Therapeutic Factors in a Psychiatric Group Therapy: a Preliminary Validation of Therapeutic Factors Inventory-8, Italian Version.

Several studies support group therapy effectiveness due to the activation in patients of unique psychological mechanisms defined as non-specific therapeutic factors (Therapeutic Factors-TFs), which shape the setting and, at the same time, enhance the specific group therapeutic factors. The objectives of this study were to preliminarly validate Therapeutic Factors Inventory-8 (TFI-8) Italian version and identify group therapeutic factors. In a psychiatric residential facility, a weekly psychotherapeutic group was evaluated during 1 year. One scale on group process (TFI-8, Ferrara-Group Experience Scale) and three clinical scales (Brief Symptom Inventory-53, Sheehan Disability Scale, WHO Quality of Life-Bref) were administered to participating patients. Internal consistency, Exploratory Factor Analysis (EFA), convergent validity of TFI-8 were assessed. Correlations between TFI-8 and other scale scores and selected variables were pwerformed. Our sample consisted of 64 participants. TFI-8 showed good internal consistency (Chronbach's alpha = 0.84), concurrent validity with Fe-GES (Rho = 0.42, p = 0.0008). EFA highlighted a single Factor, accounting for 92% of variance. TFI-8 was not significantly related to clinical scale scores. TFI-8 Italian version proved to be a valid and reliable tool which allowed us to identify one therapeutic factor indicating relational attraction in group therapy, composed of three dimensions: infusion of hope, cohesion and social learning.

Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-ß peptide in Alzheimer's disease.

N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid ß peptide (Aß) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aß neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC50 = 6.9 µM). In addition, at 10 µM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aß production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aß burden and oxidative damage.

Modulation of Keap1/Nrf2/ARE Signaling Pathway by Curcuma- and Garlic-Derived Hybrids.

Nrf2 is a basic leucine zipper transcription factor that binds to the promoter region of the antioxidant response element (ARE), inducing the coordinated up-regulation of antioxidant and detoxification genes. We recently synthesized a set of new molecules by combining the functional moieties of curcumin and diallyl sulfide, both known to induce the expression of antioxidant phase II enzymes by activating Nrf2 pathway. The aim of the study is to investigate the ability of such compounds to activate Keap1/Nrf2/ARE cytoprotective pathway, in comparison with two reference Nrf2-activators: curcumin and dimethyl fumarate, a drug approved for the treatment of relapsing-remitting multiple sclerosis. Furthermore, since Nrf2 pathway is known to be regulated also by epigenetic modifications, including key modifications in microRNA (miRNA) expression, the effects of the hybrids on the expression levels of selected miRNAs, associated with Nrf2 signaling pathway have also been investigated. The results show that compounds exert antioxidant effect by activating Nrf2 signaling pathway and inducing the ARE-regulated expression of its downstream target genes, such as HO-1 and NQO1, with two hybrids to a higher extent than curcumin. In addition, some molecules induce changes in the expression levels of miR-125b-5p, even if to a lesser extent than curcumin. However, no changes have been observed in the expression levels of mRNA coding for glutathione synthetase, suggesting that the modulation of this mRNA is not strictly under the control of miR-125b-5p, which could be influenced by other miRNAs.

Use and Propensity to Use Substances as Cognitive Enhancers in Italian Medical Students.

International media has paid attention to the use of substances by healthy subjects to enhance cognitive performance. Medical students are liable to use cognitive enhancers (CE) with the aim of improving academic performance. The study explored use and attitudes toward the use of CE in Italian medical students. The authors anonymously surveyed 433 medical students of the University of Modena and Reggio Emilia with an ad hoc 36-items questionnaire. CE were broadly defined as any substance taken with the purpose of improving cognitive functions, from readily available beverages and substances, such as coffee, tea, energy drinks, and supplements to prescription only medication, such as psychostimulants and modafinil. Response rate was 83.8% (n = 363). While the majority of the students (74.7%; n = 271) said that they had used substances to improve cognitive functions, only 2 students (0.6%) reported the use of prescription-only medications in the last 30 days. Main reasons for not taking prescription-only drugs were concerns about safety and side effects, reported by 83.3% of students (n = 295). A positive attitude toward use was held by 60.3% (n = 219) subjects. The surveyed Italian medical students used many substances as CE, but this did not seem to apply significantly to psychostimulants. A multivariable analysis showed that the following variables were related to the propensity to use substances as CE: male gender, self-reported memory impairment, concerns about worsening of cognitive performance, lifetime use of at least one illegal substance, use of any substance (both legal or illegal) in the last 30 days.

Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-ß aggregation.

AIM: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. METHODS: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways. RESULTS: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-ß aggregation. CONCLUSION: The compounds emerged as a suitable starting point for a further optimization process.

Quinazoline based α1-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines.

New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin. Compound 10 increased apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α1-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.

Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer's Disease: A Rational Approach.

Amyloid is a prominent feature of Alzheimer's disease (AD). Yet, a linear linkage between amyloid-ß peptide (Aß) and the disease onset and progression has recently been questioned. In this context, the crucial partnership between Aß and Nrf2 pathways is acquiring paramount importance, offering prospects for deciphering the Aß-centered disease network. Here, we report on a new class of antiaggregating agents rationally designed to simultaneously activate transcription-based antioxidant responses, whose lead 1 showed interesting properties in a preliminary investigation. Relying on the requirements of Aß recognition, we identified the catechol derivative 12. In SH-SY5Y neuroblastoma cells, 12 combined remarkable free radical scavenger properties to the ability to trigger the Nrf2 pathway and induce the Nrf2-dependent defensive gene NQO1 by means of electrophilic activation of the transcriptional response. Moreover, 12 prevented the formation of cytotoxic stable oligomeric intermediates, being significantly more effective, and per se less toxic, than prototype 1. More importantly, as different chemical features were exploited to regulate Nrf2 and Aß activities, the two pathways could be tuned independently. These findings point to compound 12 and its derivatives as promising tools for investigating the therapeutic potential of the Nrf2/Aß cellular network, laying foundation for generating new drug leads to confront AD.

Polyamine Conjugation as a Promising Strategy To Target Amyloid Aggregation in the Framework of Alzheimer's Disease.

Spermine conjugates 2-6, carrying variously decorated 3,5-dibenzylidenepiperidin-4-one as bioactive motives, were designed to direct antiaggregating properties into mitochondria, using a polyamine functionality as the vehicle tool. The study confirmed mitochondrial import of the catechol derivative 2, which displayed effective antiaggregating activity and neuroprotective effects against Aß-induced toxicity. Notably, a key functional role for the polyamine motif in Aß molecular recognition was also unraveled. This experimental readout, which was supported by in silico studies, gives important new insight into the polyamine's action. Hence, we propose polyamine conjugation as a promising strategy for the development of neuroprotectant leads that may contribute to decipher the complex picture of Aß toxicity.

In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD. In this study, we report on the in vivo pharmacological characterization of ARN14140, a new chemical entity, which was obtained through a multi-target structure-activity relationship campaign, and which showed a balanced inhibiting profile against the acetylcholinesterase enzyme and the NMDA receptor. Based on the initial promising biochemical data, ARN14140 is here studied in mice treated with the amyloidogenic fragment 25-35 of the amyloid-ß peptide, a consolidated non-transgenic AD model. Sub-chronically treating animals with ARN14140 leads to a prevention of the cognitive impairment and of biomarker levels connected to neurodegeneration, demonstrating its neuroprotective potential as new AD agent.

Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate.

Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targets the PI3K-Akt pathway whose dysregulation is implicated in many functions of cancer cells. According to these considerations, a series of multitarget molecules have been designed by combining key structural features derived from an EGFR-TKI, PD168393, and the isothiocyanate sulforaphane. Among the obtained molecules 1-6, compound 6 emerges as a promising lead compound able to exert antiproliferative and proapoptotic effects in A431 epithelial cancer cell line by covalently binding to EGFR-TK, and reducing the phosphorylation of Akt without affecting the total Akt levels.

Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics.

Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.

Nature-Inspired Multifunctional Ligands: Focusing on Amyloid-Based Molecular Mechanisms of Alzheimer's Disease.

The amyloidogenic pathway is a prominent feature of Alzheimer's disease (AD). However, growing evidence suggests that a linear disease model based on ß-amyloid peptide (Aß) alone is not likely to be realistic, which therefore calls for further investigations on the other actors involved in the play. The pro-oxidant environment induced by Aß in AD pathology is well established, and a correlation among Aß, oxidative stress, and conformational changes in p53 has been suggested. In this study, we applied a multifunctional approach to identify allyl thioesters of variously substituted trans-cinnamic acids for which the pharmacological profile was strategically tuned by hydroxy substituents on the aromatic moiety. Indeed, only catechol derivative 3 [(S)-allyl (E)-3-(3,4-dihydroxyphenyl)prop-2-enethioate] inhibited Aß fibrilization. Conversely, albeit to different extents, all compounds were able to decrease the formation of reactive oxygen species in SH-SY5Y neuroblastoma cells and to prevent alterations in the conformation of p53 and its activity mediated by soluble sub-lethal concentrations of Aß. This may support an involvement of oxidative stress in Aß function, with p53 emerging as a potential mediator of their functional interplay.

An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512.

Combined computational-experimental analyses explain and quantify the spermine-vectorized F14512's boosted potency as a topoII poison. We found that an optimized polyamine moiety boosts drug binding to the topoII/DNA cleavage complex, rather than to the DNA alone. These results provide new structural bases and key reference data for designing new human topoII poisons.

Correlation of articular involvement, skin disfigurement and unemployment with depressive symptoms in patients with systemic sclerosis: a hospital sample.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease associated with increased functional impairment, body image distress due to skin lesions, and psychosocial comorbidity, particularly depression. Prevalence of depressive symptoms in SSc patients ranges from 36% to 65% and it contributes to the worsening of any aspect of the disease. The aim of this study was to investigate the prevalence and clinical and non-clinical correlates of depressive symptoms in a sample of outpatients with SSc. METHODS: Seventy-eight consecutive SSc outpatients were recruited from February 2005 to July 2007. Socio-demographic and SSc-related clinical data were collected, including a modified Rodnan Skin Score, the Valentini Disease Activity Index and psycho-metric assessment of disability and pain. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Two questions on perception of support from relatives and impact of disfigurements were also directly addressed to subjects. RESULTS: The BDI mean score was 10.5 (± 8.3), with 36 subjects (46.2%) scoring above clinical significance. Unemployment, increased disability, pain, disease activity and articular involvement were significantly associated with more depressive symptoms. Older age, unemployment and more depressive symptoms were also related with complaints of disfigurements due to skin involvement. CONCLUSIONS: Depression is an influential prognostic factor in SSc. The present study contributes to the knowledge of the relationship between depression and clinical features routinely collected in rheumatology settings in order to develop a standardized assessment of psychosocial distress in routine rheumatologic procedures.

Multi-target design strategies in the context of Alzheimer's disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces.

In recent years, the multi-target-directed ligand concept has been used to design a variety of molecules hitting different biological targets for Alzheimer's disease. We have sought to combine, in the same molecule, the neuroprotective action of N-methyl-D-aspartate receptor antagonism with the symptomatic relief offered by cholinergic activity through acetylcholinesterase inhibition. This strategy could potentially maintain the positive outcomes of memantine-acetylcholinesterase inhibitor combinations, but with the benefits of a single molecule therapy. Herein, we discuss selected examples of multifunctional compounds, which we rationally designed to simultaneously modulate these targets. We also examine the intertwined relationship between acetylcholinesterase, N-methyl-D-aspartate receptors, and other active players in the neurotoxic cascade.

Vertigo "in the pink": The impact of female gender on psychiatric-psychosomatic comorbidity in benign paroxysmal positional vertigo patients.

BACKGROUND: Comorbidity between vestibular and psychiatric disorders in predisposed individuals is underestimated, untreated, and may result in chronicization and poor quality of life. There are few studies concerning the type and the prevalence of psychiatric-psychosomatic distress in patients with benign paroxysmal positional vertigo (BPPV). OBJECTIVE: The aim of this study was to evaluate psychiatric-psychosomatic comorbidities, in particular anxiety, depression, somatization symptoms, and alexithymia, in a group of BPPV patients compared with healthy subjects, and according to gender. METHODS: Case-control study comparing 92 BPPV patients recruited at the ENT Unit of Modena General Hospital between November 2007 and December 2010, and 141 healthy controls. The Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Diagnostic Criteria for Psychosomatic Research (DCPR), Brief Symptom Inventory (BSI), and Toronto Alexithymia Scale (TAS-20) were used to perform psychometric assessment. RESULTS: BPPV patients scored higher than controls, with statistical significance, at BDI, BSI somatization, anxiety, and phobic anxiety subscales, and STAI state anxiety; a larger proportion of BPPV patients suffered from clinically significant BDI depressive symptomatology; DCPR disease phobia, functional somatic symptoms secondary to a psychiatric disorder, and demoralization were more common among BPPV subjects. High levels of symptomatology were still found among BPPV female patients, but not among males, even after controlling for symptom severity. CONCLUSIONS: Affective symptomatology, such as depression, demoralization, phobia and anxiety, and somatization, were significantly prevalent in BPPV patients, and female gender may be a predisposing factor.

Oxidative stress in Alzheimer's disease: are we connecting the dots?

Redox impairment is a prominent feature of Alzheimer's disease (AD). It has led to the "oxidative stress hypothesis", which proposes antioxidants as beneficial therapeutic tools in AD treatment. To date, a wide variety of antioxidants have been examined as neuroprotectants. However, success has been elusive in clinical trials. Several factors have contributed to this failure, including the complexity of the redox system in vivo. Potentially critical aspects include the fine-tuned equilibrium between antioxidant defenses and free radical production, the lack of specific antioxidant target(s), and the inherent difficulty in delivering antioxidants where they are needed. Herein, we highlight significant progress in the field. Future directions of antioxidant research are also presented.

Exploring the effects of isothiocyanates on chemotherapeutic drugs.

INTRODUCTION: Chemoprevention has emerged as a promising strategy to reduce the risk and to control cancer. In this context, isothiocyanates (ITCs), found in abundance in the form of glucosinolates in cruciferous vegetables, have gained increasing consideration for their chemopreventive activity. ITCs exert their effects mainly by inducing carcinogen metabolism or by inhibiting tumor cell proliferation. AREAS COVERED: In recent years, novel combination treatments, by coupling chemopreventive agents and typical chemotherapeutics, have been exploited to increase the antitumor activities. The aim of this article is to examine the foremost studies carried out, so far, on the effects of dietary and synthetic ITCs on different signaling pathways involved in the pharmacokinetics and pharmacodynamics of chemotherapeutic agents, in order to enhance their effectiveness. EXPERT OPINION: Undoubtedly, the beneficial anticarcinogenic potential of ITCs, both singly and in combination, has emerged in in vitro and in vivo studies. However, only a few clinical trials have been carried out so far with ITCs, which try to better define both the pharmacokinetic and pharmacodynamic impacts in humans. More toxicological evaluations after long-term administration of ITCs in different species are required for the clinical development of ITCs as anticarcinogenic agents.

Quinones bearing non-steroidal anti-inflammatory fragments as multitarget ligands for Alzheimer's disease.

The anti-amyloid properties shared by several quinones inspired the design of a new series of hybrids derived from the multi-target drug candidate memoquin (1). The hybrids consist of a central benzoquinone core and a fragment taken from non-steroidal anti-inflammatory drugs, connected through polyamine linkers. The new hybrids retain the potent anti-aggregating activity of the parent 1, while exhibiting micromolar AChE inhibitory activities. Remarkably, 2, 4, (R)-6 and (S)-6 were Aß aggregation inhibitors even more potent than 1. The balanced amyloid/cholinesterase inhibitory profile is an added value that makes the present series of compounds promising leads against Alzheimer's disease.

Multifunctional tacrine derivatives in Alzheimer's disease.

Tacrine (1) was the first acetylcholinesterase inhibitor (AChEI) introduced in therapy for the treatment of Alzheimer's disease (AD), but similarly to the most recent approved AChEIs and memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, it does not represent an effective drug in halting the progression of AD. The continuous research in this field has contributed to delineate AD as a multifactorial syndrome with several biological targets involved in its etiology. On these bases, the development of new effective therapeutics becomes crucial and the design of molecules that address more than one specific AD target should represent thus a succeeded strategy for AD treatment. This review will focus on and summarize multifunctional 1 derivatives starting from our last paper published on the same topic in 2010. In the last three years, the design and synthesis of 1 homo- and heterodimers, as well as of 1-hybrid structures for AD therapy, was aimed mainly to discover safer drugs, with decreased hepatotoxicity in comparison to 1, taking also into account the multifactorial pathogenesis of the disease. Most of these new hetero/homo-dimers and/or hybrids of 1, although addressed mainly to acetylcholinesterase (AChE) and Aß aggregation inhibition, are able to hit additional targets relevant to AD, among which, ß-secretase (BACE1), reactive oxygen species (ROS), calcium channels, NMDAR and M1- muscarinic receptors.