0.05) levels were found at T2 compared to T1. CPR levels were also decreased at T2 in comparison to T1 both before and after Yo-Yo R2 test (P≤0.05), while IMA and AOPP levels showed only a season effect (P≤0.05)., Conclusions: The tapering strategy was successful considering players presented lower levels of muscle damage, inflammation and oxidative stress makers before T2, which preceded the main championship of the year. These results are of great relevance, considering the team won the FIFA ® -Intercontinental-Futsal-Cup, which happened at T2. Thus, it seems that routine-based biochemical markers may be useful as training control means in this population., (Copyright © 2017 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Sp. z o.o. All rights reserved.)

Objectives: This study investigate the effects of a high intensity interval training (HIIT) and 2 weeks of detraining in functional and body composition parameters, lipoproteins, glucose metabolismand inflammation markers in postmenopausal women with metabolic syndrome (MS). Design: 17 untrained women with MS underwent a HIIT program for 12 weeks. Methods: The training was performed in treadmills, 3 days per week, with intensity ranging from 70-90% of the maximum heart rate (HR max ) and 2 weeks untrained (inactive). Functional and body composition parameters were evaluated before and after the training, while maximal oxygen uptake, lipoprotein and inflammation markers were analyzed before, after training and also in detraining. Results: The HITT program resulted in changesparameters as glucose, HbA1cand NOx after training. In addition, a reduction in pro-inflammatory interleukins and an increase in IL-10 after the HIIT program were found. However, an increase in plasma levels of lipoprotein was found and body composition parameters remain unaltered.Besides, only 2 weeks of detraining are able to revert the effects on inflammatory parameters afforded by the HIIT program. Conclusions: The HIIT program used here positively affected inflammatory profile and other parameters, as glucose, HbA1cand NOx, on postmenopausal women with MS. Moreover, 2 weeks of detraining can reverse the beneficial effects of HIIT program. Our results point out the necessity to aply acontinuous HITT program, in order maintain the benefits detected, to post menopausal women with MS., (© Georg Thieme Verlag KG Stuttgart · New York.)

Although the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) intake by athletes prevents soreness, little is known concerning their role in exercise performance. This study assessed the effects of ibuprofen intake on an exhaustive protocol test after 6 weeks of swimming training in rats. Animals were divided into sedentary and training groups. After training, animals were subdivided into two subsets: saline or ibuprofen. Afterwards, three repeated swimming bouts were performed by the groups. Ibuprofen (15 mg/kg) was administered once a day. Pain measurements were performed and inflammatory and oxidative stress parameters were assayed in cerebral cortex and gastrocnemius muscle. Training, ibuprofen administration, or both combined (P < 0.05; 211 ± 18s, 200 ± 31s, and 279 ± 23s) increased exercise time to exhaustion. Training decreased the acetylcholinesterase (AChE) activity (P < 0.05; 149 ± 11) in cerebral cortex. Ibuprofen intake decreased the AChE activity after exhaustive protocol test in trained and sedentary rats (P < 0.05; 270 ± 60; 171 ± 38; and 273 ± 29). It also prevented neuronal tumor necrosis factor-α (TNF-α) and interleukin (IL 1β) increase. Fatigue elicited by this exhaustive protocol may involve disturbances of the central nervous system. Additive anti-inflammatory effects of exercise and ibuprofen intake support the hypothesis that this combination may constitute a more effective approach. In addition, ergogenic aids may be a useful means to prevent exercise-induced fatigue., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: It is well-known that unaccustomed exercise, especially eccentric exercise, is associated to delayed onset muscle soreness (DOMS). Whether DOMS is associated with reactive oxygen species (ROS) and the transient receptor potential vanilloid 1 (TRPV1) is still an open question. Thus, the aim of this study was to investigate the association between TRPV1 and xanthine oxidase-related ROS production in muscle and DOMS after a bout of eccentric exercise., Main Methods: Male Wistar rats performed a downhill running exercise on a treadmill at a -16° tilt and a constant speed for 90min (5min/bout separated by 2min of rest). Mechanical allodynia and grip force tests were performed before and 1, 3, 6, 9, 12, 24, 48 and 72h after the downhill running. Biochemical assays probing oxidative stress, purine degradation, xanthine oxidase activity, Ca(2+) ATPase activity and TRPV1 protein content were performed in gastrocnemius muscle at 12, 24, and 48h after the downhill running., Key Findings: Our statistical analysis showed an increase in mechanical allodynia and a loss of strength after the downhill running. Similarly, an increase in carbonyl, xanthine oxidase activity, uric acid levels and TRPV1 immunoreactivity were found 12h post-exercise. On the other hand, Ca(2+) ATPase activity decreased in all analyzed times., Significance: Our results suggest that a possible relationship between xanthine oxidase-related ROS and TRPV1 may exist during the events preceding eccentric exercise-related DOMS., (Copyright © 2016 Elsevier Inc. All rights reserved.)