Alkyl esters of hydroxycinnamic acids with improved antioxidant activity and lipophilicity protect PC12 cells against oxidative stress

Hydroxycinnamic acids (HCAs) are phenolic compounds present in dietary plants, which possess considerable antioxidant activity. In order to increase the lipophilicity of HCAs, with the aim of improving their cellular absorption and expansion of their use in lipophilic media, methyl, ethyl, propyl and butyl esters of caffeic acid and ferulic acid have been synthesized. All caffeate esters had a slightly lower DPPH IC(50) (13.5-14.5 μM) and higher ferric reducing antioxidant power (FRAP) values (1490-1588 mM quercetin/mole [mMQ/mole]) compared to caffeic acid (16.6 μM and 1398 mMQ/mole, respectively) in antioxidant assays. In contrast, ferulate esters were less active in DPPH (56.3-74.7 μM) and FRAP assays (193-262 mMQ/mole) compared to ferulic acid (44.6 μM and 324 mMQ/mole, respectively). Redox properties of HCAs were in line with their antioxidant capacities, so that compounds with higher antioxidant activities had lower oxidation potentials. Measurement of partition coefficients disclosed the higher lipophilicity of the esters compared to parent compounds. All esters of caffeic acid significantly inhibited hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay at 5 and 25 μM. However, caffeic acid, ferulic acid and ferulate esters were not able to protect the cells. In conclusion, these findings suggest that alkyl esterification of some HCAs augments their antioxidant properties as well as their lipophilicity and as a consequence, improves their cell protective activity against oxidative stress. These compounds could have useful applications in conditions where oxidative stress plays a pathogenic role.     

Endothelial cell barriers: Transport of molecules between blood and tissues

An endothelial cell monolayer separates interstitia from blood and lymph, and determines the bidirectional transfer of solutes and macromolecules across these biological spaces. We review advances in transport modalities across these endothelial barriers. Glucose is a major fuel for the brain and peripheral tissues, and insulin acts on both central and peripheral tissues to promote whole‐body metabolic signalling and anabolic activity. Blood‐brain barrier endothelial cells display stringent tight junctions and lack pinocytic activity. Delivery of blood glucose and insulin to the brain occurs through their respective carrier (Glucose transporter 1) and receptor (insulin receptor), enacting bona fide transcytosis. At supraphysiological concentrations, insulin is also likely transferred by fluid phase cellular uptake and paracellular transport, especially in peripheral microvascular endothelia. The lymphatic microvasculature also transports insulin but in this case from tissues to lymph and therefrom to blood. This serves to end the hormone's action and to absorb highly concentrated subcutaneously injected insulin in diabetic individuals. The former function may involve receptor‐mediated transcytosis into lymphatic endothelial cells, the latter fluid phase uptake and paracellular transport. Lymphatic capillaries also mediate carrier‐dependent transport of other nutrients and macromolecules. These findings challenge the notion that lymphatic capillaries only transport macromolecules through intercellular flaps.     

MiRNA‐145‐5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor

The roles of specific microRNAs (miRNA) in oligodendrocyte (OL) differentiation have been studied in depth. However, miRNAs in OL precursors and oligodendrocyte progenitor cells (OPCs) have been less extensively investigated. MiR‐145‐5p is highly expressed in OPCs relative to differentiating OLs, suggesting this miRNA may serve a function specifically in OPCs. Knockdown of miR‐145‐5p in primary OPCs led to spontaneous differentiation, as evidenced by an increased proportion of MAG⁺ cells, increased cell ramification, and upregulation of multiple myelin genes including MYRF, TPPP, and MAG, and OL cell cycle exit marker Cdkn1c. Supporting this transition to a differentiating state, proliferation was reduced in miR‐145‐5p knockdown OPCs. Further, knockdown of miR‐145‐5p in differentiating OLs showed enhanced differentiation, with increased branching, myelin membrane production, and myelin gene expression. We identified several OL‐specific genes targeted by miR‐145‐5p that exhibited upregulation with miR‐145‐5p knockdown, including myelin gene regulatory factor (MYRF), that could be regulating the prodifferentiation phenotype in both miR‐145 knockdown OPCs and OLs. Indeed, spontaneous differentiation with knockdown of miR‐145‐5p was fully rescued by concurrent knockdown of MYRF. However, proliferation rate was only partially rescued with MYRF knockdown, and overexpression of miR‐145‐5p in OPCs increased proliferation rate without affecting expression of already lowly expressed differentiation genes. Taken together, these data suggest that in OPCs miR‐145‐5p both prevents differentiation at least in part by preventing expression of MYRF and promotes proliferation via as‐yet‐unidentified mechanisms. These findings clarify the need for differential regulation of miR‐145‐5p between OPCs and OLs and may have further implications in demyelinating diseases such as multiple sclerosis where miR‐145‐5p is dysregulated.     

Energy-aware routing considering load balancing for SDN: a minimum graph-based Ant Colony Optimization

Software-Defined Network (SDN) technology is a network management approach that facilitates a high level of programmability and centralized manageability. By leveraging the control and data plane separation, an energy-aware routing model could be easily implemented in the networks. In the present paper, we propose a two-phase SDN-based routing mechanism that aims at minimizing energy consumption while providing a certain level of QoS for the users’ flows and realizing the link load balancing. To reduce the network energy consumption, a minimum graph-based Ant Colony Optimization (ACO) approach is used in the first phase. It prunes and optimizes the network tree by turning unnecessary switches off and providing an energy-minimized sub-graph that is responsible for the network existing flows. In the second phase, an innovative weighted routing approach is developed that guarantees the QoS requirements of the incoming flows and routes them so that to balance the loads on the links. We validated our proposed approach by conducting extensive simulations on different traffic patterns and scenarios with different thresholds. The results indicate that the proposed routing method considerably minimizes the network energy consumption, especially for congested traffics with mice-type flows. It can provide effective link load balancing while satisfying the users’ QoS requirements.

     

Design and In Silico Evaluation of a Novel Cyclic Disulfide-Rich anti-VEGF Peptide as a Potential Antiangiogenic Drug

International Journal of Peptide Research and Therapeutics - The vascular endothelial growth factor (VEGF) signaling pathway has a crucial role in regulating tumor angiogenesis. VEGF-A shows...     

Designing of a Novel Fusion Protein Vaccine Candidate Against Human Visceral Leishmaniasis (VL) Using Immunoinformatics and Structural Approaches

Leishmaniasis is caused by an obligate intracellular protozoan parasite. The clinical forms of leishmaniasis differ from cutaneous leishmaniasis, mucocutaneous leishmaniasis and visceral leishmaniasis (VL) which depend on the parasite species and the host’s immune responses. There are significant challenges to the available anti-leishmanial drug therapy, particularly in severe forms of disease, and the rise of drug resistance has made it more difficult. Currently, no licensed vaccines have been introduced to the market for the control and elimination of VL. A potential target for use in candidate vaccines against leishmaniasis has been shown to be leishmania Kinetoplastid membrane protein-11 (KMP-11) antigen. In this study, we chose KMP-11 antigen as target antigen in our vaccine construct. In addition, B-type flagellin (fliC) was used as an adjuvant for enhancing vaccine immunogenicity. The GSGSGSGSGSG linker was applied to link the KMP-11 antigen and fliC (KMP-11-fliC) to construct our fusion protein. Bioinformatics approaches such as; 3D homology modeling, CTL, B-cell, MHC class I and II epitopes prediction, allergenicity, antigenicity evaluations, molecular docking, fast simulations of flexibility of docked complex and in silico cloning were employed to analysis and evaluation of various properties of the designed fusion construct. Computational results showed that our engineered structure has the potential for proper stimulation of cellular and humoral immune responses against VL. Consequently, it could be proposed as a candidate vaccine against VL according to these data and after verifying the efficacy of the candidate vaccine through in vivo and in vitro immunological tests.

     

New species of <Emphasis Type="Italic">Spauligodon</Emphasis> Skrjabin,Schikhobalova &; Lagodovskaja, 1960 and <Emphasis Type="Italic">Thubunea</Emphasis> Seurat, 1914 (Nematoda) from the gastro-intestinal tract of lizards in Iran

Based on light and electron microscopical studies, the following four species of Philometra Costa, 1845 (Nematoda: Philometridae) are described from marine fishes from off Basrah, southern Iraq (Arabian Gulf): P. brachiri n. sp. (males and females) from the ovary of the Oriental sole Brachirus orientalis (Bloch & Schneider) (Pleuronectiformes; Soleidae), P. piscaria Moravec & Justine, 2014 (female) from the ovary of the orange-spotted grouper Epinephelus coioides (Hamilton) (Perciformes: Serranidae), P. otolithi Moravec & Manoharan, 2013 (male and females) from the ovary of the tigerteeth croaker Otolithes ruber (Bloch & Schneider) (Perciformes: Sciaenidae) and P. tricornuta n. sp. (female) from the musculature of the caudal peduncle of the greater lizardfish Saurida tumbil (Bloch) (Aulopiformes: Synodontidae). Philometra brachiri is mainly characterised by the structure of the distal tip of the gubernaculum and the length of the spicules (132–135 μm) in male. Philometra tricornuta is distinguished by the presence of three large sclerotised oesophageal teeth and two tandem bulbous inflations at the anterior end of oesophagus in female. The female of P. piscaria is described for the first time. Philometra brachiri is the first species of this genus described from a fish belonging to the family Soleidae. The findings of P. piscaria and P. otolithi in Iraqi marine waters represent new geographical records.     

Potential impacts of climate change on distribution range of Nabis pseudoferus and N. palifer (Hemiptera: Nabidae) in Iran

Nabis pseudoferus Remane and N. palifer Seidenstucker are predators that feed on a wide range of insect pests. To reveal their current potential habitats, the effects of climate change and their future distribution in various areas of Iran we used maximum entropy modeling (Maxent). To produce the models, samples were collected from 218 areas of Iran resulting in discovering 271 points where the nabids were found. The accuracy and performance of distribution models were also evaluated by the area under receiver operating characteristic curve and jack‐knife analysis. In the Maxent model, the climatic, elevation and land cover layers were the major bases for the current models. In modeling future distribution, the land cover layer was excluded. The distribution of N. pseudoferus was independent of the type of vegetation while the distribution of N. palifer varied according to differences in type of vegetation. Using jack‐knife analysis, the land cover and precipitation were the most effective predictors driving the two Nabis species range expansion. From 2013 to 2050 the impacts of climate change on N. pseudoferus distribution was predicted to have a negative impact but have a positive effect on N. palifer range expansion. Results could be used in preparation of predators' conservation, translocation and reintroduction programs and application in pest management strategies.     

The Epigenetic Drug 5-Azacytidine Interferes with Cholesterol and Lipid Metabolism

DNA methylation and histone acetylation inhibitors are widely used to study the role of epigenetic marks in the regulation of gene expression. In addition, several of these molecules are being tested in clinical trials or already in use in the clinic. Antimetabolites, such as the DNA-hypomethylating agent 5-azacytidine (5-AzaC), have been shown to lower malignant progression to acute myeloid leukemia and to prolong survival in patients with myelodysplastic syndromes. Here we examined the effects of DNA methylation inhibitors on the expression of lipid biosynthetic and uptake genes. Our data demonstrate that, independently of DNA methylation, 5-AzaC selectively and very potently reduces expression of key genes involved in cholesterol and lipid metabolism (e.g. PCSK9, HMGCR, and FASN) in all tested cell lines and in vivo in mouse liver. Treatment with 5-AzaC disturbed subcellular cholesterol homeostasis, thereby impeding activation of sterol regulatory element-binding proteins (key regulators of lipid metabolism). Through inhibition of UMP synthase, 5-AzaC also strongly induced expression of 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) and promoted triacylglycerol synthesis and cytosolic lipid droplet formation. Remarkably, complete reversal was obtained by the co-addition of either UMP or cytidine. Therefore, this study provides the first evidence that inhibition of the de novo pyrimidine synthesis by 5-AzaC disturbs cholesterol and lipid homeostasis, probably through the glycerolipid biosynthesis pathway, which may contribute mechanistically to its beneficial cytostatic properties.     

Method for assembling and expressing multiple genes in the nucleus of microalgae

The green alga, Chlamydomonas reinhardtii, is a model organism used in the study of photosynthesis and biotechnological research. Despite its importance, a complete set of genetic tools has yet to be developed. Here, we report the development of a new method for constructing a multi-gene pathway in Saccharomyces cerevisiae and integrating the assembled pathway into the nuclear genome of C. reinhardtii. To demonstrate the use of this method, we assembled and functionally expressed up to three reporter proteins (Ble, AphVIII, and GFP) simultaneously in the nucleus of C. reinhardtii. This new molecular tool should aid efforts to engineer microalgae for biofuel and biopharmaceutical production.