Computational Approach to Identify Enzymes That Are Potential Therapeutic Candidates for Psoriasis

Psoriasis is well known as a chronic inflammatory dermatosis. The disease affects persons of all ages and is a burden worldwide. Psoriasis is associated with various diseases such as arthritis. The disease is characterized by well-demarcated lesions on the skin of the elbows and knees. Various genetic and environmental factors are related to the pathogenesis of psoriasis. In order to identify enzymes that are potential therapeutic targets for psoriasis, we utilized a computational approach, combining microarray analysis and protein interaction prediction. We found 6,437 genes (3,264 upregulated and 3,173 downregulated) that have significant differences in expression between regions with and without lesions in psoriasis patients. We identified potential candidates through protein-protein interaction predictions made using various protein interaction resources. By analyzing the hub protein of the networks with metrics such as degree and centrality, we detected 32 potential therapeutic candidates. After filtering these candidates through the ENZYME nomenclature database, we selected 5 enzymes: DNA helicase (RUVBL2), proteasome endopeptidase complex (PSMA2), nonspecific protein-tyrosine kinase (ZAP70), I-kappa-B kinase (IKBKE), and receptor protein-tyrosine kinase (EGFR). We adopted a computational approach to detect potential therapeutic targets; this approach may become an effective strategy for the discovery of new drug targets for psoriasis

Voltage-independent SK-channel dysfunction causes neuronal hyperexcitability in the hippocampus of Fmr1 knock-out mice

Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (

The Korean urban rural elderly cohort study: study design and protocol

BACKGROUND: Korea is one of the fastest aging countries and is expected to become a super-aged society within 12 years. The Korean Urban Rural Elderly (KURE) study was developed to evaluate the epidemiological characteristics and establish the prevention and management of major disorders of the elderly in Korea. METHODS/DESIGN: The KURE study is a community-based prospective cohort study on health, aging, and common geriatric disorders of Korean elderly persons aged at least 65 years. To construct a cohort reflecting both urban and rural areas, we selected 2 representative communities in the country. To establish multidisciplinary approaches to geriatric health, this study was performed by researchers in the divisions of geriatrics, preventive medicine, endocrinology, and sociology. The baseline examinations began in 2012; the study will follow more than 4,000 elderly Koreans over 10 years. The first and second follow-up health examinations will be performed every 4 years. Every 2 years after each health examination, inter-assessment interview will be conducted to improve participant retention. DISCUSSION: The KURE study will provide longitudinal epidemiologic data on health, aging, and common geriatric disorders of the elderly in Korea. This is a comprehensive, multidisciplinary study of the elderly with respect to biological, physical, socio-economic, and environmental factors. The results of this study will contribute to improve public health and welfare policies for the aging society in Korea

Anti-obesity effects of Yerba Mate (Ilex Paraguariensis): a randomized, double-blind, placebo-controlled clinical trial

Dietary assessment parameters of the Yerba Mate and placebo groups measured at 0, 6 and 12 weeks. (DOC 37.5 kb

Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT

Telomere homeostasis is regulated by telomerase and a collection of associatedproteins. Telomerase is, in turn, regulated by post-translational modifications of the rate-limiting catalytic subunit hTERT. Here we show that disruption of Hsp90 by geldanamycin promotes efficient ubiquitination and proteasome-mediated degradation of hTERT. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length. Our data suggest that MKRN1 plays an important role in modulating telomere length homeostasis through a dynamic balance involving hTERT protein stability

Chfr is linked to tumour metastasis through the downregulation of HDAC1

Chfr is a ubiquitin ligase that functions in the mitotic checkpoint by delaying entry into metaphase in response to mitotic stress. It has been suggested that Chfr is a tumour suppressor as Chfr is frequently silenced in human cancers. To better understand how Chfr activity relates to cell-cycle progression and tumorigenesis, we sought to identify Chfr-interacting proteins using affinity purification combined with mass spectrometry. Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Ectopic expression of Chfr in cancer cells that normally do not express it results in downregulation of HDAC1, leading to upregulation of the Cdk inhibitor p21^(CIP1/WAF1) and the metastasis suppressors KAI1 and E-cadherin. Coincident with these changes, cells arrest in the G1 phase of the cell cycle and become less invasive. Collectively, our data suggest that Chfr functions as a tumour suppressor by regulating HDAC1

Voiding Dysfunction after Total Mesorectal Excision in Rectal Cancer

Purpose The aim of this study was to assess the voiding dysfunction after rectal cancer surgery with total mesorectal excision (TME). Methods This was part of a prospective study done in the rectal cancer patients who underwent surgery with TME between November 2006 and June 2008. Consecutive uroflowmetry, post-voided residual volume, and a voiding questionnaire were performed at preoperatively and postoperatively. Results A total of 50 patients were recruited in this study, including 28 male and 22 female. In the comparison of the preoperative data with the postoperative 3-month data, a significant decrease in mean maximal flow rate, voided volume, and post-voided residual volume were found. In the comparison with the postoperative 6-month data, however only the maximal flow rate was decreased with statistical significance (P=0.02). In the comparison between surgical methods, abdominoperineal resection patients showed delayed recovery of maximal flow rate, voided volume, and post-voided residual volume. There was no significant difference in uroflowmetry parameters with advances in rectal cancer stage. Conclusions Voiding dysfunction is common after rectal cancer surgery but can be recovered in 6 months after surgery or earlier. Abdominoperineal resection was shown to be an unfavorable factor for postoperative voiding. Larger prospective study is needed to determine the long-term effect of rectal cancer surgery in relation to male and female baseline voiding condition

Interleukin-2 induces the in vitro maturation of human pluripotent stem cell-derived intestinal organoids.

Human pluripotent stem cell (hPSC)-derived intestinal organoids (hIOs) form 3D structures organized into crypt and villus domains, making them an excellent in vitro model system for studying human intestinal development and disease. However, hPSC-derived hIOs still require in vivo maturation to fully recapitulate adult intestine, with the mechanism of maturation remaining elusive. Here, we show that the co-culture with human T lymphocytes induce the in vitro maturation of hIOs, and identify STAT3-activating interleukin-2 (IL-2) as the major factor inducing maturation. hIOs exposed to IL-2 closely mimic the adult intestinal epithelium and have comparable expression levels of mature intestinal markers, as well as increased intestine-specific functional activities. Even after in vivo engraftment, in vitro-matured hIOs retain their maturation status. The results of our study demonstrate that STAT3 signaling can induce the maturation of hIOs in vitro, thereby circumventing the need for animal models and in vivo maturation

Mesenchymal Stem Cell-Extracellular Vesicle Therapy for Stroke: Scalable Production and Imaging Biomarker Studies

A major clinical hurdle to translate MSC-derived extracellular vesicles (EVs) is the lack of a method to scale-up the production of EVs with customized therapeutic properties. In this study, we tested whether EV production by a scalable 3D-bioprocessing method is feasible and improves neuroplasticity in animal models of stroke using MRI study. MSCs were cultured in a 3D-spheroid using a micro-patterned well. The EVs were isolated with filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, and small RNA sequencing. Compared to conventional 2D culture, the production-reproduction of EVs (the number/size of particles and EV purity) obtained from 3D platform were more consistent among different lots from the same donor and among different donors. Several microRNAs with molecular functions associated with neurogenesis were upregulated in EVs obtained from 3D platform. EVs induced both neurogenesis and neuritogenesis via microRNAs (especially, miR-27a-3p and miR-132-3p)-mediated actions. EV therapy improved functional recovery on behavioral tests and reduced infarct volume on MRI in stroke models. The dose of MSC-EVs of 1/30 cell dose had similar therapeutic effects. In addition, the EV group had better anatomical and functional connectivity on diffusion tensor imaging and resting-state functional MRI in a mouse stroke model. This study shows that clinical-scale MSC-EV therapeutics are feasible, cost-effective, and improve functional recovery following experimental stroke, with a likely contribution from enhanced neurogenesis and neuroplasticity