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Insulin is a peptide hormone produced by beta cells of the pancreas. The roles of insulin in energy metabolism have been well studied, with most of the attention focused on glucose utilization, but the roles of insulin in cell proliferation and differentiation remain unclear. In this study, we observed for the first time that 10 nmol/L insulin treatment induces cell proliferation and cardiac differentiation of P19 CL6 cells, whereas 50 and 100 nmol/L insulin treatment induces P19 CL6 cell apoptosis and blocks cardiac differentiation of P19 CL6 cells. By using real-time polymerase chain reaction ( PCR) and Western blotting analysis, we found that the m RNA levels of cyclin D1 and α myosin heavy chain (α- MHC) are induced upon 10 nmol/L insulin stimulation and inhibited upon 50/100 nmol/L insulin treatment, whereas the m RNA levels of BCL-2-antagonist of cell death ( BAD) exists a reverse trend. The similar results were observed in P19 CL6 cells expressing GATA-6 or peroxisome proliferator-activated receptor α ( PPARα). Our results identified the downstream targets of insulin, cyclin D1, BAD, α- MHC, and GATA-4, elucidate a novel molecular mechanism of insulin in promoting cell proliferation and differentiation. [ABSTRACT FROM AUTHOR]

Aim:To investigate the reverse mode function of Na+/Ca2+ exchangers NCX1.1 and NCX1.5 expressed in CHO cells as well as their modulations by PKC and PKA.Methods:CHO-K1 cells were transfected with pcDNA3.1 (+) plasmid carrying cDNA of rat cardiac NCX1.1 and brain NCX1.5. The expression of NCX1.1 and NCX1.5 was examined using Western blot analysis. The intracellular Ca2+ level ([Ca2+]i) was measured using Ca2+ imaging. Whole-cell NCX currents were recorded using patch-clamp technique. Reverse mode NCX activity was elicited by perfusion with Na+-free medium. Ca2+ paradox was induced by Ca2+-free EBSS medium, followed by Ca2+-containing solution (1.8 or 3.8 mmol/L CaCl2).Results:The protein levels of NCX1.1 and NCX1.5 expressed in CHO cells had no significant difference. The reverse modes of NCX1.1 and NCX1.5 in CHO cells exhibited a transient increase of [Ca2+]i, which was followed by a Ca2+ level plateau at higher external Ca2+ concentrations. In contrast, the wild type CHO cells showed a steady increase of [Ca2+]i at higher external Ca2+ concentrations. The PKC activator PMA (0.3-10 μmol/L) and PKA activator 8-Br-cAMP (10-100 μmol/L) significantly enhanced the reverse mode activity of NCX1.1 and NCX1.5 in CHO cells. NCX1.1 was 2.4-fold more sensitive to PKC activation than NCX1.5, whereas the sensitivity of the two NCX isoforms to PKA activation had no difference. Both PKC- and PKA-enhanced NCX reverse mode activities in CHO cells were suppressed by NCX inhibitor KB-R7943 (30 μmol/L).Conclusion:Both NCX1.1 and NCX1.5 are functional in regulating and maintaining stable [Ca2+]i in CHO cells and differentially regulated by PKA and PKC. The two NCX isoforms might be useful drug targets for heart and brain protection. [ABSTRACT FROM AUTHOR]

With daily precipitation records at 586 stations in China for 1960-2004, this study investigates the spatio-temporal variation of the number of extreme wet days (NEWD) for each season in China and its relationship with SST anomalies and associated atmospheric circulation anomaly patterns, in which a threshold of extreme precipitation for a season and a station is defined as the value of the 90th percentile when the precipitation records for wet days during the season are ranked in an increasing order. Results show that there are significant increases of the NEWD along the Yangtze River valley during winter and summer, in North China during winter, in South China during spring, in Northeast China during winter and spring, and in Northwest China throughout the seasons, while there is a remarkable decrease in North China during summer. Besides the linear trend, the NEWD also exhibits considerable interannual and interdecadal variabilities. After eliminating the linear trend, the NEWD anomalies show distinct seasonal patterns. The NEWD anomalies are characterized by a "dipole" mode with opposite phases between northern and southern China in spring and autumn, a "tri-pole" mode with opposite phases between Yangtze River valley and southern and northern China in summer, and a "monopole" mode with the same phase over most of China in winter. The relationship of the NEWD anomalies in China with the SST anomalies in Indian and Pacific Oceans is found to be mainly dependent on the ENSO, and associated atmospheric circulation anomaly patterns for the ENSO's impact on the NEWD in China are identified. [ABSTRACT FROM AUTHOR]

Abstract: Since the estimation of distribution algorithm(EDA) was introduced, different approaches for continuous problems solving have been developed. Through the efforts of many scholars, the EDAs brought some success in continuous domain, but there are still some deficiencies: Gaussian-based EDA doesn’t perform well in problems with many optima, such as Schwefel function; histogram-based EDA doesn’t perform well in problems with singular global optimum, such as Three-Peak function. Because of this, based on improved histogram-based EDA and referred to the idea of k-Means clustering, we built cooperative EDA. Experimental results showed that the improved algorithm in this paper can give comparable with or better performance than those improved algorithms. [Copyright &y& Elsevier]

Abstract: To solve the problem of Bayesian network structure learning with uncertain prior information, a new structure learning method is proposed. In this paper, first the deficiency of current methods that used for gathering prior information is discussed, and a new method of gathering prior information based on belief map is proposed; second minimum description length principle is modified so that it can fuse uncertain prior information; third simulated annealing is modified according to the character of the problem needed to solve and used to search the required structure; last the new structure method is validated by experiments. [Copyright &y& Elsevier]

Characteristics and inadequateness of present score functions in the vague set theory are analyzed, and main factors of score functions are discussed. From the perspective of risk aversion and considering the effect of uncertainty degree, the concept of vague value expectation is proposed and a risk aversion type score function constructed based on it. The character of the new score function is discussed and an example is given showing that it can reflect the decision-making preferences and maintain the consistency of the decision making method. [ABSTRACT FROM AUTHOR]

Agmatine is an endogenous amine derived from decarboxylation of arginine catalysed by arginine decarboxylase. Agmatine is considered a novel neuromodulator and possesses neuroprotective properties in the central nervous system. The present study examined whether agmatine has neuroprotective effects against repeated restraint stress-induced morphological changes in rat medial prefrontal cortex and hippocampus. Sprague-Dawley rats were subjected to 6 h of restraint stress daily for 21 days. Immunohistochemical staining with β-tubulin III showed that repeated restraint stress caused marked morphological alterations in the medial prefrontal cortex and hippocampus. Stress-induced alterations were prevented by simultaneous treatment with agmatine (50 mg/kg/day, i.p.). Interestingly, endogenous agmatine levels, as measured by high-performance liquid chromatography, in the prefrontal cortex and hippocampus as well as in the striatum and hypothalamus of repeated restraint rats were significantly reduced as compared with the controls. Reduced endogenous agmatine levels in repeated restraint animals were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. Moreover, administration of exogenous agmatine to restrained rats abolished increases of arginine decarboxylase protein levels. Taken together, these results demonstrate that exogenously administered agmatine has neuroprotective effects against repeated restraint-induced structural changes in the medial prefrontal cortex and hippocampus. These findings indicate that stress-induced reductions in endogenous agmatine levels in the rat brain may play a permissive role in neuronal pathology induced by repeated restraint stress. [ABSTRACT FROM AUTHOR]

Abstract: Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-d-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 μM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property. [Copyright &y& Elsevier]

Abstract: ISL1 is a LIM homeodomain protein that plays an important role in insulin gene transcriptional activation and islet cell formation. BETA2 is a transcription factor in the basic helix–loop–helix (bHLH) family, which activates expression of tissue-specific genes in several developmental systems. In this study, we investigated the functional and physical interactions of ISL1 and BETA2 in promoting insulin gene transcription in non-β cells. Using the luciferase assay, we demonstrated that ISL1 and BETA2 could activate insulin gene transcription synergistically. Co-immunoprecipitation also supported that ISL1 and BETA2 appear in one complex and this physical interaction mediates the synergy between these two proteins. [Copyright &y& Elsevier]

Abstract: Activity and expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis, are modified in response to antidepressant-treatment. We examined effects of the selective norepinephrine-transporter (NET) inhibitor antidepressant desipramine (DMI) on expression of TH in human neuroblastoma cells (SK-N-BE[2]M17) and in rat brain regions. TH mRNA levels were determined by Northern blot in vitro, and by in situ hybridization ex vivo; TH protein levels were measured by western blot. Brief exposure of neuroblastoma cells to 0 vs. 5, 50, or 500 nM of DMI had little effect on TH mRNA levels, but exposure to 50 and 500 nM DMI for 14 days increased the mRNA by up to 72%, with a continuous rise from 3 to 14 days of exposure to 500 nM DMI. In contrast, 500 nM DMI led to an initial slight increase, followed by a continuous and sustained decrease in TH protein level by up to 53%, from day 3 to day 14. Daily treatment of rats with DMI (10 mg/kg, i.p.) for 3 or 14 days significantly increased postmortem cerebral TH mRNA in the locus coeruleus (LC) area by 47–68%. Again, TH protein concentrations in LC decreased at 3 and 14 days, by 25–40%, with transient significant reduction in amygdala tissue after 3 days of treatment that were not sustained. These findings indicate that DMI exerts complex, typically opposite and perhaps compensatory, gradually evolving effects on the expression of TH protein (decreases) and its message (increases), possibly in response to increased synaptic availability of NE. [Copyright &y& Elsevier]

Arachidonic acid release from membrane phospholipids is essential for tumour cell proliferation. Lipoxygenases constitute a pathway for arachidonate metabolism. The present study investigated the expression of 12-lipoxygenase and its effect on cell proliferation as well as survival in two human gastric cancer cell lines (AGS and MKN-28). RT–PCR and western blots, respectively, showed 12-LOX mRNA and protein expression in both AGS and MKN-28 cell lines. Treatment with a 12-LOX inhibitor, baicalein, significantly inhibited cancer cell proliferation, but a metabolite of 12-LOX activity, 12 hydroxyeicosatetraenoic acid (12-HETE) reversed baicalein-induced growth inhibition. Furthermore, the blockade of the 12-LOX pathway through a 12-LOX inhibitor and antisense induced apoptosis of gastric cancer cell lines. The biochemical characteristics of apoptosis were p53-independent combined with a decrease in bcl-2 expression. Caspase-7 was proteolytically activated and responsible for the apoptosis execution. [ABSTRACT FROM PUBLISHER]

Presents information on a study which investigated the involvement of heat-shock proteins in the mediation of delayed cardioprotection of K-opioid receptor stimulation. Materials and methods; Results; Discussion.

Objective: This study was conducted to investigate key long noncoding RNAs (lncRNAs) involved in competitive endogenous RNA (ceRNA) network associated with laryngeal squamous cell carcinoma (LSCC). Materials and Methods: Three mRNA datasets, two miRNA datasets, and one lncRNA dataset of LSCC were downloaded from GEO database. Following the identification of differentially expressed mRNAs (DEmRNAs), (microRNAs) miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) in LSCC compared with adjacent tissues, functional enrichment of DEmRNAs was performed. Then, construction of the ceRNA (DElncRNA‐DEmiRNA‐DEmRNA) regulatory network and functional analyses of all DEmRNAs in ceRNA regulatory network were conducted. Quantitative real‐time polymerase chain reactions (qRT‐PCR) were used to detect the expression levels of selected DEmRNAs, DEmiRNAs, and DElncRNAs. Results: A total of 3449 DEmRNAs, 40 DEmiRNAs, and 100 DElncRNAs were identified in LSCC. The ceRNA networks, which contained 132 DElncRNA‐DEmiRNA pairs and 287 DEmiRNA‐DEmRNA pairs, involving 44 lncRNAs, 3 miRNAs, and 271 mRNAs, were obtained. DEmRNAs in ceRNA regulatory networks were significantly enriched in pathways in cancer, prostate cancer, and aldosterone‐regulated sodium reabsorption. Except for HCG22 and hsa‐miR‐1246, expressions of the others in the qRT‐PCR results played the same pattern with that in our integrated analysis, generally. Conclusions: We concluded that HCG22/EGOT‐hsa‐miR‐1275‐FAM107A and HCG22/EGOT‐hsa‐miR‐1246‐Glycerol‐3‐phosphate dehydrogenase 1 like interaction pairs may play a central role in LSCC. [ABSTRACT FROM AUTHOR]

After the discovery of endogenous dinitrosyl iron complexes (DNICs) as a potential biological equivalent of nitric oxide (NO), bioinorganic engineering of [Fe(NO)2] unit has emerged to develop biomimetic DNICs [(NO)2Fe(L)2] as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) was explored for oral delivery of NO to the brain and for the activation of hippocampal neurogenesis. However, the kinetics and mechanism for cellular uptake and intracellular release of NO, as well as the biocompatibility of synthetic DNICs, remain elusive. Prompted by the potential application of NO to dermato-physiological regulations, in this study, cellular uptake and intracellular delivery of DNIC [Fe2(μ-SCH2CH2COOH)2(NO)4] (DNIC-2) and its regulatory effect/biocompatibility toward epidermal cells were investigated. Upon the treatment of DNIC-2 to human fibroblast cells, cellular uptake of DNIC-2 followed by transformation into protein-bound DNICs occur to trigger the intracellular release of NO with a half-life of 1.8 ± 0.2 h. As opposed to the burst release of extracellular NO from diethylamine NONOate (DEANO), the cell-penetrating nature of DNIC-2 rationalizes its overwhelming efficacy for intracellular delivery of NO. Moreover, NO-delivery DNIC-2 can regulate cell proliferation, accelerate wound healing, and enhance the deposition of collagen in human fibroblast cells. Based on the in vitro and in vivo biocompatibility evaluation, biocompatible DNIC-2 holds the potential to be a novel active ingredient for skincare products. [ABSTRACT FROM AUTHOR]

One-dimensional (1D) oxide nanostructures have been widely investigated to find novel properties. The study prepared titania nanobelts doped with iron (Fe) and niobium (Nb) at ultralow concentrations by one-step hydrothermal synthesis and post-calcination, and explored their electronic structure by spectroscopic and electrochemical analyses. The Fe and Nb doping generated Ti3+ donor levels and trap states as well as induced band-edge shift. The doped nanobelts produced higher photocurrents and quantum efficiencies, when evaluated as anode materials in dye-sensitized solar cells. Formation of the shallow states exerts a major influence on charge carrier diffusion in titania nanobelts, because of their roles as photoactive sites to facilitate electron transport via hopping and trapping/de-trapping events. The Fe and Nb dopants have a synergistic effect in the electronic conduction by increasing electron density and lifetime. Results demonstrate a feasibility of using aliovalent substitution by co-dopants to tailor extrinsic 1D oxide semiconductors. [ABSTRACT FROM AUTHOR]

Objective:Dyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH. Methods:Skin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals. Results:Histopathological analysis showed melanocytes in normal control’s skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6. Conclusion:Our data add new variants to the repertoire of ABCB6 mutations with DUH. [ABSTRACT FROM AUTHOR]

Abstract: Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that regulates energy metabolism, but its precise mechanisms remain unknown. Here, we demonstrate that the PPARα agonist fenofibrate activated expression of the glucose transporter Glut4. Moreover, PPARα was associated with the Glut4 promoter through GATA sites upon fenofibrate stimulation in cardiomyocytes. This occupancy is achieved through an interaction between amino acids 1–136 of PPARα with amino acids 276–443 of the cardiac transcription factor GATA-6. In addition, the interaction of PPARα with GATA-6 activated Glut4 gene expression, improved glucose consumption, and enhanced activity of mitochondrial citrate synthase in C2C12 myoblasts; both mutants of PPARα (1–101 aa) and GATA-6 (227–331 aa) were unable to cooperate in Glut4 activation. Thus, GATA-6 is an important component of the transcription network required for energy metabolism mediated by PPARα, and these findings provide a molecular basis for understanding the role of GATA-6 proteins in muscle development and disease. [Copyright &y& Elsevier]

Iron-doped titania nanobelts were prepared by a one-step alkaline hydrothermal method with use of iron(III) nitrate for in-situ Fe doping. The synthesis ensured Fe substitution for Ti in the oxide lattice and anatase growth. The Fe addition increased electronic donor density and induced a negative shift in the flat-band potential of titanium oxide. The single-crystalline Fe-titania nanobelts produced a higher photocurrent and higher voltage than pure titania nanobelts, after both were evaluated as anode materials in dye-sensitized solar cells. The improved photovoltaic efficiency is related to electron transport over photoactive shallow Fe donor traps, faster diffusion through anatase structure and suppressed charge recombination arising from Fermi level shift. Results demonstrate the feasibility of iron dopant for use to modify crystal and electronic structures in one-dimensional semiconducting oxide for efficient charge collection. [ABSTRACT FROM AUTHOR]