1,2,3,4-dithiadiazole derivatives as a novel class of calcium signaling modulators.

Aberrant calcium signaling is associated with a diverse range of pathologies, including cardiovascular and neurodegenerative diseases, diabetes, cancer, etc… So, therapeutic strategies based on the correction of pathological calcium signaling are becoming extremely in demand. Thus, the development of novel calcium signaling modulators remains highly actual. Previously we found that 1,2,3,4-dithiadiazole derivative 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide can strongly reduce calcium uptake through store-operated calcium (SOC) channels. Here we tested several structurally related compounds and found that most of them can effectively affect SOC channels and attenuate calcium content in the endoplasmic reticulum, thus, establishing 1,2,3,4-dithiadiazoles as a novel class of SOC channel inhibitors. Comparing different 1,2,3,4-dithiadiazole derivatives we showed that previously published 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide and newly tested 3-(3,5-difluorophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole 2-oxide demonstrated the highest efficacy of SOC entry reduction, supposing the important role of electron-withdrawing substituents to realize the inhibitory activity of 1,2,3,4-dithiadiazoles.

Contrasting Metacognitive, Emotion Recognition and Alexithymia Profiles in Bulimia, Anorexia, and Schizophrenia.

ABSTRACT: Alexithymia, or deficits in emotion recognition, and metacognitive capacity have been noted both in psychosis and eating disorders and potentially linked to psychopathology. This study sought to compare levels of impairments in these phenomena and their associations with psychopathology in groups with eating disorders and psychosis. Participants with diagnoses of a schizophrenia spectrum disorder (SSD; n = 53), anorexia (n = 40), or bulimia (n = 40) were recruited from outpatient clinics. Alexithymia was measured with the Toronto Alexithymia Scale; emotion recognition, with the Ekman Faces Test; and metacognition, with the Metacognitive Assessment Scale-Abbreviated. Psychopathology was measured with the Eating Attitudes Test, Body Image Questionnaire, and Positive and Negative Syndrome Scale. Results indicated that the SSD group had significantly poorer metacognitive function than either eating disorder group. Metacognition was related to body image in the anorexia group and a range of different forms of general psychopathology in the bulimia group. Alexithymia was related to eating disorder behaviors in the bulimia group.

Dithiadiazole derivative 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide - Novel modulator of store-operated calcium entry.

Pathological calcium homeostasis accompanies the development of a large number of different diseases, therefore, the search for new modulators of calcium signaling remains highly actual. Last decades store-operated calcium channels have been repeatedly postulated as a therapeutic target, so the compounds acting on them can be considered promising drug prototypes. Here, we tested several derivatives of 1,2,3,4-dithiadiazole, 1,3-thiazine, pyrazolopyrimidine and thiohydrazides for the ability to affect the thapsigargin-induced calcium response. Using calcium imaging and the patch-clamp technique we found that dithiadiazole derivative3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxidehad a strong inhibitory effect on store-operated calcium entry at the micromolar concentration in HEK293 cells. Moreover, incubation of the cells with this compound also resulted in the decrease of ER calcium content. Thus, we have postulated 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide as a novel inhibitor of store-operated calcium entry and suggested the derivatives of 1,2,3,4-dithiadiazole as a prospective class of compounds for searching new calcium modulators.

Chromone-Containing Allylmorpholines Influence Ion Channels in Lipid Membranes via Dipole Potential and Packing Stress.

Herein, we report that chromone-containing allylmorpholines can affect ion channels formed by pore-forming antibiotics in model lipid membranes, which correlates with their ability to influence membrane boundary potential and lipid-packing stress. At 100 µg/mL, allylmorpholines 1, 6, 7, and 8 decrease the boundary potential of the bilayers composed of palmitoyloleoylphosphocholine (POPC) by about 100 mV. At the same time, the compounds do not affect the zeta-potential of POPC liposomes, but reduce the membrane dipole potential by 80-120 mV. The allylmorpholine-induced drop in the dipole potential produce 10-30% enhancement in the conductance of gramicidin A channels. Chromone-containing allylmorpholines also affect the thermotropic behavior of dipalmytoylphosphocholine (DPPC), abolishing the pretransition, lowering melting cooperativity, and turning the main phase transition peak into a multicomponent profile. Compounds 4, 6, 7, and 8 are able to decrease DPPC's melting temperature by about 0.5-1.9 °C. Moreover, derivative 7 is shown to increase the temperature of transition of palmitoyloleoylphosphoethanolamine from lamellar to inverted hexagonal phase. The effects on lipid-phase transitions are attributed to the changes in the spontaneous curvature stress. Alterations in lipid packing induced by allylmorpholines are believed to potentiate the pore-forming ability of amphotericin B and gramicidin A by several times.

Utilizing MERIT to promote recovery in schizotypal personality disorder: An illustrative case study.

INTRODUCTION: Difficulties forming an integrated sense of oneself, others, and one's place in the community have been observed to pose a barrier to recovery from schizophrenia spectrum disorders (SSD). This has promoted the development of metacognitive approaches to psychotherapy that seek to assist persons in making sense of and managing their psychosocial challenges. One of these approaches, Metacognitive Reflection Insight Therapy (MERIT), has begun to be more broadly explored among adults with schizophrenia. Persons with other forms of SSD, including schizotypal personality disorder (SPD), also experience difficulties forming an integrated sense of themselves and others and could potentially be amenable to MERIT. METHODS: To explore this possibility, this study reports the application of MERIT to an adult with SPD in a unique cultural context. RESULTS: Evidence of acceptability and meaningful resultant clinical gains are described. CONCLUSIONS: Taken as a whole, this study provides a rich illustration of how metacognition can be successfully targeted by MERIT in forms of SSD potentially less severe than schizophrenia, including SPD in a unique cultural setting.

The association of metacognition with emotion recognition and perspective taking in a Russian sample with psychosis.

OBJECTIVE: Schizophrenia may reflect an interactive network of disturbances in cognition. In this study we have examined the relationship between two forms of cognition: metacognition and social cognition among a sample with schizophrenia (n = 41), early episode psychosis (n = 37), and major depression (n = 30) gathered in Moscow, Russia. METHODS: Metacognition was assessed with the Metacognition Assessment Scale-Abbreviated. Social cognition was assessed with the Ekman 60 Faces Test and the Interpersonal Reactivity Index. Verbal memory and global psychopathology were included as potential covariates. RESULTS: Partial correlations controlling for demographics, neurocognition, and psychopathology revealed greater metacognitive capacity was linked to better facial emotion recognition and perspective taking in the prolonged schizophrenia group. Greater metacognitive capacity in the early psychosis group was linked with greater facial emotion recognition. Metacognition and social cognition were not related to one another in the depression group. CONCLUSIONS: Social cognition and metacognition may be uniquely related in psychosis.

The paradoxical moderating effects of metacognition in the relationships between self-esteem, depressive symptoms, and quality of life in anorexia and bulimia.

BACKGROUND: Self-esteem and depressive symptoms contribute to a lower quality of life in people suffering from eating disorders. However, limited research has examined whether other factors may affect how these variables influence one another over time. Metacognition is a previously unexplored determinant that may impact the relationships between self-esteem, depressive symptoms, and quality of life in instances of eating disorders. AIM: This study sought to examine metacognitive self-reflectivity and mastery as moderators of the relationships between self-esteem, depressive symptoms, and quality of life and to determine if these relationships are different in people with anorexia compared with people with bulimia. METHODS: Participants with anorexia (n=40) and bulimia (n=40) were recruited from outpatient clinics. The participants were assessed on their metacognitive ability and self-reported on measures to assess their depressive symptoms, self-esteem, and quality of life. RESULTS: The results indicate that metacognitive self-reflectivity moderates the relationship between self-esteem, depressive symptoms, and quality of life in people with anorexia such that when self-reflectivity is high, lower self-esteem and higher depressive symptoms are associated with a lower quality of life. These relationships did not appear to be significant when self-reflectivity was low. In contrast, in the anorexia and bulimia groups, metacognitive mastery appeared to moderate the relationships between self-esteem, depressive symptoms, and quality of life such that when mastery was low, lower self-esteem and higher depressive symptoms were associated with a lower quality of life. These relationships did not appear significant when mastery was high. CONCLUSION: Metacognitive self-reflectivity and mastery seem to play paradoxical moderating roles in the relationships between self-esteem, depressive symptoms, and quality of life in people with anorexia and bulimia. These findings pave the way toward further research and have important clinical implications.

A Flexible Synthetic Approach to Fluorescent Chromeno[4,3-b]pyridines and Pyrano[3,2-c]chromenes from Electron-Deficient 3-Vinylchromones.

We report a flexible approach to the synthesis of phenanthrene-like heterocycles through organocatalytic ANRORC (Addition of the Nucleophile, Ring Opening, and Ring Closure) reaction of electron-deficient 3-vinylchromones with cyanoacetamide. Addition of highly basic DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or tetramethylguanidine (TMG) at 80 °C leads to chromeno[4,3-b]pyridines in good yields, whereas Et3 N at 20 °C made it possible to obtain the less accessible pyrano[3,2-c]chromenes and their 2-imines. The synthesis proceeds in mild conditions (EtOH, 20-80 °C), is versatile and applicable for a wide scope of reactants. The obtained compounds show bright fluorescence in the range 460-595 nm with high quantum yields (up to 0.84) in various solvents (MeCN, DMSO, EtOH, H2 O).

Clinical insight, cognitive insight and metacognition in psychosis: Evidence of mediation.

OBJECTIVE: Schizophrenia is increasingly understood as an interactive network of disturbances in different elements of self-awareness. In this study we have examined the relationship between disturbances in two forms of awareness: cognitive insight and clinical insight by exploring whether their relationship is mediated by a third form of larger awareness: metacognition. METHODS: Participants were 41 outpatients with schizophrenia and 37 outpatients with early episode psychosis gathered in Moscow, Russia. Metacognition was assessed with the Metacognition Assessment Scale - Abbreviated. Verbal memory and positive symptoms were assessed for use as additional mediators. RESULTS: Mediation analyses revealed that after accounting for the effects of positive symptoms and verbal memory, the relationship between the self-reflection domain of cognitive insight and clinical insight was significantly mediated by overall metacognitive capacity. Further, positive symptoms were a significant mediator between the cognitive insight self-reflection domain and clinical insight. Neither metacognition nor positive symptoms or verbal memory were found to mediate the relationship of the cognitive insight domain of self-certainty with clinical insight. CONCLUSIONS: Decrements in some forms of ability to reflect upon one's thinking may reduce the ability to form complex and integrated ideas of oneself and others, leading to less coherent and complete accounts of the experience of schizophrenia.

Contrasting metacognitive profiles and their association with negative symptoms in groups with schizophrenia, early psychosis and depression in a Russian sample.

Research has suggested that negative symptoms in psychotic disorders may be in part fueled by deficits in metacognition or the ability to form integrated ideas about oneself and others. One limitation of this work is that it has largely come from North America and Western Europe. To further the literature, we assessed symptoms using the Positive and Negative Syndrome Scale and Metacognition using the Metacognitive Assessment Scale - Abbreviated in a sample of outpatients with prolonged schizophrenia (n = 41), early episode psychosis (n = 37) and major depression (n = 30) gathered in Moscow, Russia. Verbal memory was assessed for use as a potential covariate. ANOVA revealed the two groups with psychosis had significantly poorer metacognitive function in terms of self-reflectivity and awareness of the other, than the group with depression. In both psychosis groups negative symptoms were more robustly related to metacognition than other forms of symptoms after controlling for neurocognition. Results support the possibility that metacognitive deficits are a psychological factor which cross culturally contributes to negative symptoms and point to metacognition as a potentially important target for intervention.