SUMO-Specific Protease 2 (SENP2) Is an Important Regulator of Fatty Acid Metabolism in Skeletal Muscle

Small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) that reverse protein modification by SUMO are involved in the control of numerous cellular processes, including transcription, cell division, and cancer development. However, the physiological function of SENPs in energy metabolism remains unclear. Here, we investigated the role of SENP2 in fatty acid metabolism in C2C12 myotubes and in vivo. In C2C12 myotubes, treatment with saturated fatty acids, like palmitate, led to nuclear factor-B-mediated increase in the expression of SENP2. This increase promoted the recruitment of peroxisome proliferator-activated receptor (PPAR) and PPAR, through desumoylation of PPARs, to the promoters of the genes involved in fatty acid oxidation (FAO), such as carnitine-palmitoyl transferase-1 (CPT1b) and long-chain acyl-CoA synthetase 1 (ACSL1). In addition, SENP2 overexpression substantially increased FAO in C2C12 myotubes. Consistent with the cell culture system, muscle-specific SENP2 overexpression led to a marked increase in the mRNA levels of CPT1b and ACSL1 and thereby in FAO in the skeletal muscle, which ultimately alleviated high-fat diet-induced obesity and insulin resistance. Collectively, these data identify SENP2 as an important regulator of fatty acid metabolism in skeletal muscle and further implicate that muscle SENP2 could be a novel therapeutic target for the treatment of obesity-linked metabolic disorders.11116Ysciescopu

STK295900, a Dual Inhibitor of Topoisomerase 1 and 2, Induces G<inf>2</inf> Arrest in the Absence of DNA Damage

STK295900, a small synthetic molecule belonging to a class of symmetric bibenzimidazoles, exhibits antiproliferative activity against various human cancer cell lines from different origins. Examining the effect of STK295900 in HeLa cells indicates that it induces G2 phase arrest without invoking DNA damage. Further analysis shows that STK295900 inhibits DNA relaxation that is mediated by topoisomerase 1 (Top 1) and topoisomerase 2 (Top 2) in vitro. In addition, STK295900 also exhibits protective effect against DNA damage induced by camptothecin. However, STK295900 does not affect etoposide-induced DNA damage. Moreover, STK295900 preferentially exerts cytotoxic effect on cancer cell lines while camptothecin, etoposide, and Hoechst 33342 affected both cancer and normal cells. Therefore, STK295900 has a potential to be developed as an anticancer chemotherapeutic agent. © 2013 Kim et al

Trends of Mammography Use in a National Breast Cancer Screening Program, 2004-2008

Purpose: Korea started breast cancer screening as part of the National Cancer Screening Program (NCSP) in 1999. In order to identify under-served groups, we investigated mammography uptake in the National Breast Cancer Screening Program. Materials and Methods: The study population was participants in the National Breast Cancer Screening Program from 2004 to 2008. We analyzed participation rates by insurance type, age group, and area of residence. Results: Total participation rates for breast cancer screening increased from 18.2% in 2004 to 35.0% in 2008. The participation rate in the group aged 60 to 69 years showed the greatest increase, 21.3%, among the four age groups. Although the screening rate increased continuously, the participation rate of the Medical Aid Program (MAP) group was low compared to the National Health Insurance (NHI) group. Moreover, the increasing trend of mammography uptake in the MAP group was much lower than that of the NHI group. Conclusion: The participation rate for breast cancer screening in the NCSP in Korea has increased. However, the participation rate in mammography among MAP recipients is still lower than that of NHI beneficiaries. To increase mammography uptake, it is important to make it available to everyone by ensuring inclusion of all population subgroups.ope

Identifying the structure of Zn-N-2 active sites and structural activation

Identification of active sites is one of the main obstacles to rational design of catalysts for diverse applications. Fundamental insight into the identification of the structure of active sites and structural contributions for catalytic performance are still lacking. Recently, X-ray absorption spectroscopy (XAS) and density functional theory (DFT) provide important tools to disclose the electronic, geometric and catalytic natures of active sites. Herein, we demonstrate the structural identification of Zn-N-2 active sites with both experimental/theoretical X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectra. Further DFT calculations reveal that the oxygen species activation on Zn-N-2 active sites is significantly enhanced, which can accelerate the reduction of oxygen with high selectivity, according well with the experimental results. This work highlights the identification and investigation of Zn-N-2 active sites, providing a regular principle to obtain deep insight into the nature of catalysts for various catalytic applications

The Effects of Dietary Mobile Apps on Nutritional Outcomes in Adults with Chronic Diseases : A Systematic Review and Meta-Analysis

Abstract Background Dietary interventions are effective prevention and treatment strategies for chronic diseases; however, they require extensive commitment, time, and resources. Dietary mobile applications (apps) have gained popularity and are thus being incorporated into dietary management. Objective The aim of this review is to assess the effects of the use of dietary mobile apps on nutritional outcomes in adults with chronic diseases. Methods A systematic review was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using MEDLINE, PubMed, Embase, and CINAHL databases. The protocol was registered on PROSPERO. Intervention studies evaluating the nutritional outcomes of dietary apps, published in English between January 1, 2007 and November 15, 2017 were included. The methodological quality of included articles was assessed via the Academy of Nutrition and Dietetics\u27 Quality Criteria Checklist: Primary Research. Heterogeneity was confirmed using the I2 index and a random-effects meta-analysis was performed for randomized controlled trials. Estimates of the pooled mean difference were calculated for app usage compared to no app usage. Main outcomes measure Nutritional outcomes, categorized as food-/nutrition-related, anthropometric measurements, pertinent clinical/biochemical data, and nutrition-focused physical findings, were extracted from the included intervention studies. Results Upon completion of the searches, 18,649 articles were identified, and data were extracted from 22 articles. Pooled estimates showed a significantly greater decrease in weight ( “2.45 kg, 95% CI “3.33 to “1.58 kg; P Conclusions The findings of this systematic review and meta-analysis indicate that dietary mobile apps are effective self-monitoring tools, and that their use results in positive effects on measured nutritional outcomes in chronic diseases, especially weight loss

Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA

Correlations between charged particles in deep inelastic ep scattering have been studied in the Breit frame with the ZEUS detector at HERA using an integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in terms of the angular separation between current-region particles within a cone centred around the virtual photon axis. Long-range correlations between the current and target regions have also been measured. The data support predictions for the scaling behaviour of the angular correlations at high Q2 and for anti-correlations between the current and target regions over a large range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations and Monte Carlo models correctly describe the trends of the data at high Q2, but show quantitative discrepancies. The data show differences between the correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C

The Necrotic Signal Induced by Mycophenolic Acid Overcomes Apoptosis-Resistance in Tumor Cells

The amount of inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP), is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA) are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42.Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA–mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL–overexpressing cells). All tested cells remained sensitive to MPA–mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers.These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells

Pulmonary Arterial Hypertension Affects the Rat Gut Microbiome

We have analysed whether pulmonary arterial hypertension (PAH) alters the rat faecal microbiota. Wistar rats were injected with the VEGF receptor antagonist SU5416 (20 mg/kg s.c.) and followed for 2 weeks kept in hypoxia (10% O2, PAH) or injected with vehicle and kept in normoxia (controls). Faecal samples were obtained and microbiome composition was determined by 16S rRNA gene sequencing and bioinformatic analysis. No effect of PAH on the global microbiome was found (α- or β-diversity). However, PAH-exposed rats showed gut dysbiosis as indicated by a taxonomy-based analysis. Specifically, PAH rats had a three-fold increase in Firmicutes-to-Bacteroidetes ratio. Within the Firmicutes phylum, there were no large changes in the relative abundance of the bacterial families in PAH. Among Bacteroidetes, all families were less abundant in PAH. A clear separation was observed between the control and PAH clusters based on short chain fatty acid producing bacterial genera. Moreover, acetate was reduced in the serum of PAH rats. In conclusion, faecal microbiota composition is altered as a result of PAH. This misbalanced bacterial ecosystem might in turn play a pathophysiological role in PAH by altering the immunologic, hormonal and metabolic homeostasis.This study is supported by grants from Mineco (SAF2014-55399-R, SAF2014-55523-R, SAF2016-77222 and SAF2017-84494-C2-1R), Instituto de Salud Carlos III (PI15/01100), with funds from the European Union (Fondo Europeo de Desarrollo Regional FEDER). M.C., G.M-P. and S.E-R. are funded by Universidad Complutense, Fondo de Garantía Juvenil (Comunidad de Madrid) and Ciberes grant with funds from Fundación Contra la Hipertensión Pulmonar, a FPU grant from Ministerio de Educación, respectively. J.L.I.G is a CNIC IPP COFUND Fellow and has received funding from the People Programme (Marie Curie Actions) of the FP7/2007-2013 under REA grant agreement n° 600396. The CNIC is supported by MEIC-AEI and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505)

Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus

A major barrier to research on Parkinson's disease is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells from patients and differentiate them into neurons affected by disease. Triplication of SNCA, encoding α-synuclein, causes a fully penetrant, aggressive form of Parkinson's disease with dementia. α-Synuclein dysfunction is the critical pathogenic event in Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. Here we produce multiple induced pluripotent stem cell lines from an SNCA triplication patient and an unaffected first-degree relative. When these cells are differentiated into midbrain dopaminergic neurons, those from the patient produce double the amount of α-synuclein protein as neurons from the unaffected relative, precisely recapitulating the cause of Parkinson's disease in these individuals. This model represents a new experimental system to identify compounds that reduce levels of α-synuclein, and to investigate the mechanistic basis of neurodegeneration caused by α-synuclein dysfunction

hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas

The c-Met receptor tyrosine kinase (MetR) is frequently overexpressed and constitutively phosphorylated in a number of human malignancies. Activation of the receptor by its ligand, hepatocyte growth factor (HGF), leads to increased cell proliferation, motility, survival and disruption of adherens junctions. In this study, we show that hTid-1, a DNAJ/Hsp40 chaperone, represents a novel modulator of the MetR signaling pathway. hTid-1 is a co-chaperone of the Hsp70 family of proteins, and has been shown to regulate a number of cellular signaling proteins including several involved in tumorigenic and apoptotic pathways. In this study we demonstrate that hTid-1 binds to unphosphorylated MetR and becomes dissociated from the receptor upon HGF stimulation. Overexpression of the short form of hTid-1 (hTid-1S) in 786-0 renal clear cell carcinomas (RCCs) enhances MetR kinase activity leading to an increase in HGF-mediated cell migration with no discernible effect on cell proliferation. By contrast, knockdown of hTid-1 markedly impairs both the onset and amplitude of MetR phosphorylation in response to HGF without altering receptor protein levels. hTid-1-depleted cells display defective migratory properties, coincident with inhibition of ERK/MAP kinase and STAT3 pathways. Taken together, our findings denote hTid-1S as an essential regulatory component of MetR signaling. We propose that the binding of hTid-1S to MetR may stabilize the receptor in a ligand-competent state and this stabilizing function may influence conformational changes that take place during the catalytic cycle that promote kinase activation. Given the prevalence of HGF/MetR pathway activation in human cancers, targeted inhibition of hTid-1 may be a useful therapeutic in the management of MetR-dependent malignancies