Evidence of transfer of miRNAs from the diet to the blood still inconclusive

MicroRNAs (miRNAs) are short, non-coding, single-strand RNA molecules that act as regulators of gene expression in plants and animals. In 2012, the first evidence was found that plant miRNAs could enter the bloodstream through the digestive tract. Since then, there has been an ongoing discussion about whether miRNAs from the diet are transferred to blood, accumulate in tissues, and regulate gene expression. Different research groups have tried to replicate these findings, using both plant and animal sources. Here, we review the evidence for and against the transfer of diet-derived miRNAs from plants, meat, milk and exosome and their assimilation and putative molecular regulation role in the consuming organism. Some groups using both miRNAs from plant and animal sources have claimed success, whereas others have not shown transfer. In spite of the biological barriers that may limit miRNA transference, several diet-derived miRNAs can transfer into the circulating system and targets genes for transcription regulation, which adds arguments that miRNAs can be absorbed from the diet and target specific genes by regulating their expression. However, many other studies show that cross-kingdom transfer of exogenous miRNAs appears to be insignificant and not biologically relevant. The main source of controversy in plant studies is the lack of reproducibility of the findings. For meat-derived miRNAs, studies concluded that the miRNAs can survive the cooking process; nevertheless, our evidence shows that the bovine miRNAs are not transferred to human bloodstream. The most important contributions and promising evidence in this controversial field is the transference of milk miRNAs in exosomes and the finding that plant miRNAs in beebread regulate honeybee caste development, and cause similar changes when fed to Drosophila. MiRNAs encapsulated in exosomes ensure their stability and resistance in the harsh conditions presented in milk, bloodstream, and gastrointestinaltract to reinforce the idea of transference. Regardless of the model organism, the idea of source of miRNAs, or the approach—bioinformatics or in vivo—the issue of transfer of miRNAs from the diet remains in doubt. Our understanding of the cross-kingdom talk of miRNAs needs more research to study the transfer of “xenomiRs” from different food sources to complement and expand what we know so far regarding the interspecies transfer of miRNAs.

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The Mechanisms Behind the Biological Activity of Flavonoids

Current Medicinal Chemistry ◽

10.2174/0929867325666180706104829 ◽

2019 ◽

Vol 26 (39) ◽

pp. 6976-6990 ◽

Cited By ~ 12

Author(s):

Ana María González-Paramás ◽

Begoña Ayuda-Durán ◽

Sofía Martínez ◽

Susana González-Manzano ◽

Celestino Santos-Buelga

Keyword(s):

Gene Expression ◽

Biological Activity ◽

Phenolic Compounds ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Radical Scavenging ◽

Model Organism ◽

Stress Theory ◽

Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

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Targeting of microRNAs for therapeutics

Biochemical Society Transactions ◽

10.1042/bst0361197 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1197-1200 ◽

Cited By ~ 38

Author(s):

Jan Stenvang ◽

Morten Lindow ◽

Sakari Kauppinen

Keyword(s):

Gene Expression ◽

Cardiovascular Diseases ◽

High Stability ◽

Viral Infections ◽

Modified Oligonucleotides ◽

Rna Molecules ◽

Locked Nucleic Acids ◽

Non Coding Rnas ◽

High Binding Affinity

miRNAs (microRNAs) comprise a class of small endogenous non-coding RNAs that post-transcriptionally repress gene expression by base-pairing with their target mRNAs. Recent evidence has shown that miRNAs play important roles in a wide variety of human diseases, such as viral infections, cancer and cardiovascular diseases, and thus miRNAs have rapidly emerged as potential targets for therapeutics. LNAs (locked nucleic acids) comprise a class of bicyclic conformational analogues of RNA, which exhibit high binding affinity to complementary RNA molecules and high stability in blood and tissues in vivo. Recent reports on LNA-mediated miRNA silencing in rodents and primates support the potential of LNA-modified oligonucleotides in studying miRNA functions in vivo and in the future development of miRNA-based therapeutics.

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Transcriptional signatures of somatic neoblasts and germline cells in Macrostomum lignano

eLife ◽

10.7554/elife.20607 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 23

Author(s):

Magda Grudniewska ◽

Stijn Mouton ◽

Daniil Simanov ◽

Frank Beltman ◽

Margriet Grelling ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

De Novo ◽

Transcriptome Assembly ◽

Model Organism ◽

Proliferating Cells ◽

Macrostomum Lignano ◽

Germline Cells

The regeneration-capable flatworm Macrostomum lignano is a powerful model organism to study the biology of stem cells in vivo. As a flatworm amenable to transgenesis, it complements the historically used planarian flatworm models, such as Schmidtea mediterranea. However, information on the transcriptome and markers of stem cells in M. lignano is limited. We generated a de novo transcriptome assembly and performed the first comprehensive characterization of gene expression in the proliferating cells of M. lignano, represented by somatic stem cells, called neoblasts, and germline cells. Knockdown of a selected set of neoblast genes, including Mlig-ddx39, Mlig-rrm1, Mlig-rpa3, Mlig-cdk1, and Mlig-h2a, confirmed their crucial role for the functionality of somatic neoblasts during homeostasis and regeneration. The generated M. lignano transcriptome assembly and gene expression signatures of somatic neoblasts and germline cells will be a valuable resource for future molecular studies in M. lignano.

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Enhancers predominantly regulate gene expression in vivo via transcription initiation

10.1101/844191 ◽

2019 ◽

Author(s):

Martin S. C. Larke ◽

Takayuki Nojima ◽

Jelena Telenius ◽

Jacqueline A. Sharpe ◽

Jacqueline A. Sloane-Stanley ◽

...

Keyword(s):

Gene Expression ◽

Rna Polymerase Ii ◽

Transcription Initiation ◽

Genetically Engineered ◽

Control Gene ◽

Transcriptional Initiation ◽

Pol Ii ◽

Rna Molecules ◽

Control Gene Expression

ABSTRACTGene transcription occurs via a cycle of linked events including initiation, promoter proximal pausing and elongation of RNA polymerase II (Pol II). A key question is how do transcriptional enhancers influence these events to control gene expression? Here we have used a new approach to quantify transcriptional initiation and pausing in vivo, while simultaneously identifying transcription start sites (TSSs) and pause-sites (TPSs) from single RNA molecules. When analyzed in parallel with nascent RNA-seq, these data show that differential gene expression is achieved predominantly via changes in transcription initiation rather than Pol II pausing. Using genetically engineered mouse models deleted for specific enhancers we show that these elements control gene expression via Pol II recruitment and/or initiation rather than via promoter proximal pause release. Together, our data show that enhancers, in general, control gene expression predominantly by Pol II recruitment and initiation rather than via pausing.

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Spontaneous driving forces give rise to protein-RNA condensates with coexisting phases and complex material properties

10.1101/492793 ◽

2018 ◽

Cited By ~ 1

Author(s):

Steven Boeynaems ◽

Alex S Holehouse ◽

Venera Weinhardt ◽

Denes Kovacs ◽

Joris Van Lindt ◽

...

Keyword(s):

Material Properties ◽

Driving Forces ◽

Coarse Grained ◽

Biologically Relevant ◽

Rna Molecules ◽

Heterotypic Interactions ◽

Collective Interactions

Collective phase transitions, including phase separation and gelation of multivalent protein and RNA molecules appears to underlie the biogenesis of biomolecular condensates such as membraneless organelles. In vivo, these condensates encompass hundreds of distinct types of molecules that are often organized into multi-layered structures supporting the differential partitioning of molecules into distinct regions with distinct material properties. The interplay between driven (active) versus spontaneous (passive) processes that are required for enabling the formation of condensates with coexisting layers of distinct material properties remains unclear. Here, we investigate the role of spontaneous driving forces as determinants of protein-RNA condensates with complex morphologies and distinct material properties. Through the use of systematic in vitro experiments and simulations based on coarse-grained models we find that that the collective interactions among the simplest, biologically relevant proteins and archetypal RNA molecules are sufficient for driving the spontaneous emergence of multi-layered condensates with distinct material properties. Our results demonstrate that key properties of protein-RNA condensates such as their overall morphologies, internal dynamics, and the selective partitioning of substrates are governed specific amino acid chemistries as well as RNA sequence and secondary structure. Our findings yield a clear set of heuristics regarding homo- and heterotypic interactions that are likely to be relevant for understanding the interplay between active and passive processes that control the formation of functional biomolecular condensates.

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SIRNA-MEDIATED INHIBITION OF INTERLEUKINE-13 PRODUCTION IN VITRO

Rossiiskii Allergologicheskii ZHurnal ◽

10.36691/rja683 ◽

2012 ◽

Vol 9 (6) ◽

pp. 24-27

Author(s):

I P Shilovskiy ◽

D V Mazurov ◽

N N Shershakova ◽

M R Khaitov

Keyword(s):

Gene Expression ◽

Protein Product ◽

Spleen Cells ◽

Rna Molecules ◽

In Vitro Methods ◽

Gene Coding ◽

Interfering Rna

Background. According to current views, one of the major mediators involved in the development of allergic process is IL-13. The goal of this work was to design small interfering RNA molecules to effectively inhibit il-13 gene expression of mice in experiments in vitro. Methods. For the expression of IL-13 in in vitro gene coding sequence il-13 was amplified using cDNA ConA-stimulated spleen cells from BALE / c mice as a template and cloned into the expression vector pUCHR IRES GFP. Using a computer analysis were designed six variants of siRNA, directed against mRNA-il-13. To test the efficiency of siRNA a co-transfection of 1x 105 cells HEK293T mixture (0,5 mg and 1 mg of plasmid siRNA) coupled with Lipofectamine 2000 reagent was carried out. Twenty-four hours later, the gene expression changes in il-13 recorded by flow cytometry on the fluorescence intensity of GFP+-cells. Gene expression of il-13 mRNA was assessed by quantitative PCR, and the level of the protein product by ELISA. results. As a result, siRNA molecules were obtained and three of them were able to effectively inhibit the gene expression of il-13. Conclusion. Thereby variants of siRNA, which can effectively inhibit the production of mice’s IL-13 in vitro; can be used later in experiments in vivo so to understand the role of IL-13 in the pathogenesis of allergic conditions as to develop new therapy approaches.

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Epigenetherapy, a new concept

BioMolecular Concepts ◽

10.1515/bmc.2011.012 ◽

2011 ◽

Vol 2 (3) ◽

pp. 127-134

Author(s):

Tiia Husso ◽

Mikko P. Turunen ◽

Nigel Parker ◽

Seppo Ylä-Herttuala

Keyword(s):

Gene Expression ◽

Small Rnas ◽

Basic Research ◽

Clinical Applications ◽

Regulate Gene Expression ◽

Endogenous Gene ◽

Rna Molecules ◽

Regulate Gene

AbstractSmall RNAs have been shown to regulate gene transcription by interacting with the promoter region and modifying the histone code. The exact mechanism of function is still unclear but the feasibility to activate or repress endogenous gene expression with small RNA molecules has already been demonstrated in vitro and in vivo. In traditional gene therapy non-mutated or otherwise useful genes are inserted into patient's cells to treat a disease. In epigenetherapy the action of small RNAs is utilized by delivering only the small RNAs to patient's cells where they then regulate gene expression by epigenetic mechanisms. This method could be widely useful not only for basic research but also for clinical applications of small RNAs.

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Progress in micro RNA focused research in endocrinology

Endocrine Regulations ◽

10.1515/enr-2016-0012 ◽

2016 ◽

Vol 50 (2) ◽

pp. 83-105 ◽

Cited By ~ 1

Author(s):

K. Voglova ◽

J. Bezakova ◽

Iveta Herichova

Keyword(s):

Gene Expression ◽

Physiological Role ◽

Micro Rna ◽

Mirna Biogenesis ◽

Rna Molecules ◽

Micro Rnas ◽

Influence Gene Expression

AbstractMicro RNAs (miRNAs) are small regulatory molecules of increasing biologists’ interest. miRNAs, unlikely mRNA, do not encode proteins. It is a class of small double stranded RNA molecules that via their seed sequence interact with mRNA and inhibit its expression. It has been estimated that 30% of human gene expression is regulated by miRNAs. One miRNA usually targets several mRNAs and one mRNA can be regulated by several miRNAs. miRNA biogenesis is realized by key enzymes, Drosha and Dicer. miRNA/mRNA interaction depends on binding to RNA-induced silencing complex. Today, complete commercially available methodical proposals for miRNA investigation are available. There are techniques allowing the identification of new miRNAs and new miRNA targets, validation of predicted targets, measurement of miRNAs and their precursor levels, and validation of physiological role of miRNAs under in vitro and in vivo conditions. miRNAs have been shown to influence gene expression in several endocrine glands, including pancreas, ovary, testes, hypothalamus, and pituitary.

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S-MiRAGE: A quantitative, secreted RNA-based reporter of gene expression and cell persistence

10.1101/325092 ◽

2018 ◽

Author(s):

Kinshuk Mitra ◽

William N. Feist ◽

Simone Anfossi ◽

Enrique Fuentes-Mattei ◽

Maria Ines Almeida ◽

...

Keyword(s):

Gene Expression ◽

Longitudinal Research ◽

Embryonic Stem ◽

Cell Therapies ◽

Rna Molecules ◽

Cellular Processes ◽

Prognostic Assessment ◽

Differentiation Status

AbstractNon-destructive measurements of cell persistence and gene expression are crucial for longitudinal research studies and for prognostic assessment of cell therapies. Here we describe S-MiRAGE, a platform that utilizes small secreted RNA molecules as sensitive and quantitatively accurate reporters of cellular processes. We demonstrate the utility of S-MiRAGE by monitoring the differentiation status of human embryonic stem cells in vitro, and tumor growth in a mouse model in vivo.

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Methods detecting rhythmic gene expression are biologically relevant only for strong signal

10.1101/730937 ◽

2019 ◽

Author(s):

David Laloum ◽

Marc Robinson-Rechavi

Keyword(s):

Gene Expression ◽

Reference Group ◽

Biologically Relevant ◽

Rna Molecules ◽

Time Points ◽

Rhythmic Expression ◽

Large Sets ◽

Naive Method ◽

Highly Expressed Genes ◽

Rhythmic Gene

AbstractThe nycthemeral transcriptome embodies all genes displaying a rhythmic variation of their mRNAs periodically every 24 hours, including but not restricted to circadian genes. In this study, we show that the nycthemeral rhythmicity at the gene expression level is biologically functional and that this functionality is more conserved between orthologous genes than between random genes. We used this conservation of the rhythmic expression to assess the ability of seven methods (ARSER, Lomb Scargle, RAIN, JTK, empirical-JTK, GeneCycle, and meta2d) to detect rhythmic signal in gene expression. We have contrasted them to a naive method, not based on rhythmic parameters. By taking into account the tissue-specificity of rhythmic gene expression and different species comparisons, we show that no method is strongly favored. The results show that these methods designed for rhythm detection, in addition to having quite similar performances, are consistent only among genes with a strong rhythm signal. Rhythmic genes defined with a standard p-value threshold of 0.01 for instance, could include genes whose rhythmicity is biologically irrelevant. Although these results were dependent on the datasets used and the evolutionary distance between the species compared, we call for caution about the results of studies reporting or using large sets of rhythmic genes. Furthermore, given the analysis of the behaviors of the methods on real and randomized data, we recommend using primarily ARS, empJTK, or GeneCycle, which verify expectations of a classical distribution of p-values. Experimental design should also take into account the circumstances under which the methods seem more efficient, such as giving priority to biological replicates over the number of time-points, or to the number of time-points over the quality of the technique (microarray vs RNAseq). GeneCycle, and to a lesser extent empirical-JTK, might be the most robust method when applied to weakly informative datasets. Finally, our analyzes suggest that rhythmic genes are mainly highly expressed genes.Author SummaryTo be active, genes have to be transcribed to RNA. For some genes, the transcription rate follows a circadian rhythm with a periodicity of approximately 24 hours; we call these genes “rhythmic”. In this study, we compared methods designed to detect rhythmic genes in gene expression data. The data are measures of the number of RNA molecules for each gene, given at several time-points, usually spaced 2 to 4 hours, over one or several periods of 24 hours. There are many such methods, but it is not known which ones work best to detect genes whose rhythmic expression is biologically functional. We compared these methods using a reference group of evolutionarily conserved rhythmic genes. We compared data from baboon, mouse, rat, zebrafish, fly, and mosquitoes. Surprisingly, no method was particularly effective. Furthermore, we found that only very strong rhythmic signals were relevant with each method. More precisely, when we use a usual cut-off to define rhythmic genes, the group of genes considered as rhythmic contains many genes whose rhythmicity cannot be confirmed to be biologically relevant. We also show that rhythmic genes mainly contain highly expressed genes. Finally, based on our results, we provide recommendations on which methods to use and how, and suggestions for future experimental designs.

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