Over-expression of miR-34c leads to early-life visceral fat accumulation and insulin resistance.

Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis.

H-MRS Quantitation of Age-Dependent Taurine Changes in Mouse Brain.

Purpose: A mouse model of Alzheimer's disease demonstrates reduced beta-amyloid levels in the whole brain, associated with a gain of hippocampal memory, after drinking taurine-enriched water; this suggests that a taurine supplement could be a promising treatment for cognitive deficit. The objective of this study is to establish a methodology for quantifying taurine in the whole brain, taking advantage of the rapid development of non-invasive imaging techniques such as magnetic resonance imaging and magnetic resonance spectroscopy (MRS).

Procedures: Single-voxel proton MRS was used to obtain quantifiable taurine peaks at 3.

MicroRNAs as predictive biomarkers for myocardial injury in aged mice following myocardial infarction.

The occurrence of myocardial infarction (MI) increases appreciably with age. In the Framingham Heart Study, the incidence of MI more than doubles for men and increases more than five-fold in women (ages 55-64 years compared to 85-94 years). MicroRNAs (miRNAs) quantitatively regulate their target's expression post-transcriptionally by either silencing action through binding at the 3'UTR domains or degrading the messages at their coding regions.

Maternally induced intraclutch cannibalism: an adaptive response to predation risk?

Theory on condition-dependent risk-taking indicates that when prey are in poor condition, their anti-predator responses should be weak. However, variation in responses resulting from differences in condition is generally considered an incidental by-product of organisms living in a heterogeneous environment. Using Leptinotarsa decemlineata beetles and stinkbug (Podisus maculiventris) predators, we hypothesised that in response to predation risk, parents improve larval nutritional condition and expression of anti-predator responses by promoting intraclutch cannibalism.

Mucin-Inspired Thermoresponsive Synthetic Hydrogels Induce Stasis in Human Pluripotent Stem Cells and Human Embryos.

Human pluripotent stem cells (hPSCs; both embryonic and induced pluripotent) rapidly proliferate in adherent culture to maintain their undifferentiated state. However, for mammals exhibiting delayed gestation (diapause), mucin-coated embryos can remain dormant for days or months in utero, with their constituent PSCs remaining pluripotent under these conditions. Here we report cellular stasis for both hPSC colonies and preimplantation embryos immersed in a wholly synthetic thermoresponsive gel comprising poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) [PGMA55-PHPMA135] diblock copolymer worms.

Loss of protein targeting to glycogen sensitizes human hepatocellular carcinoma cells towards glucose deprivation mediated oxidative stress and cell death.

Protein targeting to glycogen (PTG) is a ubiquitously expressed scaffolding protein that critically regulates glycogen levels in many tissues, including the liver, muscle and brain. However, its importance in transformed cells has yet to be explored in detail. Since recent studies have demonstrated an important role for glycogen metabolism in cancer cells, we decided to assess the effect of PTG levels on the ability of human hepatocellular carcinoma (HepG2) cells to respond to metabolic stress.

NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging.

Though defective genome maintenance and DNA repair have long been known to promote phenotypes of premature aging, the role protein methylation plays in these processes is only now emerging. We have recently identified the first N-terminal methyltransferase, NRMT1, which regulates protein-DNA interactions and is necessary for both accurate mitotic division and nucleotide excision repair. To demonstrate if complete loss of NRMT1 subsequently resulted in developmental or aging phenotypes, we constructed the first NRMT1 knockout (Nrmt1(-/-)) mouse.

Heme oxygenase-1 modulates microRNA expression in cultured astroglia: implications for chronic brain disorders.

Background: Over-expression of the heme-degrading enzyme, heme oxygenase-1 (HO-1) promotes iron deposition, mitochondrial damage, and autophagy in astrocytes and enhances the vulnerability of nearby neuronal constituents to oxidative injury. These neuropathological features and aberrant brain microRNA (miRNA) expression patterns have been implicated in the etiopathogeneses of various neurodevelopmental and aging-related neurodegenerative disorders.

Objective: To correlate glial HO-1 overexpression with altered miRNA patterns, which have been linked to the aforementioned "core" neuropathological features.

Increased microRNA-34c abundance in Alzheimer's disease circulating blood plasma.

Circulating microRNAs, present either in the cellular component, peripheral blood mononuclear cells (PBMC), or in cell-free plasma, have emerged as biomarkers for age-dependent systemic, disease-associated changes in many organs. Previously, we have shown that microRNA (miR)-34a is increased in circulating PBMC of Alzheimer's disease (AD) patients. In the present study, we show that this microRNA's sister, miR-34c, exhibits even greater increase in both cellular and plasma components of AD circulating blood samples, compared to normal age-matched controls.

Chitosan dressing promotes healing in third degree burns in mice: gene expression analysis shows biphasic effects for rapid tissue regeneration and decreased fibrotic signaling.

Burns are a significant health challenge and healing can result in scar formation. Chitosan, a derivative of chitin, has been used to promote wound healing. In this study we used gene expression profiling in a mouse model of full thickness cutaneous burn to assess the benefits of treating with a chitosan lactate dressing.

Full-length 3'-untranslated region reporter construction with recombineering.

Complexity in higher animals derives in part from various modalities of protein-coding gene expression regulation, including microRNA repression by binding to 3'-untranslated regions (UTRs) of specific genes. Reporter constructs containing candidate microRNA target sites are a popular approach of functional studies, and full-length 3'-UTR sequences are preferred because they contain all regulatory elements and preserve higher order structure as much as possible. However, this approach is often handicapped by the extreme length of the 3'-UTR.

Circulatory miR34a as an RNAbased, noninvasive biomarker for brain aging.

MicroRNAs in blood samples have been identified as an important class of biomarkers, which can reflect physiological changes from cancer to brain dysfunction. In this report we identify concordant increases in levels of expression of miR-34a in brain and two components of mouse blood samples, peripheral blood mononuclear cells (PBMCs) and plasma, from 2 day old neonates through young adulthood and mid-life to old age at 25 months. Levels of this microRNA's prime target, silent information regulator 1 (SIRT1), in brain and the two blood-derived specimens decrease with age inversely to miR-34a, starting as early as 4 months old, when appreciable tissue aging has not yet begun.

Post-transcriptional regulation of IGF1R by key microRNAs in long-lived mutant mice.

Long-lived mutant mice, both Ames dwarf and growth hormone receptor gene-disrupted or knockout strains, exhibit heightened cognitive robustness and altered IGF1 signaling in the brain. Here, we report, in both these long-lived mice, that three up-regulated lead microRNAs, miR-470, miR-669b, and miR-681, are involved in posttranscriptional regulation of genes pertinent to growth hormone/IGF1 signaling. All three are most prominently localized in the hippocampus and correspond to reduced expression of key IGF1 signaling genes: IGF1, IGF1R, and PI3 kinase.

Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice.

The decline in cognitive robustness with aging can be attributed to complex genetic pathways involving many cellular dysfunctions, cumulative over time, precipitating in frailty and loss of wellness in the elderly brain. The size and health of the neuronal cell population determines cognitive robustness in mammals. A transgenic mouse model over-expressing Bcl-2 has been shown to rescue neurons from naturally occurring cell death (NOCD).

Increased expression of miR-34a and miR-93 in rat liver during aging, and their impact on the expression of Mgst1 and Sirt1.

Age-dependent loss of oxidative defense is well recognized in rodent models, although the control mechanism is still obscure; a few studies have shown how microRNAs, a non-coding RNA species, regulate the expression of their target genes at the post-transcriptional level. In the current study, miR-34a and miR-93 are observed to increase in middle- and old-age rat liver, compared to young rats; the up-regulation of these two miRNAs is determined by qPCR through a grind-and-find approach, and histochemical in situ hybridization. Three commonly used miRNA target prediction programs suggest four candidate targets of miR-34a and miR-93: Sp1, Nrf2 (Nfe2l2), Sirt1 and Mgst1; their expression is found to be reduced inversely to the up-regulation of the two miRNAs by Western blotting of protein extracts, as well as immunofluorescence staining of intact liver tissues.

Prosaposin in the secretome of marrow stroma-derived neural progenitor cells protects neural cells from apoptotic death.

Functionally, adult stem cells not only participate in replication and differentiation to various cell lineages, but also may be involved in rescuing cells from apoptosis. Identifying functional factors secreted by stem cells, as well as their target cells, may advance our understanding of stem cells' multifaceted physiologic functions. Here, we report that mouse bone marrow stromal cell-derived neuroprogenitor cells (mMSC-NPC) provide a protective function by secreting a key factor, prosaposin (PSAP), capable of rescuing mature neurons from apoptotic death.

MicroRNA group disorganization in aging.

Among non-coding RNAs, microRNAs may be one of the best known subgroups, due to their unique function of negatively controlling gene expression, by either degrading target messages or binding to their 3'-untranslated region to inhibit translation. Thus gene expression can be repressed through post-transcriptional regulation, implemented as a 'dimmer switch', in contrast to the all-or-none mode of suppression. Work from our laboratory and others shows that during aging, dysregulated expression of microRNAs generally occurs in groups, suggesting that their actions may be functionally coordinated as a 'pack' by common transcriptional regulators; the accumulation of these 'pack' disorganizations may be the underlying culprit contributing to the pathoetiology of many age-dependent disease states.

Epigenetic Control of MicroRNA Expression and Aging.

MicroRNAs are a major category among the noncoding RNA fraction that negatively regulate gene expression at the post-transcriptional level, by either degrading the target messages or inhibiting their translation. MicroRNAs may be referred to as 'dimmer switches' of gene expression, because of their ability to repress gene expression without completely silencing it. Whether through up-regulating specific groups of microRNAs to suppress unwanted gene expressions, or by down-regulating other microRNAs whose target genes' expression is necessary for cellular function, such as cell proliferation, apoptosis, or differentiation, these regulatory RNAs play pivotal roles in a wide variety of cellular processes.

MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders.

Understanding complex diseases such as sporadic Alzheimer disease (AD) has been a major challenge. Unlike the familial forms of AD, the genetic and environmental risks factors identified for sporadic AD are extensive. MicroRNAs are one of the major noncoding RNAs that function as negative regulators to silence or suppress gene expression via translational inhibition or message degradation.

MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging.

The Ames dwarf mouse is well known for its remarkable propensity to delay the onset of aging. Although significant advances have been made demonstrating that this aging phenotype results primarily from an endocrine imbalance, the post-transcriptional regulation of gene expression and its impact on longevity remains to be explored. Towards this end, we present the first comprehensive study by microRNA (miRNA) microarray screening to identify dwarf-specific lead miRNAs, and investigate their roles as pivotal molecular regulators directing the long-lived phenotype.

Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain.

Although significant advances have been made in the study of the molecular mechanisms controlling brain aging, post-transcriptional gene regulation in normal brain aging has yet to be explored. Our lab recently reported that predominant microRNA up-regulation is observed in liver during aging, with key microRNAs predicted to target detoxification genes. Here we examine the role of microRNA regulation in brain during the normal aging process.

Stepwise up-regulation of microRNA expression levels from replicating to reversible and irreversible growth arrest states in WI-38 human fibroblasts.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate diverse genetic expression networks through their control of mRNA stability or translation. Their role in aging mechanisms has been proposed in various model systems. In this report, the expression profiling of 462 human miRNAs in the reversible growth arrest state of quiescence, and irreversible states of replicative senescence and hydrogen peroxide-induced premature senescence, are compared to young replicating lung fibroblasts.

Methodology for discovery of Alzheimer's disease blood-based biomarkers.

Alzheimer's disease (AD) is a degenerative brain disorder. The disease also affects peripheral tissue such as peripheral blood mononuclear cells (PBMCs). Delineating biochemical alterations in AD blood constituents may possibly allow the identification of accessible footprints that reflect degenerative processes within the central nervous system.

The impact of noncoding RNA on the biochemical and molecular mechanisms of aging.

As the molecular mechanisms associated with aging become more understood, it is apparent that the normal processes involved in the development and metabolism of an organism are subject to changes that upset its crucial homeostatic balance, which in turn sets in motion the weakening and disease-prone process of senescence. This imbalance is the result of a variety of effectors, such as environmental insults, endogenous toxins, and genetic mishaps. In addition, it is highly probable that posttranscriptional regulatory events play a large role in the changes associated with aging.

Secretome from mesenchymal stem cells induces angiogenesis via Cyr61.

It is well known that bone marrow-derived mesenchymal stem cells (MSCs) are involved in wound healing and regeneration responses. In this study, we globally profiled the proteome of MSCs to investigate critical factor(s) that may promote wound healing. Cysteine-rich protein 61 (Cyr61) was found to be abundantly present in MSCs.