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In the present study, non-conventional and green technology (ultrasonication) was utilized to recover bioactive compounds from the small, medium and large sized defatted date seed powder (DDSP) particles. Bioactive compounds recovered from DDSP and the remaining fiber-rich residue were incorporated as functional ingredient in the biscuit dough to enhance the functionality and the quality characteristics of the dough and biscuit. The polyphenolic extract and 2.5 %, 5 % and 7.5 % substitution levels of fiber-rich extraction residue were incorporated in formulations followed by investigating the effect on rheological, physical and microstructural properties of dough and biscuit. Loss and storage moduli, G’’ and G’, respectively, of dough increased with decreasing particle size and increasing substitution level while tan δ decreased with increasing substitution level of fiber-rich extraction residue. The smallest particles at 7.5 % substitution level resulted in the lowest creep strain value in dough. Hardness of the dough and biscuit increased with decreasing particle size and increasing substitution level of the residue. The 7.5 % substitution level of the smallest particle size resulted in the darkest dough and biscuit. Spread ratio and diameter of the biscuit decreased with increasing substitution level of the residue. The smallest diameter of 50.61 mm and spread ratio of 8.36 was observed in the biscuits substituted with the largest particle size with 7.5 % substitution level. Microstructural images of dough and biscuit revealed that the continuity of the gluten network was disrupted by the incorporation of the fiber-rich extraction residue. This study provided valuable insights into extracting bioactive components from date by-products using green ultrasonication technique and utilizing such compounds to improve functional attributes of bakery products, as a sustainable approach for valorizing date by-products.

Date seeds contain various nutrients and bioactive compounds which can be utilized as functional food ingredients in a sustainable manner. This study optimized microwave-assisted extraction (MAE) of bioactive compounds from defatted date seed powder (DSP) and investigated the physicochemical properties of the remaining residues from seeds of three different date varieties (Khalas, Fardh, and Khenaizi). Both, the extracts and the residues were incorporated as functional ingredients in the biscuits. Under optimal conditions: power 700 W, time 6 min, temperature 45 °C, and particle size

The Src family kinases (SFKs) Lck and Lyn are crucial for lymphocyte development and function. Albeit tissue-restricted expression patterns the two kinases share common functions; the most pronounced one being the phosphorylation of ITAM motifs in the cytoplasmic tails of antigenic receptors. Lck is predominantly expressed in T lymphocytes; however, it can be ectopically found in B-1 cell subsets and numerous pathologies including acute and chronic B-cell leukemias. The exact impact of Lck on the B-cell signaling apparatus remains enigmatic and is followed by the long-lasting question of mechanisms granting selectivity among SFK members. In this work we sought to investigate the mechanistic basis of ectopic Lck function in B-cells and compare it to events elicited by the predominant B-cell SFK, Lyn. Our results reveal substrate promiscuity displayed by the two SFKs, which however, is buffered by their differential susceptibility toward regulatory mechanisms, revealing a so far unappreciated aspect of SFK member-specific fine-tuning. Furthermore, we show that Lck- and Lyn-generated signals suffice to induce transcriptome alterations, reminiscent of B-cell activation, in the absence of receptor/co-receptor engagement. Finally, our analyses revealed a yet unrecognized role of SFKs in tipping the balance of cellular stress responses, by promoting the onset of ER-phagy, an as yet completely uncharacterized process in B lymphocytes.

Background: Emergence of antibiotic-resistant bacteria makes exploration of natural antibacterial products imperative. Like other fruit processing industry by-products, date kernels, a waste from date processing industry is rich in its extractable polyphenols. The rich polyphenolic content suggests that date kernel extracts (DKE) can be a cost-effective source of antimicrobial agents, however, their antibacterial activity is poorly understood. Hence, a systematic review of available literature to establish DKE’s antibacterial activity is warranted.Methods: A systematic PRISMA approach was employed, and relevant studies were identified using defined keywords from Google Scholar, Scopus, PubMed, and Web of Science databases. The search results were screened based on predefined eligibility criteria and data extraction, organization, pooling, and descriptive statistical analyses of original research records conducted.Results: A total of 888 published records were retrieved from databases. Preliminary screening by applying specific eligibility criteria reduced records to 96 which after full text screening further decreased to 14 records. Escherichia coli and Staphylococcus aureus were the most studied organisms. Results indicate moderate to highly active effect shown by the less polar solvent based DKE’s against Gram-positive and by the aqueous based DKE’s against Gram-negative bacteria. The review confirms antibacterial activity of DKE against both Gram-positive and -negative bacteria. Heterogeneity in reported polyphenolic content and antibacterial activity are due to differences in cultivars, extraction methods, test methods, model organisms, etc. Use of standardized protocols for isolation, characterization, testing of DKE’s active polyphenols to elucidate its antibacterial activity is recommended to establish the clinical efficacy of natural antibacterial compounds from DKE.Conclusion: This review outlines the current knowledge regarding antibacterial activity of polyphenolic DKE, identifying gaps in information and provides key recommendations for future research directions.

Ice cream is a popular product worldwide. Unfortunatelly, it contains a significant amount of fat. In this review, promising strategies for the use of w/o/w multiple emulsion structures in creams are assessed. W/o/w multiple emulsions (MEs) enable reduction the fat without losing the creamy taste and mouthfeel and also encapsulation of sensitive compounds. The encouraging application and formation of MEs in ice cream mixtures is supported by the use of natural food ingredients, such as fiber, which helps to stabilize the whole system and improves nutritional value. The future trends may be focused on the target stabilizations using Pickering paticles (PPs). The possible advantages, manufacture, evaluation methods, and predicted future prospects of MEs in ice creams are discussed.

There is a growing demand for efficient medical therapies without undesired side effects that limit their application. Targeted therapies such as deliveries of pharmacologically active compounds to a specific site of action in the human body are still a big challenge. Encapsulation is an effective tool for targeted deliveries of drugs and sensitive compounds. It has been exploited as a technique that can manage the required distribution, action and metabolism of encapsulated agents. Food supplements or functional foods containing encapsulated probiotics, vitamins, minerals or extracts are often part of therapies and currently also a consumption trend. For effective encapsulation, optimal manufacturing has to be ensured. Thus, there is a trend to develop new (or modify existing) encapsulation methods. The most-used encapsulation approaches are based on barriers made from (bio)polymers, liposomes, multiple emulsions, etc. In this paper, recent advances in the use of encapsulation in the fields of medicine, food supplements and functional foods are highlighted, with emphasis on its benefits within targeted and supportive treatments. We have focused on a comprehensive overview of encapsulation options in the field of medicine and functional preparations that complement them with their positive effects on human health.

The La protein (lupus antigen) is a ubiquitous RNA-binding protein found in all human cells. It is mainly localized in the nucleus, associates with all RNA polymerase III (Pol III) transcripts, as the first factor they interact with, and modulates subsequent processing events. Export of La to the cytoplasm has been reported to stimulate the decoding of specific cellular and viral mRNAs through IRES-dependent (Internal ribosome entry site) binding and translation. Using NMR (Nuclear Magnetic Resonance) spectroscopy, we provide atomic-level-resolution structural insights on the dynamical properties of human La (hLa) protein in solution. Moreover, using a combination of NMR spectroscopy and isothermal titration calorimetry (ITC), we provide evidence about the role and ligand specificity of the C-terminal domain of the La protein (RRM2 and C-terminal region) that could mediate the recognition of HCV-IRES.

Mutations in human mitochondrial tRNAs (mt-tRNAs) are responsible for several and sometimes severe clinical phenotypes, classified among mitochondrial diseases. In addition, post-transcriptional modifications of mt-tRNAs in correlation with several stress signals can affect their stability similarly to what has been described for their nuclear-encoded counterparts. Many of the perturbations related to either point mutations or aberrant modifications of mt-tRNAs can lead to specific cleavage and the production of mitochondrial tRNA-derived fragments (mt-tRFs). Although mt-tRFs have been detected in several studies, the exact biogenesis steps and biological role remain, to a great extent, unexplored. Several mt-tRFs are produced because of the excessive oxidative stress which predominantly affects mitochondrial DNA integrity. In addition, mt-tRFs have been detected in various diseases with possible detrimental consequences, but also their production may represent a response mechanism to external stimuli, including infections from pathogens. Finally, specific point mutations on mt-tRNAs have been reported to impact the pool of the produced mt-tRFs and there is growing evidence suggesting that mt-tRFs can be exported and act in the cytoplasm. In this review, we summarize current knowledge on mitochondrial tRNA-deriving fragments and their possible contribution to gene expression regulation.

Riboswitches are structured non-coding RNAs found in the 5′ UTR of important genes for bacterial metabolism, virulence and survival. Upon the binding of specific ligands that can vary from simple ions to complex molecules such as nucleotides and tRNAs, riboswitches change their local and global mRNA conformations to affect downstream transcription or translation. Due to their dynamic nature and central regulatory role in bacterial metabolism, riboswitches have been exploited as novel RNA-based targets for the development of new generation antibacterials that can overcome drug-resistance problems. During recent years, several important riboswitch structures from many bacterial representatives, including several prominent human pathogens, have shown that riboswitches are ideal RNA targets for new compounds that can interfere with their structure and function, exhibiting much reduced resistance over time. Most interestingly, mainstream antibiotics that target the ribosome have been shown to effectively modulate the regulatory behavior and capacity of several riboswitches, both in vivo and in vitro, emphasizing the need for more in-depth studies and biological evaluation of new antibiotics. Herein, we summarize the currently known compounds that target several main riboswitches and discuss the role of mainstream antibiotics as modulators of T-box riboswitches, in the dawn of an era of novel inhibitors that target important bacterial regulatory RNAs.

The hemoglobin switch from fetal (HbF) to adult (HbA) has been studied intensively as an essential model for gene expression regulation, but also as a beneficial therapeutic approach for β-hemoglobinopathies, towards the objective of reactivating HbF. The transcription factor LRF (Leukemia/lymphoma-related), encoded from the ZBTB7A gene has been implicated in fetal hemoglobin silencing, though has a wide range of functions that have not been fully clarified. We thus established the LRF/ZBTB7A-overexpressing and ZBTB7A-knockdown K562 (human erythroleukemia cell line) clones to assess fetal vs. adult hemoglobin production pre- and post-induction. Transgenic K562 clones were further developed and studied under the influence of epigenetic chromatin regulators, such as DNA methyl transferase 3 (DNMT3) and Histone Deacetylase 1 (HDAC1), to evaluate LRF’s potential disturbance upon the aberrant epigenetic background and provide valuable information of the preferable epigenetic frame, in which LRF unfolds its action on the β-type globin’s expression. The ChIP-seq analysis demonstrated that LRF binds to γ-globin genes (HBG2/1) and apparently associates BCL11A for their silencing, but also during erythropoiesis induction, LRF binds the BGLT3 gene, promoting BGLT3-lncRNA production through the γ-δ intergenic region of β-type globin’s locus, triggering the transcriptional events from γ- to β-globin switch. Our findings are supported by an up-to-date looping model, which highlights chromatin alterations during erythropoiesis at late stages of gestation, to establish an “open” chromatin conformation across the γ-δ intergenic region and accomplish β-globin expression and hemoglobin switch.

Emulsions stabilized by adsorbed particles—Pickering particles (PPs) instead of surfactants and emulsifiers are called Pickering emulsions. Here, we review the possible uses of Pickering multiple emulsions (PMEs) in the food industry. Food-grade PMEs are very complex systems with high potential for application in food technology. They can be prepared by traditional two-step emulsification processes but also using complex techniques, e.g., microfluidic devices. Compared to those stabilized with an emulsifier, PMEs provide more benefits such as lower susceptibility to coalescence, possible encapsulation of functional compounds in PMEs or even PPs with controlled release, etc. Additionally, the PPs can be made from food-grade by-products. Naturally, w/o/w emulsions in the Pickering form can also provide benefits such as fat reduction by partial replacement of fat phase with internal water phase and encapsulation of sensitive compounds in the internal water phase. A possible advanced type of PMEs may be stabilized by Janus particles, which can change their physicochemical properties and control properties of the whole emulsion systems. These emulsions have big potential as biosensors. In this paper, recent advances in the application of PPs in food emulsions are highlighted with emphasis on the potential application in food-grade PMEs.

Utilising major waste products from the food industry can have both a great environmental impact and be a means to improve consumer health. Date seed is a food industry byproduct that has been proven to have high nutritional value. The aim of this work was to measure the total polyphenolic content (TPC), flavonoids, and antioxidant activity of the seeds of six date fruit varieties, Fard, Khalas, Khinaizi, Sukkary, Shaham, and Zahidi, and to use those seeds to enhance the antioxidant value of cookies by partially substituting flour with ground date seed. Date seed powder (DSP) was extracted at three levels of sample to solvent ratio (5:1, 10:1 and 15:1 mg/mL). Cookies were prepared using three substitution levels of wheat flour (2.5, 5.0, and 7.5%, w/w) by DSP and two types of flour (white and whole wheat), and were baked at two different temperatures, 180 and 200 °C. The composite cookies were found to contain a significant amount of TPC and flavonoids, and showed increased antioxidant activity compared with the control samples.

Date seeds are a major waste product that can be utilised as a valuable and nutritional material in the food industry. The aim of the present study was to improve cookies quality in terms of functional and textural value and assess the effect of date seed powder flour substitution on the physical and chemical characteristics of cookies. Three substitution levels (2.5, 5 and 7.5%) of flour by fine date seed powder from six varieties locally named Khalas, Khinaizi, Sukkary, Shaham, Zahidi and Fardh were prepared. Two types of flour were used (white flour and whole wheat) at two different baking temperatures: 180 and 200 °C. The incorporation of date seed had no or slight effect on moisture, ash, fat and protein content of the baked cookies. On the other hand, incorporation significantly affected the lightness and hardness of cookies; the higher level of addition, the darker and crispier the resulting cookies. The sensory analysis indicated that the produced cookies were acceptable in terms of smell, taste, texture and overall acceptability. The results indicate that the most acceptable cookies across all evaluated parameters were produced using whole wheat flour with 7.5% levels of date seed powder using Khalas and Zahidi varieties. Overall, the analysis indicated that cookies with acceptable physical characteristics and an improved nutritional profile could be produced with partial replacement of the white/whole wheat flour by date seed powder.

The diagnostic and prognostic value of miRNAs in cutaneous melanoma (CM) has been broadly studied and supported by advanced bioinformatics tools. From early studies using miRNA arrays with several limitations, to the recent NGS-derived miRNA expression profiles, an accurate diagnostic panel of a comprehensive pre-specified set of miRNAs that could aid timely identification of specific cancer stages is still elusive, mainly because of the heterogeneity of the approaches and the samples. Herein, we summarize the existing studies that report several miRNAs as important diagnostic and prognostic biomarkers in CM. Using publicly available NGS data, we analyzed the correlation of specific miRNA expression profiles with the expression signatures of known gene targets. Combining network analytics with machine learning, we developed specific non-linear classification models that could successfully predict CM recurrence and metastasis, based on two newly identified miRNA signatures. Subsequent unbiased analyses and independent test sets (i.e., a dataset not used for training, as a validation cohort) using our prediction models resulted in 73.85% and 82.09% accuracy in predicting CM recurrence and metastasis, respectively. Overall, our approach combines detailed analysis of miRNA profiles with heuristic optimization and machine learning, which facilitates dimensionality reduction and optimization of the prediction models. Our approach provides an improved prediction strategy that could serve as an auxiliary tool towards precision treatment.

Ribonuclease P (RNase P) is an important ribonucleoprotein (RNP), responsible for the maturation of the 5′ end of precursor tRNAs (pre-tRNAs). In all organisms, the cleavage activity of a single phosphodiester bond adjacent to the first nucleotide of the acceptor stem is indispensable for cell viability and lies within an essential catalytic RNA subunit. Although RNase P is a ribozyme, its kinetic efficiency in vivo, as well as its structural variability and complexity throughout evolution, requires the presence of one protein subunit in bacteria to several protein partners in archaea and eukaryotes. Moreover, the existence of protein-only RNase P (PRORP) enzymes in several organisms and organelles suggests a more complex evolutionary timeline than previously thought. Recent detailed structures of bacterial, archaeal, human and mitochondrial RNase P complexes suggest that, although apparently dissimilar enzymes, they all recognize pre-tRNAs through conserved interactions. Interestingly, individual protein subunits of the human nuclear and mitochondrial holoenzymes have additional functions and contribute to a dynamic network of elaborate interactions and cellular processes. Herein, we summarize the role of each RNase P subunit with a focus on the human nuclear RNP and its putative role in flawless gene expression in light of recent structural studies.

Hydroxy-substituted tetrachlorodibenzo[b,e][1,4]dioxin and tetrachlorodibenzo[b,d]furans have been synthesized using 3,4-dichloroanisole, 2,3,6-trichlorophenol and 4,5-dichlorocatechol as starting materials and electrophilic and/or nucleophilic aromatic substitution reactions for the assembly of the dibenzo[b,e][1,4]dioxin and dibenzo[b,d]furan systems. The thus-obtained phenolic compounds were then alkylated with N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde)-protected 3-bromopropan-1-amine to give the corresponding N-Dde protected 3-aminopropoxy-substituted tetrachlorodibenzo[b,e][1,4]dioxin and tetrachlorodibenzo[b,d]furans, respectively. Hydrazinolysis-mediated Dde removal from the former compound provided the corresponding amino-substituted dioxin, which was coupled to carboxy-substituted magnetic beads affording magnetic beads coated by the amino-substituted dioxin. The latter is an attractive intermediate for the development of selective single-standard DNA (ssDNA) aptamers, which constitute molecular recognition elements in photonic biosensors with potential application to the monitoring of the dangerous environmental pollutants, dioxins having serious implications in human health.

KRASG12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS oncogenic signaling is responsible for modulation of tumor microenvironment, with translation factors being among the most prominent deregulated targets. In the present study, we used TALENs to edit EGFRWT CL1-5 and A549 cells for integration of a Tet-inducible KRASG12C expression system. Subsequent analysis of both cell lines showed that cap-dependent translation was impaired in CL1-5 cells via involvement of mTORC2 and NF-κB. In contrast, in A549 cells, which additionally harbor the KRASG12S mutation, cap-dependent translation was favored via recruitment of mTORC1, c-MYC and the positive regulation of eIF4F complex. Downregulation of eIF1, eIF5 and eIF5B in the same cell line suggested a stringency loss of start codon selection during scanning of mRNAs. Puromycin staining and polysome profile analysis validated the enhanced translation rates in A549 cells and the impaired cap-dependent translation in CL1-5 cells. Interestingly, elevated translation rates were restored in CL1-5 cells after prolonged induction of KRASG12C through an mTORC1/p70S6K-independent way. Collectively, our results suggest that KRASG12C signaling differentially affects the regulation of the translational machinery. These differences could provide additional insights and facilitate current efforts to effectively target KRAS.

Ribosomal RNA (rRNA) biogenesis takes place in the nucleolus, the most prominent condensate of the eukaryotic nucleus. The proper assembly and integrity of the nucleolus reflects the accurate synthesis and processing of rRNAs which in turn, as major components of ribosomes, ensure the uninterrupted flow of the genetic information during translation. Therefore, the abundant production of rRNAs in a precisely functional nucleolus is of outmost importance for the cell viability and requires the concerted action of essential enzymes, associated factors and epigenetic marks. The coordination and regulation of such an elaborate process depends on not only protein factors, but also on numerous regulatory non-coding RNAs (ncRNAs). Herein, we focus on RNA-mediated mechanisms that control the synthesis, processing and modification of rRNAs in mammals. We highlight the significance of regulatory ncRNAs in rRNA biogenesis and the maintenance of the nucleolar morphology, as well as their role in human diseases and as novel druggable molecular targets.

We document linezolid dependence among 5 highly linezolid-resistant (LRSE) Staphylococcus epidermidis bloodstream isolates that grew substantially faster at 32 µg/mL linezolid presence. These isolates carried the mutations T2504A and C2534T in multiple 23S rRNA copies and 2 mutations leading to relevant amino acid substitutions in L3 protein. Linezolid dependence could account for increasing LRSE emergence.

Poly(A)-specific ribonuclease (PARN) is an exoribonuclease/deadenylase that degrades 3'-end poly(A) tails in almost all eukaryotic organisms. Much of the biochemical and structural information on PARN comes from the human enzyme. However, the existence of PARN all along the eukaryotic evolutionary ladder requires further and thorough investigation. Although the complete structure of the full-length human PARN, as well as several aspects of the catalytic mechanism still remain elusive, many previous studies indicate that PARN can be used as potent and promising anti-cancer target. In the present study, we attempt to complement the existing structural information on PARN with in-depth bioinformatics analyses, in order to get a hologram of the molecular evolution of PARNs active site. In an effort to draw an outline, which allows specific drug design targeting PARN, an unequivocally specific platform was designed for the development of selective modulators focusing on the unique structural and catalytic features of the enzyme. Extensive phylogenetic analysis based on all the publicly available genomes indicated a broad distribution for PARN across eukaryotic species and revealed structurally important amino acids which could be assigned as potentially strong contributors to the regulation of the catalytic mechanism of PARN. Based on the above, we propose a comprehensive in silico model for the PARN's catalytic mechanism and moreover, we developed a 3D pharmacophore model, which was subsequently used for the introduction of DNP-poly(A) amphipathic substrate analog as a potential inhibitor of PARN. Indeed, biochemical analysis revealed that DNP-poly(A) inhibits PARN competitively. Our approach provides an efficient integrated platform for the rational design of pharmacophore models as well as novel modulators of PARN with therapeutic potential.

Recombination in Poliovirus vaccine strains is a very frequent phenomenon. In this report 23 polio/Sabin strains isolated from healthy vaccinees or from VAPP patients after OPV administration, were investigated in order to identify recombination sites from 2C to 3D regions of the poliovirus genome. RT-PCR, followed by Restriction Fragment Length Polymorphism (RFLP) screening analysis were applied in four distant genomic regions (5′ UTR, VP1, 2C and 3C–3D) in order to detect any putative recombinant. The detected recombinants were sequenced from 2C to the end of the genome (3′ UTR) and the exact recombination sites were determined with computational analysis. Five of the 23 isolated strains were recombinant in one genomic region, two of them in 2C, isolates EP16:S3/S2, EP23:S3/S1, two in 3D isolates EP6:S2/S1, EP12:S2/S1 and one in 3A isolate EP9:S2/Sl. Point mutations were found in strains EP3, EP6, EP9 and EP12. Recombination specific types and sites re-occurrence along with point mutations are discussed concerning the polioviruses evolution. [ABSTRACT FROM AUTHOR]