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To investigate the regulatory effects of anagliptin, a DPP-IV inhibitor used to treat type 2 diabetes mellitus (T2DM), on myoblast differentiation and mitochondrial biogenesis in C2C12 mouse skeletal muscle cells. C2C12 myoblasts were differentiated into myotubes and then treated with anagliptin (10, 25, and 50 μmol/L) for 24 hours. In C2C12 myotubes, anagliptin treatment was significantly increased the expression of MHC, PGC1α, Sirt-1, NRF-1, and TFAM and the phosphorylation of AMPK and ACC in a concentration-dependent manner. Anagliptin also significantly increased the total ATP levels in the myotubes. These results suggest that anagliptin can help prevent skeletal muscle dysfunction in T2DM by promotion of myoblast differentiation and enhancement of energy production via upregulation of mitochondrial biogenetic factors and activation of the AMPK/ACC signalling pathway.

Aims and objectives This study attempts to develop and determine the effect a rational-emotive-behaviour-therapy-based self-management programme can have on the self-efficacy, self-care, depression and dyssomnia of patients undergoing early renal dialysis. Background When renal dialysis is initiated, changes in everyday life are inevitable, and patients can suffer from both psychological and physical symptoms. Hence, to obtain the best results from renal dialysis, active self-management is required. Design Quasi-experimental and longitudinal. Methods Forty-eight early-stage renal dialysis patients registered for and undergoing renal dialysis at a hospital located in S city participated in this study. These individuals were divided into an experimental and control group. The former group engaged in a self-management programme consisting of eight weekly sessions of 50 min in duration, while the latter received traditional nursing care. Data were collected from June 2012-May 2014 through the use of a preliminary survey, a postsurvey that was distributed after the eight sessions of the self-management programme had been completed, and a follow-up survey allocated 4 weeks after the postsurvey. Data collection was conducted using the Self-efficacy Scale, Self-care Practice Scale, Beck Depression Inventory, and Korean Sleep Scale, and a repeated-measures ANOVA was used to perform analysis. Results The experimental group significantly differed from the control group in regard to self-efficacy (p = 0.006) and self-care (p = 0.031), but differences in terms of depression (p = 0.492) and dyssomnia (p = 0.141) were nonsignificant. In the experimental group, the depression decreased but then increased again, while the dyssomnia gradually decreased. Conclusions The provision of a rational-emotive-behaviour-therapy-based self-management programme that involves lectures, discussions, teach-backs, demonstrations and posters explaining diet choices improves the self-efficacy and self-care of patients receiving renal dialysis. Relevance to clinical practice Rational-emotive-behaviour-therapy-based self-management programmes can be used in clinical nursing sites to improve the self-efficacy and self-care of early renal dialysis patients.

Background Gemigliptin is a new dipeptidyl peptidase-IV inhibitor. We investigated the efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes (T2D). Methods A total of 433 T2D patients with a glycosylated haemoglobin (HbA1c) level of 7.5% to 11.0% and a fasting plasma glucose (FPG) concentration

C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling. Expression of integrin α2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin α2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcγ receptor Fcγ receptor I (FcγRI), and induces activation of paxillin, FAK and ERKs. Integrin α2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcγRI and integrin α2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin α2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB-231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin α2 and FcγRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment.

Elevated expression and aberrant activation of Ras have been implicated in breast cancer aggressiveness. H-Ras, but not N-Ras, induces breast cell invasion. A crucial link between lipid rafts and H-Ras function has been suggested. This study sought to identify the lipid raft protein(s) responsible for H-Ras-induced tumorigenicity and invasiveness of breast cancer. We conducted a comparative proteomic analysis of lipid raft proteins from invasive MCF10A human breast epithelial cells engineered to express active H-Ras and non-invasive cells expressing active N-Ras. Here, we identified a lipid raft protein flotillin-1 as an important regulator of H-Ras activation and breast cell invasion. Flotillin-1 was required for epidermal growth factor-induced activation of H-Ras, but not that of N-Ras, in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Flotillin-1 knockdown inhibited the invasiveness of MDA-MB-231 and Hs578T TNBC cells in vitro and in vivo. In xenograft mouse tumor models of these TNBC cell lines, we showed that flotillin-1 played a critical role in tumor growth. Using human breast cancer samples, we provided clinical evidence for the metastatic potential of flotillin-1. Membrane staining of flotillin-1 was positively correlated with metastatic spread (p = 0.013) and inversely correlated with patient disease-free survival rates (p = 0.005). Expression of flotillin-1 was associated with H-Ras in breast cancer, especially in TNBC (p

Background and Aim Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is interrelated with renal dysfunction and disturbed bone metabolism, both of which play a key role in calcium and phosphorus homeostasis. We investigated the association between NAFLD and serum calcium and phosphorus levels in Korean subjects. Methods We performed a cross-sectional analysis of 16 592 subjects undergoing a general health checkup. NAFLD was assessed based on ultrasonographically detected fatty liver in the absence of excessive alcohol consumption and other causes of liver disease. Results The proportion of the population with fatty liver detected by ultrasonography was 43.2% for males and 17.6% for females. We observed that a higher serum albumin-corrected calcium (Cac) level was associated with smoking, hypertension, and unfavorable metabolic parameters in both genders, but the serum phosphorus levels showed an inconsistent correlation with metabolic abnormalities. After adjusting for age, gender, waist circumference, body mass index, smoking status, exercise, diabetes, hypertension, lipid profiles, and renal function, serum Cac, phosphorus, and Cac-phosphorus products were independent risk factors for fatty liver (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.49–1.95, P

Aims/Introduction Early initiation of basal insulin therapy is recommended for normalizing fasting blood glucose in type 2 diabetes mellitus. However, basal insulin treatment might not adequately control postprandial glucose levels. The present study evaluated whether the combination of the α-glucosidase inhibitor, acarbose, and basal insulin improved blood glucose control under daily-life treatment conditions in a large sample of Korean patients. Materials and Methods The present study was a multicenter, prospective, observational study under daily-life treatment conditions. A total of 539 patients with type 2 diabetes who were treated with basal insulin and additional acarbose were enrolled and followed up for 20 weeks. Changes in hemoglobin A1c, fasting and postprandial blood glucose were evaluated at baseline and at the end of the observation period. The physician and patient satisfaction of the combination treatment and safety were assessed. Results Hemoglobin A1c decreased by 0.55 ± 1.05% from baseline (P

Background Recent advances in genetics revealed that 25% to 30% of head and neck paragangliomas (PGLs) are inherited tumors associated with germline mutation, mainly in the succinate dehydrogenase (SDH) gene. Methods DNA was isolated from whole blood and polymerase chain reaction (PCR) products were sequenced with an ABI3730 × 1 Genetic Analyzer. Results A 30-year-old Korean woman underwent resection of a carotid PGL. Fourteen years later, she was readmitted for a cervical mass. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT revealed a hot spot in the adrenal gland, besides the carotid mass. Surgical pathology confirmed recurrence of the carotid PGL and a concomitant pheochromocytoma. Genetic analysis revealed SDHD c.119del T (p.I40TfsX46) mutation. One daughter has been identified as a carrier. Conclusion We found a novel SDHD mutation from a Korean family that shows similar clinical features to those in other SDHD mutations, mostly from Western countries. Further studies are needed to determine whether similar genotype-phenotype correlations exist in the Asian patients with familial PGLs. © 2014 Wiley Periodicals, Inc. Head Neck 36: E131–E135, 2014

Background Signal transducer and activator of transcription-1 (STAT1) plays a critical role in tumorigenesis by controlling several functions in both tumor cells and the immune system, and is considered to be a tumor suppressor. The present study evaluated the activity of STAT1 in human papillary thyroid carcinomas (PTC). Methods STAT1 activity was measured in nuclear extracts of tumor tissues from 35 PTC patients using an ELISA-based kit. Results STAT1 activity was significantly lower in tumors than in the surrounding normal thyroid tissues (P

Lipopolysaccharide (LPS) triggers deleterious systemic inflammatory responses when released into the circulation. LPS-binding protein (LBP) in the serum plays an important role in modifying LPS toxicity by facilitating its interaction with LPS signaling receptors, which are expressed on the surface of LPS-responsive cells. We have previously demonstrated that high mobility group box 1 (HMGB1) can bind to and transfer LPS, consequently increasing LPS-induced TNF-α production in human peripheral blood mononuclear cells (PBMCs). We report here on the identification of two LPS-binding domains within HMGB1. Furthermore, using 12 synthetic HMGB1 peptides, we define the LPS-binding regions within each domain. Among them, synthetic peptides HPep1 and HPep6, which are located in the A and B box domains of HMGB1, bind to the polysaccharide and lipid A moieties of LPS respectively. Both HPep1 and HPep6 peptides inhibited binding of LPS to LBP and HMGB1, LBP-mediated LPS transfer to CD14, and cellular uptake of LPS in RAW264.7 cells. These peptides also inhibited LPS-induced TNF-α release in human PBMCs and induced lower levels of TNF-α in the serum in a subclinical endotoxemia mouse model. These results indicate that HMGB1 has two LPS-binding peptide regions that can be utilized to design anti-sepsis or LPS-neutralizing therapeutics.

Summary Streptomyces coelicolor produces an extracellular protease inhibitor protein, STI (Streptomyces trypsin inhibitor). We show that post-growth elimination of STI is needed for colonies to develop aerial mycelium efficiently. Inactivation of STI, and thus the normal progression of colony development, at least partly involves an extracellular protease specified by gene SCO5913. Two-hybrid analysis identified two possible targets of STI inhibition (the products of SCO1355 and SCO5447), both extracellular proteases containing a domain homologous with the P-domain of eukaryotic convertases, proteases that mediate the processing of many precursors with important cellular or developmental roles. At least the SCO1355 protease is needed for the normal progression of development. Two components of the proposed cascade are dependent on the tRNA for the rare UUA (leucine) codon, which is specified by the developmental gene bldA. A model is presented that links intracellular regulatory events with an extracellular protease cascade to facilitate normal development.

Recent studies have shown that keratinocytes can sense temperature via thermo-transient receptor potential (TRP) channels. It is not known whether other thermosensitive ion channels such as TREK-1, TREK-2 and TRAAK (TREKs/TRAAK) that are members of the two-pore domain K(+) (K(2P)) channel family are expressed in human keratinocytes. Here, we identified the expression of TREKs/TRAAK in human keratinocytes-derived cell line HaCaT cells using RT-PCR, immunocytochemistry, Western blot analysis and patch-clamp technique. RT-PCR showed that all six K(2P) channels tested (TASK-1, TASK-3, TREK-1, TREK-2, TRAAK and TASK-2) were expressed in HaCaT cells, as well as in skin and dorsal root ganglion (DRG) of rat. The expression of TREKs/TRAAK mRNA identified by RT-PCR was further studied at the protein level. Using anti-TREK-1, -TREK-2 and -TRAAK, bands of approximately 46, approximately 60 and approximately 43 kDa, respectively, were observed at plasma membrane of HaCaT cells. Immunostaining also showed that TREK-1, TREK-2 and TRAAK were expressed in all area of cells including plasma membrane. Whole-cell K(+) currents recorded from HaCaT cells were activated by arachidonic acid and heat. These results suggest that TREKs/TRAAK channels could act as thermosensors in human keratinocytes.

During the search for anticholinesterase compounds from marine organisms, two known plastoquinones, sargaquinoic acid (1) and sargachromenol (2), were isolated from Sargassum sagamianum. Both compounds showed moderate acetylcholinesterase (AChE) inhibitory activity in a micromole range (IC50 23.2 and 32.7 µm, respectively). However, for butyrylcholinesterase (BuChE), a new target for the treatment of Alzheimer's disease (AD), compound 1 showed particularly potent inhibitory activity (IC50 26 nm), which is 1000-fold greater than for AChE. Hence, sargaquinoic acid represents an effective and selective inhibitor of BuChE with a potency similar to or greater than the anticholinesterases in current clinical use, making it an interesting potential drug candidate for AD. Copyright © 2007 John Wiley & Sons, Ltd.

The present study aimed to elucidate the molecular link between S1P and CRP during the invasive process of breast epithelial cells. This is the first report showing that transcription of CRP was ma...

Summary background In some instances, thyroid cancer may be diagnosed with histological examination after resection of putative or suspected benign nodule. In these cases, completion thyroidectomy followed by radioiodine ablation is usually recommended to prevent recurrence. If small intrathyroidal cancer is found, completion thyroidectomy may not be performed. Many patients have separate cancers in the contralateral lobe and in these cases completion thyroidectomy is essential even though primary tumour is small and limited within thyroid. objective We analysed the frequency of malignant lesions in the contralateral lobe after completion thyroidectomy and assessed the predictive factors that may anticipate the presence of malignant lesion that may necessitate completion thyroidectomy. patients Between 1995 and 2001, 243 patients were operated under the cytological diagnosis of follicular neoplasm. A total of 214 of them underwent lobectomy and isthmectomy and 81 turned out to have malignant disease in the resected lobe and they underwent completion thyroidectomy within a week to 6 months after the permanent section diagnosis of cancer. Their mean age was 40·7 ± 12·1 years (range 14–71 years). results After initial surgery, 53 patients had follicular carcinoma, 24 papillary carcinoma, one Hurthle cell carcinoma, one medullary, one insular and one anaplastic carcinoma. Mean tumour size was 4·1 ± 2·6 cm (range 0·9–11 cm). After completion thyroidectomy, factors predicting the presence of cancer in the contralateral lobe were assessed according to clinical parameters and pathologic findings in ipsilateral lobe. First surgery revealed cancer multifocality in 34 cases, perithyroidal tumour extension in six and regional lymph node metastases in three. After completion thyroidectomy, 29 of the 81 patients revealed additional cancer in the contralateral lobe. Age, sex, size or pathologic type of the primary tumour was not associated with the presence of additional tumour in the contralateral lobe. Cancer multifocality in the ipsilateral lobe was the only significant variable to predict the presence of additional cancer in the contralateral lobe (relative risk = 6·03, confidence interval 2·23–16·35). Coexistence of benign nodule in ipsilateral lobe was not associated with increased cancer risk in the contralateral lobe. conclusions When diagnosed as thyroid cancer after unilateral surgery, the only predictive factor for the presence of additional contralateral cancer was multifocality of cancer in the ipsilateral lobe. We suggest that completion thyroidectomy is mandatory if multifocal cancers are found in the resected lobe, even though the cancers are very small and limited within the thyroid.

Summary objective Previous studies have shown a high rate of visualization of uptake and a decrease in serum thyroglobulin (Tg) after therapeutic doses of 131I in well-differentiated thyroid cancer patients with elevated thyroglobulinaemia but negative diagnostic 131I whole-body scan (DxWBS), but its therapeutic effect remains controversial. We evaluate the effect of therapeutic doses of 131I in patients with elevated thyroglobulin level but negative DxWBS. design Among papillary thyroid carcinoma patients who underwent total or near-total thyroidectomy and remnant ablation with radioiodine during 1996 to 2000 in our hospital, the patients who showed elevated serum Tg levels and no abnormal uptake in DxWBS were selected. The selection for treatment or no treatment was decided according to the preference of the patients, considering side-effects of therapeutic doses of 131I, and the patients were thereafter studied retrospectively. patients Sixty papillary thyroid carcinoma patients with elevated thyroglobulinaemia but negative DxWBS were included. Twenty-eight patients were treated, and 32 were untreated. measurements We compared serum Tg levels measured at less than 3 months before the administration of therapeutic doses of 131I or DxWBS with the levels at 6–12 months after administration between two groups. Comparable data on changes in serum Tg levels during TSH suppression (Tg-on) and those in hypothyroid phase (Tg-off) were available in 25 and 49 patients, respectively. results Percentage decreases in both Tg-on and Tg-off levels of the treated group [41·2 (10·1–94·1)% and 37·0 (−176·6–88·4)%, respectively] were significantly higher than those of the untreated group [−43·6 (−180·1–7·3)% and −66·6 (−10644·2–39·1)%, respectively] (P

Recent evidence suggests that inflammation is involved in malignant progression of breast cancer. Sphingosine 1-phosphate (S1P), acting on the G-protein-coupled receptors, is known as a potent inflammatory mediator. In this study, the effect of the inflammatory lipid S1P on the regulation of invasive/migratory phenotypes of MCF10A human breast epithelial cells was investigated to elucidate a causal relationship between inflammation and the control of invasiveness of breast cells. We show that S1P causes induction of matrix metalloproteinase-9 (MMP-9) in vitro and in vivo, and thus enhances invasion and migration. We also show that fos plays a crucial role in the transcriptional activation of MMP-9 by S1P. In addition, activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2), p38 and alpha serine/threonine-protein kinase (Akt) are involved in the process of S1P-mediated induction of MMP-9 expression and invasion. Activation of the S1P receptor S1P3 and Gαq are required for S1P-induced invasive/migratory responses, suggesting that the enhancement of S1P-mediated invasiveness is triggered by the specific coupling of S1P3 to the heterotrimeric Gαq subunit. Activation of phospholipase C-β4 and intracellular Ca2+ release are required for S1P-induced MMP-9 upregulation. Taken together, this study demonstrated that S1P regulates MMP-9 induction and invasiveness through coupling of S1P3 and Gαq in MCF10A cells, thus providing a molecular basis for the crucial role of S1P in promoting breast cell invasion.

Caspase 3, a member of cysteine protease family, is well known as a major apoptosis effector and is involved in cell death as a result of ischemic diseases such as stroke and myocardial infarction, therefore the inhibition of caspase 3 may protect those apoptotic cell damages. During the high-throughput screening of the compounds from the Korea Chemical Bank, berberine derivatives (A and B), an isoquinoline alkaloid, have been identified as potential inhibitors for caspase 3. Based on this finding we carried out molecular modeling study to identify the pharmacophoric elements of berberine structure which interact with a substrate-recognition binding site of caspase 3 and came up with several novel scaffolds. In this report, we will discuss the molecular modeling, syntheses and the enzyme inhibitory activities of these novel compounds.

To develop new anticancer agents, 3-allylthio-6-aminopyridazine derivatives were synthesized from maleic anhydrides or phthalic anhydrides by formation of a pyridazine nucleus, dichlorination, allylthiolation and amination. The pyridazine nuclei were obtained by condensing a hydrazine monohydrate with maleic anhydride. An allylthio group as a pharmacologically active group was introduced into one side of a pyridazine ring. Arylalkylamines with benzene or pyridine moieties or heterocycloalkylamines with heterocycle moieties such as morpholine, piperidine, or pyrrolidine were also introduced into the para-position of allylthio pyridazine. These new compounds showed antiproliferative activities against SK-Hep-1 human liver cancer cells in MTT assays. These compounds are thus promising candidates for chemotherapy of hepatocellular carcinomas. Two compounds, 20c and 22a, showed higher potencies for inhibiting growth of hepatocellular carcinoma cells than did K6 (ID 50 =1.08 mM). This suggests the potential anticancer activity of these two compounds.