Antiproliferative activity of glycosaminoglycan-like polysaccharides derived from marine molluscs

Despite the increasing availability of new classes of cancer treatment, such as immuneand targeted therapies, there remains a need for the development of new antiproliferative/cytotoxic drugs with improved pharmacological profiles that can also overcome drug resistant forms of cancer. In this study, we have identified, and characterised, a novel marine polysaccharide with the potential to be developed as an anticancer agent. Sulphated polysaccharides isolated from the common cockle (Cerastoderma edule) were shown to have antiproliferative activity on chronic myelogenous leukaemia and relapsed acute lymphoblastic leukaemia cell lines. Disaccharide and monosaccharide analysis of these marine polysaccharides confirmed the presence of glycosaminoglycan-like structures that were enriched in ion-exchange purified fractions containing antiproliferative activity. The antiproliferative activity of these glycosaminoglycan-like marine polysaccharides was shown to be susceptible to heparinase but not chondrotinase ABC digestion. This pattern of enzymatic and antiproliferative activity has not previously been seen, with either marine or mammalian glycosaminoglycans. As such, our findings suggest we have identified a new type of marine derived heparan sulphate/heparin-like polysaccharide with potent anticancer properties

The role of pannexin hemichannels in inflammation and regeneration

Tissue injury involves coordinated systemic responses including inflammatory response, targeted cell migration, cell-cell communication, stem cell activation and proliferation, and tissue inflammation and regeneration. The inflammatory response is an important prerequisite for regeneration. Multiple studies suggest that extensive cell-cell communication during tissue regeneration is coordinated by purinergic signaling via extracellular adenosine triphosphate (ATP). Most recent data indicates that ATP release for such communication is mediated by hemichannels formed by connexins and pannexins. The Pannexin family consists of three vertebrate proteins (Panx 1, 2, and 3) that have low sequence homology with other gap junction proteins and were shown to form predominantly non-junctional plasma membrane hemichannels. Pannexin-1 (Panx1) channels function as an integral component of the P2X/P2Y purinergic signaling pathway and is arguably the major contributor to pathophysiological ATP release. Panx1 is expressed in many tissues, with highest levels detected in developing brain, retina and skeletal muscles. Panx1 channel expression and activity is reported to increase significantly following injury/inflammation and during regeneration and differentiation. Recent studies also report that pharmacological blockade of the Panx1 channel or genetic ablation of the Panx1 gene cause significant disruption of progenitor cell migration, proliferation, and tissue regeneration. These findings suggest that pannexins play important roles in activation of both post-injury inflammatory response and the subsequent process of tissue regeneration. Due to wide expression in multiple tissues and involvement in diverse signaling pathways, pannexins and connexins are currently being considered as therapeutic targets for traumatic brain or spinal cord injuries, ischemic stroke and cancer. The precise role of pannexins and connexins in the balance between tissue inflammation and regeneration needs to be further understood

HDAC6 Regulates Mitochondrial Transport in Hippocampal Neurons

Background: Tubulin is a major substrate of the cytoplasmic class II histone deacetylase HDAC6. Inhibition of HDAC6 results in higher levels of acetylated tubulin and enhanced binding of the motor protein kinesin-1 to tubulin, which promotes transport of cargoes along microtubules. Microtubule-dependent intracellular trafficking may therefore be regulated by modulating the activity of HDAC6. We have shown previously that the neuromodulator serotonin increases mitochondrial movement in hippocampal neurons via the Akt-GSK3b signaling pathway. Here, we demonstrate a role for HDAC6 in this signaling pathway. Methodology/Principal Findings: We found that the presence of tubacin, a specific HDAC6 inhibitor, dramatically enhanced mitochondrial movement in hippocampal neurons, whereas niltubacin, an inactive tubacin analog, had no effect. Compared to control cultures, higher levels of acetylated tubulin were found in neurons treated with tubacin, and more kinesin-1 was associated with mitochondria isolated from these neurons. Inhibition of GSK3b decreased cytoplasmic deacetylase activity and increased tubulin acetylation, whereas blockade of Akt, which phosphorylates and down-regulates GSK3b, increased cytoplasmic deacetylase activity and decreased tubulin acetylation. Concordantly, the administration of 5-HT, 8-OH-DPAT (a specific 5-HT1A receptor agonist), or fluoxetine (a 5-HT reuptake inhibitor) increased tubulin acetylation. GSK3b was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3b resulted in decrease

Changes in freshwater sediment microbial populations during fermentation of crude glycerol

This work was supported by the Latvian Council of Science , project NN-CARMA, project No. lzp-2018/1-0194.Background: This work studied how the exposure to an unusual substrate forced a change in microbial populations during anaerobic fermentation of crude glycerol, a by-product of biodiesel production, with freshwater sediment used as an inoculum. Results: The microbial associations almost completely (99.9%) utilized the glycerol contained in crude glycerol 6 g L−1 within four days, releasing gases, organic acids (acetic, butyric) and alcohols (ethanol, n-butanol) under anaerobic conditions. In comparison with control medium without glycerol, adding crude glycerol to the medium increased the amount of ethanol and n-butanol production and it was not significantly affected by incubation temperature (28 °C or 37 °C), nor incubation time (4 or 8 d), but it resulted in reduced amount of butyric acid. Higher volume of gas was produced at 37 °C despite the fact that the overall bacterial count was smaller than the one measured at 20 °C. Main microbial phyla of the inoculum were Actinobacteria, Proteobacteria and Firmicutes. During fermentation, significant changes were observed and Firmicutes, especially Clostridium spp., began to dominate, and the number of Actinobacteria and Gammaproteobacteria decreased accordingly. Concentration of Archaea decreased, especially in medium with crude glycerol. These changes were confirmed both by culturing and culture-independent (concentration of 16S rDNA) methods. Conclusions: Crude glycerol led to the adaptation of freshwater sediment microbial populations to this substrate. Changes of microbial community were a result of a community adaptation to a new source of carbon. How to cite: Paiders M, Nikolajeva V, Makarenkova G, et al. Changes in freshwater sediment microbial populations during fermentation of crude glycerol.Latvian Council of Science lzp-2018/1-0194; Institute of Solid State Physics, University of Latvia as the Center of Excellence has received funding from the European Union’s Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART

Investigating the influence of extracellular matrix and glycolytic metabolism on muscle stem cell migration on their native fibre environment

The composition of the extracellular matrix (ECM) of skeletal muscle fibres is a unique environment that supports the regenerative capacity of satellite cells; the resident stem cell population. The impact of environment has great bearing on key properties permitting satellite cells to carry out tissue repair. In this study, we have investigated the influence of the ECM and glycolytic metabolism on satellite cell emergence and migration- two early processes required for muscle repair. Our results show that both influence the rate at which satellite cells emerge from the sub-basal lamina position and their rate of migration. These studies highlight the necessity of performing analysis of satellite behaviour on their native substrate and will inform on the production of artificial scaffolds intended for medical uses

FGF Gradient Controls Boundary Position Between Proliferating and Differentiating Cells and Regulates Lacrimal Gland Growth Dynamics

Fibroblast growth factor (FGF) signaling plays an important role in controlling cell proliferation, survival, and cell movements during branching morphogenesis of many organs. In mammals branching morphogenesis is primarily regulated by members of the FGF7-subfamily (FGF7 and FGF10), which are expressed in the mesenchyme, and signal to the epithelial cells through the “b” isoform of fibroblast growth factor receptor-2 (FGFR2). Our previous work demonstrated that FGF7 and FGF10 form different gradients in the extracellular matrix (ECM) and induce distinct cellular responses and gene expression profiles in the lacrimal and submandibular glands. The last finding was the most surprising since both FGF7 and FGF10 bind signal most strongly through the same fibroblast growth factor receptor-2b isoform (FGFR2b). Here we revisit this question to gain an explanation of how the different FGFs regulate gene expression. For this purpose, we employed our ex vivo epithelial explant migration assay in which isolated epithelial explants are grown near the FGF loaded beads. We demonstrate that the graded distribution of FGF induces activation of ERK1/2 MAP kinases that define the position of the boundary between proliferating “bud” and differentiating “stalk” cells of growing lacrimal gland epithelium. Moreover, we showed that gene expression profiles of the epithelial explants exposed to distinct FGFs strictly depend on the ratio between “bud” and “stalk” area. Our data also suggests that differentiation of “stalk” and “bud” regions within the epithelial explants is necessary for directional and persistent epithelial migration. Gaining a better understanding of FGF functions is important for development of new approaches to enhance tissue regeneration

Morphoregulatory Functions of the RNA-Binding Motif Protein 3 in Cell Spreading, Polarity and Migration

RNA-binding proteins are emerging as key regulators of transitions in cell morphology. The RNA-binding motif protein 3 (RBM3) is a cold-inducible RNA-binding protein with broadly relevant roles in cellular protection, and putative functions in cancer and development. Several findings suggest that RBM3 has morphoregulatory functions germane to its roles in these contexts. For example, RBM3 helps maintain the morphological integrity of cell protrusions during cell stress and disease. Moreover, it is highly expressed in migrating neurons of the developing brain and in cancer invadopodia, suggesting roles in migration. We here show that RBM3 regulates cell polarity, spreading and migration. RBM3 was present in spreading initiation centers, filopodia and blebs that formed during cell spreading in cell lines and primary myoblasts. Reducing RBM3 triggered exaggerated spreading, increased RhoA expression, and a loss of polarity that was rescued by Rho kinase inhibition and overexpression of CRMP2. High RBM3 expression enhanced the motility of cells migrating by a mesenchymal mode involving extension of long protrusions, whereas RBM3 knockdown slowed migration, greatly reducing the ability of cells to extend protrusions and impairing multiple processes that require directional migration. These data establish novel functions of RBM3 of potential significance to tissue repair, metastasis and development

Influence of flow velocity, river size, a dam, and an urbanized area on biodiversity of lowland rivers

Biodiversity of aquatic organisms is formed under the influence of not only natural, but also anthropogenic factors. In this work, the influence of the flow velocity, river size, flow regulation and urbanization on various groups of aquatic organisms was studied in several lowland rivers. The study was conducted in 2013 on six tributaries of the Upper Sukhona River. Five sampling sites were in different parts of the Vologda River and five sites on small rivers, Losta, Lukhta, Komya, Chernyj Shingar, and Belyj Shingar (one site per river). Phytoplankton, zooplankton and zoobenthos were sampled six times, from April to October, and macrophytes were studied in August. In total, 469 species of aquatic organisms were found in the tributaries of the Upper Sukhona River, belonging to the following phyla: Cyanophyta (5 species), Chrysophyta (8), Bacillariophyta (62), Xanthophyta (1), Cryptophyta (10), Dinophyta (4), Euglenophyta (12), Chlorophyta (17), Streptophyta (1), Bryophyta (2), Marchantiophyta (3), Equisetophyta (1), Magnoliophyta (63), Rotifera (22), Cnidaria (1), Platyhelmintes (1), Annelida (29), Mollusca (33), Arthropoda (194). The maximum number of species was found in the Vologda River, the largest of all the tributaries. The number of zoobenthos species was similar at different sites in the Vologda River and in the small rivers. The number of species of other groups of aquatic organisms in the small rivers was lower than those registered in the Vologda River. The greatest number of macrophyte and zoobenthos species was recorded in the Upper Vologda River and Belyj Shingar River, where the flow is strong all the year round. The greatest number of phyto- and zooplankton species was found at the extra-city sites where current is almost absent. In the dam backwater, species richness was higher than that registered downstream of the dam. At the same time, the species richness of macrophytes and zoobenthos in the dam backwater was lower. The smallest number of species was found in the Vologda River, downstream of the city of Vologda. Decreases in the species richness and Shannon’s biodiversity index were witnessed in the Vologda River city site and in the small rivers, as they get closer to the city. Cluster analyses performed for the studied groups of aquatic organisms showed dissimilar results; however, the studied sites on the Vologda River having the highest anthropogenic load formed a cluster. Aquatic organisms of the Upper Sukhona tributaries experience both natural (flow velocity and size of the watercourse) and anthropogenic factors (proximity to the city and flow regulation)

Выявление характерных акустических признаков пациентов с ХОЗЛ на основе биспектрального анализа легочных звуков

Мета даних досліджень – виявлення найбільш інформативних характеристик звуків дихання, що визначають аускультативні, діагностичні ознаки у хворих хронічним обструктивним захворюванням легенів (ХОЗЛ) на основі поліспектрального аналізу. Була розроблена методика ітераційного поліспектрального аналізу звуків дихання на основі розрахунку непараметричного біспектру (за допомогою прямого і непрямого методів обчислення)і параметричного біспектру. Запропоновані графічні та чисельні показники, що об’єктивізують характерні діагностичні ознаки ХОЗЛ. Розроблений метод може служити допоміжним засобом для лікарів при ідентифікації ХОЗЛ у пацієнтів.The aim of this research is to identify the most informative characteristics of breath sounds that define auscultative, diagnostic features in patients with chronic obstructive lung disease (COLD). The method based on polyspectral analysis. The iterative technique of polyspectral analysis of respiratory sounds was developed and it based on nonparametric bispectrum calculation (using direct and indirect methods of calculation) and parametric bispectrum. Graphical and numerical indicators that objectify typical diagnostic features of COLD was proposed. The method can use as additional tool for physicians in identifying COLD patients.Цель данных исследований – выявление наиболее информативных характеристик звуков дыхания, определяющих аускультативные, диагностические признаки у больных хроническим обструктивным заболеванием легких (ХОЗЛ) на основе полиспектрального анализа. Была разработана методика итерационного полиспектрального анализа звуков дыхания на основе расчета непараметрического биспектра (с помощью прямого и косвенного методов вычисления) и параметрического биспектра. Предложены графические и численные показатели, которые объективизируют характерные диагностические признаки ХОЗЛ. Разработанный метод может служить вспомогательным средством для пульмонологов при идентификации ХОЗЛ у пациентов