A new series of compounds bearing a pyrazolopyridine scaffold was synthesized as integrated anti-Alzheimer's disease (AD) multi-targeted ligands. Compounds 49 and 51 showed remarkable activity as ...hAChE inhibitors with IC50 values of 0.17 and 0.16 μM, respectively; and proved to be active hBuChE inhibitors with IC50 values 0.17 and 0.69 μM, eight and two-fold more active than the reference compound rivastigmine, respectively. Compounds 49 and 51 showed potent GSK3β inhibition with IC50 values of 0.21 and 0.26 μM, respectively compared to L807mts. Also, 49 and 51 showed 66.0 and 60.0% as tau protein aggregation inhibitors; and Aβ1-42 self-aggregation inhibitors with 79.0 and 75.0% respectively. Furthermore, 49 and 51 could bind virtually with the PAS affecting Aβ aggregation, thus preventing Aβ-dependent neurotoxicity. They proved to have the ability to chelate bio-metals such as Fe2+, Cu2+, and Zn2+ preventing their oxidative damage in the brain of AD patients, in addition to their safety upon WI-38 cell line. Both compounds could virtually penetrate BBB and obeyed Lipinski's rule of five. Compounds 49 and 51 could be considered as MTDLs for AD patients and the obtained model and pattern of substitution could be used for further development of new multi-targeted anti-Alzheimer's agents.
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•Compounds 49 and 51 proved to be potent multi-targeted anti-Alzheimer's agents.•Compounds 49 and 51 proved to be potent hAChE, hBuChE and Gsk3β inhibitors.•Compounds 49 and 51 proved to be potent tau protein and Aβ1-42 aggregation inhibitors.•Compounds 49 and 51 showed wide safety margin and metal chelating activity.•Compounds 49 and 51 obeyed Lipinski's rule of five.
•Consort and Coronet had the highest concentrations of total anthocyanins, total polyphenols, and antioxidants.•Blackcurrants favorably inhibited dipeptidyl peptidase-IV, α-amylase, and ...α-glucosidase.•Whistler presented the highest concentrations of the major anthocyanins in blackcurrants.•Antioxidant capacity was correlated with total polyphenols and total anthocyanins.
The objective was to analyze the phenolic composition, antioxidant capacity, and physical characteristics of 10 blackcurrant cultivars, their juices, and the enzymatic inhibition of dipeptidyl peptidase-IV, α-amylase, α-glucosidase, nitric oxide synthase, and cyclooxygenase-2. Fruit masses ranged from 0.47 to 1.22 g and diameters from 7.42 to 14.42 mm. For the juices, pH ranged from 2.80 to 2.96, soluble solids from 11.33% to 17.5%, total acidity from 3.17 to 4.26 g/100 mL, and viscosity from 1.28 to 273.83 mPa·s. Total anthocyanins (TA) ranged from 1.81 to 5.48 mg eq cyanidin 3-O-glucoside/100 g, total polyphenols (TP) from 7.67 to 39.70 mg eq gallic acid/100 g, total condensed tannins from 3.24 to 7.76 g eq catechin/100 g, and antioxidant capacity from 219.24 to 499.26 μmol eq Trolox/100 g. Juices of the cultivars Coronet and Consort contained the highest levels of TA, TP, and antioxidants. Whistler cultivar contained high concentrations of major anthocyanins. Juices from all cultivars favorably inhibited the activities of enzymes used as surrogate biochemical markers for T2 diabetes and inflammation.
Inhibitory control describes the suppression of goal-irrelevant stimuli and behavioral responses. Current developmental taxonomies distinguish between Response Inhibition - the ability to suppress a ...prepotent motor response, and Attentional Inhibition - the ability to resist interference from distracting stimuli. Response Inhibition and Attentional Inhibition have exhibited moderately strong positive correlations in previous studies, suggesting they are closely related cognitive abilities. These results may reflect the use of cognitive tasks combining Stimulus-Stimulus- and Stimulus-Response-conflict as indicators of both constructs, which may have conflated their empirical association. Additionally, previous statistical modeling studies have not controlled for individual differences in Working Memory Capacity, which may account for some of the empirical overlap between Response Inhibition and Attentional Inhibition. The aim of the current study was to test a hierarchical model of inhibitory control that specifies Working Memory Capacity as a higher-order cognitive construct. Response Inhibition and Attentional Inhibition were conceptualized as lower-order cognitive mechanisms that should be empirically independent constructs apart from their shared reliance on Working Memory Capacity for active maintenance of goal-relevant representations. Measures of performance on modified stimulus-response compatibility tasks, complex memory span, and non-selective stopping tasks were obtained from 136 preadolescent children (
= 11 years, 10 months,
= 8 months). Consistent with hypotheses, results from Structural Equation Modeling demonstrated that the Response Inhibition and Attentional Inhibition factors were empirically independent constructs that exhibited partial statistical dependence on the Working Memory Capacity factor. These findings have important implications for current theories and models of inhibitory control during development.
To achieve fluent language processing as a bilingual, a dominant theoretical framework assumes that the nontarget language is inhibited. This assumption is based on several empirical effects that are ...typically explained with inhibitory control. In the current article, we discuss four prominent effects linked to bilingual inhibition in language production (i.e., asymmetrical switch costs, n−2 language repetition costs, reversed language dominance, and the blocked language order effect). We argue that these effects require more empirical examination in order to arrive at a firmer basis for the assumption that inhibition plays a major role during bilingual language control. In particular, the empirical replicability of the phenomena themselves needs to be established more firmly, the underlying theoretical assumptions need further examination, and the alternative explanations of the empirical effects need to be scrutinized. In turn, we conclude that inhibitory control may provide a coherent framework for bilingual language production while outlining the challenges that the inhibition account still needs to face.
The widespread and the recognition of the multifactorial nature of Alzheimer disease (AD) increased the demands for multi-targeted directed ligands (MTDLs) to overcome possible drug-drug interactions ...of the combination therapy, and to acquire superior therapeutic profile than single targeted molecules. Two main scaffolds namely: pyrazolopyridine and tetrahydroacridine (THA) were used to synthesize four different series of integrated multi-targeted synthons possessing ChE (hAChE or hBuChE), Aβ1-42 aggregation inhibition potency, in addition to optimum metal chelating capability. Structure modifications were performed to 9-amino function of THA core of tacrine and the pyrazolopyridine scaffolds linked to a variety of cyclic secondary amines directly or using amide spacers or ethylamine bridge or engaging THA with pyrazolopyridine to produce hybrid compounds. Different 9-amino substitutions improved the in vitro hAChE activity of 7- or 6,7-disubstituted THA derivatives. Compounds 16 and 28 proved to be multimodal anti-AD agents as they were potent hAChE inhibitors, in addition, they could bind with the amino acids of the peripheral anionic site (PAS) affecting Aβ aggregation and hence Aβ-dependent neurotoxicity especially compound 16 which was almost twofold more active than donepezil. Furthermore, both compounds directly inhibited Aβ1-42 self-aggregation and chelated bio-metals such as Fe2+, Zn2+ and Cu2+ preventing reactive oxygen species (ROS) generation by Aβ and its oxidative damage in the brain regions of AD patients. Compound 28 had superior privilege by its dual ChE activity resulting in better cognitive improvement. Compounds 16 and 28 showed acceptable relative safety upon hepG2 cell line and excellent BBB penetration with wide safety margin as their LD50 were higher than 120 mg/kg.
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•Compounds 16 and 28 proved to be potent multi-targeted anti-Alzheimer's agents.•Compound 16 proved to be potent active hAChE and Aβ1-42 aggregation inhibitor.•Compound 28 proved to be active ChE and Aβ1-42 aggregation inhibitor.•The lead compounds showed metal chelating activity, wide safety margin, and excellent ex vivo BBB penetration.•Docking into hAChE, hBuChE and Aβ1-42 were conducted to interpret the obtained results.
In 2003 Rubenstein and Merzenich hypothesized that some forms of Autism (ASD) might be caused by a reduction in signal-to-noise in key neural circuits, which could be the result of changes in ...excitatory-inhibitory (E-I) balance. Here, we have clarified the concept of E-I balance, and updated the original hypothesis in light of the field's increasingly sophisticated understanding of neuronal circuits. We discuss how specific developmental mechanisms, which reduce inhibition, affect cortical and hippocampal functions. After describing how mutations of some ASD genes disrupt inhibition in mice, we close by suggesting that E-I balance represents an organizing framework for understanding findings related to pathophysiology and for identifying appropriate treatments.
Auranofin is an oral gold(I) compound, initially developed for the treatment of rheumatoid arthritis. Currently, Auranofin is under investigation for oncological application within a drug repurposing ...plan due to the relevant antineoplastic activity observed both in vitro and in vivo tumor models. In this review, we analysed studies in which Auranofin was used as a single drug or in combination with other molecules to enhance their anticancer activity or to overcome chemoresistance. The analysis of different targets/pathways affected by this drug in different cancer types has allowed us to highlight several interesting targets and effects of Auranofin besides the already well‐known inhibition of thioredoxin reductase. Among these targets, inhibitory‐κB kinase, deubiquitinates, protein kinase C iota have been frequently suggested. To rationalize the effects of Auranofin by a system biology‐like approach, we exploited transcriptomic data obtained from a wide range of cell models, extrapolating the data deposited in the Connectivity Maps website and we attempted to provide a general conclusion and discussed the major points that need further investigation.
The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. ...Analysis of the first “wave” (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS “wave” (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients.
PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, “wave” (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness.
ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across “waves” (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of “wave” or “wave x diagnosis” interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits.
Schizophrenia-linked PPI deficits were replicable across two multi-site “waves” of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.
Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a ...potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C
82
(OH)
22
can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C
82
(OH)
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effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C
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(OH)
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not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C
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(OH)
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–MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C
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(OH)
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inhibits MMP-9 mainly via an exocite interaction, whereas the well-known zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C
82
(OH)
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exhibits specific binding modes near the ligand-specificity loop S1′, thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C
82
(OH)
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a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.
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