In the title compound, C27H22N2O4, the two indole ring systems are approximately perpendicular to each other, with a dihedral angle of 84.5 (5)° between their planes; the benzene ring is twisted with respect to the two indole ring systems at angles of 78.5 (5) and 86.5 (3)°. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, weak C—H⋯O and C—H⋯N hydrogen bonds, and C—H⋯π interactions into a three-dimensional supramolecular architecture.
Spermatocytic seminoma (SS) is a rare testicular neoplasm characterized by a palpable, painless, slowly enlarging mass in the testis. Even more rare is a synchronous bilateral presentation. Only eight cases of bilateral SS have been reported in the literature, of which three cases were present with synchronous testis enlargement, and five were sequential. Here, we report an additional case of synchronous bilateral SS and present a comprehensive relevant literature review concerning clinical features, histopathology, and treatment.
Spermatocytic seminoma; Fine-needle aspiration cytology; Bilateral spermatocytic seminoma; Testicular cancer
Directed carotid cavernous fistula means high blood flow shunts between the internal carotid artery and the cavernous sinus. Obstructing the abnormal shunt between the internal carotid artery and the cavernous sinus while preserving the internal carotid artery is the key role in fistula treatment. Transarterial balloon embolization is currently the gold standard treatment for most of the carotid cavernous fistulas. But there are still some technical difficulties in the use of detachable balloon to treat carotid cavernous fistulas. Here, we describe undetachable balloon-assisted technique in the embolization of three patients who got complete immediate occlusion of the shunt and preserved the internal carotid artery at the same time.
Morphological transition and iron metabolism are closely relevant to Candida albicans pathogenicity and virulence. In our previous study, we demonstrated that C. albicans Aft2 plays an important role in ferric reductase activity and virulence. Here, we further explored the roles of C. albicans Aft2 in numerous cellular processes. We found that C. albicans Aft2 exhibited an important role in iron metabolism through bi-directional regulation effects on iron-regulon expression. Deletion of AFT2 reduced cellular iron accumulation under iron-deficient conditions. Furthermore, both reactive oxygen species (ROS) generation and superoxide dismutase (SOD) activity were remarkably increased in the aft2Δ/Δ mutant, which were thought to be responsible for the defective responses to oxidative stress. However, we found that over-expression of C. albicans AFT2 under the regulation of the strong PGK1 promoter could not effectively rescue Saccharomyces cerevisiae aft1Δ mutant defects in some cellular processes, such as cell-wall assembly, ion homeostasis and alkaline resistance, suggesting a possibility that C. albicans Aft2 weakened its functional role of regulating some cellular metabolism during the evolutionary process. Interestingly, deletion of AFT2 in C. albicans increased cell surface hydrophobicity, cell flocculation and the ability of adhesion to polystyrene surfaces. In addition, our results also revealed that C. albicans Aft2 played a dual role in regulating hypha-specific genes under solid and liquid hyphal inducing conditions. Deletion of AFT2 caused an impaired invasive growth in solid medium, but an increased filamentous aggregation and growth in liquid conditions. Moreover, iron deficiency and environmental cues induced nuclear import of Aft2, providing additional evidence for the roles of Aft2 in transcriptional regulation.
Cortical feed-back projections to primary sensory areas terminate most heavily in layer (L) 11,2, where they make synapses with tuft dendrites of pyramidal neurons. L1 input is thought to provide ‘contextual’ information3, but the signals transmitted by L1 feedback remain uncharacterized. In the rodent somatosensory system, the spatially diffuse4 vibrissal motor cortex (vM1)→ vibrissal somatosensory cortex (barrel cortex, vS1) feedback projection may allow whisker touch to be interpreted in the context of whisker position to compute object location5,6. When mice palpate objects with their whiskers to localize object features7,8, whisker touch excites vibrissal somatosensory cortex (barrel cortex, vS1)9 and later vibrissal motor cortex (vM1) in a somatotopic manner10,11,12,13. Here we used axonal calcium imaging to track activity in vM1→ vS1 afferents in L1 of barrel cortex, while mice performed whisker-dependent object localization. Spatially intermingled individual axons represented whisker movements, touch, and other behavioral features. In a subpopulation of axons, activity depended on object location and persisted for seconds after touch. Neurons in the barrel cortex thus have information to integrate movements and touches of multiple whiskers over time, key components of object identification and navigation by active touch.
N-myc downstream-regulated gene 2 (NDRG2) has been documented to be a pro-differentiative and anti-proliferative gene in cancer research. Our previous study found a significant NDRG2 up-regulation in reactive astrocytes of penumbra after transient focal cerebral ischemia, which was parallel to the enhancement of TUNEL-positive signals. However, it is still uncertain whether NDRG2 participates in cellular apoptosis induced by ischemia-reperfusion injury in brain. In this study, we investigated the role of NDRG2 in cellular apoptosis induced by oxygen-glucose deprivation (OGD) in IL-6-differentiated C6 glioma cells. The results showed that NDRG2 was up-regulated and translocated from the cytoplasm to the nucleus after OGD exposure. NDRG2 over-expression exhibited an anti-proliferative effect and increased the Bax/Bcl-2 ratio after OGD exposure, while NDRG2 silencing promoted the cellular proliferation and attenuated the up-regulation of Bax/Bcl-2 ratio. The pro-apoptotic effect of p53 was verified by the results in which p53 silencing greatly reduced the percentage of OGD-induced apoptotic cells. p53 silencing also reduced the OGD-induced NDRG2 up-regulation. However, over-expression of p53 did not further improve the NDRG2 up-regulation. In conclusion, NDRG2 is a p53-associated regulator of apoptosis in C6-originated astrocytes after OGD exposure. These findings bring insight to the roles of NDRG2 in ischemic-hypoxic injury and provide potential targets for future clinical therapies on stroke.
By using silver cations (Ag+) as the ionic reagent in reactive extractive electrospray ionization mass spectrometry (EESI-MS), the concentrations of acetonitrile in exhaled breath samples from the volunteers including active smokers, passive smokers, and non-smokers were quantitatively measured in vivo, without any sample pretreatment. A limit of detection (LOD) and relative standard deviation (RSD) were 0.16 ng/L and 3.5% (n = 8), respectively, for the acetonitrile signals in MS/MS experiments. Interestingly, the concentrations of acetonitrile in human breath continuously increased for 1–4 hours after the smoker finished smoking and then slowly decreased to the background level in 7 days. The experimental data of a large number of (> 165) samples indicated that the inhaled acetonitrile is excreted most likely by facilitated diffusion, instead of simple diffusion reported previously for other volatile compounds.
Liposarcoma of the spermatic cord (LSC) is a rare condition characterized by a painless inguinal or scrotal mass. To our knowledge, only about 200 cases have been previously reported in the literature. These tumors are often mistaken for common scrotal swellings, such as hydroceles and hernias. We present a LSC case in which a definitive diagnosis was obtained upon histological examination. We also provide a literature review of other cases that have been reported.
Liposarcoma; Spermatic cord; Inguinal hernia; Literature review
Objective: To perform a prospective randomized trial comparing the efficacy and safety of percutaneous nephrolithotomy (PCNL) in the prone and modified supine positions.
Methods: Between August 2010 and August 2011, 102 patients with renal calculi and 20 patients with ureteral calculi were randomized to undergo fluoroscopy and ultrasound-guided PCNL procedures in the prone or modified supine position. Baseline characteristics, puncture position, numbers of punctures, operation time, stone free rate, loss of blood, hospital stay and second phase PCNL were compared in the two groups.
Results: There were no significant differences in gender, age, body mass index, stone location, stone size and the presence of hydronephrosis between the two groups. The rate of second PCNL was significantly higher and the stone clearance rate was significantly lower in the modified supine than in the prone position group. Mean operation time was significantly lower in the prone than in the modified supine position group (78 min vs 88 min, P<0.05). There were no significant differences in rates of rib and calyx puncture, numbers of punctures, mean blood loss, and mean hospital stay between the two groups.
Conclusions: Both the prone and modified supine positions are effective and safe for PCNL. Operation time was longer in the modified supine group, and patients undergoing PCNL in the modified supine position more frequently required a second operation due to a lower stone clearance rate.
percutaneous nephrolithotomy; prone position; modified supine position; prospective randomized trial
One method used to correct geometric and intensity distortions in Echo Planar images is to register them to undistorted images via nonrigid deformations. However some areas in the Echo Planar images are more distorted than others, thus suggesting the use of deformations whose characteristics are adapted spatially. In this paper, we incorporate into our previously developed registration algorithm a spatially varying scale mechanism, which adapts the local scale properties of the transformation by means of a scale map. To compute the scale map, a technique is proposed that relies on an estimate of the expected deformation field. This estimate is generated using knowledge of the physical processes that induce distortions in EPI images. We evaluate the method of spatially varying scale on both simulated and real data. We find that, in comparison with our earlier method using fixed scale, our new method finds deformation fields that are smoother and finds them faster without sacrificing accuracy.
Nonrigid registration; spatially varying scale; distortion correction; echo planar images; regularization
Nasal embryonic LHRH factor (NELF) has been hypothesized to participate in the migration of GnRH and olfactory neurons into the forebrain, a prerequisite for normal hypothalamic-pituitary-gonadal function in puberty and reproduction. However, the biological functions of NELF, which has no homology to any human protein, remain largely elusive. Although mRNA expression did not differ, NELF protein expression was greater in migratory than postmigratory GnRH neurons. Pituitary Nelf mRNA expression was also observed and increased three-fold after exogenous GnRH administration. Contrary to a previous report, NELF displayed predominant nuclear localization in GnRH neurons, confirmed by mutagenesis of a putative nuclear localization signal resulting in impaired nuclear expression. NELF knockdown impaired GnRH neuronal migration of NLT cells in vitro. These findings and the identification of two putative zinc fingers suggest that NELF could be a transcription factor. Collectively, our findings implicate NELF as a nuclear protein involved in the developmental function of the reproductive axis.
NELF; Nasal embryonic LHRH factor; GnRH neuron migration; Kallmann syndrome; hypogonadotropic hypogonadism
The title compound, C5H8ClNO3, was prepared by the nucleophilic substitution reaction of (2S)-2-chloropropanoyl chloride with glycine. The acetate group forms a dihedral angle of 84.6 (1)° with the mean plane of the C—NH—C=O fragment. In the crystal, the molecules are linked by N—H⋯O and O—H⋯O hydrogen bonds, generating a three-dimensional network, which consolidates the crystal packing.
In the title compound, C29H26N2O4, the benzene ring is twisted by 73.5 (5) and 84.9 (3)° with respect to the mean planes of the two indole ring systems; the mean planes of the indole ring systems are oriented at a dihedral angle of 82.0 (5)°. In the crystal, molecules are linked by pairs of N—H⋯O hydrogen bonds into chains.
Lignocellulose is the most abundant biomass on earth. However, biomass recalcitrance has become a major factor affecting biofuel production. Although cellulose crystallinity significantly influences biomass saccharification, little is known about the impact of three major wall polymers on cellulose crystallization. In this study, we selected six typical pairs of Miscanthus samples that presented different cell wall compositions, and then compared their cellulose crystallinity and biomass digestibility after various chemical pretreatments.
A Miscanthus sample with a high hemicelluloses level was determined to have a relatively low cellulose crystallinity index (CrI) and enhanced biomass digestibility at similar rates after pretreatments of NaOH and H2SO4 with three concentrations. By contrast, a Miscanthus sample with a high cellulose or lignin level showed increased CrI and low biomass saccharification, particularly after H2SO4 pretreatment. Correlation analysis revealed that the cellulose CrI negatively affected biomass digestion. Increased hemicelluloses level by 25% or decreased cellulose and lignin contents by 31% and 37% were also found to result in increased hexose yields by 1.3-times to 2.2-times released from enzymatic hydrolysis after NaOH or H2SO4 pretreatments. The findings indicated that hemicelluloses were the dominant and positive factor, whereas cellulose and lignin had synergistic and negative effects on biomass digestibility.
Using six pairs of Miscanthus samples with different cell wall compositions, hemicelluloses were revealed to be the dominant factor that positively determined biomass digestibility after pretreatments with NaOH or H2SO4 by negatively affecting cellulose crystallinity. The results suggested potential approaches to the genetic modifications of bioenergy crops.
Pertussis is a reported vaccine-preventable respiratory disease in China. Because the routine laboratory methods for diagnosis are not in use, the reported cases are mainly in infants with classical paroxysmal cough and the true incidence related to pertussis is most likely under estimated. In China, however, few studies have attempted to address this issue. The purpose of this cross sectional study was to estimate the incidence rates using the method of sero-epidemiology of immunoglobulin (Ig) G antibodies against pertussis toxin (PT) among healthy populations in China.
Blood samples were obtained from 1313 healthy individuals aged 0 to 95 years in Guangdong province of China throughout September 2010. Serum IgG antibodies against PT were determined by commercial ELISA kits. Subjects with concentration of anti-PT IgG higher than 30 IU/mL were indicated to have recent Bordetella pertussis infection, if they have not received a booster dose of pertussis vaccine within one year.
Of the 1313 study subjects, 117 (8.91%) were found to have anti-PT antibodies higher than 30 IU/mL. The estimated incidence of recent infection was thus 9395 per 100,000 for individuals older than 7 years. Peaks of the estimated incidence rate of recent infection were found to be 11561 per 100,000 in age group of 41–50 years and 11428 per 100,000 in the group aged 13–19 years.
Our study indicated that B.pertussis infections are considerablely common, particularly in adolescents and adults in China. The study also stresses the importance of laboratory diagnosis for pertussis and employment of booster dose of pertussis vaccine in adolescents and adults in this country.
Pertussis; Cross-sectional study; Sero-epidemiology; Anti-PT IgG; China
The term RNA silencing (RNA interference, RNAi) describes a set of mechanisms that regulate gene expression in eukaryotes. Small interfering RNAs (siRNA) and microRNAs (miRNAs) are two major types of RNAi-associated small RNAs (smRNAs) found in most eukaryotic organisms. Despite the presence of a plethora of non-coding RNAs longer than 50-nucleotide (nt) in length in various species of Archaea, little is known about smRNAs in archaea that resemble the 20–24-nt long smRNAs found in eukaryotes, which have been implicated in the post-transcriptional control of gene expression. Here, we report the finding of a large number of smRNAs approximatelly 20-nt in length, including phased smRNAs and potential miRNAs, from the hyperthermophilic archaeon Sulfolobus solfataricus p2 (Ssp2) based on deep sequencing. The expression of some of the miRNA candidates in Ssp2 was confirmed. Consistent with the Ssp2 hyperthermophilic properties, we found that higher temperatures more efficiently induced the production of the miRNA candidates in an in vitro system using the putative foldback precursor transcripts incubated with Ssp2 extract. Although we initially predicted putative target genes of some miRNA candidates, further analysis mapped the cleavage sites downstream of the miRNA candidate complementary regions, similar to those involved in plant miRNA-mediated TAS transcript cleavage. We also identified smRNAs from clustered, regularly interspaced, short palindromic repeat (CRISPR) loci, which play important roles in prokaryotic microbial defense systems. Archaea represent a unique life form next to Bacteria and Eukarya, and our results may provide a useful resource for further in-depth study on the regulation and evolution of smRNAs in this special organism.
We have previously reported that electroacupuncture (EA) pretreatment induced tolerance against cerebral ischemic injury, but the mechanisms underlying this effect of EA are unknown. In this study, we assessed the effect of EA pretreatment on the expression of α7 nicotinic acetylcholine receptors (α7nAChR), using the ischemia-reperfusion model of focal cerebral ischemia in rats. Further, we investigated the role of high mobility group box 1 (HMGB1) in neuroprotection mediated by the α7nAChR and EA.
Rats were treated with EA at the acupoint "Baihui (GV 20)" 24 h before focal cerebral ischemia which was induced for 120 min by middle cerebral artery occlusion. Neurobehavioral scores, infarction volumes, neuronal apoptosis, and HMGB1 levels were evaluated after reperfusion. The α7nAChR agonist PHA-543613 and the antagonist α-bungarotoxin (α-BGT) were used to investigate the role of the α7nAChR in mediating neuroprotective effects. The roles of the α7nAChR and HMGB1 release in neuroprotection were further tested in neuronal cultures exposed to oxygen and glucose deprivation (OGD).
Our results showed that the expression of α7nAChR was significantly decreased after reperfusion. EA pretreatment prevented the reduction in neuronal expression of α7nAChR after reperfusion in the ischemic penumbra. Pretreatment with PHA-543613 afforded neuroprotective effects against ischemic damage. Moreover, EA pretreatment reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis and HMGB1 release following reperfusion, and the beneficial effects were attenuated by α-BGT. The HMGB1 levels in plasma and the penumbral brain tissue were correlated with the number of apoptotic neurons in the ischemic penumbra. Furthermore, OGD in cultured neurons triggered HMGB1 release into the culture medium, and this effect was efficiently suppressed by PHA-543,613. Pretreatment with α-BGT reversed the inhibitory effect of PHA-543,613 on HMGB1 release.
These data demonstrate that EA pretreatment strongly protects the brain against transient cerebral ischemic injury, and inhibits HMGB1 release through α7nAChR activation in rats. These findings suggest the novel potential for stroke interventions harnessing the anti-inflammatory effects of α7nAChR activation, through acupuncture or pharmacological strategies.
α7 nicotinic acetylcholine receptor; Cerebral ischemia; Electroacupuncture; Pretreatment; High-mobility group box 1
In the title molecule, C5H6BrN3, the pyrimidine ring is essentially planar, with an r.m.s. deviation of 0.007 Å. The Br and N atoms substituted to the pyrimidine ring are coplanar with the ring [displacements = 0.032 (1) and 0.009 (5) Å, respectively], while the methyl C atom lies 0.100 (15) Å from this plane with a dihedral angle between the pyrimidine ring and the methylamine group of 4.5 (3)°. In the crystal, C—H⋯N, C—H⋯Br and N—H⋯N hydrogen bonds link the molecules into a two-dimensional network in the (011) plane.
The pathogenesis of polycystic ovary syndrome (PCOS) is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA) of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT) harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD), testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD P<0.05). Among these two sets of genes, we identified several significant pathways, including the antiproliferative role of TOB in T cell signaling and transforming growth factor-β (TGF-β) signaling. Our results suggest PA may modify DNA methylation patterns in both infant and adult VAT. This pilot study suggests that excess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans.
Apolipoprotein M (apoM) may have potential antiatherosclerotic properties. It has been reported that apoM expression could be regulated by many intracellar and extracellar factors. In the present study we further investigated regulation of apoM expression in Caco-2 cells stimulated by a liver X receptor (LXR) agonist, TO901317.
Materials and methods
Caco-2 cells were cultured in the presence of either TO901317, farnesoid X receptor (FXR) antagonist guggulsterone or TO901317 together with guggulsterone at different concentrations for 24 hrs. The mRNA levels of ATP-binding cassette transporter A1 (ABCA1), apoA1, apoM, liver receptor homologue-1 (LRH-1) and short heterodimer partner 1 (SHP1) were determined by real-time RT-PCR.
When Caco-2 cell cultured with TO901317 alone, the mRNA levels of ABCA1, apoA1, apoM, LRH-1 and SHP1 were significantly increased with dose-dependent manners (p < 0.05), whereas when the cells cultured with guggulsterone alone, the mRNA levels of apoM, SHP1 and LRH-1 (p < 0.05) were strongly inhibited. Moreover, guggulsterone could abolish the TO901317 enhanced mRNA levels of apoA1 apoM, SHP1 and LRH-1.
The present study demonstrated that LXR agonist TO901317 induced apoM expression in Caco-2 cells might be mediated via the LXR/FXR pathway.
Liver X Receptor; Farnesoid X Receptor; Caco-2 cell line; Apolipoprotein M
To investigate effects of lipid lowering drug, simvastatin, on apolipoprotein M expression in the hyperlipidemic mice and in hepatic cell line, HepG2 cells.
Swiss male mice were randomly divided into the high fat group and control group, and were intragastrically fed with 0.9% saline (control group) or lipid emulsion (high fat group) at the daily dosage of 15 ml/kg body weight, respectively. After 8 weeks feeding, the hyperlipidemic model was successfully induced and these hyperlipidemic mice were then randomly divided into three experimental groups: vehicle control group, high-dose simvastatin-treated group (100 mg/kg body weight), and low-dose simvastatin-treated group (10 mg/kg body weight). Mice were dosed daily for 6 weeks of simvastatin before mice were sacrificed for determining serum lipid profile and apoM protein levels that was determined by using dot blotting analysis. Effects of simvastatin on apoM mRNA expression in the HepG2 cells were determined by real-time RT-PCR.
Comparing to high fat model mice without simvastatin treatment, 100 mg/kg simvastatin could significantly increase serum total cholesterol (P < 0.05). Serum apoM levels, in all mice, were significantly lower in the mice at the age of 26 weeks than the mice at 12 weeks old (P < 0.05), which indicated that serum apoM levels were significantly correlated to the mice age. It demonstrated also that treatment of simvastatin did not influence serum apoM levels in these mouse model, although serum apoM levels were increased by about 13% in the 10 mg/kg simvastatin group than in the vehicle control group without simvastatin. In HepG2 cell cultures, simvastatin could significantly decrease apoM mRNA levels with dose- and time-dependent manners. At 10 μM simvastatin treatment, apoM mRNA decreased by 52% compared to the controls.
The present study suggested that simvastatin, in vivo, had no effect on apoM levels in the hyperlipidemic mouse model. ApoM serum levels in mice were significantly correlated to the animal's age, whereas in cell cultures simvastatin does inhibit apoM expression in the HepG2 cells. The mechanism behind it is not known yet.
The percent global methylation of peripheral blood DNA was not significantly altered in 20 PCOS women compared to 20 controls. The study of specific tissues and target genomic regions will be required to further determine whether epigenetic alteration influences the development of PCOS.
Epigenetics; DNA methylation; Polycystic ovary syndrome
G protein-coupled receptors (GPCRs) activate mitogen-activated protein kinases through a number of distinct pathways in cells. Increasing evidence has suggested that endosomal signaling has an important role in receptor signal transduction. Here we investigated the involvement of endocytosis in α1A-adrenergic receptor (α1A-AR)-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Agonist-mediated endocytic traffic of α1A-AR was assessed by real-time imaging of living, stably transfected human embryonic kidney 293A cells (HEK-293A). α1A-AR was internalized dynamically in cells with agonist stimulation, and actin filaments regulated the initial trafficking of α1A-AR. α1A-AR-induced activation of ERK1/2 but not p38 MAPK was sensitive to disruption of endocytosis, as demonstrated by 4°C chilling, dynamin mutation and treatment with cytochalasin D (actin depolymerizing agent). Activation of protein kinase C (PKC) and C-Raf by α1A-AR was not affected by 4°C chilling or cytochalasin D treatment. U73122 (a phospholipase C [PLC] inhibitor) and Ro 31–8220 (a PKC inhibitor) inhibited α1B-AR- but not α1A-AR-induced ERK1/2 activation. These data suggest that the endocytic pathway is involved in α1A-AR-induced ERK1/2 activation, which is independent of Gq/PLC/PKC signaling.
There are two independent molecules in the asymmetric unit of the title compound, C13H9Cl2NO, in which the dihedral angles between the phenyl and dichlorophenyl rings have significantly different values [48.5 (3) and 65.1 (3)°]. In the crystal, the molecules are linked via intermolecular N—H⋯O hydrogen bonds into chains running parallel to the c axis.
The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc–induced neuroblastoma.
The class III histone deacetylase SIRT1 is repressed by tumor suppressor genes and exerts divergent effects on tumorigenesis depending on its down-stream targets. Small molecule SIRT1 inhibitors have shown promising anti-cancer effects both in vitro and in vivo. Here we identified SIRT1 as a gene directly up-regulated by N-Myc and identified SIRT1-mediated transcriptional repression as a novel mechanism responsible for maintaining N-Myc oncoprotein stability. Moreover, SIRT1 contributed to N-Myc–induced cell proliferation, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in N-Myc transgenic mice. Our data identify SIRT1 as an important co-factor for N-Myc oncogenesis and provide important evidence for the potential application of SIRT1 inhibitors in the prevention and therapy of N-Myc–induced neuroblastoma.