MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases

MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.     

MicroRNAs regulate dendritic cell differentiation and function

MicroRNAs (miRNAs) are an important class of cellular regulators that modulate gene expression and thereby influence cell fate and function. In the immune system, miRNAs act at checkpoints during hematopoietic development and cell subset differentiation, they modulate effector cell function, and they are implicated in the maintenance of homeostasis. Dendritic cells (DCs), the professional APCs involved in the coordination of adaptive immune responses, are also regulated by miRNAs. Some DC-relevant miRNAs, including miR-155 and miR-146a, are shared with other immune cells, whereas others have been newly identified. In this review, we summarize the current understanding of where miRNAs are active during DC development from myeloid precursors and differentiation into specialized subsets, and which miRNAs play roles in DC function.     

MicroRNAs regulate synaptic plasticity underlying drug addiction

Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction‐relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug‐addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction‐relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction.     

MicroRNAs transcriptionally regulate promoter activity in Arabidopsis thaliana

Micro RNAs(mi RNAs) are vital regulators that repress gene expression in the cytoplasm in two main ways: m RNA degradation and translational inhibition. Several animal studies have shown that mi RNAs also target promoters, thereby activating expression.Whether this mi RNA action also occurs in plants is unknown. In this study, we demonstrated that several mi RNAs regulate target promoters in Arabidopsis thaliana. For example, mi R5658 was predominantly present in the nucleus and activated the expression of AT3 G25290 directly by binding to its promoter. Our observations suggest that this mode of action may be a general feature of plant mi RNAs, and thus provide insight into the vital roles of plant mi RNAs in the nucleus.     

Evidence that truncated TrkB isoform, TrkB-Shc can regulate phosphorylated TrkB protein levels

Tropomyosin receptor kinase B (TrkB) is best known as the receptor for brain-derived neurotrophic factor (BDNF). In humans, three major isoforms of TrkB, the full-length receptor (TrkB-TK+) and two C-terminal truncated receptors (TrkB-TK- and TrkB-Shc) are expressed in various tissues. In comparison to TrkB-TK+ and TrkB-TK-, TrkB-Shc is less well characterized. In this study, we analyzed the biological function of the TrkB-Shc receptor in response to exogenous BDNF treatment. In experiments transiently overexpressing TrkB-Shc in CHOK1 cells, we found that TrkB-Shc protein levels were rapidly decreased when cells were exposed to exogenous BDNF. When we assessed the functional impact of TrkB-Shc on TrkB-TK+ activity, we found that phosphorylated TrkB-TK+ protein levels were significantly decreased in the presence of TrkB-Shc and moreso following BDNF exposure. Interestingly, while the reduction of phosphorylated TrkB-TK+ protein was more pronounced in the presence of TrkB-Shc following BDNF exposure, the stability of TrkB-Shc protein itself was increased. Our findings suggest that cells may increase TrkB-Shc protein levels in response to exogenous BDNF exposure to regulate TrkB-TK+ activity by increasing degradation of activated receptor complexes as a means to prevent overactivation or inappropriate temporal and spatial activation of BDNF/TrkB-TK+ signaling.     

In vivo evidence that Agxt2 can regulate plasma levels of dimethylarginines in mice

Elevated plasma concentrations of the asymmetric (ADMA) and symmetric (SDMA) dimethylarginine have repeatedly been linked to adverse cardiovascular clinical outcomes. Both dimethylarginines can be degraded by alanine–glyoxylate aminotransferase 2 (Agxt2), which is also the key enzyme responsible for the degradation of endogenously formed β-aminoisobutyrate (BAIB). In the present study we wanted to investigate the effect of BAIB on Agxt2 expression and Agxt2-mediated metabolism of dimethylarginines. We infused BAIB or saline intraperitoneally for 7 days in C57/BL6 mice via minipumps. Expression of Agxt2 was determined in liver and kidney. The concentrations of BAIB, dimethylarginines and the Agxt2-specific ADMA metabolite α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid (DMGV) was determined by LC–MS/MS in plasma and urine. As compared to controls systemic administration of BAIB increased plasma and urine BAIB levels by a factor of 26.5 (p < 0.001) and 25.8 (p < 0.01), respectively. BAIB infusion resulted in an increase of the plasma ADMA and SDMA concentrations of 27% and 31%, respectively, (both p < 0.05) and a 24% decrease of plasma DMGV levels (p < 0.05), while expression of Agxt2 was not different.Our data demonstrate that BAIB can inhibit Agxt2-mediated metabolism of dimethylarginines and show for the first time that endogenous Agxt2 is involved in the regulation of systemic ADMA, SDMA and DMGV levels. The effect of BAIB excess on endogenous dimethylarginine levels may have direct clinical implications for humans with the relatively common genetic trait of hyper-β-aminoisobutyric aciduria.     

Selenium can regulate the differentiation and immune function of human dendritic cells

BioMetals - Selenium is an essential trace element that can regulate the function of immnue cells via selenoproteins. However, the effects of selenium on human dendritic cell (DCs) remain unclear....     

miRNA调控骨髓增生异常综合征的发生发展

骨髓增生异常综合征(MDS)是一组起源于造血干细胞(HSC)的异质性克隆性疾患,以形态学改变(病态造血)和造血功能异常(无效造血)为主要特征,然而其发生、发展及白血病转化的分子机制尚不明确。MicroRNA(miRNA)是一类重要的非编码小分子RNA,在调控造血干细胞发育进程中起着重要作用,其在MDS的发生发展及白血病转化中的作用也逐渐被认识,以miRNA为分子靶点诊治造血干细胞受损疾患的研究具有广阔的应用前景。     

MicroRNAs and human retroviruses

MicroRNAs (miRNAs) are small non-coding RNAs that control a multitude of critical processes in mammalian cells. Increasing evidence has emerged that host miRNAs serve in animal cells to restrict viral infections. In turn, many viruses encode RNA silencing suppressors (RSS) which are employed to moderate the potency of the cell's miRNA selection against viral replication. Some viruses also encode viral miRNAs. In this review, we summarize findings from human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) that illustrate examples of host cell miRNAs that target the viruses, of RSS encoded by viruses, and of host cell miRNA profile changes that are seen in infected cells. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.     

MicroRNAs in human diseases

The discovery of microRNAs (miRNAs), a new class of negative regulator that represses gene expression by pairing with their target messenger RNAs (mRNAs), has revealed a natural pathway for controlling gene expression. There are hundreds of miRNAs encoded in the human genome and thousands of target mRNAs, which illustrates the important regulatory roles of miRNAs in cell developmental, differentiation, proliferation and apoptosis pathways. In this scenario, it is not surprising that deregulated miRNAs have been involved in the pathogenesis of many human diseases. The recent development of technologies and compounds to identify and modulate miRNAs has opened new avenues for diagnosis, prognosis and therapeutic applications. Here, we summarize most of the recent patents related to the detection and profiling of miRNAs from pathological samples and to miRNA modulators used as new therapies for disease, including cancer and viral infections, as well as methods for their delivery.     

MusTRD can regulate postnatal fiber-specific expression

Human MusTRD1alpha1 was isolated as a result of its ability to bind a critical element within the Troponin I slow upstream enhancer (TnIslow USE) and was predicted to be a regulator of slow fiber-specific genes. To test this hypothesis in vivo, we generated transgenic mice expressing hMusTRD1alpha1 in skeletal muscle. Adult transgenic mice show a complete loss of slow fibers and a concomitant replacement by fast IIA fibers, resulting in postural muscle weakness. However, developmental analysis demonstrates that transgene expression has no impact on embryonic patterning of slow fibers but causes a gradual postnatal slow to fast fiber conversion. This conversion was underpinned by a demonstrable repression of many slow fiber-specific genes, whereas fast fiber-specific gene expression was either unchanged or enhanced. These data are consistent with our initial predictions for hMusTRD1alpha1 and suggest that slow fiber genes contain a specific common regulatory element that can be targeted by MusTRD proteins.     

MicroRNAs expressed by human cytomegalovirus

The detection of antibodies against capripoxvirus has become easier with a commercially available ELISA validated for serum and plasma. In order to explore its suitability for immunological investigations on alternative samples, this study targeted milk as sample matrix available through non-invasive sampling. Samples for this study were collected from dairy cows vaccinated against LSD in an area without reported LSD virus circulation. Paired serum and milk (individual and bulk) samples were tested by ELISA without and with modifications of the sample incubation time for the milk samples. For the evaluation of the test specificity, 352 milk samples from a milk repository in Germany were used as negative control. Receiver operating characteristic analysis was performed for determination of the Youden index and determination of the most suitable cut-off value for maximum specificity. From 154 analyzed serum samples from Serbia, 75 were detected as positive in the ELISA. Sensitivity and specificity of the ELISA test for milk samples reached values of 88 to 91% using Youden criteria. A cut-off of 10 was determined aiming for maximum specificity. This cut-off value was used for further analysis. Using the protocol for serum, out of 154 milk samples, 38 were detected as positive, number of positive detected milk samples increase up to 48 with modified protocol. Milk samples from Germany reacted negative, except two samples that had borderline results using modified protocol. Significant statistical difference (p < 0.05) was observed between two incubation protocols. The detection of LSD-specific antibodies from bulk milk samples (pools of 2–10 individuals) came along with a reduced sensitivity over the sample of individual animals. Results show that the detection of capripoxvirus specific antibodies in milk samples using the commercially available ELISA from IDvet is feasible and can represent a helpful tool for LSDV monitoring programs.     

How cellular membranes can regulate microtubule network

Microtubule array in eukaryotic cells supports directed transport of various cargoes driven by motor proteins. The arrangement of microtubules in cytoplasm is not stochastic; they are organized in a certain way setting a system of coordinates for intracellular transport. Most cultured fibroblast-like cells possess a radial microtubule array with the minus ends of microtubules gathered on the centrosome and plus ends directed towards the periphery of the cell. Mechanisms that regulate the formation of radial microtubule system remain unclear. Usually centrosome works as a microtubule-organizing center; however, the radial system of microtubules can be formed without centrosome participation. At least in some cases microtubule network can be organized by dynein-dynactin complexes associated with membrane vesicles. Membrane vesicles can nucleate microtubules, anchor them and move along them. However, the role of membrane organelles in microtubule organization began to attract attention of researches only recently. It this review we summarize the data indicating that membrane organelles can organize microtubules, providing “tracks” for their subsequent transport.