Search

Previously, we found that dual therapy by the CXCR4 inhibitor Plerixafor and cytosine arabinoside (Ara-C) effectively eradicated leukemia cells and concurrently activated immune cells in acute myeloid leukemia (AML). To reveal the significance of programmed death-ligand1 (PD-L1) in AML and as a strategic approach, we investigated the anti-leukemic effect of a triple combinational therapy by utilizing Plerixafor and anti-PD-L1 in combination with chemotherapy in an AML mouse model. We examined leukemic myeloid blast cells in multiple organs after the successive treatment with Ara-C, Plerixafor, and anti-PD-L1. The results showed that noticeable benefits of triple combinational therapy for eradication of myeloid blast cells in vivo with prolonged survival rates. The frequencies of regulatory T cells (Tregs), monocytic-myeloid-derived suppressor cells (M-MDSCs), and granulocytic-myeloid-derived suppressor cells (G-MDSCs), in the peripheral blood of leukemic mice were consistently decreased, even when mice were sacrificed alive at D + 26 after completion of the triple combinational therapy, compared to the other subgroups. These findings imply that the modulation by the triple combinational therapy may lead to more efficient leukemic myeloid blast cell ablation through the suppression of Tregs or M-MDSCs and G-MDSCs in AML. Although Plerixafor and PD-L1 antagonist do not have a direct anti-leukemic role, our results provide some clues and guidelines to develop clinically therapeutic strategies for chemotherapy-resistant patients by the modulation of leukemic microenvironments.

The bone marrow microenvironment (BMM) provides a protective niche that supports the growth and survival of leukemic stem cells. It is known that a regulation of homing to BM and retention of hematopoietic stem cells (HSCs) occur by SDF-1/CXCR4 axis in BMM. Previously, we found that altering the BMM by the CXCR4 antagonist led to enhanced cytotoxic activity of immune cells, which leads to increased susceptibility of leukemic cells to chemotherapeutic agents such as cytosine arabinoside (Ara-C) in leukemic BMM. However, no reports have yet shown an architectural change of BMM such as the sinusoidal vessel and megakaryocyte by plerixafor treatment. Thus, we performed immunohistochemistry and observed that the capillary density of sinusoidal vessels was highly increased by CXCR4 antagonist with Ara-C in leukemia, showing the reconstruction of BMM with megakaryocytes in sinusoidal vessels by dual treatment. The number of megakaryocytes was also increased in the Plerixafor treated group, compared to that of leukemic or wild groups. Ultimately, we addressed the normalization of megakaryocyte and BMM in leukemia by showing the reconstitution of the sinusoidal vasculature by Plerixafor. This study proposed that chemotherapy with CXCR4 antagonist represents an advanced therapeutic strategy of targeting the leukemic niche.

Doxorubicin (DOX) is a widely used anti-cancer drug; however, it has limited application due to cardiotoxicity. Extracorporeal shock waves (ESW) have been suggested to treat inflammatory and ischemic diseases, but the concrete effect of ESW in DOX-induced cardiomyopathy remain obscure. After H9c2 cells were subjected to ESW (0.04 mJ/cm2), they were treated with 1 μM DOX. As a result, ESW protected cardiomyocytes from DOX-induced cell death. H9c2 cells treated with DOX downregulated p-Akt and survivin expression, whereas the ESW treatment recovered both, suggesting its anti-apoptotic effect. ESW activated integrin αvβ3 and αvβ5, cardiomyocyte mechanosensors, followed by upregulation of ILK, p-Akt and survivin levels. Further, Sp1 and p53 were determined as key transcriptional factors mediating survivin expression via Akt phosphorylation by ESW. In in vivo acute DOX-induced cardiomyopathy model, the echocardiographic results showed that group subjected to ESW recovered from acute DOX-induced cardiomyopathy; left ventricular function was improved. The immunohistochemical staining results showed increased survivin and Bcl2 expression in ESW + DOX group compared to those in the DOX-injected group. In conclusion, non-invasive shockwaves protect cardiomyocytes from DOX-induced cardiomyopathy by upregulating survivin via integrin-ILK-Akt-Sp1/p53 pathway. In vivo study proposed ESW as a new kind of specific and safe therapy against acute DOX-induced cardiomyopathy.

Internet gaming disorder (IGD) is a newly identified potential addiction disorder associated with compulsive internet-game playing behavior and attentional bias toward online gaming- related cues. Attentional bias toward addiction-related cues is the core feature of addiction that is associated with craving, but the pathophysiology of attentional bias in IGD is not well-understood, such as its relationship to compulsivity. In this study, we used the electrophysiological marker of late positive potential (LPP) to compare attentional bias in IGD and obsessive compulsive disorder (OCD). Twenty patients with IGD, 20 patients with OCD, and 23 healthy control (HC) subjects viewed a series of game-related, OCD-related, and neutral pictures while their event-related potentials (ERPs) were recorded. The game-related cues included in-game screen captures of popular internet games. The OCD-related cues included pictures which provokes obsessive and compulsive symptoms of contamination/washing or checking. LPPs were calculated as the mean value of amplitudes between 350 and 750 ms at the centro-parietal (CP1, CPz, CP2) and parietal (P1, Pz, P2) electrode sites. Higher LPP amplitudes were found for game-related cues in the IGD group than in the HCs, and higher LPP amplitudes were observed in the OCD group for OCD-related cues. The IGD group did not exhibit LPP changes in response to OCD-related cues. Subjective scales demonstrated increased arousal to game-related cues and OCD-related cues in both the IGD and OCD groups compared with the HC group. Increased LPPs in response to disorder-specific cues (game-related and OCD-related) were found in both IGD and OCD groups respectively, although the groups showed overlapping arousal on subjective scales. Our results indicate that LPP is a candidate neurophysiological marker for cue-related craving in IGD.

The stem cell factor (SCF)/c-KIT axis plays an important role in the hematopoietic differentiation of human pluripotent stem cells (hPSCs), but its regulatory mechanisms involving microRNAs (miRs) are not fully elucidated. Here, we demonstrated that supplementation with SCF increases the hematopoietic differentiation of hPSCs via the interaction with its receptor tyrosine kinase c-KIT, which is modulated by miR-221 and miR-222. c-KIT is comparably expressed in undifferentiated human embryonic and induced pluripotent stem cells. The inhibition of SCF signaling via treatment with a c-KIT antagonist (imatinib) during hPSC-derived hematopoiesis resulted in reductions in the yield and multi-lineage potential of hematopoietic progenitors. We found that the transcript levels of miR-221 and miR-222 targeting c-KIT were significantly lower in the pluripotent state than they were in terminally differentiated somatic cells. Furthermore, suppression of miR-221 and miR-222 in undifferentiated hPSC cultures induced more hematopoiesis by increasing c-KIT expression. Collectively, our data implied that the modulation of c-KIT by miRs may provide further potential strategies to expedite the generation of functional blood cells for therapeutic approaches and the study of the cellular machinery related to hematologic malignant diseases such as leukemia.

Ginseng is one of the well-known medicinal plants, exhibiting diverse medicinal effects. Its roots possess anticancer and antiaging properties and are being used in the medical systems of East Asian countries. It is grown in low-light and low-temperature conditions, and its growth is strongly inhibited at temperatures above 25°C. However, the molecular responses of ginseng to heat stress are currently poorly understood, especially at the protein level.We used a shotgun proteomics approach to investigate the effect of heat stress on ginseng leaves. We monitored their photosynthetic efficiency to confirm physiological responses to a high-temperature stress.The results showed a reduction in photosynthetic efficiency on heat treatment (35°C) starting at 48 h. Label-free quantitative proteome analysis led to the identification of 3,332 proteins, of which 847 were differentially modulated in response to heat stress. The MapMan analysis showed that the proteins with increased abundance were mainly associated with antioxidant and translation-regulating activities, whereas the proteins related to the receptor and structural-binding activities exhibited decreased abundance. Several other proteins including chaperones, G-proteins, calcium-signaling proteins, transcription factors, and transfer/carrier proteins were specifically downregulated.These results increase our understanding of heat stress responses in the leaves of ginseng at the protein level, for the first time providing a resource for the scientific community.

Background: This study aimed to explore relationships between impulsivity, interpersonal relationships, depression, and Internet Gaming Disorder (IGD) symptoms. Methods: A total of 118 young adults participated in this study: 67 IGD patients who met five or more of the DSM-5 diagnostic criteria for IGD and 56 healthy controls. We administered questionnaires to assess IGD symptoms (Young’s Internet Addiction Test; Y-IAT), impulsivity (Barratt Impulsiveness Scale; BIS-11), interpersonal relationship (Relationship Change Scale; RCS), and depression (Beck Depression Inventory; BDI). We used PROCESS macro in SPSS to perform mediation analysis. Results: IGD symptom was positively related to depression and impulsivity, and negatively related to the quality of interpersonal relationships. Mediation analysis revealed full mediation effects of interpersonal relationships and depression on the association between impulsivity and IGD symptoms in the IGD group. Specifically, even after adjusting for gender as a covariate, high impulsivity was associated with greater difficulty with interpersonal relationships; which further affected depression and increased the risk of IGD. Conclusions: These results demonstrate the importance of early intervention in IGD patients, particularly in young adults with high impulsivity. When intervening in adults’ IGD, we should consider not only individual factors (e.g., depression) but also socioenvironmental factors (e.g., interpersonal relationships).

Corosolic acid (CA), a triterpenoid compound isolated from Lagerstroemia speciosa L. (Banaba) leaves, exerts anti-inflammatory effects by regulating phosphorylation of interleukin receptor-associated kinase (IRAK)-2 via the NF-κB cascade. However, the protective effect of CA against endotoxic shock has not been reported. LPS (200 ng/mL, 30 min) induced phosphorylation of IRAK-1 and treatment with CA (10 μM) significantly attenuated this effect. In addition, CA also reduced protein levels of NLRP3 and ASC which are the main components of the inflammasome in BMDMs. LPS-induced inflammasome assembly through activation of IRAK-1 was down-regulated by CA challenge. Treatment with Bay11-7082, an inhibitor of IκB-α, had no effect on CA-mediated inhibition of IRAK-1 activation, indicating that CA-mediated attenuation of IRAK-1 phosphorylation was independent of NF-κB signaling. These results demonstrate that CA ameliorates acute inflammation in mouse BMDMs and CA may be useful as a pharmacological agent to prevent acute inflammation. [BMB Reports 2016; 49(5): 276-281].

Suicide is a major public health problem around the world. Some studies have found that hormone replacement therapy (HRT) is associated with depression in postmenopausal women. Depression is a well-known risk factor for suicide; therefore, we investigated the relationship between HRT and suicidal ideation in postmenopausal Korean women.We included 2286 postmenopausal women with or without HRT from the Korean National Health and Nutrition Examination Survey 2010-2012. The use and duration of HRT and mental health status, including stress, depressive mood, and suicidal ideation and attempts, were assessed by self-report questionnaires.The proportion of participants with depressive mood and suicidal ideation was higher in the HRT group than the non-HRT group (all p values0.05). As the duration of HRT increased, the percentage of participants with suicidal ideation increased (p for trend=0.006). After adjusting for all covariates, the odds ratio (95% confidence intervals) for suicidal ideation was 1.742 (1.223-2.482) in the women with HRT, compared to women without HRT. HRT duration longer than 10 years was associated with suicidal ideation (odds ratio=2.089 and 95% confidence intervals=1.069-4.084).The cross-sectional design, a possibility of incorrect answer about menopausal status, and no assessment of the type of HRT are the main limitations of this study.Postmenopausal women receiving HRT, especially for more than 10 years, showed increased suicidal ideation compared with postmenopausal women without HRT. Physicians should pay attention to mood symptoms and suicidal ideation in postmenopausal women with HRT.

The bone marrow microenvironment (BMM) provides a protective niche that supports growth and survival of normal and leukemic hematopoietic stem cells. The SDF-1/CXCR4 interaction is critical for regulation of homing to and retention of hematopoietic cells in the bone marrow (BM), which leads to increased chemoresistance. SDF-1/CXCR4 plays pivotal roles in cross-interactions between blasts and the BMM to prevent retention and mobilization of leukemic cells, as well as in normal hematopoiesis including the development of immune cells. We show that the CXCR4 antagonist, plerixafor, decreased the level of CXCR4 expression and inhibited SDF-1-induced migration of leukemic cells. Further, the inhibition of the interaction between leukemic cells and the BMM by the plerixafor enhanced cytotoxic activity of immune cells as a result of increased susceptibility of leukemic cells to chemotherapeutic agents such as cytosine arabinoside (Ara-C) in a mouse model of acute myeloid leukemia (AML), suggesting biological effects of the BMM through immune cell activation. Because alterations in the BMM promote retention and survival of leukemic cells, targeting the niche is regarded as an advanced strategy to eradicate drug-resistant leukemic blasts. This study demonstrates that the effects of CXCR4 inhibition on blast suppression and immune cell function in the tumor microenvironment and chemotherapy with plerixafor represents an advanced therapeutic strategy of targeting the leukemic niche.

1)ABSTRACTThis study examines the relationships between stress and eating habits of adolescents based on the assumption that adolescents require large amounts of nut rients and that eating habits affect their physical development, academic achievement, and em otional development. For this purpose, 213 adolescents in Gangwondo, Korea, were surveyed. Ma ny studies have reported that stress causes changes in eating habits and affects health status. Based on the dietary action guide scores according to stress categories, eating instant foo ds less was significant (p

The purpose of this study was to investigate the effects of diabetes on mesenchymal stem cells (MSCs) in terms of their angiogenic and therapeutic potential for repairing tissue ischemia. We culture-isolated MSCs from streptozotocin-induced diabetic rats (D-MSCs) and compared their proliferation, differentiation, and angiogenic effects with those from normal rats (N-MSCs). The angiogenic effects of MSCs were evaluated by real-time PCR, in vitro tube formation assay, and transplantation of the MSCs into a hindlimb ischemia model followed by laser Doppler perfusion imaging. The number of MSCs derived from diabetic rats was smaller, and their proliferation rate was slower than N-MSCs. Upon induction of differentiation, the osteogenic and angiogenic differentiation of D-MSCs were aberrant compared to N-MSCs. The expression of angiogenic factors was lower in D-MSCs than N-MSCs. D-MSCs cocultured with endothelial cells resulted in decreased tube formation compared to N-MSCs. D-MSCs were ineffective to improve hindlimb ischemia and showed lower capillary density and angiogenic gene expression in ischemic limbs than N-MSCs. D-MSCs have defective proliferation and angiogenic activities and are ineffective for repairing hindlimb ischemia. Newer measures are needed before MSCs can be employed as a source for autologous cell therapy.

A humanized mice (hu-mice) model is extremely valuable to verify human cell activity in vivo condition and is regarded as an important tool in examining multimodal therapies and drug screening in tumor biology. Moreover, hu-mice models that simply received human CD34 + blood cells and tissue transplants are also overwhelmingly useful in immunology and stem cell biology. Because generated hu-mice harboring a human immune system have displayed phenotype of human CD45 + hematopoietic cells and when played partly with functional immune network, it could be used to evaluate human cell properties in vivo. Although the hu-mice model does not completely recapitulate human condition, it is a key methodological factor in studying human hematological malignancies with impaired immune cells. Also, an advanced humanized leukemic mice (hu-leukemic-mice) model has been developed by improving immunodeficient mice. In this review, we briefly described the history of development on immunodeficient SCID strain mice for hu-and hu-leukemic-mice model for immunologic and tumor microenviromental study while inferring the potential benefits of hu-leukemic-mice in cancer biology.

1. The metabolites of fimasartan (FMS), a new angiotensin II receptor antagonist, were characterized in human liver microsomes (HLM) and human subjects. 2. We developed a method for a simultaneous quantitative and qualitative analysis using predictive multiple reaction monitoring information-dependent acquisition-enhanced product ion scanning. To characterize metabolic reactions, FMS metabolites were analyzed using quadrupole-time of flight mass spectrometer in full-scan mode. 3. The structures of metabolites were confirmed by comparison of chromatographic retention times and mass spectra with those of authentic metabolite standards. 4. In the cofactor-dependent microsomal metabolism study, the half-lives of FMS were 56.7, 247.9 and 53.3 min in the presence of NADPH, UDPGA and NADPH + UDPGA, respectively. 5. The main metabolic routes in HLM were S-oxidation, oxidative desulfuration, n-butyl hydroxylation and N-glucuronidation. 6. In humans orally administered with 120 mg FMS daily for 7 days, the prominent metabolites were FMS S-oxide and FMS N-glucuronide in the 0-8-h pooled plasma sample of each subject. 7. This study characterizes, for the first time, the metabolites of FMS in humans to provide information for its safe use in clinical medicine.

The study was designed (1) to examine the hypothesis that circulating progenitor cells play a role in the process of de novo regeneration in human liver transplants and that these cells arise from a cell population originating in, or associated with, the bone marrow and (2) to investigate whether the transplanted liver volume has an effect on the circulating recipient-derived progenitor cells that generate hepatocytes during this process. Clinical data and liver tissue characteristics were analyzed in male individuals who underwent sex-mismatched adult-to-adult living donor liver transplantation using dual left lobe grafts. Dual left lobe grafts were examined at the time of transplantation and 19 to 27 days after transplantation. All recipients showed recovery of normal liver function and a significant increase in the volume of the engrafted left lobes after transplantation. Double staining for a Y-chromosome probe and the CD31 antigen showed the presence of hybrid vessels composed of recipient-derived cells and donor cells within the transplanted liver tissues. Furthermore, CD34-expressing cells were observed commingling with Y-chromosome+ cells. The ratio of recipient-derived vessels and the number of Y+ CD34+ cells tended to be higher when smaller graft volumes underwent transplantation. These findings suggest that the recruitment of circulating bone marrow-derived progenitor cells could contribute to vessel formation and de novo regeneration in human liver transplants. Moreover, graft volume may be an important determinant for the active mobilization of circulating recipient-derived progenitor cells and their contribution to liver regeneration.

We investigated to compare species differences in amitriptyline (AMI) metabolism among mouse, rat, dog, and human liver microsomes. We developed a method for simultaneous determination of metabolic stability and metabolite profiling using predictive multiple reaction monitoring information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) scanning. In the cofactor-dependent microsomal metabolism study, AMI was metabolized more rapidly in rat and human liver microsomes incubated with NADPH than UDPGA. AMI incubated with NADPH+UDPGA in rat, dog, or mouse liver microsomes disappeared rapidly with a half-life of 3.5, 8.4, or 9.2 min, respectively, but slowly in human liver microsomes with a half-life of 96 min. In total, 9, 10, 11, and 6 putative metabolites of AMI were detected in mouse, rat, dog, and human liver microsomes, respectively, based on mass spectrometric analyses. Kinetic analysis of metabolites in liver microsomes from each species over 120 min showed common metabolic routes of AMI, such as N-demethylation, hydroxylation, and glucuronidation, and subtle interspecies differences in AMI metabolism. The main metabolic routes in mouse, rat, dog, and human liver microsomes were hydroxylation followed by glucuronide conjugation, methyl hydroxylation, and N-demethylation, respectively. The MRM-IDA-EPI method can provide quantitative and qualitative information about metabolic stability and metabolite profiling simultaneously. Moreover, time course analysis of metabolites can not only eliminate false identification of metabolites, but also provide a rationale for proposed metabolic pathways. The MRM-IDA-EPI method combined with time course analysis of metabolites is useful for investigating drug metabolism at the early drug discovery stage.

It is known that the primo vascular system (PVS) includes the primo nodes and vessels. However, the relevant genes in the PVS system for both pathologic and physiologic condition are poorly understood. Here, we first examined the gene expression in primo vessels (PVs) floating in lymphatic endothelium by isolation of PVS and lymphatic vessels (LVs) containing PVS. To investigate therapeutic effects, both PVs and LVs containing PVS were isolated after lipopolysaccharide injection and acupuncture electric stimulation at two acupoints Joksamni (ST36) and Hapgok (LI04) following lipopolysaccharide injection. We used reverse transcriptase–polymerase chain reaction to examine expression of lymphatic endothelial cell markers and inflammatory related genes. We found that lymphatic endothelial cell markers such as fms-related tyrosine kinase 4 (Flt4), lymphatic vessel endothelial receptor (Lyve-1), prospero homeobox protein 1 (Prox-1), and podoplanin (Pdpn) were highly expressed in PV compared to that of lymphatic endothelium, suggesting pivotal roles of PV in LV under inflammation. Furthermore, lymphatic-related genes including metal-response element-binding transcription factor 2 (Mtf2), hypoxia inducible factor (Hif1a), angiotensin II type 1 receptor (Agtr1), and angiotensin II type 2 receptor (Agtr2) were also overall increased in PV, and remarkably increased and these genes except peroxisome proliferator–activated receptor gamma (Pparg) after acupuncture electric stimulation in two acupoints implying central role of PV by gene activation. Keywords: acupuncture electric stimulation, gene expression, Hapgok (LI04), Joksamni (ST36), lymph vessel, primo vessel

The bone marrow microenvironment (BMM) provides a protective niche that supports the growth and survival of leukemic stem cells. It is known that a regulation of homing to BM and retention of hematopoietic stem cells (HSCs) occur by SDF-1/CXCR4 axis in BMM. Previously, we found that altering the BMM by the CXCR4 antagonist led to enhanced cytotoxic activity of immune cells, which leads to increased susceptibility of leukemic cells to chemotherapeutic agents such as cytosine arabinoside (Ara-C) in leukemic BMM. However, no reports have yet shown an architectural change of BMM such as the sinusoidal vessel and megakaryocyte by plerixafor treatment. Thus, we performed immunohistochemistry and observed that the capillary density of sinusoidal vessels was highly increased by CXCR4 antagonist with Ara-C in leukemia, showing the reconstruction of BMM with megakaryocytes in sinusoidal vessels by dual treatment. The number of megakaryocytes was also increased in the Plerixafor treated group, compared to that of leukemic or wild groups. Ultimately, we addressed the normalization of megakaryocyte and BMM in leukemia by showing the reconstitution of the sinusoidal vasculature by Plerixafor. This study proposed that chemotherapy with CXCR4 antagonist represents an advanced therapeutic strategy of targeting the leukemic niche.

Lactobacilli are bacteria that are beneficial to host health, but information on communication between Lactobacilli and host cells in the intestine is lacking. In this study, we examined the proteomes of the Lactobacillus mucosae strain LM1, as a model of beneficial bacteria, and the intestinal porcine epithelial cell line (IPEC-J2) after co-culture. Label-free proteomics demonstrated the high-throughput capability of the technique, and robust characterization of the functional profiles and changes in the bacteria and intestinal cells was achieved in pure and mixed cultures. After co-culture, we identified totals of 376 and 653 differentially expressed proteins in the LM1 and IPEC-J2 proteomes, respectively. The major proteomic changes in the LM1 strain occurred in the functional categories of transcription, general function, and translation, whereas those in IPEC-J2 cells involved metabolic and cellular processes, and cellular component organization/biogenesis. Among them, elongation factor Tu, glyceraldehyde 3-phosphate dehydrogenase, and phosphocarrier protein HPr, which are known to be involved in bacterial adhesion, were upregulated in LM1. In contrast, proteins involved in tight junction assembly, actin organization, and genetic information processing (i.e., histones and signaling pathways) were significantly upregulated in IPEC-J2 cells. Furthermore, we identified functional pathways that are possibly involved in host–microbe crosstalk and response. These findings will provide novel insights into host–bacteria communication and the molecular mechanism of probiotic establishment in the intestine.

Objective Supplementation with serine attenuates alcoholic fatty liver by regulating homocysteine metabolism and lipogenesis. However, little is known about serine metabolism in fatty liver disease (FLD). We aimed to investigate the changes in serine biosynthetic pathways in humans and animal models of fatty liver and their contribution to the development of FLD. Methods High-fat diet (HFD)-induced steatosis and methionine-choline-deficient diet-induced steatohepatitis animal models were employed. Human serum samples were obtained from patients with FLD whose proton density fat fraction was estimated by magnetic resonance imaging. 3-Phosphoglycerate dehydrogenase (Phgdh)-knockout mouse embryonic fibroblasts (MEF) and transgenic mice overexpressing Phgdh (Tg-phgdh) were used to evaluate the role of serine metabolism in the development of FLD. Results Expression of Phgdh was markedly reduced in the animal models. There were significant negative correlations of the serum serine with the liver fat fraction, serum alanine transaminase, and triglyceride levels among patients with FLD. Increased lipid accumulation and reduced NAD+ and SIRT1 activity were observed in Phgdh-knockout MEF and primary hepatocytes incubated with free fatty acids; these effects were reversed by overexpression of Phgdh. Tg-Phgdh mice showed significantly reduced hepatic triglyceride accumulation compared with wild-type littermates fed a HFD, which was accompanied by increased SIRT1 activity and reduced expression of lipogenic genes and proteins. Conclusions Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.

In recent years, coding education has been globally emphasized and the Free Semester System will be executed to the public schools in Korea from 2016. With the introduction of the Free Semester System and the rising demand of Computational Thinking (CT) capacity, this research aims to design ``learning environment`` in which learners can design and construct mathematical objects through computers and print them out through 3D printers. Furthermore, it will design learning mathematics by constructing the figurate number patterns from ``soma cubes`` in the playing context and connecting those to algebraic and combinatorial patterns, which will allow students to experience mathematical connectivity. It is expected that the activities of designing figurate number patterns suggested in this research will not only strengthen CT capacity in relation to mathematical thinking but also serve as a meaningful program for the Free Semester System in terms of career experience as 3D printers can be widely used.

Aim Sharing clinical information across care settings is a cornerstone to providing quality care to older people with complex conditions. The purpose of the present study was to examine the reliability of the interRAI Long Term Care Facilities (interRAI LTCF) and the interRAI Home Care (interRAI HC), comprehensive and integrated assessment instruments with common core items, in Korea, an Asian county where comprehensive geriatric assessment is not widely used in long-term care. Methods The Korean version of the instruments was developed through field tests, as well as multiple iterations of translations, back-translations and expert reviews. For the reliability test, a random sample of 908 older people in 27 long-term care hospitals or nursing homes, or at home with home care, were assessed by regular staff, among which a subsample of 534 people were dually assessed. The Cronbach's alphas of seven major composite scales in the instruments were examined for internal consistency. Interrater reliability was tested using agreement, kappa coefficients and interclass correlation coefficients. Results The internal consistencies of all key measures were adequate (Cronbach's alpha ≥0.75). The overall mean kappa statistics of the items in the interRAI LTCF and those in the interRAI HC were 0.78 and 0.89, respectively. All key common items in the interRAI LTCF and the interRAI HC had almost perfect (κ ≥ 0.81) or substantial (0.61 ≤ κ ≤ 0.80) interrater reliability. Conclusions The findings show the interRAI LTCF and the interRAI HC have adequate reliability for assessing the function and health of frail older adults across various long-term settings, which can promote continuity of care for the aged. Geriatr Gerontol Int 2015; 15: 220–228.

1. The herb-drug interaction potential of Hwang-Ryun-Hae-Dok-Tang (HR) extracts mediated by cytochrome P450 (CYP) inhibition was determined using human liver microsomes. 2. HR strongly inhibited CYP1A2 and moderately inhibited CYP2C19, CYP2D6, and CYP3A4 (testosterone) but not CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 (midazolam). 3. The enzyme kinetic results suggest that CYP1A2 inhibition is competitively reversible (Ki, 13.4±1.8 μg/ml), and CYP2D6 inhibition is quasi-irreversible (KI, 0.234±0.138 μg/ml; kinact, 0.067±0.006 min(-1)). 4. Fermentation using Lactobacillus acidophilus attenuated the HR-induced inhibition of CYP2D6, but not the other isoforms. 5. Neither CYP1A2 nor CYP3A4 was markedly inhibited by berberine, palmatine, and geniposide-major components in HR-and CYP2D6 was inhibited by berberine (IC50, 13.8 μg/ml) in a metabolism-dependent manner. 6. The results suggest the possibility of HR-drug interaction through inhibition of CYP-particularly CYP2D6-which may be attenuated by fermentation using L. acidophilus.

Although cytochrome P450 inhibition is the major drug-drug interaction (DDI) mechanism in clinical pharmacotherapy, DDI of a number of well-established drugs have not been investigated. Rifampicin, isoniazid, pyrazinamide and ethambutol combination therapy inhibits clearance of theophylline in patients with tuberculosis. We determined the inhibitory effects of ethambutol on the activities of nine CYP isoforms including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in pooled human liver microsomes (HLM). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, ethambutol exhibited strong inhibitory potential against CYP1A2 and CYP2E1, moderate against CYP2C19 and CYP2D6 and weak against CYP2A6, CYP2C9 and CYP3A4, based on the IC50 values. The K(i) value of ethambutol for CYP1A2 was 1.4 μM and for CYP2E1 was 2.9 μM. Inhibition of CYP1A2 and CYP2E1 was not increased by preincubation with ethambutol and β-nicotinamideadenine dinucleotide phosphate (NADPH), suggesting that the ethambutol-induced CYP inhibition may not be metabolism-dependent. Kinetic analysis showed that the inhibition of CYP1A2 and CYP2E1 by ethambutol was best fit to a competitive inhibition model. Formation of 1-methylxanthene and 1,3-dimethyluric acid from theophylline in HLM was decreased to 47% and 36%, respectively, by 3.0 μM ethambutol, which is comparable to its IC50 value against CYP1A2. Considering its maximal plasma concentrations of ~10 μM and long half-life of ~22 h, our findings raise the possibility that ethambutol causes significant DDIs in clinical situations with drugs with narrow therapeutic index, such as theophylline, in clinical situations.

The primary human acute myeloid leukemia (AML) cell injection xenograft mouse model is used to investigate multimodal therapies and drug screening on tumor growth. Since xenograft models using human cell lines to examine drug response are not correlated with the clinical outcomes observed in patients, a xenograft model using primary human cells has been used as a more appropriate model with which to minimize this problem. Although bone marrow (BM) cells from patients are often regarded as superior sources to establish xenograft models due to the high frequency of stem cell populations, there is a fatal drawback; only small volumes can be obtained and used for the generation of the leukemic xenograft model. Indeed, longevity of AML characteristics, as well as sufficient stem cells in the xenograft model, should be guaranteed to analyze the therapeutic response to a drug. Therefore, we examined whether leukapheresed peripheral blood (LPB) consists of reliable leukemic stem cells (LSCs) and ALDHdim‑expressing CD34+CD38- cells, and functions in grafting human AML with virulence compared to that of BM. LPB cells showed an advantage for the xenograft mouse model with AML cell homing, engraftment and a high human ALDHdim-expressing CD34+CD38- cell population, suggesting an alternative cell source to BM. Overall, this xenograft model using LPB offers the possibility of overcoming the small volume limitation of BM and prevents individual variation by using a single LPB sample. This result is noteworthy in identifying cell sources capable of generating a stable xenograft model.

ObjectivesChronic degenerative diseases are closely related to daily eating habits, nutritional status, and, in particular, energy intake. In clarifying these relationships it is very important for dietary surveys to report accurate information about energy intake. This study attempted to identify the prevalence of the under-reporting of energy intake and its related characteristics based on the Korean National Health and Nutrition Examination Survey conducted in the years 2007–2009.MethodsThe present study analyzed dietary intake data from 15,133 adults aged ≥19 years using 24-hour dietary recalls. Basal metabolic rates were calculated from the age- and gender-specific equations of Schofield and under-reporting was defined as an energy intake

The development of new improved varieties is one of the major goals of plant breeding. Concomitantly, the demand for stable, eco-friendly, and high-quality rice production is constantly increasing. However, most farmers prefer to cultivate familiar rice varieties developed more than 10 years ago to minimize economic risk. A strategy is needed to develop rice varieties without the limitations of the preferred old varieties. Here, we tested the rapid development of near isogenic lines (NILs) using a rapid generation advance system together with marker-assisted backcrossing to overcome the shortcomings of parental materials. For this purpose, we chose rice stripe virus (RSV) susceptible variety Unkwang and RSV resistant variety Haedamssal as experimental materials. First, we backcrossed and screened BC1F1 and BC2F1 plants having similar agronomic traits as Unkwang and the heterozygous genotype for RSV resistant specific marker InDel7 from Haedamssal. Secondly, the genetic background of 11 BC2F1 plants was identified with 73 KASP markers; plants of line YR32548-8 showed 84.5% of recovery of the recurrent parent genome. Among 28 BC2F2 plants, YR32548-8-16 was the line that showed maximum recovery of the recurrent parent genome (96.2%) while effectively introgressed with RSV-resistance loci on chromosome 11. Finally, we selected line YR32548-8-16 as an NIL showing an RSV resistant phenotype and similar agronomic traits to Unkwang. This fast breeding approach will be useful in rice breeding programs for the improvement of varieties preferred by farmers for their stress tolerance, yield, or quality.

Internet gaming disorder (IGD) has become the subject of growing concern as an addictive behavior and has been compared with substance/non-substance-related addiction. Although IGD show clinical impairments and social dysfunction, neurobiological alterations in IGD have not been clearly elucidated. We used 18F-fluorodeoxyglucose PET to investigate differences in glucose metabolism and metabolic connectivity in young men [thirty-six patients with IGD, twenty-six patients with alcohol use disorder (AUD) and thirty-nine healthy controls (HC)]. Compared with the HC, IGD showed hypometabolism in the anterior cingulate cortex (ACC), temporal, frontal, parietal and striatum and AUD exhibited hypometabolism in the occipital, temporal and parietal lobule. Furthermore, IGD showed negative correlations between the ACC and game duration and between the orbitofrontal cortex and impulsivity. Also, IGD had lower metabolic connectivity between temporal and limbic regions and between the motor area and occipital region. And AUD showed greater metabolic connectivity between the orbitofrontal and parietal regions, and between the somatosensory or parietal and temporal regions, but lower metabolic connectivity in the fronto-striatal or fronto-limbic regions. Our results provide evidences that hypometabolism and altered metabolic connectivity in IGD might be related to the abnormal sensory function by longtime gaming and dysfunction of impulsive/motivational states.

Background Although internet gaming disorder (IGD) is considered an addictive disorder, evidence of the neurobiological underpinnings of IGD as an addictive disorder is currently lacking. We investigated whether attentional bias toward game-related stimuli was altered in IGD patients using an eye-tracking method during an anti-saccade task. Methods Twenty-three IGD patients and 27 healthy control (HC) subjects participated in the anti-saccade task with game-related, neutral, and scrambled images during eye tracking. Participants rated subjective scores of valence, arousal, and craving for each image stimulus after finishing eye tracking. Mixed design analysis of variance was performed to compare the differences between eye movement latency and error rate in the pro-saccade and anti-saccade conditions according to image type across the IGD and HC groups. Results In the anti-saccade task, the IGD group exhibited higher error rates in the case of game-related images than in neutral or scrambled images. However, ratings on valence, arousal, and craving did not vary among image types. The error rates of the HCs did not vary across image types, but higher arousal/craving and lower valence were reported with respect to the game-related images. Conclusions Increased error rate during anti-saccade tasks with game-related stimuli in IGD may be due to disabilities in goal-directed behavior or inhibitory control, as observed in other addictive disorders. These findings suggest that attentional bias toward game-related stimuli can be a sensitive biological marker of IGD as an addictive disorder.

Introduction: Major depressive disorder (MDD) is a common condition worldwide, and leads to degradation in quality of life and large socioeconomic costs. There has been increasing demand for new therapies with fewer side effects. SOCG (SOCG tablet) is a modified prescription of So-ochim-tang, which is widely used in Traditional Korean Medicine to treat MDD. We aim to evaluate the efficacy of SOCG in treating MDD, and identify the optimum dose. Design: The protocol we are following is that of a Phase II clinical trial with a randomized, double blinded, placebo controlled, and parallel design. One hundred forty-eight participants will be randomly divided into 4 groups and treated for 8 weeks. Outcome measures: The primary outcome will be the score in the Korean Version of the Hamilton Depression Rating Scale. Scores in the Korean version of the Beck Depression Inventory-II Korean Symptom Check List-95 (KSCL-95), State Trait Anxiety Inventory-Korean version, State- Trait Anger Expression Inventory- Korean version (STAXI-K), Insomnia Severity Index (ISI), and the EuroQol-5 Dimension (EQ-5D) will be considered as secondary outcomes. Discussion and Conclusions: Demonstration of human safety and efficacy of SOCG in the present trial and identification of the appropriate dose will justify a New Drug Application and a phase III clinical trial. Further, we expect that this new antidepressant will be able to increase cure rates, and alleviate the burden of medical expenses. Trial registration number: Clinical Research Information Service, Republic of Korea (KCT0002763).

Objectives Because primary mesenchymal progenitor cells (adult‐MPCs) have various functions that depend on the tissue origin and donor, de novo MPCs from human pluripotent stem cells (hPSCs) would be required in regenerative medicine. However, the characteristics and function of MPCs derived from reprogrammed hPSCs have not been well studied. Thus, we show that functional MPCs can be successfully established from a single cell‐derived clonal expansion following MPC derivation from somatic cell nuclear transfer‐derived (SCNT)‐hPSCs, and these cells can serve as therapeutic contributors in an animal model of Asherman's syndrome (AS). Materials and methods We developed single cell‐derived clonal expansion following MPC derivation from SCNT‐hPSCs to offer a pure population and a higher biological activity. Additionally, we investigated the therapeutic effects of SCNT‐hPSC‐MPCs in model mice of Asherman's syndrome (AS), which is characterized by synechiae or fibrosis with endometrial injury. Results Their humoral effects in proliferating host cells encouraged angiogenesis and decreased pro‐inflammatory factors via a host‐dependent mechanism, resulting in reduction in AS. We also addressed that cellular activities such as the cell proliferation and population doubling of SCNT‐hPSC‐MPCs resemble those of human embryonic stem cell‐derived MPCs (hESC‐MPCs) and are much higher than those of adult‐MPCs. Conclusions Somatic cell nuclear transfer‐derived‐hPSCs‐MPCs could be an advanced therapeutic strategy for specific diseases in the field of regenerative medicine.

Indium zinc oxide (IZO) thin films were fabricated via self-combustion of In and Zn salts coordinated with fuel and oxidizer ligands. The intense heat generated from the exothermic reaction compensated for the energy required for oxide formation and reduced the temperature required to anneal the oxide films. Thermal analysis of the fuel and oxidizer precursors confirmed the generation of exothermic heat at a relatively low annealing temperature. With the aid of the internal energy that evolved as heat from the combustion reaction, the formation of the metal–oxygen–metal lattice and the removal of organic ligands could be easily accomplished with lower amounts of externally supplied energy. IZO thin-film transistors (TFTs), obtained from this combustive In–Zn pair at a low annealing temperature of 350 °C, showed a significantly enhanced field-effect mobility of 13.8 cm2 V−1 s−1 and a high on/off current ratio of 1.06 × 108. Inkjet printing of the combustive precursors yielded TFTs with a high field-effect mobility of 5.3 cm2 V−1 s−1 and an on/off ratio of 106. The high performance, good device uniformity, and high yield of TFTs fabricated by our self-combustion method demonstrate the potential of the proposed system to facilitate the processing of flexible printed electronics.

We aimed to develop a cell culture model of type 2 diabetes by treating SK-Hep-1 cells with four free fatty acids [i.e., palmitic acid, stearic acid (SA), linoleic acid and oleic acid]. The results showed that Akt phosphorylation was increased in SK-Hep-1 cells treated with insulin in a time- and concentration-dependent manner, which was inhibited by saturated fatty acids, but not by unsaturated fatty acids. Moreover, protein levels of NADPH oxidase (NOX) 4 but not NOX2 were increased following SA treatment and, consequently, increased reactive oxygen species production and decreased cellular glutathione were observed. Apocynin, a NOX4 inhibitor, restored the SA-induced inhibition of Akt phosphorylation, suggesting the role of NOX4 in insulin resistance induced by SA. Neither phosphorylation level nor protein level of the stress signaling kinases, such as c-Jun N-terminal kinase or p38 mitogen activated protein kinase, was changed by SA treatment. Although binding immunoglobulin protein, a marker of endoplasmic reticulum stress, was transiently increased in SKHep-1 cells treated with SA, 4-phenyl butyric acid, a chemical chaperone, had no effect on the insulin-mediated Akt phosphorylation inhibited by SA. The present study provides a useful model for screening anti-insulin resistance drugs and finding new drug targets for treatment of diabetes.