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Abstract Three new chromophores based on difluoroborondipyrromethene dyes (Bodipy‐1, Bodipy‐2, and Bodipy‐3) are used as precursors to prepare luminescent solar concentrators (LSC) based on poly‐acrylate, following a thermally activated polymerization involving lauryl methacrylate as monomer, ethyl glycol dimethacrylate as cross‐linking agent, and lauroyl peroxide as initiator. The new dyes exhibit typical BODIPY absorption and emission properties in dichloromethane fluid solution, assigned to the lower‐lying singlet π–π∗ level, which in the case of Bodipy‐2 and Bodipy‐3, both containing diamino‐substituted styryl subunits in their structure, has a strong charge transfer contribution. The LSCs obtained starting from each of the three Bodipys are interfaced to silicon photovoltaic (PV) cells, and the PV light‐to‐energy conversion efficiencies ηopt for the three systems are calculated. The results yield ηopt of 4.53% for LSC‐Bodipy‐1, 5.26% for LSC‐Bodipy‐2, and 8.23% for LSC‐Bodipy‐3. The optical efficiency for LSC‐Bodipy‐3 is a remarkable value among the LSC based on organic dyes.

A low level of Neurotrophins (NTs), their Tyrosine Kinase Receptors (Trks), Vascular Endothelial Growth Factors (VEGFs) and their receptors, mainly VEGFR1 and VEGFR2, characterizes AD brains. The use of NTs and VEGFs as drugs presents different issues due to their low permeability of the blood−brain barrier, the poor pharmacokinetic profile, and the relevant side effects. To overcome these issues, different functional and structural NT mimics have been employed. Being aware that the N-terminus domain as the key domain of NTs for the binding selectivity and activation of Trks and the need to avoid or delay proteolysis, we herein report on the mimicking ability of two cyclic peptide encompassing the N-terminus of Brain Derived Growth Factor (BDNF), (c-[HSDPARRGELSV-]), cBDNF(1-12) and of Neurotrophin3 (NT3), (c-[YAEHKSHRGEYSV-]), cNT3(1-13). The two cyclic peptide features were characterized by a combined thermodynamic and spectroscopic approach (potentiometry, NMR, UV-vis and CD) that was extended to their copper(II) ion complexes. SH-SY5Y cell assays show that the Cu2+ present at the sub-micromolar level in the complete culture media affects the treatments with the two peptides. cBDNF(1-12) and cNT3(1-13) act as ionophores, induce neuronal differentiation and promote Trks and CREB phosphorylation in a copper dependent manner. Consistently, both peptide and Cu2+ stimulate BDNF and VEGF expression as well as VEGF release; cBDNF(1-12) and cNT3(1-13) induce the expression of Trks and VEGFRs.

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (−)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation.

The treatment of biological samples, especially from complex matrices, has consistently challenged analytical operators. The classic problems to be faced for any analysis, regardless of the origin of the sample, such as for example contamination and loss of analyte, in biological samples, are particularly emphasized. In particular, the main cause of the error is due to the degradation of the analyte which in several cases due to biological interaction. Many factors can influence the stability of drugs, chief among them the physicochemical properties of the drug, characteristics of the matrix, the tendency to conjugation/deconjugation, sample collection procedure, container characteristics (e.g., oxidation, adsorption), and the use of preservatives or other additives. The problem is severe in the toxicological and forensic fields, especially for analyzes considered ''non-repeatable.'' In this review, we will explore all the major problems in the pre-extraction phase for the chemical-analytical aspect in the pharmacotoxicological and forensic fields.

Stem cell differentiation requires dramatic changes in gene expression and global remodeling of chromatin architecture. How and when chromatin remodels relative to the transcriptional, behavioral, and morphological changes during differentiation remain unclear, particularly in an intact tissue context. Here, we develop a quantitative pipeline which leverages fluorescently-tagged histones and longitudinal imaging to track large-scale chromatin compaction changes within individual cells in a live mouse. Applying this pipeline to epidermal stem cells, we reveal that cell-to-cell chromatin compaction heterogeneity within the stem cell compartment emerges independent of cell cycle status, and instead is reflective of differentiation status. Chromatin compaction state gradually transitions over days as differentiating cells exit the stem cell compartment. Moreover, establishing live imaging of Keratin-10 (K10) nascent RNA, which marks the onset of stem cell differentiation, we find that Keratin-10 transcription is highly dynamic and largely precedes the global chromatin compaction changes associated with differentiation. Together, these analyses reveal that stem cell differentiation involves dynamic transcriptional states and gradual chromatin rearrangement.

Robustness in developing and homeostatic tissues is supported by various types of spatiotemporal cell-to-cell interactions. Although live imaging and cell tracking are powerful in providing direct evidence of cell coordination rules, extracting and comparing these rules across many tissues with potentially different length and timescales of coordination requires a versatile framework of analysis. Here we demonstrate that graph neural network (GNN) models are suited for this purpose, by showing how they can be applied to predict cell fate in tissues and utilized to infer the cell interactions governing the multicellular dynamics. Analyzing the live mammalian epidermis data, where spatiotemporal graphs constructed from cell tracks and cell contacts are given as inputs, GNN discovers distinct neighbor cell fate coordination rules that depend on the region of the body. This approach demonstrates how the GNN framework is powerful in inferring general cell interaction rules from live data without prior knowledge of the signaling involved.

A series of copper(II) complexes with the formula [Cu2+Hy(x)Car%] varying the molecular weight (MW) of Hyaluronic acid (Hy, x = 200 or 700 kDa) conjugated with carnosine (Car) present at different loading were synthesized and characterized via different spectroscopic techniques. The metal complexes behaved as Cu, Zn-superoxide dismutase (SOD1) mimics and showed some of the most efficient reaction rate values produced using a synthetic and water-soluble copper(II)-based SOD mimic reported to date. The increase in the percentage of Car moieties parallels the enhancement of the I50 value determined via the indirect method of Fridovich. The presence of the non-functionalized Hy OH groups favors the scavenger activity of the copper(II) complexes with HyCar, recalling similar behavior previously found for the copper(II) complexes with Car conjugated using β-cyclodextrin or trehalose. In keeping with the new abilities of SOD1 to activate protective agents against oxidative stress in rheumatoid arthritis and osteoarthritis diseases, Cu2+ interaction with HyCar promotes the nuclear translocation of erythroid 2-related factor that regulates the expressions of target genes, including Heme-Oxigenase-1, thus stimulating an antioxidant response in osteoblasts subjected to an inflammatory/oxidative insult.

Arthroscopic rotator cuff repair can be challenging and requires adequate visualization and space. However, the narrow subacromial space can make difficult to perform tendon release and repair under arthroscopy. Inadequate visualization may lead to inaccurate suture placement, compromising the reduction and fixation of the repaired rotator cuff tendons. Manual or mechanical distraction (using an arm positioner) can be used to increase the working space. However, consistent distraction is very difficult to maintain manually over time due to fatigue, whereas mechanical distraction may overstretch the brachial plexus. To overcome these difficulties, we describe a technique using a specific laminar spreader for subacromial distraction during arthroscopic rotator cuff repair. The arthroscopic laminar spreader, inserted into the subacromial space, is used to distract the humeral head inferiorly from the acromion, improving subacromial space visualization and enabling easily rotator cuff release and repair. The shoulder distraction device improves the surgeon’s performance without surgical assistance and allows reducing the operative time with safety. It can be also used anteriorly (to repair the subscapularis) or posteriorly (to repair the infraspinatus and teres minor) or to perform other procedures like superior capsular reconstruction or additional patch.

One of the most discussed topics concerns the sample preparation before the analysis and, therefore, all the operations necessary to eliminate the interferents, clean up the specimens, and extract the analytes of interest, reducing the matrix effect. This review highlights the fundamental steps in the treatment of postmortem samples used in forensic analysis. Through critical literature research, it was possible to choose among the countless works that could provide a general overview of the state-of-the-art in this field. Different biological matrices have been considered; blood and urine (the traditional biological fluids) are used to investigate the presence of substances that may have caused death, whilst other body fluids, such as bile and oral fluids, are still under discussion for their usability (and suitability). In the second part of the review, all the solid matrices obtained after autopsy were further divided into conventional and unconventional matrices to facilitate proper understanding. The choice of literature was also made according to the most widely used pretreatment techniques and the most representative innovative techniques.

The primary cause of poor and ambiguous results obtained from the bioanalytical process is the sample pre-treatment, especially in clinical analysis because it involves dealing with complex sample matrices, such as whole blood, urine, saliva, serum, and plasma. So, the aim of this review is to focus attention on the classical and new techniques of pre-treatment for biological samples used in the bioanalytical process. We discussed the methods generally used for these types of complex samples. Undoubtedly, it is a daunting task to deal with biological samples because the analyst may encounter a substantial loss of the analytes of interest, or the overall analysis may be too time-consuming. Nowadays, we are inclined to use green solvents for the environment, but without sacrificing analytical performance and selectivity. All the characteristics mentioned above should be added to the difficulty of the withdrawal of samples like blood because it can be an invasive practice. For these reasons, now we can also find in the literature the use of saliva as alternative biological samples and new techniques that do not require substantial sample pre-treatment, such as fabric phase sorptive extraction (FPSE). The text has been divided into the following two distinct parts: firstly, we described clinical applications under different subsections, such as anticancer drugs, antibiotics, vitamins, antivirals, non-steroidal anti-inflammatory drugs, statin, imidazoles, and triazoles. The second part is dedicated to sample preparation techniques for diagnostic purposes and is divided into the following different sample preparation techniques: solid-phase microextraction (SPME), microextraction by packed sorbent (MEPS), dispersive liquid–liquid microextraction (DDLME), and fabric phase sorptive extraction (FPSE).

Hyaluronic acid (Hy) is a natural linear polymer that is widely distributed in different organisms, especially in the articular cartilage and the synovial fluid. During tissue injury due to oxidative stress, Hy plays an important protective role. All the beneficial properties of Hy make the polymer attractive for many biomedical uses; however, the low stability and short biological half-life limit Hy application. To overcome these problems, the addition of small antioxidant molecules to Hy solution has been employed to protect the molecular integrity of Hy or delay its degradation. Carnosine (β-alanyl-L-histidine, Car) protects cells from the damage due to the reactive species derived from oxygen (ROS), nitrogen (RNS) or carbonyl groups (RCS). Car inhibits the degradation of hyaluronan induced by free radical processes in vitro but, like Hy, the potential protective action of Car is drastically hampered by the enzymatic hydrolysis in vivo. Recently, we conjugated Hy to Car and the derivatives (HyCar) showed protective effects in experimental models of osteoarthritis and rheumatoid arthritis in vivo. Here we report the antioxidant activity exerted by HyCar against ROS, RNS and RCS. Moreover, we tested if the covalent conjugation between Hy and Car inhibits the enzymatic hydrolysis of the polymer and the dipeptide backbone. We found that the antioxidant properties and the resistance to the enzymatic hydrolysis of Hy and Car are greatly improved by the conjugation.

Several studies demonstrated the pharmacological actions of carnosine as well as hyaluronic acid (HA) during joint inflammation. In that regard, the aim of this study was to investigate the protective effect of a new HA -Carnosine conjugate (FidHycarn) on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA). CIA was induced by two intradermal injections of 100 μl of an emulsion of collagen (CII) and complete Freund's adjuvant (CFA) at the base of the tail on day 0 and 21. At 35 day post CIA induction, the animals were sacrificed.CII injection caused erythema and edema in the hind paws, histological alterations with erosion of the joint cartilage as well as behavioral changes. Oral treatment with FidHycarn starting at the onset of arthritis (day 25) ameliorated the clinical signs, improved behavioral deficits as well as decreased histological and radiographic alterations. The degree of oxidative damage evaluated by inducible nitric oxide synthase (iNOS), nitrotyrosine, poly-ADP-ribose (PAR) expressions and malondialdehyde (MDA) levels, was also significantly reduced in Carnosine+HA association and FidHycarn treated mice. Moreover, the levels of proinflammatory cytokines and chemokines and cyclo-oxygenase COX-2 enzyme were also more significantly reduced by Carnosine+HA and FidHycarn compared to carnosine alone. However, interestingly, in some cases, the effects of FidHycarn were more important than Carnosine+HA association and not statistically different to methotrexate (MTX) used as positive control.Thus, the conjugation of Carnosine with HA (FidHycarn) could represent an interesting therapeutic strategy to combat arthritis disorders.

Efficient, wide-scale testing for SARS-CoV-2 is crucial for monitoring the incidence of the infection in the community. The gold standard for COVID-19 diagnosis is the molecular analysis of epithelial secretions from the upper respiratory system captured by nasopharyngeal (NP) or oropharyngeal swabs. Given the ease of collection, saliva has been proposed as a possible substitute to support testing at the population level. Here, we used a novel saliva collection device designed to favour the safe and correct acquisition of the sample, as well as the processivity of the downstream molecular analysis. We tested 1003 nasopharyngeal swabs and paired saliva samples self-collected by individuals recruited at a public drive-through testing facility. An overall moderate concordance (68%) between the two tests was found, with evidence that neither system can diagnose the infection in 100% of the cases. While the two methods performed equally well in symptomatic individuals, their discordance was mainly restricted to samples from convalescent subjects. The saliva test was at least as effective as NP swabs in asymptomatic individuals recruited for contact tracing. Our study describes a testing strategy of self-collected saliva samples, which is reliable for wide-scale COVID-19 screening in the community and is particularly effective for contact tracing.

l-carnosine (β-alanyl-l-histidine) (Car hereafter) is a natural dipeptide widely distributed in mammalian tissues and reaching high concentrations (0.7–2.0 mM) in the brain. The molecular features of the dipeptide underlie the antioxidant, anti-aggregating and metal chelating ability showed in a large number of physiological effects, while the biological mechanisms involved in the protective role found against several diseases cannot be explained on the basis of the above-mentioned properties alone, requiring further research efforts. It has been reported that l-carnosine increases the secretion and expression of various neurotrophic factors and affects copper homeostasis in nervous cells inducing Cu cellular uptake in keeping with the key metal-sensing system. Having in mind this l-carnosine ability, here we report the copper-binding and ionophore ability of l-carnosine to activate tyrosine kinase cascade pathways in PC12 cells and stimulate the expression of BDNF. Furthermore, the study was extended to verify the ability of the dipeptide to favor copper signaling inducing the expression of VEGF. Being aware that the potential protective action of l-carnosine is drastically hampered by its hydrolysis, we also report on the behavior of a conjugate of l-carnosine with trehalose that blocks the carnosinase degradative activity. Overall, our findings describe a copper tuning effect on the ability of l-carnosine and, particularly its conjugate, to activate tyrosine kinase cascade pathways.

Glycyrrhetic acid (GA) and stearyl glycyrrhetinate (SG) are two interesting compounds from Glycyrrhiza glabra, showing numerous biological properties widely applied in the pharmaceutical and cosmetic fields. Despite these appreciable benefits, their potential therapeutic properties are strongly compromised due to unfavourable physical-chemical features. The strategy exploited in the present work was to develop solid lipid nanoparticles (SLNs) as carrier systems for GA and SG delivery. Both formulations loaded with GA and SG (GA-SLNs and SG-SLNs, respectively) were prepared by the high shear homogenization coupled to ultrasound (HSH-US) method, and we obtained good technological parameters. DSC was used to evaluate their thermotropic behaviour and ability to act as carriers for GA and SG. The study was conducted by means of a biomembrane model (multilamellar vesicles; MLVs) that simulated the interaction of the carriers with the cellular membrane. Unloaded and loaded SLNs were incubated with the biomembranes, and their interactions were evaluated over time through variations in their calorimetric curves. The results of these studies indicated that GA and SG interact differently with MLVs and SLNs; the interactions of SG-SLNs and GA-SLNs with the biomembrane model showed different variations of the MLVs calorimetric curve and suggest the potential use of SLNs as delivery systems for GA.

Moringa oleifera (MO) is a medicinal plant that has been shown to possess antioxidant, anticarcinogenic and antibiotic activities. In a rat model, MO extract (MOe) has been shown to have a protective effect against brain damage and memory decline. As an extending study, here, we have examined the protective effect of MOe against oxidative stress and apoptosis caused in human neuroblastome (SH-SY5Y) cells by di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to induce neurotoxicity. Our data show that MOe prevents oxidative damage by lowering reactive oxygen species (ROS) formation, restoring mitochondrial respiratory chain complex activities, and, in addition, by modulating the expression of vitagenes, i.e., antioxidant proteins Nrf2 and HO-1. Moreover, MOe prevented neuronal damage by partly inhibiting endoplasmic reticulum (ER) stress response, as indicated by decreased expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and Glucose-regulated protein 78 (GRP78) proteins. MOe also protected SH-SY5Y cells from DEHP-induced apoptosis, preserving mitochondrial membrane permeability and caspase-3 activation. Our findings provide insight into understanding of molecular mechanisms involved in neuroprotective effects by MOe against DEHP damage.

Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (β-alanyl-L-histidine) and hydrogen sulfide (H2S) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The pathophysiological link of this crosstalk is represented by oxidative stress and inflammatory processes which contribute to the high prevalence of neuropsychiatric disorders, cognitive impairment, and dementia during the natural history of chronic kidney disease. Herein, we provide an overview of the main pathophysiological mechanisms related to high levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and neurotoxins, which play a critical role in the kidney–brain crosstalk. The present paper also explores the respective role of H2S and carnosine in the modulation of oxidative stress and inflammation in the kidney–brain axis. It suggests that these activities are likely mediated, at least in part, via hormetic processes, involving Nrf2 (Nuclear factor-like 2), Hsp 70 (heat shock protein 70), SIRT-1 (Sirtuin-1), Trx (Thioredoxin), and the glutathione system. Metabolic interactions at the kidney and brain axis level operate in controlling and reducing oxidant-induced inflammatory damage and therefore, can be a promising potential therapeutic target to reduce the severity of renal and brain injuries in humans.

Eggplant peels containing delphinidin-3-rutinoside or delphinidin-3-(p-coumaroylrutinoside)-5-glucoside (nasunin) were compared and characterized for antioxidant properties, using three cell-free assays with electron paramagnetic resonance (EPR) and two biological assays on human neutrophils with luminol amplified chemiluminescence (LACL). Antioxidant solutions were made with semi-purified extracts depleted in chlorogenic acid or with purified anthocyanin crystals. The semi-purified nasunin extract was higher in scavenging capacity than delphinidin-3-rutinoside in four assays (superoxide anion, hydroxyl radical, LACL, and Fremy's salt). Nasunin crystals showed higher antioxidant indices in Fremy's salt and LACL assays, with no detectable activity against the hydroxyl radical. The EC50 against free radicals was 0.4–20.6 nmol/mL in semi-purified extracts, and 1.7–73.6 nmol/mL for anthocyanin crystals. The higher activity of semi-purified extracts than crystals was attributed to other antioxidants, such as ascorbic acid, glutathione and biogenic amines, thus representing a percentage close to 30% of the total antioxidant content of eggplant peels.

Osteoarthritis (OA) is a disease that currently has no cure. There are numerous studies showing that carnosine and hyaluronic acid (HA) have a positive pharmacological action during joint inflammation. For this reason, the goal of this research was to discover the protective effect of a new carnosine conjugate with hyaluronic acid (FidHycarn) on the inflammatory response and on the cartilage degradation in an in vivo experimental model of OA. This model was induced by a single intra-articular (i.ar.) injection of 25 µL of normal saline with 1 mg of monosodium iodoacetate solution (MIA) in the knee joint of rats. MIA injection caused histological alterations and degradation of the cartilage, as well as behavioral changes. Oral treatment with FidHycarn ameliorated the macroscopic signs, improved thermal hyperalgesia and the weight distribution of the hind paw, and decreased histological and radiographic alterations. The oxidative damage was analyzed by evaluating the levels of nitrotyrosine and inducible nitric oxide synthase (iNOS) that were significantly reduced in FidHycarn rats. Moreover, the levels of pro-inflammatory cytokines and chemokines were also significantly reduced by FidHycarn. Therefore, for the first time, the effectiveness of oral administration of FidHycarn has been demonstrated in an osteoarthritis model. In conclusion, the new FidHycarn could represent an interesting therapeutic strategy to combat osteoarthritis.

Most tissues in our bodies undergo constant cellular turnover. This process requires a dynamic balance between cell production and elimination. Stem cells have been shown in many of these tissues to be the major source of new cells. However, despite the tremendous advances made, it still remains unclear how stem cell behavior and activity are regulated in vivo. Furthermore, we lack basic understanding for the mechanisms that coordinate niche/stem cell interactions to maintain normal tissue homeostasis. Our lab has established a novel imaging approach in live mice using the skin as a model system to investigate these fundamental processes in both physiological and pathological settings such as cancer, with the goal of understanding how tissues successfully orchestrate tissue regeneration throughout the lifetime of an organism.

Neuroblastoma is the most common pediatric cancer, arising from the neural crest cells of the sympathetic nervous system. Its most aggressive subtype, characterized by the amplification of the MYCN oncogene, has a dismal prognosis and no effective treatment is available. Understanding the alterations induced by the tumor on the various layers of gene expression is therefore important for a complete characterization of this neuroblastoma subtype and for the discovery of new therapeutic opportunities. Here we describe the profiling of 13 MYCN-amplified neuroblastoma cell lines at the genome (copy number), transcriptome, translatome and miRome levels (GEO series GSE56654, GSE56552 and GSE56655). We provide detailed experimental and data analysis procedures by means of which we derived the results described in [1].