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1.  Aging-kb: a knowledge base for the study of the Aging process 
Mechanisms of Ageing and Development  2011;132(11-12):592-594.
As the science of the aging process moves forward, a recurring challenge is the integration of multiple types of data and information with classical aging theory while disseminating that information to the scientific community. Here we present AGING-kb, a public knowledge base with the goal of conceptualizing and presenting fundamental aspects of the study of the aging process. Aging-kb has two interconnected parts, the Aging-kb tree and the Aging Wiki. The Aging-kb tree is a simple intuitive dynamic tree hierarchy of terms describing the field of aging from the general to the specific. This enables the user to see relationships between areas of aging research in a logical comparative fashion. The second part is a specialized Aging Wiki which allows expert definition, description, supporting information, and documentation of each aging keyword term found in the Aging-kb tree. The Aging Wiki allows community participation in describing and defining concepts and terms in the Wiki format. This aging knowledge base provides a simple intuitive interface to the complexities of aging.
http://aging-kb.nia.nih.gov
doi:10.1016/j.mad.2011.10.008
PMCID: PMC3287063  PMID: 22100666
2.  A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development 
The Journal of pathology  2014;233(3):228-237.
Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histologic analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal appearing p53-positive epithelium that are similar to “p53 signatures” in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these noninvasive precursor lesions, we also identified invasive adenocarcinoma in the ovary of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase II-alpha, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and specifically elevated in mouse STICs, but not in surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade, and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumorigenesis, as well as for developing novel approaches for the prevention, diagnosis, and therapy of this disease.
doi:10.1002/path.4353
PMCID: PMC4149901  PMID: 24652535
transgenic mouse model; ovarian cancer; fallopian tube; intraepithelial carcinoma; p53; Top2a
3.  Similarities in features of autism and asthma and a possible link to acetaminophen use 
Medical Hypotheses  2009;74(1):7-11.
Autism and autism spectrum disorders are enigmatic conditions that have their origins in the interaction of genes and environmental factors. In this hypothesis, genes statistically associated with autism are emphasized to be important in inflammation and in innate immune pathways, including pathways for susceptibility to asthma. The role of acetaminophen (paracetamol) in an increased risk for asthma is described and a possible similar link to an increased risk for autism is suggested.
doi:10.1016/j.mehy.2009.08.033
PMCID: PMC3261751  PMID: 19748189
autism; asthma; acetaminophen; innate immunity
4.  MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL 
Nature communications  2014;5:5413.
The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself down-regulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. We propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL.
doi:10.1038/ncomms6413
PMCID: PMC4238046  PMID: 25403230
5.  Divergence of transcriptional landscape occurs early in B cell activation 
Background
Signaling via B cell receptor (BCR) and Toll-like receptors (TLRs) results in activation of B cells with distinct physiological outcomes, but transcriptional regulatory mechanisms that drive activation and distinguish these pathways remain unknown.
Results
Two hours after ligand exposure RNA-seq, ChIP-seq and computational methods reveal that BCR- or TLR-mediated activation of primary resting B cells proceeds via a large set of shared and a smaller subset of distinct signal-selective transcriptional responses. BCR stimulation resulted in increased global recruitment of RNA Pol II to promoters that appear to transit slowly to downstream regions. Conversely, lipopolysaccharide (LPS) stimulation involved an enhanced RNA Pol II transition from initiating to elongating mode accompanied by greater H3K4me3 activation markings compared to BCR stimulation. These rapidly diverging transcriptomic landscapes also show distinct repressing (H3K27me3) histone signatures, mutually exclusive transcription factor binding in promoters, and unique miRNA profiles.
Conclusions
Upon examination of genome-wide transcription and regulatory elements, we conclude that the B cell commitment to different activation states occurs much earlier than previously thought and involves a multi-faceted receptor-specific transcriptional landscape.
Electronic supplementary material
The online version of this article (doi:10.1186/s13072-015-0012-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13072-015-0012-x
PMCID: PMC4434543  PMID: 25987903
6.  Human Umbilical Cord Matrix Mesenchymal Stem Cells Suppress the Growth of Breast Cancer by Expression of Tumor Suppressor Genes 
PLoS ONE  2015;10(5):e0123756.
Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species’ breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-over-expressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression.
doi:10.1371/journal.pone.0123756
PMCID: PMC4420498  PMID: 25942583
7.  Age-related Brain Expression and Regulation of the Chemokine CCL4/MIP-1β in APP/PS1 Double Transgenic Mice 
The detrimental effect of activation of the chemokine CCL4/MIP-1β on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease (AD). Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APPswe/PS1 E9 (APP/PS1) double transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from non-transgenic littermates or single mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-β (Aβ) levels in APP/PS1 mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related Aβ deposition and CCL4 in the brains of APP/PS1 mice. Results from chromatin immunoprecipitation-quantitative PCR confirmed that ATF3 binds to the promoter region of the CCL4 gene, consistent with a potential role in regulating CCL4 transcription. Finally, elevated ATF3 mRNA expression in APP/PS1 brains was associated with hypomethylation of the ATF3 gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of the ATF3 gene, may contribute to neuropathological progression associated with amyloid deposition in AD.
doi:10.1097/NEN.0000000000000060
PMCID: PMC3977177  PMID: 24607962
Alzheimer disease; ATF3; CCL4/MIP-1β; Epigenetics; Neuroinflammation
8.  Combined treatment of rapamycin and dietary restriction have a larger effect on the transcriptome and metabolome of liver 
Aging cell  2013;13(2):311-319.
Summary
Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa+DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups. Over 2500 genes are significantly changed with either Rapa or DR compared to mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways are uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, while 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa+DR compared to AL is twice as large as the number of genes significantly altered by either DR or Rapa alone. In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.
doi:10.1111/acel.12175
PMCID: PMC3989927  PMID: 24304444
Rapamycin; dietary restriction; metabolome; transcriptome
9.  Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells 
Pigment cell & melanoma research  2014;28(2):184-195.
We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAFV600E mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated β-galactosidase (SA-β-gal), senescence associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence like SA-β-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail-vein colony forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.
doi:10.1111/pcmr.12330
PMCID: PMC4333017  PMID: 25407936
10.  Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma 
Background
The mechanistic target of rapamycin, (mTOR) kinase plays a pivotal role in controlling critical cellular growth and survival pathways, and its aberrant induction is implicated in cancer pathogenesis. Therefore, suppression of active mTOR signaling has been of great interest to researchers; several mTOR inhibitors have been discovered to date. Ethanol (EtOH), similar to pharmacologic mTOR inhibitors, has been shown to suppress the mTOR signaling pathway, though in a non-catalytic manner. Despite population studies showing that the consumption of EtOH has a protective effect against hematological malignancies, the mechanisms behind EtOH’s modulation of mTOR activity in cells and its downstream consequences are largely unknown. Here we evaluated the effects of EtOH on the mTOR pathway, in comparison to the active-site mTOR inhibitor INK128, and compared translatome analysis of their downstream effects in diffuse large B-cell lymphoma (DLBCL).
Results
Treatment of DLBCL cells with EtOH suppressed mTORC1 complex formation while increasing AKT phosphorylation and mTORC2 complex assembly. INK128 completely abrogated AKT phosphorylation without affecting the structure of mTORC1/2 complexes. Accordingly, EtOH less profoundly suppressed cap-dependent translation and global protein synthesis, compared to a remarkable inhibitory effect of INK128 treatment. Importantly, EtOH treatment induced the formation of stress granules, while INK128 suppressed their formation. Microarray analysis of polysomal RNA revealed that although both agents primarily affected cell growth and survival, EtOH and INK128 regulated the synthesis of mostly distinct genes involved in these processes. Though both EtOH and INK128 inhibited cell cycle, proliferation and autophagy, EtOH, in contrast to INK128, did not induce cell apoptosis.
Conclusion
Given that EtOH, similar to pharmacologic mTOR inhibitors, inhibits mTOR signaling, we systematically explored the effect of EtOH and INK128 on mTOR signal transduction, components of the mTORC1/2 interaction and their downstream effectors in DLBCL malignancy. We found that EtOH partially inhibits mTOR signaling and protein translation, compared to INK128’s complete mTOR inhibition. Translatome analysis of mTOR downstream target genes established that differential inhibition of mTOR by EtOH and INK128 distinctly modulates translation of specific subsets of mRNAs involved in cell growth and survival, leading to differential cellular response and survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12964-015-0091-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12964-015-0091-0
PMCID: PMC4350884  PMID: 25849580
mTOR signaling; Translation; EtOH; INK128; DLBCL; Gene expression
11.  Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates 
Journal of neurochemistry  2008;105(5):1948-1959.
Chronic manganese (Mn) exposure produces a neurological syndrome with psychiatric, cognitive, and parkinsonian features. Gene expression profiling in the frontal cortex of Cyno-mologous macaques receiving 3.3–5.0 mg Mn/kg weekly for 10 months showed that 61 genes were increased and four genes were decreased relative to controls from a total of 6766 genes. Gene changes were associated with cell cycle regulation, DNA repair, apoptosis, ubiquitin-proteasome system, protein folding, cholesterol homeostasis, axonal/vesicular transport, and inflammation. Amyloid-β (Aβ) precursor-like protein 1, a member of the amyloid precursor protein family, was the most highly up-regulated gene. Immunohistochemistry confirmed increased amyloid precursor-like protein 1 protein expression and revealed the presence of diffuse Aβ plaques in Mn-exposed frontal cortex. Cortical neurons and white matter fibers from Mn-exposed animals accumulated silver grains indicative of on-going degeneration. Cortical neurons also exhibited nuclear hypertrophy, intracytoplasmic vacuoles, and apoptosis stigmata. p53 immunolabeling was increased in the cytoplasm of neurons and in the nucleus and processes of glial cells in Mn-exposed tissue. In summary, chronic Mn exposure produces a cellular stress response leading to neurodegenerative changes and diffuse Aβ plaques in the frontal cortex. These changes may explain the subtle cognitive deficits previously demonstrated in these same animals.
doi:10.1111/j.1471-4159.2008.05295.x
PMCID: PMC4335763  PMID: 18284614
Alzheimer’s disease; amyloid-β; amyloid-β precursor-like protein 1; manganese; neurodegeneration; non-human primates; p53
12.  RNA-Binding Protein AUF1 Promotes Myogenesis by Regulating MEF2C Expression Levels 
Molecular and Cellular Biology  2014;34(16):3106-3119.
The mammalian RNA-binding protein AUF1 (AU-binding factor 1, also known as heterogeneous nuclear ribonucleoprotein D [hnRNP D]) binds to numerous mRNAs and influences their posttranscriptional fate. Given that many AUF1 target mRNAs encode muscle-specific factors, we investigated the function of AUF1 in skeletal muscle differentiation. In mouse C2C12 myocytes, where AUF1 levels rise at the onset of myogenesis and remain elevated throughout myocyte differentiation into myotubes, RNP immunoprecipitation (RIP) analysis indicated that AUF1 binds prominently to Mef2c (myocyte enhancer factor 2c) mRNA, which encodes the key myogenic transcription factor MEF2C. By performing mRNA half-life measurements and polysome distribution analysis, we found that AUF1 associated with the 3′ untranslated region (UTR) of Mef2c mRNA and promoted MEF2C translation without affecting Mef2c mRNA stability. In addition, AUF1 promoted Mef2c gene transcription via a lesser-known role of AUF1 in transcriptional regulation. Importantly, lowering AUF1 delayed myogenesis, while ectopically restoring MEF2C expression levels partially rescued the impairment of myogenesis seen after reducing AUF1 levels. We propose that MEF2C is a key effector of the myogenesis program promoted by AUF1.
doi:10.1128/MCB.00423-14
PMCID: PMC4135590  PMID: 24891619
13.  DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes 
Nucleic Acids Research  2014;43(2):943-959.
We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ+/− mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.
doi:10.1093/nar/gku1356
PMCID: PMC4333403  PMID: 25552414
14.  Autism, Asthma, Inflammation, and the Hygiene Hypothesis 
Medical hypotheses  2007;69(4):731-740.
Inflammation and the genes, molecules, and biological pathways that lead to inflammatory processes influence many important and disparate biological processes and disease states that are quite often not generally considered classical inflammatory or autoimmune disorders. These include development, reproduction, aging, tumor development and tumor rejection, cardiovascular pathologies, metabolic disorders, as well as neurological and psychiatric disorders. This paper compares parallel aspects of autism and inflammatory disorders with an emphasis on asthma. These comparisons include epidemiological, morphometric, molecular, and genetic aspects of both disease types, contributing to a hypothesis of autism in the context of the immune based hygiene hypothesis. This hypothesis is meant to address the apparent rise in the prevalence of autism in the population.
doi:10.1016/j.mehy.2007.02.019
PMCID: PMC2048743  PMID: 17412520
autism; autoimmune; inflammation
15.  MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL 
Nature Communications  2014;5:5413.
The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself downregulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. We propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive and heterogeneous type of non-Hodgkin’s lymphoma. Here the authors demonstrate that the differential regulation of eIF4E1 and eIF4E3 by the MAPK-interacting kinases is involved in DLBCL aetiology through modification of the cellular translatome.
doi:10.1038/ncomms6413
PMCID: PMC4238046  PMID: 25403230
16.  Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase 
Aging (Albany NY)  2014;6(11):957-969.
Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dys-regulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation gene expression mediated by the transcription factor NF-κB is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-κB-associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-κB up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dys-regulated basal NF-κB activity may contribute to the mild pro-inflammatory state of aging.
PMCID: PMC4276789  PMID: 25553802
CD4+ T cells; NF-κB; PI3K; human aging; gene expression
17.  CREB Phosphorylation Regulates Striatal Transcriptional Responses in the Self-Administration Model of Methamphetamine Addiction in the Rat 
Neurobiology of disease  2013;58:132-143.
Neuroplastic changes in dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1 mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2 h, 24 h, or 1 month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in ΔFosB, BDNF and TrkB protein levels, with increases after 2 and 24 h, but decreases after 1 month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2 h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.
doi:10.1016/j.nbd.2013.05.009
PMCID: PMC3748236  PMID: 23726845
methamphetamine; self-administration; dorsal striatum; ΔFosB; BDNF; pCREB
18.  SAL-RNAs: Senescence-associated long non-coding RNAs 
Aging cell  2013;12(5):890-900.
Non-coding RNAs include small transcripts, such as microRNAs and piwi-interacting RNAs, and a wide range of long non-coding RNAs (lncRNAs). Although many lncRNAs have been identified, only a small number of lncRNAs have been characterized functionally. Here, we sought to identify lncRNAs differentially expressed during replicative senescence. We compared lncRNAs expressed in proliferating, early passage, ‘young’ human diploid WI-38 fibroblasts [population doubling (PDL) 20] with those expressed in senescent, late-passage, ‘old’ fibroblasts (PDL 52) by RNA sequencing (RNA-Seq). Numerous transcripts in all lncRNA groups (antisense lncRNAs, pseudogene-encoded lncRNAs, previously described lncRNAs and novel lncRNAs) were validated using reverse transcription (RT) and real-time, quantitative (q)PCR. Among the novel senescence-associated lncRNAs (SAL-RNAs) showing lower abundance in senescent cells, SAL-RNA1 (XLOC_023166) was found to delay senescence, since reducing SAL-RNA1 levels enhanced the appearance of phenotypic traits of senescence, including an enlarged morphology, positive β-galactosidase activity, and heightened p53 levels. Our results reveal that the expression of known and novel lncRNAs changes with senescence and suggest that SAL-RNAs play direct regulatory roles in this important cellular process.
doi:10.1111/acel.12115
PMCID: PMC3773026  PMID: 23758631
post-transcriptional gene regulation; transcriptome; non-coding; proliferation; senescence-associated gene expression patterns
19.  SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass 
Aging Cell  2014;13(5):787-796.
Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.
doi:10.1111/acel.12220
PMCID: PMC4172519  PMID: 24931715
healthspan; inflammation; lifespan; muscle wasting; osteoporosis; sirtuins
20.  Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury 
Neurobiology of disease  2013;54:1-11.
Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to Alzheimer’s disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority.
doi:10.1016/j.nbd.2013.02.006
PMCID: PMC3628969  PMID: 23454194
Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; Alzheimer’s disease
21.  Molecular characterization of the transition to mid-life in Caenorhabditis elegans 
Age  2012;35(3):689-703.
We present an initial molecular characterization of a morphological transition between two early aging states. In previous work, an age score reflecting physiological age was developed using a machine classifier trained on images of worm populations at fixed chronological ages throughout their lifespan. The distribution of age scores identified three stable post-developmental states and transitions. The first transition occurs at day 5 post-hatching, where a significant percentage of the population exists in both state I and state II. The temperature dependence of the timing of this transition (Q10 ~ 1.17) is too low to be explained by a stepwise process with an enzymatic or chemical rate-limiting step, potentially implicating a more complex mechanism. Individual animals at day 5 were sorted into state I and state II groups using the machine classifier and analyzed by microarray expression profiling. Despite being isogenic, grown for the same amount of time, and indistinguishable by eye, these two morphological states were confirmed to be molecularly distinct by hierarchical clustering and principal component analysis of the microarray results. These molecular differences suggest that pharynx morphology reflects the aging state of the whole organism. Our expression profiling yielded a gene set that showed significant overlap with those from three previous age-related studies and identified several genes not previously implicated in aging. A highly represented group of genes unique to this study is involved in targeted ubiquitin-mediated proteolysis, including Skp1-related (SKR), F-box-containing, and BTB motif adaptors.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9401-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9401-2
PMCID: PMC3636400  PMID: 22610697
Machine classifier; Biomarker of aging; Metastable aging state; Microarray analysis
22.  The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet 
Cell reports  2014;6(5):836-843.
The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD+ deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of pro-inflammatory gene expression both in the liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice.
doi:10.1016/j.celrep.2014.01.031
PMCID: PMC4010117  PMID: 24582957
SRT1720; healthspan; standard diet; mice; longevity; SIRT1
23.  Naïve rat umbilical cord matrix stem cells significantly attenuate mammary tumor growth through modulation of endogenous immune responses 
Cytotherapy  2013;15(5):586-597.
Background aims
Un-engineered human and rat umbilical cord matrix stem cells (UCMSCs) attenuate growth of several types of tumors in mice and rats. However, the mechanism by which UCMSCs attenuate tumor growth has not been studied rigorously.
Methods
The possible mechanisms of tumor growth attenuation by rat UCMSCs were studied using orthotopic Mat B III rat mammary tumor grafts in female F344 rats. Tumor-infiltrating leukocytes were identified and quantified by immunohistochemistry analysis. Potential cytokines involved in lymphocyte infiltration in the tumors were determined by microarray and Western blot analysis. The Boyden chamber migration assay was performed for the functional analysis of identified cytokines.
Results
Rat UCMSCs markedly attenuated tumor growth; this attenuation was accompanied by considerable lymphocyte infiltration. Immunohistochemistry analysis revealed that most infiltrating lymphocytes in the rat UCMSC-treated tumors were CD3+ T cells. In addition, treatment with rat UCMSCs significantly increased infiltration of CD8+ and CD4+ T cells and natural killer (NK) cells throughout tumor tissue. CD68+ monocytes/macrophages and Foxp3+ regulatory T cells were scarcely observed, only in the tumors of the phosphate-buffered saline control group. Microarray analysis of rat UCMSCs demonstrated that monocyte chemotactic protein-1 is involved in rat UCMSC-induced lymphocyte infiltration in the tumor tissues.
Conclusions
These results suggest that naïve rat UCMSCs attenuated mammary tumor growth at least in part by enhancing host anti-tumor immune responses. Naïve UCMSCs can be used as powerful therapeutic cells for breast cancer treatment, and monocyte chemotactic protein-1 may be a key molecule to enhance the effect of UCMSCs at the tumor site.
doi:10.1016/j.jcyt.2013.01.006
PMCID: PMC3652627  PMID: 23474329
immune response; macrophages; mammary tumor; rat umbilical cord matrix stem cells; T cells
24.  Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver 
Aging Cell  2013;13(2):311-319.
Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups. Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone. In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.
doi:10.1111/acel.12175
PMCID: PMC3989927  PMID: 24304444
dietary restriction; metabolome; rapamycin; transcriptome
25.  Metformin improves healthspan and lifespan in mice 
Nature communications  2013;4:2192.
Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
doi:10.1038/ncomms3192
PMCID: PMC3736576  PMID: 23900241

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