Trans-Epithelial Transport,Metabolism, and Biological Activity Assessment of the Multi-Target Lupin Peptide LILPKHSDAD (P5) and Its Metabolite LPKHSDAD (P5-Met)

P5 (LILPKHSDAD) is a hypocholesterolemic peptide from lupin protein with a multi-target activity, since it inhibits both 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and proprotein convertase subtilisin/kexin type-9 (PCSK9). This work shows that, during epithelial transport experiments, the metabolic transformation mediated by intestinal peptidases produces two main detected peptides, ILPKHSDAD (P5-frag) and LPKHSDAD (P5-met), and that both P5 and P5-met are linearly absorbed by differentiated human intestinal Caco-2 cells. Extensive comparative structural, biochemical, and cellular characterizations of P5-met and the parent peptide P5 demonstrate that both peptides have unique characteristics and share the same mechanisms of action. In fact, they exert an intrinsically multi-target behavior being able to regulate cholesterol metabolism by modulating different pathways. The results of this study also highlight the dynamic nature of bioactive peptides that may be modulated by the biological systems they get in contact with.     

Fronto-temporal disconnectivity in schizotypal personality disorder: a diffusion tensor imaging study.

BACKGROUND: Using diffusion tensor imaging (DTI), we previously reported abnormalities in two critical white matter tracts in schizophrenia, the uncinate fasciculus (UF) and the cingulum bundle (CB), both related to fronto-temporal connectivity. Here, we investigate these two bundles in unmedicated subjects with schizotypal personality disorder (SPD). METHODS: Fifteen male SPD subjects and 15 male control subjects were scanned with line-scan DTI. Fractional anisotropy (FA) and mean diffusivity (D(m)) were used to quantify water diffusion, and cross-sectional area was defined with a directional threshold method. Exploratory correlation analyses were evaluated with Spearman's rho, followed by post hoc hierarchical regression analyses. RESULTS: We found bilaterally reduced FA in the UF of SPD subjects. For CB, there was no significant group difference for FA or D(m) measures. Additionally, in SPD, reduced FA in the right UF was correlated with clinical symptoms, including ideas of reference, suspiciousness, restricted affect, and social anxiety. In contrast, left UF area was correlated with measures of cognitive function, including general intelligence, verbal and visual memory, and executive performance. CONCLUSIONS: These findings in SPD suggest altered fronto-temporal connectivity through the UF, similar to findings in schizophrenia, and intact neocortical-limbic connectivity through the CB, in marked contrast with what has been reported in schizophrenia.     

Gender differences in the functional neuroanatomy of emotional episodic autobiographical memory

Autobiographical memory is based on interactions between episodic memory contents, associated emotions, and a sense of self-continuity along the time axis of one's life. The functional neuroanatomy subserving autobiographical memory is known to include prefrontal, medial and lateral temporal, as well as retrosplenial brain areas; however, whether gender differences exist in neural correlates of autobiographical memory remains to be clarified. We reanalyzed data from a previous functional magnetic resonance imaging (fMRI) experiment to investigate gender-related differences in the neural bases of autobiographical memories with differential remoteness and emotional valence. On the behavioral level, there were no significant gender differences in memory performance or emotional intensity of memories. Activations common to males and females during autobiographical memory retrieval were observed in a bilateral network of brain areas comprising medial and lateral temporal regions, including hippocampal and parahippocampal structures, posterior cingulate, as well as prefrontal cortex. In males (relative to females), all types of autobiographical memories investigated were associated with differential activation of the left parahippocampal gyrus. By contrast, right dorsolateral prefrontal cortex was activated differentially by females. In addition, the right insula was activated differentially in females during remote and negative memory retrieval. The data show gender-related differential neural activations within the network subserving autobiographical memory in both genders. We suggest that the differential activations may reflect gender-specific cognitive strategies during access to autobiographical memories that do not necessarily affect the behavioral level of memory performance and emotionality.     

Effect of Different Tube Feeding Methods on the Delivery of Docosahexaenoic and Arachidonic Acid: An In Vitro Pilot Study

Background: Arachidonic acid (AA) and docosahexaenoic acid (DHA) are crucial for neural and visual development after premature birth. Preterm infants usually require tube feeding (TF) until the achievement of adequate oral feeding skills; the impact of TF on DHA and AA delivery has not been investigated yet. This study aimed to evaluate the effect of different TF techniques on the delivery of AA and DHA contained in human milk (HM). Methods: HM samples (65 mL each) were collected and divided into three 20‐mL aliquots. The remaining 5 mL served as baseline. Three TF techniques were simulated (1 for each aliquot): gravity bolus feeding (BF), 3‐hour continuous feeding using a horizontal feeding pump, and 3‐hour continuous feeding with the feeding pump angled at 45°. For horizontal continuous feeding (HCF) and 45° angled continuous feeding (ACF), aliquots delivered between 0 and 90 minutes (T1) and 91 and 180 minutes (T2) were collected separately. AA and DHA concentration was analyzed by gas chromatography/mass spectrometry and compared among the TF methods. DHA and AA delivery at T1 and T2 was also evaluated. Results: Fifty‐one simulated feeds were performed. DHA and AA amounts after BF and ACF did not differ significantly compared with baseline, whereas HCF resulted in significantly lower DHA and AA concentration. During T2, ACF delivered almost twice the DHA and AA amounts compared with T1. Conclusion: The delivery of HM AA and DHA is significantly affected by TF, with potential clinical implications. When BF is not tolerated, ACF might represent a feasible alternative to reduce TF‐related DHA and AA loss.     

An age-matched comparison of subjects with binge eating disorder and bulimia nervosa

The purpose of this study was to compare data from a group of obese subjects with binge eating disorder (BED) with data from a group of normal weight bulimia nervosa (BN) subjects. Subjects were compared using the Eating Disorder Questionnaire (EDQ), the Eating Disorder Inventory (EDI), the Personality Disorders Questionnaire for DSM-III-R (PDQ-R), the Hamilton Anxiety and Depression Rating Scales, and the Beck Depression Inventory. A group of 35 age-matched subjects were selected retrospectively from treatment study subjects. The EDQ findings indicated that members of the BN group desired a lower body mass index, were more afraid of becoming fat, and more uncomfortable with their binge eating behavior than the BED group members. The BED subjects had a younger age of onset of binge eating behavior (14.3) than the BN subjects (19.8), even though both groups started dieting at a similar age (BED = 15.0, BN = 16.2). The EDI results showed BN subjects had more eating and weight-related pathology, with significantly higher scores on five of the eight subscales. On the PDQ-R more BN subjects endorsed Axis II impairment (BN = 69%, BED = 40%). While demonstrating greater eating pathology in the BN group, this study also found significant pathology and distress in BED subjects. © 1995 by John Wiley & Sons, Inc.     

Protein kinase inhibitors of the quinazoline class exert anti-cytomegaloviral activity in vitro and in vivo

Cytomegalovirus infection is associated with severe disease in immunocompromised individuals. Current antiviral therapy faces several limitations. In a search of novel drug candidates, we describe here the anti-cytomegaloviral properties of two compounds of the chemical class of quinazolines, gefitinib (Iressa) and Ax7396 (RGB-315389). Both compounds showed strong inhibitory effects in vitro against human and animal cytomegaloviruses with IC(50)s in a low micromolar range. Cytotoxicity did not occur at these effective concentrations. The antiviral mode of action was based on the inhibition of protein kinase activity, mainly directed to a viral target kinase (UL97/M97) in addition to cellular target candidates. This was demonstrated by a high sensitivity of the respective protein kinases in vitro and by infection experiments with viral mutants carrying genomic alterations in the ORF UL97/M97 modulating viral drug sensitivity. In a guinea pig model, gefitinib showed inhibition of cytomegaloviral loads in blood and lung tissue. Importantly, the rate of mortality of infected animals was reduced by gefitinib treatment. In contrast to the in vitro data, Ax7396 showed no significant antiviral activity in a mouse model. Further in vivo analyses have to assess the potential use of gefitinib in the treatment of cytomegalovirus disease.