Synthesis,Cancer‐Selective Antiproliferative and Apoptotic Effects of Some (±)‐Naringenin Cycloaminoethyl Derivatives

Naringenin is a naturally occurring flavonoid and due to its broad spectrum of biological activities, including anticancer properties, has attracted scientific attention in recent years. To contribute to these studies, we synthesized some new (±)‐naringenin cyclic aminoethyl derivatives, analyzed the cytotoxic and anti‐proliferative properties of them via 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay, and mitochondrial apoptosis signaling response and gene expressions belong to caspase‐3 depended apoptosis as biomarkers in both healthy and cancer cell lines. Our results suggest that some of our naringenin derivatives are potential anticancer agents with a selective death potential and targeting properties for mitochondrial apoptosis signaling against at least human cervix and breast cancer.     

Antirotaviral potential of lactoferrin from different origin: effect of thermal and high pressure treatments

Rotaviral gastroenteritis causes a high rate of infant mortality and severe healthcare implications worldwide. Several studies have pointed out that human milk and dairy fractions, such as whey and buttermilk, possess antirotaviral activity. This activity has been mainly associated with glycoproteins, among them lactoferrin (LF). Thermal treatments are necessary to provide microbiological safety and extend the shelf life of milk products, though they may diminish their biological value. High hydrostatic pressure (HHP) treatment is a non-thermal method that causes lower degradation of food components than other treatments. Thus, the main objective of this study was to prove the antirotaviral activity of LFs from different origin and to evaluate the effect of several thermal and HHP treatments on that activity. LF exerted a high antirotaviral activity, regardless of its origin. Native LFs from bovine, ovine, swine and camel milk, and the human recombinant forms, at 1 mg/mL, showed neutralizing values in the range 87.5–98.6%, while human LF neutralized 58.2%. Iron saturation of bovine LF did not modify its antirotaviral activity. Results revealed interspecies differences in LFs heat susceptibility. Thus, pasteurization at 63 °C for 30 min led to a decrease of 60.1, 44.5, 87.1, 3.8 and 8% of neutralizing activity for human, bovine, swine, ovine and camel LFs, respectively. Pasteurization at 75 °C for 20 s was less harmful to the activity of LFs, with losses ranging from 0 to 13.8%. HHP treatment at 600 MPa for 15 min did not cause any significant decrease in the neutralizing activity of LFs.     

Computational screening of dipeptidyl peptidase IV inhibitors from micoroalgal metabolites by pharmacophore modeling and molecular docking

Dipeptidyl peptidase IV (DPP‐IV) catalyzes conversion of GLP‐1 (glucagon like peptide 1) to inert structure, which results in insufficient secretion of insulin and increase in postprandial blood glucose level. The present study attempts to identify novel inhibitors from bioactive metabolites present in microalgae against DPP‐IV through virtual screening, molecular docking, and pharmacophore modeling for the active target. Possible binding modes of all 60 ligands against DPP‐IV receptor were constructed using MTiOpenScreen virtual screening server. Pharmacophore model was built based on identified 38 DPP‐IV test ligands by using the web‐based PharmaGist program which encompasses hydrogen‐bond acceptors, hydrophobic groups, spatial features, and aromatic rings. The pharmacophore model having highest scores was selected to screen active DPP‐IV ligands. Highest scoring model was used as a query in ZincPharmer screening. All identified ligands were filtered, based on the Lipinski's rule‐of‐five and were subjected to docking studies. In the process of docking analyses, we considered different bonding modes of one ligand with multiple active cavities of DPP‐IV with the help of AutoDock 4.0. The docking analyses indicate that the bioactive constituents, namely, β‐stigmasterol, barbamide, docosahexaenoic acid, arachidonic acid, and harman showed the best binding energies on DPP‐IV receptor and hydrogen bonding with ASP545, GLY741, TYR754, TYR666, ARG125, TYR547, SER630, and LYS554 residues. This study concludes that docosahexaenoic acid, arachidonic acid, β‐stigmasterol, barbamide, harman, ZINC58564986, ZINC56907325, ZINC69432950, ZINC69431828, ZINC73533041, ZINC84287073, ZINC69849395, and ZINC10508406 act as possible DPP‐IV inhibitors.     

Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay,Hypotonia, Scoliosis,and Cerebellar Atrophy

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.     

Does education ‘trump’ nationality? Boundary-drawing practices among highly educated migrants from Turkey

Inspired by a super-diversity approach, this paper seeks to explore the influence of the ‘ethnic hierarchy’ of ‘old’ minority groups over the way ‘new’ migrants from Turkey negotiate their interaction in the daily life in three settings: Amsterdam, London and Barcelona. By focusing on highly educated migrants from Turkey who by virtue of their country of origin or religion are positioned at the bottom of ‘ethnic hierarchies’, it strives to understand the significance of these different sources of diversity in daily interaction. Applying boundary-drawing strategies developed for ethnic boundaries, this paper argues that education does not necessarily ‘trump’ nationality, but allows for substantial claims of difference. New migrants from Turkey carve out a space for themselves by on the one hand homogenizing Turkish or other Muslim communities through attributing ‘unwanted’ behaviours and on the other re-defining the boundaries of their individual identity with emphasis on different sources of diversity.     

Potent Inhibitory Effects of Some Phenolic Acids on Lactoperoxidase

Lactoperoxidase (LPO) plays a key role in immune response against pathogens. In this study, we examined the effects of some phenolic acids on LPO. For this purpose, bovine milk LPO was purified 380.85‐fold with a specific activity of 26.66 EU/mg and overall yield of 73.33% by using Amberlite CG‐50 H⁺ resin and CNBr‐activated Sepharose‐4B‐l ‐tyrosine‐sulfanilamide affinity chromatography. After purification, the in vitro effects of phenolic acids (tannic acid, 3,4‐dihydroxybenzoic acid, 3,5‐ dihydroxybenzoic acid, chlorogenic acid, sinapic acid, 4‐hydroxybenzoic acid, vanillic acid, salicylic acid, and 3‐hydroxybenzoic acid) were investigated on LPO. These phenolic acids showed potent inhibitory effect on LPO. K_i values for these phenolic acids were found as 0.0129 nM, 0.132 μM, 0.225 μM, 0.286 μM, 0.333 μM, 2.33 μM, 10.82 μM, 0.076 mM, and 0.405 mM, respectively. Sinapic acid and 4‐hydroxybenzoic acid exhibited noncompetitive inhibition; 3,4‐dihydroxybenzoic acid showed uncompetitive inhibition, and other phenolic acids showed competitive inhibition.     

Novel 4,4′-diether-2,2′-bipyridine cisplatin analogues are more effective than cisplatin at inducing apoptosis in cancer cell lines

The synthesis and characterization of dichloro(4,4′-bis[methoxy]-2,2′-bipyridine)platinum (1) and dichloro(4,4′-bis[3-methoxy-n-propyl]-2,2′-bipyridine)platinum (2) are described. As analogues to CDDP, these 4,4′-disubstituted 2,2′-bipyridine complexes exhibit decreased EC₅₀ values of 10–100 times in cancer cell lines of the lung, prostate, and melanoma with several combinations of complex and cell line less than 10 μM. Flow cytometry data indicate ‘blocks’ of MDA-MD-435 cycle by 1 (G2/M) and 2 (S). Observed cell survival trends in the presence of 1, 2 under ionizing radiation mimic those of CDDP. Preliminary structure activity relationships are discussed for the 4,4′-substitutions made on the bipyridine ring.