Reactivity of a Morita-Baylis-Hillman adduct derivative bearing a triphenylamine moiety with lysine models.

The reactivity of Morita-Baylis-Hillman Adduct (MBHA) derivative 7 was studied with different primary amine derivatives such as n-butylamine, Na-acetyl-L-lysine methyl ester, and a poly-(L-lysine) derivative as lysine models to obtain information about the possible reactions in complex protein environments. MBHA derivative 7 reacted with n-butylamine or Na-acetyl-L-lysine methyl ester producing monoadducts 9a or 9c, which showed bright emission features in the green region at 526-535 nm with photoluminescence quantum yield values in solutions of 73% and 51%, respectively. Based on these results, MBHA derivative 7 can be considered an interesting new fluorogenic probe potentially useful in the labelling of basic amino acid residues. Furthermore, similar to other MBHA derivatives, compound 7 showed the tendency to produce diadducts especially in polar solvents system where specific interactions between the extended aromatic moieties may play a major role.

Cross-Linked Hyaluronan Derivatives in the Delivery of Phycocyanin.

An easy and viable crosslinking technology, based on the "click-chemistry" reaction copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (click-crosslinking), was applied to graft copolymers of medium molecular weight (i.e., 270 kDa) hyaluronic acid (HA) grafted with ferulic acid (FA) residues bearing clickable propargyl groups, as well as caffeic acid derivatives bearing azido-terminated oligo(ethylene glycol) side chains. The obtained crosslinked materials were characterized from the point of view of their structure and aggregation liability to form hydrogels in a water environment. The most promising materials showed interesting loading capability regarding the antioxidant agent phycocyanin (PC). Two novel materials complexes (namely HA(270)-FA-TEGEC-CL-20/PC and HA(270)-FA-HEGEC-CL-20/PC) were obtained with a drug-to-material ratio of 1:2 (w/w). Zeta potential measurements of the new complexes (-1.23 mV for HA(270)-FA-TEGEC-CL-20/PC and -1.73 mV for HA(270)-FA-HEGEC-CL-20/PC) showed alterations compared to the zeta potential values of the materials on their own, suggesting the achievement of drug-material interactions. According to the in vitro dissolution studies carried out in different conditions, novel drug delivery systems (DDSs) were obtained with a variety of characteristics depending on the desired route of administration and, consequently, on the pH of the surrounding environment, thanks to the complexation of phycocyanin with these two new crosslinked materials. Both complexes showed excellent potential for providing a controlled/prolonged release of the active pharmaceutical ingredient (API). They also increased the amount of drug that reach the target location, enabling pH-dependent release. Importantly, as demonstrated by the DPPH free radical scavenging assay, the complexation process, involving freezing and freeze-drying, showed no adverse effects on the antioxidant activity of phycocyanin. This activity was preserved in the two novel materials and followed a concentration-dependent pattern similar to pure PC.

A Facile Access to Green Fluorescent Albumin Derivatives.

A Morita-Baylis-Hillman Adduct (MBHA) derivative bearing a triphenylamine moiety was found to react with human serum albumin (HSA) shifting its emission from the blue to the green-yellow thus leading to green fluorescent albumin (GFA) derivatives and enlarging the platform of probes for aggregation-induced fluorescent-based detection techniques. A possible interaction of MBHA derivative 7 with a lipophilic pocket within the HSA structure was suggested by docking studies. DLS experiments showed that the reaction with HSA induce a conformational change of the protein contributing to the aggregation process of GFA derivatives. The results of investigations on the biological properties suggested that GFA retained the ability of binding drug molecules such as warfarin and diazepam. Finally, cytotoxicity evaluation studies suggested that, although the MBHA derivative 7 at 0.1 µg/mL affected the percentage of cell viability in comparison to the negative control, it cannot be considered cytotoxic, whereas at all the other concentrations≥0.5 µg/mL resulted cytotoxic at different extent.

Ferulated Poly(vinyl alcohol) based hydrogels.

New graft copolymers were prepared by reaction of poly (vinyl alcohol) (PVA) with mono-imidazolide or bis-imidazolide derivatives of ferulic acid (FA) with the formation of ester bonds. The obtained graft copolymers, thanks to the crosslinking capability of FA, formed in water strong gels as verified by rheological analyses. The resulting hydrogels were characterized to evaluate their applicability as wound dressing. In this perspective, their capability to absorb and retain a large amount of fluid without dissolving was verified by swelling kinetics and Moisture Vapour Transmission Rate measurements. Their stability towards mechanical solicitations was assessed by quantifying elasticity, compliance, stress-relaxation, and adhesivity properties. The analyses pointed out that hydrogel PVA-FA2-3 obtained by feruloylation of PVA with bis-imidazole derivative of ferulic acid using an acylation agent/polymer molar ratio 0.03/1 resulted the best candidate for the foreseen application.

A tri(ethylene glycol)-tethered Morita-Baylis-Hillman dimer in the formation of macrocyclic crown ether-paracyclophane hybrid structures.

A Morita-Baylis-Hillman acetate was dimerized by a click-chemistry Copper(i)-Catalysed Azide-Alkyne Cycloaddition (CuAAC) reaction employing a tri(ethylene glycol) diazide derivative to obtain a dimeric MBHA derivative. The reaction of this dimeric MBHA derivative with n-butylamine afforded a photoisomerizable macrocyclic crown ether-paracyclophane hybrid architecture that is potentially useful in a large variety of applications as well as those already well-known for crown ethers.

Investigation on Novel E/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity.

The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes.

[Grief: from the physiological reaction to the psychopathology.] / Lutto: dalla reazione fisiologica al disturbo da lutto prolungato.

The death of a loved one is a universal experience, and marker of the human condition. Grief, the cognitive, emotional, and behavioral responses to bereavement, is both a ubiquitous and a unique psychological process. Thus, health providers often find themselves in a dilemma, caught between the need to alleviate an individual's distress and impairment, and the danger of overly "pathologizing" their grief reaction. This chapter reviews how acute grief reactions generally evolve over time, the clinical presentation of complicated grief, and finally, other psychiatric disorders that might develop or be precipitated in the aftermath of the death of a loved one, particularly prolonged grief disorder.

PTSD trajectories across different mental disorders in the second year of the COVID-19 pandemic in Italy: a naturalistic, longitudinal, multicenter study.

The potentially traumatic impact of the COVID-19 pandemic in subjects with pre-existing mental disorders is still unclear, especially regarding its long-term consequences. The aim of this study was to prospectively assess post-traumatic stress disorder (PTSD) and post-traumatic stress symptoms (PTSS) in patients with mental disorders, during the 3rd wave of the infection (T0, March-April 2021) while strict containment measures were applied in Italy, and after 3 months (T1, June-July 2021), with reduced restrictive measures. A total sample of 527 subjects, with different DSM-5 diagnoses, was consecutively enrolled at nine Italian psychiatric outpatient services. Assessments at T0 included: the Trauma and Loss Spectrum-Self Report (TALS-SR), the Impact of Event Scale-Revised (IES-R) and the Work and Social Adjustment Scale (WSAS). These two latter were repeated at T1. Results showed that at T0, 43.6% of the sample reported symptoms of PTSD, with females (p = .004), younger subjects (p = .011), unemployed/students (p = .011), and living with their parental families (p = .017), resulting more affected. Differences in PTSD rates emerged across diagnostic groups ranging from 10% in patients with psychoses up to 59% in those with feeding and eating disorders. An improvement at T1 emerged in all diagnostic groups for the IES-R scores, while WSAS scores improved only in subjects with mood disorders. In conclusions, subjects with mental disorders presented relevant rates of PTSD and PTSS at 1-year into the pandemic. Further long-term studies are needed to follow-up the course of pandemic traumatic burden especially in patients with severe mental disorders.

Towards the engineering of a photon-only two-stroke rotary molecular motor.

The rational engineering of photoresponsive materials, e.g., light-driven molecular motors, is a challenging task. Here, we use structure-related design rules to prepare a prototype molecular rotary motor capable of completing an entire revolution using, exclusively, the sequential absorption of two photons; i.e., a photon-only two-stroke motor. The mechanism of rotation is then characterised using a combination of non-adiabatic dynamics simulations and transient absorption spectroscopy measurements. The results show that the rotor moiety rotates axially relative to the stator and produces, within a few picoseconds at ambient T, an intermediate with the same helicity as the starting structure. We discuss how such properties, that include a 0.25 quantum efficiency, can help overcome the operational limitations of the classical overcrowded alkene designs.

Design, synthesis and biological evaluation of light-driven on-off multitarget AChE and MAO-B inhibitors.

Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. In addition, an interesting tool to refine personalized therapies may arise from the use of bioactive species able to modify their activity as a result of light irradiation. To this aim, we designed and synthesized a small library of cinnamic acid-inspired isomeric compounds with light modulated activity able to inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), with remarkable selectivity over butyrylcholinesterase (BChE) and MAO-A, which have been investigated as the enzyme targets related to Alzheimer's disease (AD). The inhibitory activities were evaluated for the pure E-diastereomers and the E/Z-diastereomer mixtures, obtained upon UV irradiation. Molecular docking studies were carried out to rationalize the differences in the inhibition potency of the E and Z diastereomers of the best performing analogue 1c. Our preliminary findings may open-up the way for developing innovative multitarget photo-switch drugs against neurodegenerative diseases.

Novel analgesic/anti-inflammatory agents: 1,5-Diarylpyrrole nitrooxyethyl sulfides and related compounds as Cyclooxygenase-2 inhibitors containing a nitric oxide donor moiety endowed with vasorelaxant properties.

The design of compounds able to combine the selective inhibition of cyclooxygenase-2 (COX-2) with the release of nitric oxide (NO) is a promising strategy to achieve potent anti-inflammatory agents endowed with an overall safer profile and reduced toxicity upon gastrointestinal and cardiovascular systems. With the aim of generating novel and selective COX-2 inhibiting NO-donors (CINOD) and encouraged by the promising results obtained with our nitrooxy- and hydroxyethyl ethers 11 and 12 reported in previous works, we shifted our attention on the synthesis of isosteric thioanalogs nitrooxy- and hydroxy ethyl sulfides 13a-c and 14a-c, respectively, along with their oxidation products nitrooxy- and hydroxyethyl sulfoxides 15a-c and 16a-c, respectively, also referred to as thio-CINOD. Preliminary data and metabolic analysis highlighted how the isosteric substitution of the ethereal oxygen atom of 11a-c with sulfur in compounds 13a-c, independently from the presence and the number of fluorine atoms in N1-phenyl ring, leads to new selective and highly potent COX-2 inhibitors, capable to induce vasorelaxant responses in vivo. The same behavior is observed with their oxidized counterparts nitrooxyethyl sulfoxides 15a-c, in which the oxidation state of the sulfur atom and the presence of the additional oxygen atom play a substantial role in enhancing compounds activity and vasorelaxation. In addition, the screened compounds proved significantly efficacious in mouse models of inflammation and nociception at the dose of 20 mg/kg.

Design, Synthesis and Characterization of a Visible-Light-Sensitive Molecular Switch and Its PEGylation Towards a Self-Assembling Molecule.

HBDI-like chromophores represent a novel set of biomimetic switches mimicking the fluorophore of the green fluorescent protein that are currently studied with the hope to expand the molecular switch/motor toolbox. However, until now members capable of absorbing visible light in their neutral (i. e. non-anionic) form have not been reported. In this contribution we report the preparation of an HBDI-like chromophore based on a 3-phenylbenzofulvene scaffold capable of absorbing blue light and photoisomerizing on the picosecond timescale. More specifically, we show that double-bond photoisomerization occurs in both the E-to-Z and Z-to-E directions and that these can be controlled by irradiating with blue and UV light, respectively. Finally, as a preliminary applicative result, we report the incorporation of the chromophore in an amphiphilic molecule and demonstrate the formation of a visible-light-sensitive nanoaggregated state in water.

Click-Chemistry Cross-Linking of Hyaluronan Graft Copolymers.

An easy and viable crosslinking procedure by click-chemistry (click-crosslinking) of hyaluronic acid (HA) was developed. In particular, the clickable propargyl groups of hyaluronane-based HA-FA-Pg graft copolymers showing low and medium molecular weight values were exploited in crosslinking by click-chemistry by using a hexa(ethylene glycol) spacer. The resulting HA-FA-HEG-CL materials showed an apparent lack of in vitro cytotoxic effects, tuneable water affinity, and rheological properties according to the crosslinking degree that suggests their applicability in different biomedical fields.

Catatonia Spectrum: Validation of a Questionnaire Investigating Catatonia Spectrum.

Aim: A growing body of literature has demonstrated the utility of a dimensional perspective on mental disorders. The current study aims to determine the psychometric properties of the Catatonia Spectrum (CS), a new questionnaire specifically tailored to assess the spectrum of catatonia, from full blown forms to subthreshold ones. Methods: 86 adults with at least three symptom criteria for catatonia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 81 adults affected by borderline personality disorder (BPD), 104 adults with a diagnosis of major depressive disorder (MDD), and 105 subjects without mental disorders (CTL), were recruited from six Italian University Departments of Psychiatry and administered the: Bush-Francis Catatonia Rating Scale (BFCRS), Bush-Francis Catatonia Screening Instrument (BFCSI), and CS. Results: CS scale demonstrated a high level of internal consistency and excellent test-retest reliability for total and domain scores. CS domain scores were positively and significantly correlated with each other (p < 0.001) with Pearson's coefficients ranging from 0.337 to 0.663. All the CS domain scores were highly correlated with the CS total score. The correlation coefficients between CS and alternative measures of catatonia appeared all significant and positive. Significant differences among diagnostic groups on both CS domains and total scores were found. CS total scores increased significantly and progressively from the CTL, to the MDD and the BDP group, up to the catatonia group, which reported the highest value. Conclusion: The CS showed excellent internal consistency and test-retest reliability and strong convergent validity with alternative dimensional measures of catatonia. The questionnaire performed differently across the four diagnostic groups, with an increasing score gradient from healthy controls to patients with MDD, BPD and up to the catatonia group.

A longitudinal study of post-traumatic stress, depressive, and anxiety symptoms trajectories in subjects with bipolar disorder during the COVID-19 pandemic.

BACKGROUND: Bipolar disorder (BD) is recognized to be at high risk for developing negative psychopathological sequelae to potentially traumatic events. Nevertheless, scant data are still available about the effects of the COVID-19 emergency on the clinical course of BD. The present study examined prospectively the development and trajectories of post-traumatic stress, depressive, and anxiety symptoms among subjects with BD that were followed in an outpatient psychiatric clinic at the time of pandemic onset. METHODS: A cohort of 89 subjects with BD was enrolled during the first wave of the COVID-19 pandemic, and assessed at baseline (T0), 2-months (T1), and 6-months (T2) follow-up. A K-means cluster analysis was used to identify distinct trajectories of depressive, anxiety, and post-traumatic stress symptoms during the three time points. RESULTS: We identified three trajectories: the Acute reaction (13.5%); the Increasing severity (23.6%); and the Low symptoms (62.9%) groups, respectively. In the Acute reaction group a significant prevalence of female gender was reported with respect to the Low symptoms one. Subjects in the Increasing severity group reported significantly lower employment rate, and higher rate of relatives at risk for COVID-19 medical complications. Subjects in the Increasing Severity group reported higher rates of previous hospitalization and manic symptoms at baseline than those included in the Low symptoms one. CONCLUSIONS: Our results describe three distinct symptom trajectories during the COVID-19 emergency in a cohort of subjects suffering from BD, suggesting the need of a long-term follow-up for detecting the impact of the COVID-19 pandemic in this vulnerable population.

Investigating the relationship between orthorexia nervosa and autistic traits in a university population.

BACKGROUND: Orthorexia nervosa (ON) is an emerging condition featuring restrictive eating behaviors on the basis of subjective beliefs about food healthiness. Many authors have stressed the similarities between ON and anorexia nervosa (AN) in both cognitive and behavioral patterns. Despite that, while the link between AN and female autism presentations is well known in the literature, no study has yet investigated the relationship between ON and autism spectrum. This work aims to investigate the relationship between ON and autistic traits in a university population. METHODS: An e-mail invitation was sent to all the students and University workers of University of Pisa. Subjects were asked to fulfill the ORTO-15 and the Adult Autism Subthreshold spectrum (AdAS spectrum) questionnaires. RESULTS: A total of 2426 subjects joined the survey: 623 subjects (26.3%) reported a score associated with significant orthorexic symptoms according to ORTO-15 (ON group), while 1789 subjects (73.7%) did not report ON symptomatology and were considered as healthy controls (HC). The ON group scored significantly higher on almost all AdAS spectrum domains. Moreover, being female and scoring higher on AdAS spectrum were statistically predictive factors for the presence of ON symptomatology. Among AdAS spectrum domains, higher scores on AdAS spectrum inflexibility and adherence to routine and restricted interests and rumination domains, as well as lower scores on verbal communication domain, were statistically predictive of orthorexic symptoms. CONCLUSIONS: Our findings highlight an overlap between ON and autism spectrum psychopathology. Further studies are needed to clarify the relationship between restrictive eating disorders and female autism phenotypes.

Xanthopsin-Like Systems via Site-Specific Click-Functionalization of a Retinoic Acid Binding Protein.

The use of light-responsive proteins to control both living or synthetic cells, is at the core of the expanding fields of optogenetics and synthetic biology. It is thus apparent that a richer reaction toolbox for the preparation of such systems is of fundamental importance. Here, we provide a proof-of-principle demonstration that Morita-Baylis-Hillman adducts can be employed to perform a facile site-specific, irreversible and diastereoselective click-functionalization of a lysine residue buried into a lipophilic binding pocket and yielding an unnatural chromophore with an extended π-system. In doing so we effectively open the path to the in vitro preparation of a library of synthetic proteins structurally reminiscent of xanthopsin eubacterial photoreceptors. We argue that such a library, made of variable unnatural chromophores inserted in an easy-to-mutate and crystallize retinoic acid transporter, significantly expand the scope of the recently introduced rhodopsin mimics as both optogenetic and "lab-on-a-molecule" tools.

Portable technologies for digital phenotyping of bipolar disorder: A systematic review.

BACKGROUND: Bias-prone psychiatric interviews remain the mainstay of bipolar disorder (BD) assessment. The development of digital phenotyping promises to improve BD management. We present a systematic review of the evidence about the use of portable digital devices for the identification of BD, BD types and BD mood states and for symptom assessment. METHODS: We searched Web of KnowledgeSM, Scopus ®, IEEE Xplore, and ACM Digital Library databases (until 5/1/2021) for articles evaluating the use of portable/wearable digital devices, such as smartphone apps, wearable sensors, audio and/or visual recordings, and multimodal tools. The protocol is registered in PROSPERO (CRD42020200086). RESULTS: We included 62 studies (2325 BD; 724 healthy controls, HC): 27 using smartphone apps, either for recording self-assessments (n = 10) or for passively gathering metadata (n = 7) or both (n = 10); 15 using wearable sensors for physiological parameters; 17 analysing audio and/or video recordings; 3 using multiple technologies. Two thirds of the included studies applied artificial intelligence (AI)-based approaches. They achieved fair to excellent classification performances. LIMITATIONS: The included studies had small sample sizes and marked heterogeneity. Evidence of overfitting emerged, limiting generalizability. The absence of clear guidelines about reporting classification performances, with no shared standard metrics, makes results hardly interpretable and comparable. CONCLUSIONS: New technologies offer a noteworthy opportunity to BD digital phenotyping with objectivity and high granularity. AI-based models could deliver important support in clinical decision-making. Further research and cooperation between different stakeholders are needed for addressing methodological, ethical and socio-economic considerations.

Biochemical Correlates of Video Game Use: From Physiology to Pathology. A Narrative Review.

In the last few decades, video game playing progressively became a widespread activity for many people, in childhood as well in adulthood. An increasing amount of literature has focused on pathological and non-pathological correlates of video game playing, with specific attention towards Internet Gaming Disorder (IGD). While many neurobiological studies in this field were based on neuroimaging, highlighting structural and functional brain changes among video game users, only a limited number of studies investigated the presence of biochemical correlates of video gaming. The present work aims to summarize and review the available literature about biochemical changes linked to video game use in IGD patients as well as non-pathological users, and the differences in between. Results may shed light on risks and benefits of video games, providing directions for further research on IGD treatment and, on other hand, on the potential role of video games in therapeutic or preventive protocols for specific conditions.