Biochemical Alterations in White Matter Tracts of the Aging Mouse Brain Revealed by FTIR Spectroscopy Imaging.

White matter degeneration in the central nervous system (CNS) has been correlated with a decline in cognitive function during aging. Ultrastructural examination of the aging human brain shows a loss of myelin, yet little is known about molecular and biochemical changes that lead to myelin degeneration. In this study, we investigate myelination across the lifespan in C57BL/6 mice using electron microscopy and Fourier transform infrared (FTIR) spectroscopic imaging to better understand the relationship between structural and biochemical changes in CNS white matter tracts.

SIRT2 suppresses expression of inflammatory factors via Hsp90-glucocorticoid receptor signalling.

SIRT2 is a NAD -dependent deacetylase that deacetylates a diverse array of protein substrates and is involved in many cellular processes, including regulation of inflammation. However, its precise role in the inflammatory process has not completely been elucidated. Here, we identify heat-shock protein 90α (Hsp90α) as novel substrate of SIRT2.

Htra1 is a Novel Transcriptional Target of RUNX2 That Promotes Osteogenic Differentiation.

Background/aims: Runt-related transcription factor 2 (Runx2) is a master regulator of osteogenic differentiation, but most of the direct downstream targets of RUNX2 during osteogenesis are unknown. Likewise, High-temperature requirement factor A1 (HTRA1) is a serine protease expressed in bone, yet the role of Htra1 during osteoblast differentiation remains elusive. We investigated the role of Htra1 in osteogenic differentiation and the transcriptional regulation of Htra1 by RUNX2 in primary mouse mesenchymal progenitor cells.

Sirt2 epigenetically down-regulates PDGFRα expression and promotes CG4 cell differentiation.

We have previously found that Sirt2 enhanced the outgrowth of cellular processes and MBP expression in CG4 cells, where Sirt2 expression is suppressed by transcription factor Nkx2.2. However, the detailed mechanism of Sirt2 facilitating oligodendroglial cell differentiation remained unclear.

Plays an Intrinsic Role in Regulating Proliferation of Mesenchymal Cells in the Developing Palate.

Cleft palate is a common congenital abnormality that results from defective secondary palate (SP) formation. The () gene has been linked to abnormalities of craniofacial and kidney development. Our current study examined, for the first time, the specific role of in embryonic mouse SP development.

Inhibits Bone Morphogenetic Protein Signaling during Osteogenic Differentiation of the Palatal Mesenchyme.

Cleft palate is one of the most common congenital birth defects worldwide. The homeobox () family of genes are key regulators of embryogenesis, with having a direct role in secondary palate development. mice exhibit cleft palate; however, the cellular and molecular mechanisms leading to cleft palate in mice is largely unknown.

Does Sirt2 Regulate Cholesterol Biosynthesis During Oligodendroglial Differentiation In Vitro and In Vivo?

Sirtuin2 (SIRT2) is a deacetylase enzyme predominantly expressed in myelinating glia of the central nervous system (CNS). We have previously demonstrated that Sirt2 expression enhances oligodendrocyte (OL) differentiation and arborization in vitro, but the molecular targets of SIRT2 in OLs remain speculative. SIRT2 has been implicated in cholesterol biosynthesis by promoting the nuclear translocation of sterol regulatory element binding protein (SREBP)-2.

Organotypic Cultures from the Adult CNS: A Novel Model to Study Demyelination and Remyelination Ex Vivo.

Experimental models of multiple sclerosis (MS) have significantly advanced our understanding of pathophysiology and therapeutic interventions. Although in vivo rodent models are considered to most closely represent the complex cellular and molecular disease states of the human central nervous system (CNS), these can be costly to maintain and require long timelines. Organotypic slice cultures maintain the cytotypic organization observed in the intact CNS, yet provide many of the experimental advantages of in vitro cell culture models.

Expression of PTEN-long mediated by CRISPR/Cas9 can repress U87 cell proliferation.

PTEN is a tumour suppressor that is frequently mutated in a variety of cancers. Hence, PTEN has significant potential as a therapeutic molecule. PTEN-long is an alternative translation variant, with an additional 173 amino acids added to the N-terminal of the canonical PTEN when CUG of the mRNA is utilized as the start codon.

Advances in the treatment of relapsing-remitting multiple sclerosis: the role of pegylated interferon β-1a.

Multiple sclerosis (MS) is a progressive, neurodegenerative disease with unpredictable phases of relapse and remission. The cause of MS is unknown, but the pathology is characterized by infiltration of auto-reactive immune cells into the central nervous system (CNS) resulting in widespread neuroinflammation and neurodegeneration. Immunomodulatory-based therapies emerged in the 1990s and have been a cornerstone of disease management ever since.

RNA-binding Protein Quaking Stabilizes mRNA during Oligodendroglial Differentiation.

Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Sirtuin 2 (SIRT2), a NAD-dependent deacetylase, plays a critical role in OL differentiation by promoting both arborization and downstream expression of myelin-specific genes. However, the mechanisms involved in regulating SIRT2 expression during OL development are largely unknown.

Circular RNAs as potential biomarkers for cancer diagnosis and therapy.

Circular RNAs (circRNAs) are a naturally occurring type of universal and diverse endogenous noncoding RNAs which unlike linear RNAs, have covalently linked ends. They are usually stable, abundant, conserved RNA molecules and often exhibit tissue/developmental-stage specific expression. Functional circRNAs have been identified to act as microRNA sponges and RNA-binding protein (RBP) sequestering agents as well as transcriptional regulators.

Protocols for Cloning, Expression, and Functional Analysis of Sirtuin2 (SIRT2).

SIRT2 is a NAD(+)-dependent deacetylase that belongs to the sirtuin family, which is comprised of seven members (SIRT1-SIRT7) in humans. Furthermore, recent study shows that the Sirt2 gene has three transcript variants in mice. Several diverse proteins have been identified as SIRT2 substrates.

Caregivers' Attitudes towards HIV Testing and Disclosure of HIV Status to At-Risk Children in Rural Uganda.

Caregivers of HIV-positive children were interviewed in the Mbarara and Isingiro districts of Uganda to identify current trends in practices related to HIV testing and the disclosure of HIV status to the child. A total of 28 caregivers of at least one HIV-positive child participated in semi-structured interviews exploring when and why they tested the child for HIV, when the child was informed of their positive status, and what the caregiver did to prepare themselves and the child for status disclosure. For a majority (96%) of respondents, the decision to test the child for HIV was due to existing illness in either the child or a relative.

Nano-pharmaceutical formulations for targeted drug delivery against HER2 in breast cancer.

Nanotechnology has revolutionized fundamental opportunities for higher specific drug delivery with minimum side effects. Since its inception, the goal of nanotechnology has been to advance effective and reliable systems for precise anti-cancer therapy and diagnosis. To accomplish this goal, bio-conjugation strategies of therapeutic agents loaded nanoparticles with monoclonal antibodies or their analogues have demonstrated a targeted approach both in vitro and in vivo.

Pharmacogenomics of interferon-β in multiple sclerosis: what has been accomplished and how can we ensure future progress?

Multiple sclerosis (MS) is a progressive disorder of the central nervous system, often resulting in significant disability in early adulthood. The field of pharmacogenomics holds promise in distinguishing responders from non-responders to drug treatment. Most studies on genetic polymorphisms in MS have addressed treatment with interferon-β, yet few findings have been replicated.

Current developments in pharmacogenomics of multiple sclerosis.

Pharmacogenomics has a significant potential to impact how we treat diseases. It involves targeting genetically identifiable populations with therapeutic interventions that promises to yield immediate positive health outcomes with lower or no side effects. The 'trial and error' method of treatment will no longer be necessary with the successful implementation of personalized medicine.

Molecular signaling along the anterior-posterior axis of early palate development.

Cleft palate is a common congenital birth defect in humans. In mammals, the palatal tissue can be distinguished into anterior bony hard palate and posterior muscular soft palate that have specialized functions in occlusion, speech or swallowing. Regulation of palate development appears to be the result of distinct signaling and genetic networks in the anterior and posterior regions of the palate.

Mitochondrial dysfunction contributes to the cytotoxicity of some 3,5-bis(benzylidene)-4-piperidone derivatives in colon HCT-116 cells.

The objectives of this study are to investigate the possible ways by which the curcumin analogs 2a and 2b exert their antiproliferative properties. The analogs 2a and 2b have submicromolar IC(50) values towards human HCT-116 colon cancer cells but are far less toxic to human non-malignant CRL-1790 colon cells. Both compounds affected a number of mitochondrial functions in HCT-116 cells namely increasing the intracellular concentrations of reactive oxygen species, inhibiting oxygen consumption and decreasing the mitochondrial membrane potential.

Monoamine oxidase-A physically interacts with presenilin-1(M146V) in the mouse cortex.

The concentration of presenilin-1 (PS-1) protein at the mitochondrial-associated aspect of the endoplasmic reticulum supports the potential for a mitochondrial influence of PS-1. Given that carriers of certain Alzheimer's disease (AD)-related PS-1 variants are predisposed to clinical depression and that depression has been historically associated with the mitochondrial enzyme, monoamine oxidase-A (MAO-A), we investigated cortical MAO-A function in the AD-related PS-1(M146V) knock-in mouse. The MAO-A system was clearly altered in the PS-1(M146V) mouse as revealed by (a) a mismatch between MAO-A protein expression and MAO-A activity; (b) changes in MAO-A-mediated monoaminergic neurotransmitter metabolism; (c) changes in non-cognitive behavior following treatment with the irreversible MAO-A inhibitor clorgyline; and (d) an increase in the potency of clorgyline in these same mice.

Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendroglial cell differentiation.

Although Sirt2 is primarily expressed in oligodendrocytes of the central nervous system, its role in oligodendroglial lineage differentiation is not fully understood. Our findings demonstrate that the transcription factor Nkx2.2 binds to the Sirt2 promoter via histone deacetylase 1 (HDAC-1), the binding site for Nkx2.

Conditional Tet-regulated over-expression of Hoxa2 in CG4 cells increases their proliferation and delays their differentiation into oligodendrocyte-like cells expressing myelin basic protein.

Hoxa2 gene was reported to be expressed by oligodendrocytes (OLs) and down-regulated at the terminal differentiation stage during oligodendrogenesis in mice (Nicolay et al. 2004b). To further investigate the role of Hoxa2 in oligodendroglial development, a tetracycline regulated controllable expression system was utilized to establish a stable cell line (CG4-SHoxa2 [sense Hoxa2]), where the expression level of Hoxa2 gene could be up-regulated.

Matrix metalloproteinase-25 has a functional role in mouse secondary palate development and is a downstream target of TGF-β3.

Background: Development of the secondary palate (SP) is a complex event and abnormalities during SP development can lead to cleft palate, one of the most common birth disorders. Matrix metalloproteinases (MMPs) are required for proper SP development, although a functional role for any one MMP in SP development remains unknown. MMP-25 may have a functional role in SP formation as genetic scans of the DNA of human cleft palate patients indicate a common mutation at a region upstream of the MMP-25 gene.