Robustness and plasticity of epithelial cell state in development and malignancy

A better understanding of the molecular mechanisms that control pluripotency, differentiation and epithelial phenotypical plasticity is crucial for the development of the current knowledge in many general processes such as cell identity maintenance and cell fate decision-making. Embryonic stem cells (ESC) pluripotency maintenance and differentiation are of key importance to the embryonic development, as well as to the progress in stem cells technologies. The role of miR-290-295 cluster members in preserving the pluripotent state and differentiation potential of mouse ESC is well established. Nevertheless, the precise list of targets translating the microRNAs functionality is incomplete. In our study we, firstly, identified and validated miR-290 targets with high confidence. We further confirmed the expression variation of IRF2 in response to miRNAs’ depletion in ESC. Moreover, we revisited the involvement of nuclear factor kappa-B (NF-kB) pathway in the miRNA-dependent regulation in mESCs. Hence, our results provided new understanding of the role and mechanistic of miR-290-295 microRNAs involvement in ESC pluripotency and differentiation. In a similar fashion to ESC pluripotency and differentiation mechanisms, a globalanalysis-approach that compares and combines data from different epithelial to mesenchymal transition (EMT) models enabled us to construct a more detailed network of regulatory entities implicated in epithelial plasticity. The maintenance and plasticity of the epithelial cell phenotype are important events not only during normal embryonic development, but also to cancer progression and metastasis formation. Comparing this network between mouse and human, we identified a new transcription factor (TF) motif TFAP2A/C that is consistently involved in EMT. When applying the NMuMG cellular model of TGFβ-induced EMT, we found that the predicted activity of the TFAP2A/C is inversely correlated to the Tfap2a mRNA expression during the process. We have confirmed that TFAP2A directly binds to the promoter of Zeb2, a TF central to EMT. Thus, it regulates the expression of this gene. Furthermore, the TFAP2A overexpression in NMuMG cells modulates the cells’ epithelial phenotype and induces changes in cell adhesion and morphology. This overexpression was followed by increased mRNA levels of EMT master regulator TFs, together with an elevated expression of genes involved in cellular adhesion. Therefore, we identified a potentially new role of TFAP2A transcription factor, which suggests that elements of its regulatory function during neural crest development might operate in mechanisms controlling epithelial plasticity in normal breast and tumor tissues. Overall, we characterized another facet of microRNAs’ function in pluripotency and differentiation in ESC, as well as a new aspect of the implication of TFAP2A in epithelial cell state integrity and plasticity. Therefore we contributed to expanding our insight of how are regulated at molecular level the cell identity homeostasis and the unfolding of cellular phenotypical plasticity

Medical and cosmetic center or beauty salon

Provoked by the controversy over the difference between a beautician and a medical beautician, we decided to conduct a survey using the following methods: literature, magazines, documents and anonymous surveys. The subject of our study are 100 male and female respondents aged 16 to 60 + from different locations in Bulgaria

Stress-tolerance tests and postprandial low-grade inflammation response

Both tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6) are considered as proinflammatory cytokines which display marked daily and postprandial variations. The low grade inflammation is known to contribute to the development of certain states such as type 2 diabetes, metabolic syndrome and related disorders. Oral glucose tolerance test (OGTT) has been applied to diagnose diabetes and is widely used to estimate the insulin sensitivity in the postprandial phase. Application of tolerance tests with high lipid content such as oral lipid tolerance test (OLTT), high-fat meal (HFM) and mixed meal tests are informative for the metabolic response to complex diets. Postprandial hyperlipidemia and hyperglycemia are important and residual risk factors especially in patients with diabetes mellitus and related metabolic disturbances. There are data suggesting that low grade inflammation could be mediated by hyperglycemia and dyslipidemia. The aim of the review is to summarize how different challenge tests influence the postprandial circulation levels of IL-6 and TNF alpha

Mechanisms of Cyanotoxin Toxicity—Carcinogenicity, Anticancer Potential, and Clinical Toxicology

Cyanoprokaryotes are distributed worldwide and they produce various bioactive compounds, including cyanotoxins. The major route of human exposure to cyanotoxins is the oral intake by using contaminated drinking water, by incidental intake of contaminated water during recreational and professional activities, and by consuming contaminated food or dietary supplements prepared from cyanobacteria. The prolonged chronic exposure to low concentrations of cyanotoxins provokes cell damage and may increase the risk for cancer development. Due to the variety of cyanotoxin chemical structures, different mechanisms of their toxic effects are known. At the same time, some of the natural compounds produced by cyanoprokaryotes have anticancer potential and are promising sources for the development of novel drugs. This chapter is dedicated to the target mechanisms behind the effects of the widely distributed cyanotoxins with an impact on human health, microcystins, nodularins, and cylindrospermopsin

Challenge tests and their application in nutrition research to investigate phenotypic flexibility

От гледна точка на метаболизма оптималното здраве се характеризира като способността на организма да поддържа и възстановява хомеостаза в непрекъснато променящата се околна среда и особено в отговор на широк спектър от стресови фактори. Капацитетът на организма да се адаптира във времето и пространството към всички променливи, особено към вариациите в диетата, се нарича `фенотипна пластичност`. Проследяването на метаболитните промени в биологични проби в хода на стрес тестове би предоставило информация за способността на организма да се справя с ежедневните промени в храненето. Стрес тестове, базирани на суплементиране с въглехидрати, липиди, протеини и/или комбинация от тях, се използват в клиничната практика за диагностика на метаболитни нарушения. Общото в тях е, че те водят до временно нарушаване на хомеостазата на тялото. Степента на нарушенията и скоростта, с която се възстановява хомеостазата, се използват като индикатори за здравния статус. Счита се, че нормалният глюкозен толеранс е показател за добра фенотипна пластичност. Оралният глюкозотолерантен тест (ОГТТ) е най-често прилаганият стрес тест, използван от десетилетия за диагностициране на диабет. Въпреки че триглицеридите на гладно са независим рисков фактор за някои заболявания, редица автори предлагат проследяването на постпрандиалните им нива и промяната в метаболитите в хода на приложен орален липидотолерантнен тест (ОЛТТ) за по-точна диагностика. Настоящото проучване разглежда възможността и потенциала на ОГТТ, ОЛТТ, тестове със смесено хранене и техни вариации да бъдат използвани като индикатори за оценка на фенотипната пластичност при проучвания в областта на храненето и оценка на здравния статус на индивида.From a metabolic point of view, the optimum health is the ability of the organism to maintain and regain homeostasis in ever-changing environmental conditions and to a wide spectrum of stressors. The capacity of the organism to adapt to all the variables, especially to the dietary variations is called `phenotypic flexibility`. Metabolic profiling of biological samples during a challenge response phase should offer a profound view on the flexibility of a phenotype to cope with daily stressors. Stress tests based on supplementation with carbohydrates, lipids, proteins and/or combination aim temporary disturbance of body`s homeostasis. Clinical diagnostics takes advantage of such tests using them to detect metabolic impairment. The degree of disturbance and the rate of recover are indicative for the health status. The normal glucose tolerance is considered as a sign for a good phenotypic flexibility. The oral glucose tolerance test (OGTT) is the most commonly used stress test and has been applied in diabetes diagnosis for decades. Although the fasting triacylglycerol levels are an independent risk factor for certain conditions, some authors suggest measuring the postprandial levels of metabolites with an oral lipid tolerance test (OLTT) for more precise diagnostics. Thus current study explores the possible application and potential of OGTT, OLTT, mixed-meal challenge and combination of them to assess phenotypic flexibility in nutrition research and to evaluate individual`s health status.

Embryonic stem cell-specific microRNAs contribute to pluripotency by inhibiting regulators of multiple differentiation pathways

The findings that microRNAs (miRNAs) are essential for early development in many species and that embryonic miRNAs can reprogram somatic cells into induced pluripotent stem cells suggest that these miRNAs act directly on transcriptional and chromatin regulators of pluripotency. To elucidate the transcription regulatory networks immediately downstream of embryonic miRNAs, we extended the motif activity response analysis approach that infers the regulatory impact of both transcription factors (TFs) and miRNAs from genome-wide expression states. Applying this approach to multiple experimental data sets generated from mouse embryonic stem cells (ESCs) that did or did not express miRNAs of the ESC-specific miR-290-295 cluster, we identified multiple TFs that are direct miRNA targets, some of which are known to be active during cell differentiation. Our results provide new insights into the transcription regulatory network downstream of ESC-specific miRNAs, indicating that these miRNAs act on cell cycle and chromatin regulators at several levels and downregulate TFs that are involved in the innate immune respons

Metabolite Profile and Antioxidant Activity of Some Species of Genus Scutellaria Growing in Bulgaria

Until now, the interest to plants from genus Scutellaria in Bulgaria has been focused mainly on the terpenes in them. The purpose of this study is to enrich the information on the composition of the Bulgarian Scutellaria species in terms of both polyphenolic content as well as primary metabolites such as mono-, oligosaccharides and organic acids. An aerial part of three Scutellaria species growing in four low mountain regions of Southern Bulgaria was used. The flavonoids scutellarin, baicalin, baicalein, wogonin, wogonoside, luteolin, chrysin and a caffeoyl phenylethanoid glycoside-verbascoside have been identified via HPLC in different extracts from Scutellaria altissima, Scutellaria albida and Scutellaria galericulata. The antioxidant activity of the extracts has been evaluated. The Scutellaria altissima from Mezek and Scutellaria galericulata from Parvenets we studied, which are the richest in flavonoids (represented mainly by baicalin, scutellarin and wogonoside), show the highest Oxygen Radical Absorption Capacity. Hydroxyl Radical Averting Capacity of Scutellaria albida from Mezek and Scutellaria altissima from Bachkovo is the most pronounced, probably due to the content of scutellarin and luteolin and chrysin, respectively. Antioxidant activity of aqueous, methanolic and 70% and 96% ethanol extracts were also determined by the electrochemical method

Metabolite Profile and Antioxidant Activity of Some Species of Genus Scutellaria Growing in Bulgaria

Until now, the interest to plants from genus Scutellaria in Bulgaria has been focused mainly on the terpenes in them. The purpose of this study is to enrich the information on the composition of the Bulgarian Scutellaria species in terms of both polyphenolic content as well as primary metabolites such as mono-, oligosaccharides and organic acids. An aerial part of three Scutellaria species growing in four low mountain regions of Southern Bulgaria was used. The flavonoids scutellarin, baicalin, baicalein, wogonin, wogonoside, luteolin, chrysin and a caffeoyl phenylethanoid glycoside-verbascoside have been identified via HPLC in different extracts from Scutellaria altissima, Scutellaria albida and Scutellaria galericulata. The antioxidant activity of the extracts has been evaluated. The Scutellaria altissima from Mezek and Scutellaria galericulata from Parvenets we studied, which are the richest in flavonoids (represented mainly by baicalin, scutellarin and wogonoside), show the highest Oxygen Radical Absorption Capacity. Hydroxyl Radical Averting Capacity of Scutellaria albida from Mezek and Scutellaria altissima from Bachkovo is the most pronounced, probably due to the content of scutellarin and luteolin and chrysin, respectively. Antioxidant activity of aqueous, methanolic and 70% and 96% ethanol extracts were also determined by the electrochemical method

NeuroML: A Language for Describing Data Driven Models of Neurons and Networks with a High Degree of Biological Detail

Biologically detailed single neuron and network models are important for understanding how ion channels, synapses and anatomical connectivity underlie the complex electrical behavior of the brain. While neuronal simulators such as NEURON, GENESIS, MOOSE, NEST, and PSICS facilitate the development of these data-driven neuronal models, the specialized languages they employ are generally not interoperable, limiting model accessibility and preventing reuse of model components and cross-simulator validation. To overcome these problems we have used an Open Source software approach to develop NeuroML, a neuronal model description language based on XML (Extensible Markup Language). This enables these detailed models and their components to be defined in a standalone form, allowing them to be used across multiple simulators and archived in a standardized format. Here we describe the structure of NeuroML and demonstrate its scope by converting into NeuroML models of a number of different voltage- and ligand-gated conductances, models of electrical coupling, synaptic transmission and short-term plasticity, together with morphologically detailed models of individual neurons. We have also used these NeuroML-based components to develop an highly detailed cortical network model. NeuroML-based model descriptions were validated by demonstrating similar model behavior across five independently developed simulators. Although our results confirm that simulations run on different simulators converge, they reveal limits to model interoperability, by showing that for some models convergence only occurs at high levels of spatial and temporal discretisation, when the computational overhead is high. Our development of NeuroML as a common description language for biophysically detailed neuronal and network models enables interoperability across multiple simulation environments, thereby improving model transparency, accessibility and reuse in computational neuroscience