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Engraftment and homing of mesenchymal stem cells (MSCs) are modulated by priming factors including the bioactive lipid sphingosine-1-phosphate (S1P), by stimulating CXCR4 receptor signaling cascades. However, limited in vivo efficacy and the remaining priming molecules prior to administration of MSCs can provoke concerns regarding the efficiency and safety of MSC priming. Here, we showed that valproic acid (VPA), a histone deacetylase inhibitor, enforced the priming effect of S1P at a low dosage for human umbilical cord-derived MSCs (UC-MSCs). A DNA-methylation inhibitor, 5-azacytidine (5-Aza), and VPA increased the expression of CXCR4 in UC-MSCs. In particular, UC-MSCs primed with a suboptimal dose (50 nM) of S1P in combination with 0.5 mM VPA (VPA+S1P priming), but not 1 µM 5-Aza, significantly improved the migration activity in response to stromal cell-derived factor 1 (SDF-1) concomitant with the activation of both MAPKp42/44 and AKT signaling cascades. Both epigenetic regulatory compounds had little influence on cell surface marker phenotypes and the multi-potency of UC-MSCs. In contrast, VPA+S1P priming of UC-MSCs potentiated the proliferation, colony forming unit-fibroblast, and anti-inflammatory activities, which were severely inhibited in the case of 5-Aza treatment. Accordingly, the VPA+S1P-primed UC-MSCs exhibited upregulation of a subset of genes related to stem cell migration and anti-inflammation response. Thus, the present study demonstrated that VPA enables MSC priming with S1P at a low dosage by enhancing their migration and other therapeutic beneficial activities. This priming strategy for MSCs may provide a more efficient and safe application of MSCs for treating a variety of intractable disorders.

Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency‐associated transcription factor, orchestrated pluripotency and cell‐cycling in embryonic stem cells (ESCs) and was aberrantly activated in aggressive bladder cancers (BCs). In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell cycle regulation. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell cycle progression, pluripotency, and differentiation. The CDK1‐TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self‐renewal, and invasion. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. In patients with BC, high co‐expression of TFCP2L1 and CDK1 was associated with unfavorable clinical characteristics including tumor grade, lymphovascular and muscularis propria invasion, and distant metastasis and was an independent prognostic factor for cancer‐specific survival. These findings demonstrate the molecular and clinical significance of CDK1‐mediated TFCP2L1 phosphorylation in stem cell pluripotency and in the tumorigenic stemness features associated with BC progression., Aberrant activation of pluripotency genes is frequently observed in tumors. Thr177‐phosphorylation of TFCP2L1 by CDK1 stimulates pluripotency and cell cycling in embryonic stem cells and stemness features of bladder cancers, potentiating the tumorigenesis and aggressive behavior of bladder cancer.

Aims: The naive or primitive states of stem cells (SCs) residing in specific niches are unstable and difficult to preserve in vitro. Vitamin C (VitC), in addition to suppressing oxygen radicals, ex...

This study investigated the awareness, treatment, and control of type 2 diabetes mellitus (T2DM), lifestyle factors, and cardiometabolic parameters according to age groups among patients with T2DM. Data of 1507 patients with T2DM aged &ge, 35 years in the Korea National Health and Nutrition Examination Survey VI (2013&ndash, 2015) were analyzed. Multivariable logistic regression models were used to compare the awareness, treatment, and control rate of T2DM and lifestyle and cardiometabolic parameters according to age groups. The adjusted odds ratios (ORs) for lack of awareness about and non-treatment of T2DM, as well as poor glycemic control, were significantly increased with younger age in both men and women. ORs for heavy drinkers and current smokers also significantly increased with younger age in both men and women. The adjusted ORs for high low-density lipoprotein cholesterol (&ge, 100 mg/dL), hypertriglyceridemia (&ge, 150 mg/dL), and obesity significantly increased with younger age in men, but not in women. Among Korean adults with T2DM, awareness, treatment, and control rates of the condition were poorer in younger patients than in older patients. Education regarding the control of glycemia, cardiovascular risk factors, and improvement of lifestyles should be reinforced among younger-aged adults for the long-term management of T2DM.

Therapeutic options for non-Hunner type interstitial cystitis (IC), which is histologically characterized by fibrosis and mast cell infiltration, are limited. We developed a rat model that replicates chronic inflammation and fibrosis and evaluated the therapeutic effect of N-acetylcysteine (NAC), a well-known anti-fibrotic agent, on the model. Intravesical instillation of lipopolysaccharide (LPS, 750 μg) after protamine sulfate (10 mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200 mg/kg NAC (n = 10, IC + NAC group) or phosphate-buffered saline (n = 10, IC group) was daily injected intraperitoneally once daily for 5 days. LPS instillation induced bladder fibrosis, mast cell infiltration, and apoptotic tissue damage. Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2, Tgfb3, Smad2, Smad3, Cxcl10, and Card10. This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries, in the LPS-induced cystitis rat model.

Herein we review the management status of governmental financial support of bariatric surgeries in several Asia-Pacific areas of Japan, Singapore, and Australia, which were discussed in the 2016 International Congress on Obesity and Metabolic Syndrome (ICOMES). Patient's body mass index criteria of bariatric surgery for public support are different one another in the three countries. Whereas laparoscopic sleeve gastrectomy (LSG), Roux-en Y gastric bypass (RYGB), and laparoscopic adjustable gastric banding (LAGB) are applicable in both Singapore and Australia, the coverage of insurance is limited to LSG in Japan. In addition, the surgical fees and equipment costs are not fully covered by public health insurance for performing sleeve gastrectomy in Japan, but patients with morbid obesity can still use public health insurance. In Singapore, the waiting time for surgery in public hospitals is longer on average than for private hospitals. However, patients can obtain subsidies of up to 80% of the costs of surgery in public hospitals, while particularly needy patients may even be able to obtain completely free bariatric surgery through Medifund. In Australia, bariatric surgeries in public sectors are publicly funded, but most bariatric surgeries occur in the private sector and Medicare only reimburses surgical costs in the private sector. Although certain characteristics need to be improved, the access to bariatric surgery has shown steady progress through public support in each of these countries.

Airway exposure of lipopolysaccharide (LPS) is shown to regulate type I and type II helper T cell induced asthma. While high doses of LPS derive Th1- or Th17-immune responses, low LPS levels lead to Th2 responses. In this paper, we analyze a mathematical model of Th1/Th2/Th17 asthma regulation suggested by Lee ( S. Lee, H.J. Hwang, and Y. Kim, Modeling the role of TGF-$\beta$ in regulation of the Th17 phenotype in the LPS-driven immune system, Bull Math Biol., 76 (5), 1045-1080, 2014 ) and show that the system can undergo a Hopf bifurcation at a steady state of the Th17 phenotype for high LPS levels in the presence of time delays in inhibition pathways of two key regulators: IL-4/Th2 activities ($H$) and TGF-$\beta$ levels ($G$). The time delays affect the phenotypic switches among the Th1, Th2, and Th17 phenotypes in response to time-dependent LPS doses via nonlinear crosstalk between $H$ and $G$. An extended reaction-diffusion model also predicts coexistence of these phenotypes under various biochemical and bio-mechanical conditions in the heterogeneous microenvironment.

Chronic kidney disease (CKD) is characterized by a progressive loss of kidney function over a period of months or years. It is estimated that about 7.2 % of adults over the age of 30 have CKD worldwide. Although one of the major risk factors of CKD is family history, the heritability of CKD is not fully understood. It is also known that the diabetic condition is highly influential on the onset of CKD. To understand the genetic bases of CKD that remain unidentified, we performed genetic association analyses for kidney function-related traits such as blood urea nitrogen (BUN) and albumin in subjects stratified by diabetic status. In the discovery stage of the study, we used genome-wide scan data and clinical data in about 8800 subjects from the Korean Association Resource (KARE) project. Health2 study data comprising about 1800 subjects were used for the replication stage. Our two stage association analyses demonstrated that the LOC105374266 locus (rs9820070) showed strong evidence of association with BUN (P = 8.47 × 10−14) in nondiabetic normal subjects (n = ~4300). To extend our knowledge of the genetic determinants influencing kidney function, we also analyzed the association between kidney function-related traits and microRNA related variants. For this analysis, miRNA related SNPs were selected from KARE and Health2 cohort genotype data. Our study suggests the potential relevance of miRNA to the kidney function (miR-518b for BUN; miR-146a and miR-1295a for albumin) in Korean populations.

Some molecules enriched in damaged organs can contribute to tissue repair by stimulating the mobilization of stem cells. These so-called "priming" factors include bioactive lipids, complement components, and cationic peptides. However, their therapeutic significance remains to be determined. Here, we show that priming of mesenchymal stromal/stem cells (MSCs) with ceramide-1 phosphate (C1P), a bioactive lipid, enhances their therapeutic efficacy in pulmonary artery hypertension (PAH). Human bone marrow (BM)-derived MSCs treated with 100 or 200 μM C1P showed improved migration activity in Transwell assays compared with non-primed MSCs and concomitantly activated MAPK(p42/44) and AKT signaling cascades. Although C1P priming had little effect on cell surface marker phenotypes and the multipotency of MSCs, it potentiated their proliferative, colony-forming unit-fibroblast, and anti-inflammatory activities. In a monocrotaline-induced PAH animal model, a single administration of human MSCs primed with C1P significantly attenuated the PAH-related increase in right ventricular systolic pressure, right ventricular hypertrophy, and thickness of α-smooth muscle actin-positive cells around the vessel wall. Thus, this study shows that C1P priming increases the effects of MSC therapy by enhancing the migratory, self-renewal, and anti-inflammatory activity of MSCs and that MSC therapy optimized with priming protocols might be a promising option for the treatment of PAH patients.

This study investigated depot-specific mRNA expression of uncoupling protein 1 (UCP1) in human white adipose tissue (WAT) and its association with obesity-related markers. We recruited 39 normal-weight, 41 nondiabetic obese, and 22 diabetic obese women. We measured UCP1 mRNA expression in abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and investigated the associations between UCP1 mRNA expression in VAT and SAT, and obesity-related markers including mRNA expression of leptin, adiponectin, CCAAT-enhancer-binding protein homologous protein (CHOP), and positive regulatory domain-containing protein 16 (PRDM16). We also evaluated UCP1 mRNA expression in differentiated human white adipocytes after treatment with various stressors and metabolic improvement agents in vitro. UCP1 mRNA in VAT was significantly higher than in SAT in all groups. UCP1 mRNA in SAT was negatively correlated with BMI, total abdominal fat area, visceral fat area, blood pressure, fasting glucose, insulin, HOMA-IR score, triglyceride, hsCRP, fasting leptin levels, and adipocyte size. UCP1 mRNA in SAT was positively correlated with fasting adiponectin levels. UCP1 mRNA in VAT was negatively correlated with visceral-to-subcutaneous fat ratio (VSR), fasting glucose, and triglyceride levels. In SAT, UCP1 mRNA was negatively correlated with mRNA expression of leptin and CHOP, and positively correlated with mRNA expression of adiponectin. The expression of PRDM16 was positively correlated with UCP1 mRNA in both VAT and SAT. UCP1 mRNA expression in differentiated human white adipocytes was significantly reduced after incubation with thapsigargin, tunicamycin, homocysteine, TNF-α, or IL-β, and significantly increased after incubation with exendin 4, dapagliflozin, and telmisartan. This study demonstrated depot-specific mRNA expression of UCP1 and its association with obesity-related markers in human WAT. UCP1 mRNA in human white adipocytes was suppressed by inflammatory agents and enhanced by metabolic improvement agents. UCP1 in human WAT might participate in the pathogenesis of obesity-related metabolic diseases.

Background Considering the obesity-related complications in pregnancy and during delivery, prepregnancy central obesity may also affect pregnancy-related complications. This study aimed to assess the relationship between prepregnancy central obesity and adverse maternal outcomes in Korean women, by using the Korean National Health Insurance Service (NHIS) cohort. Methods In this population-based retrospective cohort study, we used data from the NHIS database, which contains information of health-care utilisation, diagnosis and prescription, and mortality for almost the whole Korean population, together with data from the NHIS health checkup database from 2005 to 2015. The NHIS health checkup data (645−280 days before childbirth) of mothers who had deliveries (total, 783,406 deliveries) from 2006 to 2015 were collected. For maternal adverse outcome data, we searched for diagnoses of maternal complications made during the period of 280 days before each delivery. The odds for maternal complications according to 8 body mass index (BMI) and 10 waist circumference (WC) categories were analysed using logistic regression. Results The incidence rates of eclampsia/preeclampsia, caesarean section, multiple gestation, and polycystic ovary syndrome (PCOS) increased according to the increase of BMI and WC. In contrast, the incidence rate of premature rupture of membrane (PROM) was inversely correlated with BMI and WC. In the low BMI ( Conclusion Prepregnancy WC was closely linked to some maternal complications, including eclampsia/preeclampsia, cesarean section, PCOS, and PROM, in a manner similar to prepregnancy BMI.

This empirical study shows how people use their smartphones by employing the rational addiction model of Becker and Murphy. The analysis uses micro-level panel data on the monthly usage of smartphone applications (so-called “apps”) derived from 10,337 users in South Korea, from 2012 to 2016. The authors find that smartphone users are “addicted” to mobile phone apps, in the sense that their prior usage has significantly influenced their current use. Nonetheless, people in the sample seem to use their smartphones in a forward-looking manner, adjusting consumption over time to maximize their utility. On the other hand, the study's result rejects the conventional belief that younger individuals behave more myopically than older ones. Furthermore, only the mother's smartphone use was found to generate a positive externality for her children.

This article investigates how adolescent Internet addiction is assessed by parents based on children's Internet use time and parental demographic characteristics. The authors measured children's level of Internet addiction based on Young's scale evaluated by their parents to mitigate the social desirability bias in self-reported surveys when children evaluate themselves. Based on Korean General Social Survey data, which is nationally representative in South Korea, they analyzed 219 individuals and found that as the time of Internet use of children increased, the level of Internet addiction evaluated by parents increased. In addition, this relationship was moderated by parental demographic characteristics such that higher age, lower educational attainment, and higher Internet use time tend to decrease the parental evaluation of their children's Internet addiction. Results suggest that policies and programs related to children's Internet addiction should be focused more on parents from specific demographic groups.

Ubiquinol cytochrome c reductase binding protein (UQCRB) is known to play crucial roles in the development of various types of diseases. However, the link between UQCRB and microRNAs remains unknown. In the present study, we performed microRNA sequencing of mutant UQCRB-expressing stable cell lines that exhibited pro-oncogenic activities caused by expression of the mutant UQCRB gene. Results showed that hsa-miR-10a-5p was significantly downregulated in the mutant UQCRB-expressing cell lines. Furthermore, mRNA sequencing and gene ontology analysis of differentially expressed genes (DEGs) revealed that the cholesterol biosynthesis pathway might be activation by mutant UQCRB expression. Moreover, inhibition of cholesterol synthesis in mutant UQCRB-expressing cells via treatment with the specific inhibitors suppressed the cell proliferation. Transfection with a hsa-miR-10a-5p mimic validated that lanosterol synthase (LSS) is a target of hsa-miR-10a-5p. In addition, hsa-miR-10a-5p was found to be downregulated in liver cancer cell lines overexpressing UQCRB. Taken together, our findings highlighted the potential use of hsa-miR-10a-5p as a biomarker for UQCRB related diseases.

This study assessed the functional role of WNT genes and the association between WNT signalling cascades and fibrosis in interstitial cystitis/bladder pain syndrome (IC/BPS) patients. Twenty-five patients (3 males, 22 females; mean age 59.7 ± 10.9 years), included 7 non-Hunner-type IC (NHIC), 18 Hunner-type IC (HIC), and 5 non-IC (control) groups. The expression of sonic hedgehog, WNT gene family, and genes previously reported as biomarkers for IC/BPS were examined using RT-PCR in biopsy specimens from the mucosa and submucosa layer of the bladder. WNT2B, WNT5A, WNT10A, and WNT11 functions in the urothelium were evaluated by silencing in an HBlEpC cell line. Pelvic Pain and Urgency/Frequency Patient Symptom Scale scores, O’Leary-Sant Symptom and Problem Index scores, and Visual Analogue Scores did not differ between the NHIC and HIC groups. However, HIC patients had significantly shorter symptom duration (30.9 vs 70.8 months, p = 0.046), higher daily urinary frequency (16.1 versus 8.5 times, p = 0.006), and smaller bladder capacity (208.6 versus 361.4 ml, p = 0.006) than NHIC patients. Overall WNT gene expression was lower in NHIC than HIC patients. Bladder epithelial tissues from HIC patients were characterised by the downregulation of WNT11. Silencing of WNT11, WNT2B, WNT5A, and WNT10A in HBlEpCs resulted in fibrotic changes, indicated by fibrotic morphology, increased fibrosis-related gene expression, and nuclear localisation of phosphorylated SMAD2, and increased vimentin and fibronectin levels. Downregulation of WNT11 results in fibrotic changes of bladder epithelial cells and is associated with the pathogenesis and differential diagnosis of NHIC. Decreased expression of WNT11 is a potential biomarker for predicting NHIC.

자격증이 남발되면서 정확한 정보가 국민에게 제공되지 못하여 혼동 을 주고 있다. 또한 잘못된 정보와 치료방법으로 인한 소비자의 불만 또한 늘어나고 있다. 이는 비만에 대한 제대로 된 교육 프로그램이 부 재한 상황에서 공인되지 않고, 근거가 약한 정보가 소비자에게 제공 되어 발생한 상황이다. 국외에서는 이러한 상황에 대처하고자, 의사 를 포함한 의료나 건강 관련 전문과정에서 6개월 이상의 비만관리 경 험이 있는 사람들을 대상으로 Specialist Certification of Obesity Professional Education (SCOPE)을 International association for the study of obesity (IASO)에서 관장하여 시행하고 있으며, 국내에서는 대한비만학회에서 2012년부터 SCOPE와 같은 국외 프로그램을 참고

Aims: Cellular senescence and its secretory phenotype (senescence-associated secretory phenotype [SASP]) develop after long-term expansion of mesenchymal stromal cells (MSCs). Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC-based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood-derived MSCs (UCB-MSCs). Results: We found that monocyte chemoattractant protein-1 (MCP-1) was secreted as a dominant component of the SASP during expansion of UCB-MSCs and reinforced senescence via its cognate receptor chemokine (c-c motif) receptor 2 (CCR2) by activating the ROS-p38-MAPK-p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCB-MSCs. Accordingly, knockdown of CCR2 in UCB-MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP-1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB-MSC senescence altered the epigenetic status of MCP-1, including the loss of H2AK119Ub, and resulted in derepression of MCP-1. Innovation: Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB-MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype. Conclusion: Senescence of UCB-MSCs is orchestrated by MCP-1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1. Antioxid. Redox Signal. 24, 471–485.

Spermatogonial stem cells (SSCs), which are unipotent stem cells in the testes that give rise to sperm, can be converted into germline-derived pluripotent stem (gPS) by self-induction. The androgenetic imprinting pattern of SSCs is maintained even after their reprogramming into gPS cells. In this study, we used an in vitro neural differentiation model to investigate whether the imprinting patterns are maintained or altered during differentiation. The androgenetic patterns of H19, Snrpn, and Mest were maintained even after differentiation of gPS cells into NSCs (gPS-NSCs), whereas the fully unmethylated status of Ndn in SSCs was altered to somatic patterns in gPS cells and gPS-NSCs. Thus, our study demonstrates epigenetic alteration of genomic imprinting during the induction of pluripotency in SSCs and neural differentiation, suggesting that gPS-NSCs can be a useful model to study the roles of imprinted genes in brain development and human neurodevelopmental disorders.

Stem cell (SC) therapy has become a potential treatment modality for pulmonary artery hypertension (PAH), but the efficacy of human SC and priming effects have not yet been established. The mobilization and homing of hematopoietic stem cells (HSCs) are modulated by priming factors that include a bioactive lipid, sphingosine-1-phosphate (S1P), which stimulates CXCR4 receptor kinase signaling. Here, we show that priming human mesenchymal stem cells (MSCs) with S1P enhances their therapeutic efficacy in PAH. Human MSCs, similar to HSCs, showed stronger chemoattraction to S1P in transwell assays. Concomitantly, MSCs treated with 0.2 μM S1P showed increased phosphorylation of both MAPKp42/44 and AKT protein compared with nonprimed MSCs. Furthermore, S1P-primed MSCs potentiated colony forming unit-fibroblast, anti-inflammatory, and angiogenic activities of MSCs in culture. In a PAH animal model induced by subcutaneously injected monocrotaline, administration of human cord blood-derived MSCs (hCB-MSCs) or S1P-primed cells significantly attenuated the elevated right ventricular systolic pressure. Notably, S1P-primed CB-MSCs, but not unprimed hCB-MSCs, also elicited a significant reduction in the right ventricular weight ratio and pulmonary vascular wall thickness. S1P-primed MSCs enhanced the expression of several genes responsible for stem cell trafficking and angiogenesis, increasing the density of blood vessels in the damaged lungs. Thus, this study demonstrates that human MSCs have potential utility for the treatment of PAH, and that S1P priming increases the effects of SC therapy by enhancing cardiac and vascular remodeling. By optimizing this protocol in future studies, SC therapy might form a basis for clinical trials to treat human PAH.

Cancer stem cells (CSCs) are cancer cells that possess the ability to undergo continuous proliferation and self-renewal. It has been postulated that CSCs are responsible for tumor growth, heterogeneity, invasion, metastasis, and recurrence. MicroRNAs (miRNAs), small non-coding RNAs of approximately 22 nucleotides, are known to be involved in the maintenance of CSCs. To gain insight into the role of miRNAs in CSCs, we investigated the differential expression of miRNAs in ovarian CSCs compared to non-CSCs. Ovarian CSCs were isolated from the human ovarian cancer cell line SK-OV-3 using two ovarian CSC-specific surface markers, CD44 and CD117. The expression levels of miRNAs in CSCs and non-CSCs were estimated by miRNA sequencing. We detected four up-regulated miRNAs (miR-29a-5p, miR-34c-5p, miR-106a-5p, and miR-424-5p) in ovarian CSCs, and miR-424-5p was validated by real-time qPCR. MiR-424-5p target genes were predicted using several validated target databases and computational algorithms. Pathway analysis indicated that most miR-424-5p target genes are involved in cancer-related biological pathways. Overall, these results suggest that miR-424-5p is a potential regulator of CSCs that endows human ovarian tissue with tumorigenic potential and thus represents a potential therapeutic target for human ovarian cancer.

Genistein, a phyto-estrogen, can potentially replace endogenous estrogens in postmenopausal women, but the underlying molecular mechanisms remain incompletely understood. To obtain insight into the effect of genistein on bone differentiation, RNA sequencing (RNA-seq) analysis was used to detect differentially expressed genes (DEGs) in genistein-treated vs. untreated MC3T3-E1 mouse osteoblastic cells. Osteoblastic cell differentiation was monitored by measuring osteoblast differentiation factors (ALP production, bone mineralization, and expression of osteoblast differentiation markers). From RNA-seq analysis, a total of 132 DEGs (including 52 up-regulated and 80 down-regulated genes) were identified in genistein-treated cells (FDR q-value 1.5). KEGG pathway and Gene Ontology (GO) enrichment analyses were performed to estimate the biological functions of DEGs and demonstrated that these DEGs were highly enriched in functions related to chemotactic cytokines. The functional relevance of DEGs to genistein-induced osteoblastic cell differentiation was further evaluated by siRNA-mediated knockdown in MC3T3-E1 cells. These siRNA knockdown experiments (of the DEGs validated by real-time qPCR) demonstrated that two up-regulated genes (Ereg and Efcab2) enhance osteoblastic cell differentiation, while three down-regulated genes (Hrc, Gli, and Ifitm5) suppress the differentiation. These results imply their major functional roles in bone differentiation regulated by genistein.

Cystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death.

Aberrant activation of transglutaminase 2 (TGase2) contributes to a variety of protein conformational disorders such as neurodegenerative diseases and age-related cataracts. The accumulation of improperly folded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), which promotes either repair or degradation of the damaged proteins. Inadequate UPR results in protein aggregation that may contribute to the development of age-related degenerative diseases. TGase2 is a calcium-dependent enzyme that irreversibly modifies proteins by forming cross-linked protein aggregates. Intracellular TGase2 is activated by oxidative stress which generates large quantities of unfolded proteins. However, the relationship between TGase2 activity and UPR has not yet been established. In the present study, we demonstrated that ER stress activated TGase2 in various cell types. TGase2 activation was dependent on the ER stress-induced increase in the intracellular calcium ion concentration but not on the TGase2 protein expression level. Enzyme substrate analysis revealed that TGase2-mediated protein modification promoted protein aggregation concurrently with decreasing water solubility. Moreover, treatment with KCC009, a TGase2 inhibitor, abrogated ER stress-induced TGase2 activation and subsequent protein aggregation. However, TGase2 activation had no effect on ER stress-induced cell death. These results demonstrate that the accumulation of misfolded proteins activates TGase2, which further accelerates the formation of protein aggregates. Therefore, we suggest that inhibition of TGase2 may be a novel strategy by which to prevent the protein aggregation in age-related degenerative diseases.

Background Hypertension is a major contributor to the global disease burden of cardiovascular and cerebrovascular disease. The aim of this study was to determine demographic and clinical factors associated with adherence to antihypertensive medication. Methods From August 2012 to February 2015, we recruited 1,523 Korean patients with hypertension who visited family physicians. The study was conducted in 24 facilities located in urban and metropolitan areas. Of these facilities, two were primary care clinics and 22 were level 2 or 3 hospitals. Adherence was assessed using the pill count method; a cut-off value of 80% was used as the criterion for good adherence. Sociodemographic and lifestyle factors were compared between the adherent and nonadherent groups using the chi-square test for categorical variables and t-test for continuous variables. Binary logistic regression analysis was performed with medication adherence as the outcome variable. Results Of the 1,523 patients, 1,245 (81.7%) showed good adherence to antihypertensive medication. In the multivariate logistic analysis, age ≥65 years, exercise, treatment in a metropolitan-located hospital, being on ≥2 classes of antihypertensive medication and concomitant medication for diabetes, and a family history of hypertension or cardiovascular diseases were associated with good adherence. Patients who had a habit of high salt intake were less adherent to medication. Conclusion Multiple classes of antihypertensive medications, concomitant medication, and exercise were associated with good adherence to antihypertensive medication, and high salt intake was associated with poor adherence to antihypertensive medication. These factors should be considered to improve hypertension control.

Mice null for wild-type p53-induced phosphatase 1 (WIP1) display defects in testis development and spermatogenesis, resulting in reduced fertility. However, the molecular mechanism underlying these abnormalities in the testis remains uncharacterized. We report that the phosphatase activity of WIP1 increases Wnt activity through Nemo-like kinase (NLK). WIP1 directly interacted with NLK, which is highly homologous to p38 MAPK, a WIP1 substrate, and dephosphorylated its activation site. The WIP1-mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer-binding factor 1 (LEF1), enhancing its interaction with β-catenin. Additionally, WIP1 depletion impaired germ cell development, as evidenced by the expression of Oct4 and the germ cell-specific markers Ddx4, Nanos3 and Dnd1 during the development of germ cells from Oct4-GFP transgenic (OG2) mouse embryonic stem cells (mESCs). The expression of WIP1, whose level was significantly lower after the differentiation of germ cells from mESCs, occurred in parallel with the expression of germ cell development markers and SRY-box 17 (Sox17), a downstream target of Wnt. These results indicate that WIP1 is essential for germ cell development, which is known to require Wnt activity.

In this paper, Neumann cracks in elastic bodies are considered. We establish a rigorous asymptotic expansion for the boundary perturbations of the displacement (and traction) vectors that are due to the presence of a small elastic linear crack. The formula reveals that the leading order term is e 2 where e is the length of the crack, and the e 3-term vanishes. We obtain an asymptotic expansion of the elastic potential energy as an immediate consequence of the boundary perturbation formula. The derivation is based on layer potential techniques. It is expected that the formula would lead to very effective direct approaches for locating a collection of small elastic cracks and estimating their sizes and orientations.

The aim of this study is to provide both qualitative and rigorous empirical evidence regarding the positive and contemporaneous impact of organisational and technical innovations on productivity in Korean firms and sectors. Econometric methods (fixed effects and generalised method of moments) are used to measure the relationship between the just-in-time process (mostly an organisational type of process), technology (R&D) and productivity. In these regressions we also include the control variables of wage gap incentive, capital-to-labour ratio, and education expenses for sales training to accommodate for other important influences. From the overall and quantitative analyses, we provide evidence to the hypothesis that both organisation and technology greatly improve productivity of Korean manufacturing firms and sectors. In addition, not all firms and industrial sectors are influenced in the same way by all these factors. This variety of organisational and technological ‘behaviour’ is clearly indicated in o...

In this paper, we describe a mathematical model about the reaction–diffusion kinetics of bicarbonate system, which it plays a key role in regulating blood pH. It is very important to know the determinants of blood pH in both experimental and theoretical studies, in order to help to investigate the hidden mechanism of acid–base disorders in the clinical setting. We explore the dynamics of the bicarbonate system under the closed condition. This condition yields that the total amount of carbon dioxide is conserved and the difference in concentrations between anions and cations is conserved. For the stability of the model, we hypothesize that the amount of initial concentrations perturbed around an equilibrium point is less than a certain constant depending on a rate constant. With an application of Liapunov's method, we prove that the model in the form of reaction–diffusion system is globally stable under the hypothesis. We also provide the blood pH profile, which is computed in our model with the experimentally observed rate constants.

Abuse of the hallucinogenic drug ketamine promotes the development of lower urinary tract symptoms that resemble interstitial cystitis. The pathophysiology of ketamine-induced cystitis (KC) is largely unknown and effective therapies are lacking. Here, using a KC rat model, we show the therapeutic effects of human umbilical cord-blood (UCB)-derived mesenchymal stem cells (MSCs). Daily injection of ketamine to Sprague-Dawley rats for 2-weeks resulted in defective bladder function, indicated by irregular voiding frequency, increased maximum contraction pressure, and decreased intercontraction intervals and bladder capacity. KC bladders were characterized by severe mast-cell infiltration, tissue fibrosis, apoptosis, upregulation of transforming growth factor-β signaling related genes, and phosphorylation of Smad2 and Smad3 proteins. A single administration of MSCs (1 × 106) into bladder tissue not only significantly ameliorated the aforementioned bladder voiding parameters, but also reversed the characteristic histological and gene-expression alterations of KC bladder. Treatment with the antifibrotic compound N-acetylcysteine also alleviated the symptoms and pathological characteristics of KC bladder, indicating that the antifibrotic capacity of MSC therapy underlies its benefits. Thus, this study for the first-time shows that MSC therapy might help to cure KC by protecting against tissue fibrosis in a KC animal model and provides a foundation for clinical trials of MSC therapy.

BACKGROUND We examined the relationship between changes in waist circumference (WC) and the incidence of nonalcoholic fatty liver disease (NAFLD). METHODS A cohort study of 37,130 men and women were followed-up annually or biennially. Differences in WC between baseline and subsequent measurements were categorized in quartiles: first (WC loss), second (no change in WC as the reference), third and highest quartiles (WC gain). The presence of fatty liver was determined using ultrasound. Parametric Cox modeling was used to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) of the incidence of NAFLD. RESULTS During 127,324.4 person-years of follow-up, 6249 participants developed NAFLD. Despite adjusting for possible confounders, the risk of development of NAFLD increased with increasing quartiles of WC change in a dose-response manner (p for trend < 0.001). Compared with the reference, WC loss was associated with a lower risk of NAFLD (men: aHR 0.79 [95% CI: 0.73-0.87]; women: 0.72 [0.63-0.81]), and the highest quartile (WC gain) was associated with a higher risk of NAFLD (men: 1.30 [1.19-1.42]; women: 1.48 [1.31-1.67]). CONCLUSION Waist gain appears to increase the risk of developing NAFLD, independently of the baseline body mass index and WC.

In this paper, we deal with the stability problem to some mathematical models that describe chemical reaction kinetics. One is a set of ordinary differential equations induced by one reversible chemical reaction mechanism containing three chemical species. The other is a set of reaction diffusion equations based on the same chemical reaction. We show that all solutions of the model are asymptotically stable by applying the Liapunov method. We thus find that the concentration of each species has certain limits as time proceeds.

We consider a system of Euler-Lagrange equations associated with the weighted Hardy-Littlewood-Sobolev inequality in $R^n$. We demonstrate that the positive solutions of the system of Euler-Lagrange equations are asymptotic to certain forms of limit around the center and near infinity, respectively. The results are proven using the optimal integrability conditions for the positive solutions of the system of equations.

Bariatric surgery has beneficial effects on weight loss and metabolic profiles. Recent evidence suggests that liver-derived hepatokines play a role in the pathophysiology of metabolic diseases. However, few studies have reported longitudinal changes in hepatokines after gastric bypass surgery. We investigated changes in the serum levels of angiopoietin-like protein 6 (Angptl6) and selenoprotein P after gastric bypass surgery. We followed 10 patients who were treated with gastric bypass for weight loss. We measured metabolic parameters and the serum levels of Angptl6 and selenoprotein P before, 1 month after, and 9 months after surgery. We investigated the changes in those hepatokines after surgery and the associations between changes in Angptl6 and selenoprotein P, respectively, and metabolic parameters. Body mass index decreased linearly. Levels of hemoglobin A1c (HbA1c), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), total cholesterol, triglyceride, LDL cholesterol, and Angptl6 were significantly lower 1 and 9 months after surgery. Fasting plasma glucose was normal throughout the study. Fasting insulin decreased 1 month after surgery but increased 9 months post-surgery. Levels of selenoprotein P increased linearly. Significant correlations were detected between the levels of Angptl6 and LDL cholesterol and fasting insulin. Changes in Angptl6 levels were significantly correlated with changes in total cholesterol and LDL cholesterol. Selenoprotein P levels were inversely correlated with GGT, and changes in selenoprotein P were inversely correlated with changes in homeostasis model assessment for insulin resistance (HOMA-IR). Our results suggest that gastric bypass may alter the serum levels of hepatokines independent of weight loss, and these changes are related to certain hepatic metabolic changes.

Interstitial cystitis (IC) is a syndrome characterized by urinary urgency, frequency, pelvic pain, and nocturia in the absence of bacterial infection or identifiable pathology. IC is a devastating disease that certainly decreases quality of life. However, the causes of IC remain unknown and no effective treatments or cures have been developed. This study evaluated the therapeutic potency of using human umbilical cord-blood-derived mesenchymal stem cells (UCB-MSCs) to treat IC in a rat model and to investigate its responsible molecular mechanism. IC was induced in 10-week-old female Sprague–Dawley rats via the instillation of 0.1 M HCl or phosphate-buffered saline (PBS; sham). After 1 week, human UCB-MSC (IC+MSC) or PBS (IC) was directly injected into the submucosal layer of the bladder. A single injection of human UCB-MSCs significantly attenuated the irregular and decreased voiding interval in the IC group. Accordingly, denudation of the epithelium and increased inflammatory responses, mast cell infiltration, neurofilament production, and angiogenesis observed in the IC bladders were prevented in the IC+MSC group. The injected UCB-MSCs successfully engrafted to the stromal and epithelial tissues and activated Wnt signaling cascade. Interference with Wnt and epidermal growth factor receptor activity by small molecules abrogated the benefits of MSC therapy. This is the first report that provides an experimental evidence of the therapeutic effects and molecular mechanisms of MSC therapy to IC using an orthodox rat animal model. Our findings not only provide the basis for clinical trials of MSC therapy to IC but also advance our understanding of IC pathophysiology.

Pluripotent stem cells (PSCs) have been considered as the most important cells in regenerative medicine as they are able to differentiate into all types of cells in the human body. PSCs have been established from several sources of embryo tissue or by reprogramming of terminally differentiated adult tissue by transduction of so-called Yamanaka factors (Oct4, Sox2, Klf4, and cMyc). Interestingly, accumulating evidence has demonstrated the residence of PSCs in adult tissue and with the ability to differentiate into multiple types of tissue-committed stem cells (TCSCs). We also recently demonstrated that a population of pluripotent Oct4(+) SSEA-1(+)Sca-1(+)Lin(-)CD45(-) very small embryonic-like stem cells (VSELs) resides in the adult murine bone marrow (BM) and in other murine tissue. These very small (∼3-6 μm) cells express pluripotent markers such as Oct4, Nanog, and SSEA-1. VSELs could be specified into several tissue-residing TCSCs in response to tissue/organ injury, and thus suggesting that these cells have a physiological role in the rejuvenation of a pool of TCSCs under steady-state conditions. In this review article, we discuss the molecular nature of the rare population of VSELs which have a crucial role in regulating the pluripotency, proliferation, differentiation, and aging of these cells.

Tissue and organ rejuvenation and senescence/aging are closely related to the function of stem cells. Thus, stem cells have been considered as guardians for the homeostasis of tissue/organ throughout life span. Recently, we identified a population of pluripotent Oct4+ very small embryonic/epiblast-like stem cells (VSELs) residing in the adult murine bone marrow (BM) and human cord blood (CB). VSELs can differentiate into cells from all three germ layers in vitro culture condition and in vivo tissue regeneration animal models. VSELs express the gene-expression and epigenetic profiling, which are similar to germ-line stem cells including (i) open/active chromatin structure in Oct4 promoter, (ii) parent-of-origin-specific reprogramming of genomic imprinting, (iii) deoxyribonucleic acid (DNA) demethylation in the promoter of germ-line lineage genes, and (iv) reactivate the X chromosome (in female pluripotent stem cells, PSCs). The unique epigenetic reprogramming in VSELs suggest that they could developmentally originate from the migratory primordial germ cells (PGCs) and the proliferation of VSELs are negatively controlled by epigenetic changes of some imprinted genes that regulate insulin/insulin-like growth-factor (Ins/Igf) signaling (Igf2, H19, Igf2R, and Rasgrf1). Since the chronic exposure to Ins/Igf signaling negatively correlates with longevity, we propose that Ins/Igf signaling mediated decrease in the number of VSELs could be a novel explanation of ageing. Therefore, VSELs could play a pivotal role in maintaining the integrity of adult tissues and these cells could provide a therapeutic alternative to stem cells isolated from embryos. Therefore, the understanding the precise molecular signature of VSELs such as reprogrammed genomic imprints could increase the regenerative power of these cells.

Introduction Persistent migraine aura without headache is an extremely rare condition. The International Headache Society defines various subtypes of migraines, including “persistent migraine aura without infarction” and “typical aura without headache.” Case presentation We describe the case of a 21-year-old Asian woman with a history of migraine without aura who had (as her first aura episode) persistent negative visual symptoms without headache for 6 months. We detected no lesions that could cause her persistent visual symptoms. Based on the patient’s history of migraine without aura and responsiveness to furosemide and lamotrigine, we concluded that the visual symptoms in this case were related to migraine visual auras. Conclusions Persistent visual aura without headache overlapped the criteria for the two migraine subtypes mentioned above and thus did not fit an exact diagnosis. Therefore, we assert that new criteria are needed to encompass uncertain visual symptoms of migraine aura.

The activation of transglutaminase 2 (TG2), an enzyme that catalyzes post-translational modifications of proteins, has been implicated in apoptosis, cell adhesion and inflammatory responses. We previously reported that intracellular TG2 is activated under oxidative stress conditions, such as ultraviolet irradiation, ischemia-reperfusion, and hypoxia. In this study, we examined the effect of genotoxic stress on the intracellular activity of TG2 using doxorubicin which generates reactive oxygen species that lead to double-strand breakage of DNA. We demonstrated that doxorubicin elicits the persistent activation of TG2. Doxorubicin-induced TG2 activity was suppressed by treatment with caffeine at the early phase, N-acetylcysteine at the mid-phase, and EGTA at the late phase. However, treatment with a blocking antibody against TGFβ or toll-like receptor 2 showed no effect on TG2 activity, indicating that at least three different signaling pathways may be involved in the process of TG2 activation. In addition, using MEF cells defective for TG2 and cells overexpressing an activesite mutant of TG2, we revealed that doxorubicin-induced cell death is inversely correlated with TG2 activity. Our findings indicate that the persistent activation of TG2 by doxorubicin contributes to cell survival, suggesting that the mechanism-based inhibition of TG2 may be a novel strategy to prevent drug-resistance in doxorubicin treatment.

PURPOSE The activation of transglutaminase 2 (TG2) by oxidative stress through TGFβ has been reported to play a crucial role in cataract formation. The authors investigated whether TG2 is involved in selenite-induced cataract formation in rats and whether cysteamine, a chemical inhibitor of TG2, can prevent cataract formation in this model. METHODS Intracellular TG2 activity was monitored in a human lens epithelial cell (HLE-B3) line and cultured rat lenses after treatment with selenite. Rat pups (13 days old) were injected subcutaneously with sodium selenite (Na(2)SeO(3); 20 μmol/kg) and intraperitoneally with cysteamine (30, 40, and 60 mg/kg) for 14 days. Lenses were evaluated photographically at days 7 and 14. The concentrations of malondialdehyde and glutathione in the lenses were determined. RESULTS In HLE-B3 cells or rat lenses, selenite induced intracellular TG activity, which was inhibited by cysteamine. In selenite-treated rats, the rate of cataract formation was significantly reduced by cysteamine (P < 0.001). The mean cataract area in the lenses of cysteamine-treated rats was smaller than that of control rats (P < 0.01). The levels of total and reduced glutathione in the lenses of cysteamine-treated rats extracted at day 14 were higher than those of control rats. CONCLUSIONS Cysteamine suppresses cataract formation induced by selenite in rats, suggesting that cysteamine can be used as a pharmaceutical intervention to prevent or delay cataract formation.

In this report we summarize an extension of Fourier analysis for the solution of the wave equation with a non‐constant coefficient corresponding to an inhomogeneous medium. The underlying physics of the problem is exploited to link pseudodifferential operators and phase space path integrals to obtain a marching algorithm that incorporates the backward scattering into the evolution of the wave. This allows us to successfully apply single‐sweep, one‐way marching methods in inherently two‐way environments, which was not achieved before through other methods for this problem.