Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype

Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration and survival in many cell types. Here the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: non-invasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt and metM-Wntliver cells 12, 29, and 25 metabolites, respectively, were significantly different (p<0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration and invasion occurred in M-Wnt and metM-Wntliver cells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype

Identification of sex hormone-binding globulin in the human hypothalamus

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin ( SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin. Copyright (c) 2005 S. Karger AG, Base

A Transcriptome Database for Astrocytes, Neurons, and Oligodendrocytes: A New Resource for Understanding Brain Development and Function

Understanding the cell–cell interactions that control CNS development and function has long been limited by the lack of methods to cleanly separate neural cell types. Here we describe methods for the prospective isolation and purification of astrocytes, neurons, and oligodendrocytes from developing and mature mouse forebrain. We used FACS (fluorescent-activated cell sorting) to isolate astrocytes from transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of an S100β promoter. Using Affymetrix GeneChip Arrays, we then created a transcriptome database of the expression levels of \u3e20,000 genes by gene profiling these three main CNS neural cell types at various postnatal ages between postnatal day 1 (P1) and P30. This database provides a detailed global characterization and comparison of the genes expressed by acutely isolated astrocytes, neurons, and oligodendrocytes. We found that Aldh1L1 is a highly specific antigenic marker for astrocytes with a substantially broader pattern of astrocyte expression than the traditional astrocyte marker GFAP. Astrocytes were enriched in specific metabolic and lipid synthetic pathways, as well as the draper/Megf10 and Mertk/integrin αvβ5 phagocytic pathways suggesting that astrocytes are professional phagocytes. Our findings call into question the concept of a “glial” cell class as the gene profiles of astrocytes and oligodendrocytes are as dissimilar to each other as they are to neurons. This transcriptome database of acutely isolated purified astrocytes, neurons, and oligodendrocytes provides a resource to the neuroscience community by providing improved cell-type-specific markers and for better understanding of neural development, function, and disease

Отдельные аспекты эффективности цифровизации растениеводства в Республике Беларусь

Digitalization, or digital transformation, is an innovative approach to solving the key task of agricultural production in the Republic of Belarus – increasing / maintaining the profitability of crop production. Digitalization makes it possible to bring crop production to a new level of development, providing a fundamental restructuring of the decision-making and implementation of agro-technological operations, reducing risks and expanding possibilities of sustainable and efficient crop production. Efficiency of digitalization of crop production is considered in relation to certain aspects of an average agricultural organization in the Republic of Belarus. The following main interrelated areas of digitalization in crop production have been identified: soil-and-agrochemical analysis, precision arable farming, prediction of the diseases and pests of crops. Due to significant growth of energy prices nowadays (basic elements in the formation of the final cost of crop production), efficiency of digitalization was assessed not directly in terms of value, but in reducing the costs of growing products and in saved crops. The greatest effect, according to the results of the assessment, is expected from such areas of digitalization as soiland-agrochemical analysis, as well as prediction of the diseases and pests of agricultural crops. The results of soil-and-agrochemical analysis can be used to improve the soil fertility – a vital condition for long-term increase of crop yields. Prediction of the diseases and pests of crops is one of the main elements of comprehensive protection of crops – a large reserve for increasing crop production. At the same time, despite the positive aspect of digitalization in agricultural branch of the Republic of Belarus, it is rather a labor-intensive process together with the high cost of necessary equipment and software, as well as the use complexity.Цифровизация, или цифровая трансформация, является инновационным подходом решения ключевой задачи сельскохозяйственного производства Республики Беларусь – повышения/поддержания рентабельности растениеводства. Цифровизация позволяет вывести растениеводство на новый уровень развития, обеспечивая фундаментальную перестройку принятия управленческих решений и выполнения агротехнологических операций, снижая риски и расширяя возможности ведения устойчивого и эффективного растениеводства. Рассмотрена эффективность цифровизации растениеводства применительно к отдельным аспектам среднестатистической сельхозорганизации Республики Беларусь. Выделены следующие основные взаимосвязанные направления цифровизации растениеводства: почвенно-агрохимический анализ, точное земледелие, прогнозирование болезней и вредителей сельхозкультур. В связи со значительным ростом в настоящее время цен на энергоресурсы (базовые элементы формирования конечной стоимости продукции растениеводства) эффективность цифровизации оценивалась не в стоимостном выражении, а в снижении издержек на выращивание продукции растениеводства и в сохраненном урожае. По результатам оценки наибольший эффект ожидается от таких направлений цифровизации, как почвенно-агрохимический анализ, а также прогнозирование болезней и вредителей сельхозкультур. Результаты почвенно-агрохимического анализа могут быть использованы при повышении плодородия почв – необходимом условии увеличения урожайности сельхозкультур в долгосрочной перспективе. Прогнозирование болезней и вредителей сельхозкультур является одним из основных элементов их комплексной защиты – большим резервом увеличения продукции растениеводства. Вместе с тем, несмотря на перспективность цифровизации сельскохозяйственной отрасли Республики Беларусь, она является достаточно трудоемким процессом в совокупности с высокой стоимостью необходимого оборудования и программного обеспечения, а также сложностью их использования

Bioinformatic and Genetic Association Analysis of MicroRNA Target Sites in One-Carbon Metabolism Genes

One-carbon metabolism (OCM) is linked to DNA synthesis and methylation, amino acid metabolism and cell proliferation. OCM dysfunction has been associated with increased risk for various diseases, including cancer and neural tube defects. MicroRNAs (miRNAs) are ∼22 nt RNA regulators that have been implicated in a wide array of basic cellular processes, such as differentiation and metabolism. Accordingly, mis-regulation of miRNA expression and/or activity can underlie complex disease etiology. We examined the possibility of OCM regulation by miRNAs. Using computational miRNA target prediction methods and Monte-Carlo based statistical analyses, we identified two candidate miRNA “master regulators” (miR-22 and miR-125) and one candidate pair of “master co-regulators” (miR-344-5p/484 and miR-488) that may influence the expression of a significant number of genes involved in OCM. Interestingly, miR-22 and miR-125 are significantly up-regulated in cells grown under low-folate conditions. In a complementary analysis, we identified 15 single nucleotide polymorphisms (SNPs) that are located within predicted miRNA target sites in OCM genes. We genotyped these 15 SNPs in a population of healthy individuals (age 18–28, n = 2,506) that was previously phenotyped for various serum metabolites related to OCM. Prior to correction for multiple testing, we detected significant associations between TCblR rs9426 and methylmalonic acid (p  =  0.045), total homocysteine levels (tHcy) (p  =  0.033), serum B12 (p < 0.0001), holo transcobalamin (p < 0.0001) and total transcobalamin (p < 0.0001); and between MTHFR rs1537514 and red blood cell folate (p < 0.0001). However, upon further genetic analysis, we determined that in each case, a linked missense SNP is the more likely causative variant. Nonetheless, our Monte-Carlo based in silico simulations suggest that miRNAs could play an important role in the regulation of OCM

DIGITALIZATION OF THE INSURANCE MARKET AS A FACTOR IN INCREASING ITS COMPETITIVENESS

В статье рассматриваются актуальные вопросы конкурентоспособности страхового рынка Республики Беларусь. Систематизированы подходы к определению понятия «конкурентоспособность». Выявлены проблемы национального рынка страховых услуг и основные направления его устойчивого развития в условиях цифровой трансформации экономики. Выявлены факторы, влияющие на конкурентоспособность страховой организации. Предложена авторская классификация факторов конкурентоспособности страховщиков, включающая основные факторы (факторы надежности), факторы поддержки и стресс-факторы. Цифровизация определена важнейшим фактором конкурентоспособности страхового рынка в условиях цифровой экономики. Обоснованы конкурентные преимущества страховщиков с учетом цифровизации. Выявлены бизнес-императивы страховщиков в условиях цифровизации, решение которых позволит сформировать цифровой потенциал отечественных страховщиков. Разработанные рекомендации могут стать мощным драйвером повышения конкурентоспособности отечественного страхового рынка, а страховщики получат ощутимое и устойчивое конкурентное преимущество в рам-ках формирования единого финансового рынка на пространстве ЕАЭС.= Abstract. Approaches to the definition of «competitiveness» are systematized. The problems of the national insurance market and the main directions of its sustainable development in the conditions of digital transformation of the economy are identified. Factors affecting the competitiveness of an insurance company are identified. The author offers a classification of factors of insurers' competitiveness, including the main factors (reliability factors), support factors and stress factors. Digitalization is defined as the most important factor in the competitiveness of the insurance market in the digital economy. Competitive advantages of insurers based on digitalization are jus-tified. Business imperatives of insurers in the conditions of digitalization are revealed. The recommendations can become a powerful driver for increasing the competitiveness of the insurance market

DIGITALIZATION OF THE INSURANCE MARKET AS A FACTOR IN INCREASING ITS COMPETITIVENESS

В статье рассматриваются актуальные вопросы конкурентоспособности страхового рынка Республики Беларусь. Систематизированы подходы к определению понятия «конкурентоспособность». Выявлены проблемы национального рынка страховых услуг и основные направления его устойчивого развития в условиях цифровой трансформации экономики. Выявлены факторы, влияющие на конкурентоспособность страховой организации. Предложена авторская классификация факторов конкурентоспособности страховщиков, включающая основные факторы (факторы надежности), факторы поддержки и стресс-факторы. Цифровизация определена важнейшим фактором конкурентоспособности страхового рынка в условиях цифровой экономики. Обоснованы конкурентные преимущества страховщиков с учетом цифровизации. Выявлены бизнес-императивы страховщиков в условиях цифровизации, решение которых позволит сформировать цифровой потенциал отечественных страховщиков. Разработанные рекомендации могут стать мощным драйвером повышения конкурентоспособности отечественного страхового рынка, а страховщики получат ощутимое и устойчивое конкурентное преимущество в рам-ках формирования единого финансового рынка на пространстве ЕАЭС.= Abstract. Approaches to the definition of «competitiveness» are systematized. The problems of the national insurance market and the main directions of its sustainable development in the conditions of digital transformation of the economy are identified. Factors affecting the competitiveness of an insurance company are identified. The author offers a classification of factors of insurers' competitiveness, including the main factors (reliability factors), support factors and stress factors. Digitalization is defined as the most important factor in the competitiveness of the insurance market in the digital economy. Competitive advantages of insurers based on digitalization are jus-tified. Business imperatives of insurers in the conditions of digitalization are revealed. The recommendations can become a powerful driver for increasing the competitiveness of the insurance market

Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype

Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration and survival in many cell types. Here the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: non-invasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wnt(liver)) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt and metM-Wnt(liver) cells 12, 29, and 25 metabolites, respectively, were significantly different (p<0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration and invasion occurred in M-Wnt and metM-Wnt(liver) cells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype. IMPLICATIONS: Metabolic reprogramming driven by folate restriction represents a therapeutic target for reducing the burden of breast cancer

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

We have previously shown that withdrawal of folic acid led to metabolic reprogramming and a less aggressive phenotype in a mouse cell model of triple-negative breast cancer (TNBC). Herein, we evaluate the effects of folic acid withdrawal on transcriptomic profiles in these cells. Murine cell lines were originally derived from a pool of spontaneous mammary tumors grown in MMTV-Wnt1 transgenic mice. Based on their differential molecular characteristics and metastatic potential, these cell lines were previously characterized as non-metastatic epithelial (E-Wnt), non-metastatic mesenchymal (M-Wnt) and metastatic mesenchymal (metM-Wntliver) cells. Using custom two-color 180K Agilent microarrays, we have determined gene expression profiles for three biological replicates of each subtype kept on standard medium (2.2 μM folic acid) or folic acid-free medium for 72 h. The analyses revealed that more genes were differentially expressed upon folic acid withdrawal in M-Wnt cells (1884 genes; Benjamini-Hochberg-adjusted P-value liver cells (108 and 222 genes, respectively). Pathway analysis has identified that type I interferon signaling was strongly affected by folic acid withdrawal, with interferon-responsive genes consistently being upregulated upon folic acid withdrawal in M-Wnt cells. Of note, repressed interferon signaling has been established as one of the characteristics of aggressive human TNBC, and hence reactivation of this pathway may be a promising therapeutic approach. Overall, while our study indicates that the response to folic acid withdrawal varies by molecular subtype and cellular phenotype, it also underscores the necessity to further investigate one-carbon metabolism as a potential therapeutic means in the treatment of advanced TNBC.</p