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Background: Helicobacter pylori (H. pylori) is an important pathogen that causes chronic gastritis and peptic ulcer, and is related to the development of gastric carcinoma. Several chemicals, including antibiotics, have been used to eradicate H.pylori. However, more studies are yet requred to accomplish a sufficient therapy. Pediococcus acidilactici (P. acidilactici) J9 were studied for inhibition of binding of H.pylori binding to human gastric cell lines. This study was performed in order to investigate the repeated-dose toxicity of P. acidilactici J9 in male and female mice. Results: C57BL/6 male and female Mus musculus were divided into four groups (n = 10 in each group). P. acidilactici J9 was administered daily by oral injection of vehicle control at dosage levels to a low-dose group (500 mg/kg/day), middle-dose group (1000 mg/kg/day), and high-dose group (2000 mg/kg/day) for 2 weeks. After 14 days of exposure, the blood biochemistry and hematology were investigated, along with a histopathology exam. There were no bacterial-related deaths or abnormal clinical signs in either gender of mouse. The data was observed during the period in terms of body weight, food intake, and water consumption. Also, no alterations in organ weights upon administration of P. acidilactici J9 alone were observed. The adhesion and growth of H. pylori were inhibited by a 24 h treatment of H. pylori and P. acidilactici J9 on adenocarcinoma gastric (AGS) cells, which are gastric cancer cells. Compared to the control group (AGS cell and H. pylori), the number of H. pylori analyzed by FACS significantly (p < 0.01) decreased after incubation of AGS cell with P. acidilactici J9 for 24 h. Conclusions: These results suggest that the oral application of P. acidilactici J9, up to a dosage level of 2000 mg/kg/day, causes no adverse effects in both male and female mice. P. acidilactici J9 inhibits the adhesion of H.pylori to AGS cancer cells. When used as probiotics, P. acidilactici J9 may help decrease the occurrence of gastritis and reduce the risk of H.pylori infection with promising safety issues. [ABSTRACT FROM AUTHOR]

Airports continuously enhance the quality of their services, adopting new technologies to improve passengers' experience. The current study explores how autonomous attributes, service quality, and passenger intentions relate to airport passenger terminals, applying factor analysis and a structural equation model. Introducing new technology impacts the service quality and influences passengers' behavioral intentions to revisit and recommend it to others. This study offers insight into how passengers perceive the integration of new technology at airport terminals and provides a clearer understanding of the relationship between passengers' travel intentions and their experiences with new technologies. [ABSTRACT FROM AUTHOR]

Studies have attempted to understand tourism issues between politically divided countries, yet few studies have argued that tourism between such states has a strong generational component. This study examines the generational differences in South Koreans' international stereotypes and tourism destination images of North Korea. While generational differences existed in international stereotypes, there were no differences in tourism destination images between generational cohorts. Young female South Koreans were likely to view North Korea more positively than males in the same generation, and generational differences were present in the intention to visit North Korea and the perception of peace through tourism. [ABSTRACT FROM AUTHOR]

Building on international marketing research on the country-of-origin image effect, this research examines how people evaluate a culturally familiar country as a tourist destination. Derived from a sample of 710 Taiwanese travelers, research findings showed that when evaluating China as a tourist destination, respondents relied on both their general image of the country (country image) as well as tourism-specific perceptions (destination beliefs), while a few respondents with low familiarity with China relied only on their general image of the country to evaluate the destination. The research also showed that respondents with high levels of familiarity with China had more positive destination beliefs, resulting in more favorable destination evaluations; however, country image was found to be persistent and difficult to be changed by destination promoting materials and/or actual visits. The paper concludes with recommendations for destination marketing in the context of international tourism. [ABSTRACT FROM PUBLISHER]

Background: Despite increased understanding of the pathophysiology of rotator cuff tears and the evolution of rotator cuff repair, healing failure remains a substantial problem. The critical roles played by biological factors have been emphasized, but little is known of the implications of gene expression profile differences at the time of repair. Purpose: To document the relationship between the perioperative gene expression of healed and unhealed rotator cuffs by RNA microarray analysis. Study Design: Case-control study; Level of evidence, 3. Methods: Superior (supraspinatus involvement) and posterosuperior (supraspinatus and infraspinatus involvement) tears were included in the study. Samples of rotator cuff tendons were prospectively collected during rotator cuff surgery. Three samples were harvested at the tendon ends of tears from the anterior, middle (apex), and posterior parts using an arthroscopic punch. Seven patients with an unhealed rotator cuff were matched one-to-one with patients with a healed rotator cuff by sex, age, tear size, and fatty degeneration of rotator cuff muscles. mRNA microarray analysis was used to identify genetic differences between healed and unhealed rotator cuff tendons. Gene ontology and gene association files were obtained from the Gene Ontology Consortium, and the Gene Ontology system in DAVID was used to identify enhanced biological processes. Results: Microarray analyses identified 262 genes that were differentially expressed by at least 1.5-fold between the healed and unhealed groups. Overall, in the healed group, 103 genes were significantly downregulated, and 159 were significantly upregulated. DAVID Functional Annotation Cluster analysis showed that in the healed group, the genes most upregulated were related to the G protein–coupled receptor protein signaling pathway and to the neurological system. On the other hand, the genes most downregulated were related to immune and inflammatory responses. BMP5 was the gene most upregulated in the healed group, and the majority of downregulated genes were involved in the immune/inflammatory response. Conclusion: The downregulation of inflammatory response genes and the upregulation of cell differentiation genes in torn rotator cuffs at the time of surgery are related to rotator cuff healing. These results provide useful baseline information for future biological studies on rotator cuff healing. [ABSTRACT FROM AUTHOR]

Neurotrophin-3 (NT-3) is a neurotrophic factor that mainly binds to the tyrosine kinase C (trkC) receptor. NT-3 has been shown to have neuroprotective effects in focal cerebral ischemia. Exercise also has ability to induce functional recovery in focal cerebral ischemia. However, the relationship between NT-3, its receptor trkC, and exercise has not been revealed. In this study, we assessed the expressions of NT-3 and trkC in focal cerebral ischemia. We also assessed the expression of NT-3 and trkC with treadmill exercise in focal cerebral ischemia. The results showed that, in a permanent middle cerebral artery occlusion rat model, exercise increased NT-3 and trkC expression. However, the patterns of expression of NT-3 and trkC at different time points varied. These results suggest that exercise-induced functional recovery in focal cerebral ischemia was related to NT-3 and trkC, but the role on times of NT-3 and trkC differed, although trkC is the receptor kinase for NT-3. [ABSTRACT FROM AUTHOR]

Technology acceptance has been studied extensively within the IS discipline. Few, if any, have studied end users’ acceptance of newly implemented technologies within organisational contexts before end users start using the technology. Thus, by integrating variables from multiple relevant literature, this research attempts to answer this research question: will the introduction of a richer model for technology acceptance in a mandatory adoption environment, specifically in the pre-implementation phase, allow us to capture and account for the complexities of organisational technology implementations? The research model was tested in an organisational setting where a new content management system was being implemented. A total of 148 employees participated in this survey and partial least squares method was used to analyse the data to test the model. Implementation climate, valence, attitude, and perceived ease of use positively influence goal commitment to technology acceptance in a mandatory environment, and the model has displayed relatively large explanatory and predictive power. Theoretical and practical implications are discussed in the paper. [ABSTRACT FROM PUBLISHER]

This study extends the leisure constraint-effects-mitigation model to the perceived behavioural control (PBC)- constraint-negotiation model by adding PBC. Three competing models were tested to determine which model best fits the data. Results suggested that PBC mediates the relationship between motivation and negotiation, and there is a direct path from motivation to participation. Findings contribute to deepening and broadening the theory of leisure constraint negotiation because the new variable was successfully added to the original model and the model was extended to new settings (i.e. solo travel and non-Western). [ABSTRACT FROM PUBLISHER]

Huntington's disease (HD) is a fatal genetic disease caused by abnormal aggregation of mutant huntingtin protein (mHtt). Reduction of mHtt aggregation decreases cell death of the brain and is a promising therapeutic strategy of HD. MicroRNAs are short non-coding nucleotides which modulate various genes and dysregulated in many diseases including HD. MicroRNA miR-27a was reported to be reduced in the brain of R6/2 HD mouse model and modulate multidrug resistance protein-1 (MDR-1). Using subventricular zone-derived neuronal stem cells (NSCs), we used in vitro HD model to test the effect of miR-27a on MDR-1 and mHtt aggregation. R6/2-derived NSCs can be differentiated under condition of growth factor deprivation, and the progression of differentiation leads to a decrease of MDR-1 level and efflux function of cells. Immunocytochemistry result also confirmed that mHtt aggregation was increased with differentiation. We transfected miR-27a in the R6/2-derived differentiated NSCs, and examined phenotype of HD, mHtt aggregation. As a result, miR-27a transfection resulted in reduction of mHtt aggregation in HD cells. In addition, MDR-1, which can transport mHtt, protein level was increased by miR-27a transfection. Conversely, knock-down of MDR-1 through MDR-1 siRNA increased mHtt aggregation in vitro . Our results indicate that miR-27a could reduce mHtt level of the HD cell by augmenting MDR-1 function. [ABSTRACT FROM AUTHOR]

This study utilized generational cohort theory to enhance understanding of the motivation and destination image of Mainland Chinese tourists visiting Taiwan (i.e., cross-strait tourism). With 350 Chinese tourists traveling to Taiwan, unique characteristics of four generations were identified (e.g., the Republican generation was more highly motivated to visit friends and relatives than the other generations, the Social Reform generation had greater hedonic motivation for visiting Taiwan than either the Consolidation or the Republican generations). The inconsistent characteristics between cohorts could be attributed to generational differences in past historical experiences. Thus, findings suggest that an individual’s life experience could play an important role in forming an image of the destination where the experience is related to, and also suggest that cross-strait tourism, one of the unique contexts of quasi-states tourism between politically divided countries, has a strong generational component, and tourism policies between such countries must take this into account. [ABSTRACT FROM AUTHOR]

This study explains electronic word of mouth (eWOM) in terms that are opposed to the traditional definitions and examines the motivations that lead to eWOM in order to clarify ethnic restaurant users’ post-consumption behavior online. To fill in the gap left by studies that have primarily relied on predetermined questionnaires (e.g., DINESERV), this study uses a qualitative methodology (i.e., netnography). Four motivations for engaging in eWOM are identified. Customers tend to articulate their dining experiences by engaging in online social networks for the purpose of evaluating services, expressing positive or negative feelings, approving other members’ contributions, or gaining positive recognition from others. [ABSTRACT FROM PUBLISHER]

Although differential pricing strategies in the tourism industries have raised fairness issues so far, price fairness studies from a consumer perspective are still lacking as opposed to pricing research based on the managerial approach. Thus, this study developed a scale to measure price fairness in line with the procedures recommended by the literature, and tested if the proposed items and dimensionality of the construct best fit the empirical data. Consequently, it was found that price fairness embraces two dimensions of cognitive and affective fairness. The valid and reliable measurement of price fairness may have far reaching theoretical and managerial implications. [ABSTRACT FROM PUBLISHER]

Charging airline fees has recently been a controversial issue in terms of price fairness. Nonetheless, few researchers have studied price fairness in the tourism literature. This study aimed to examine the antecedents and consequences of tourists’ perceived price fairness of ancillary revenues. From an attributional perspective, a conceptual model was expected to complement shortcomings of the traditional dual entitlement principle. Data were collected from U.S. domestic airline passengers through an online survey (n = 524) and analyzed using structural equation modeling (SEM). Results suggest that price comparison and cognitive attribution influence price fairness, which, in turn, leads to emotional response and behavioral intentions. Results provide potentially important directions for the development of a theoretical framework of price fairness in a tourism context. It is further expected that the findings of this study provide managerial guidance for the utilization of marketing strategy for airline management. [ABSTRACT FROM PUBLISHER]

Neurotrophin 4 (NT-4) belongs to the family of neurotrophic factors, and it interacts with the tyrosine kinase B (trkB) receptor. NT-4 has neuroprotective effects following cerebral ischemia. Its role might be similar to brain-derived neurotrophic factor (BDNF), because both interact with trkB. Exercise also improves neural function by increasing neurotrophic factors. However, expression profiles of NT-4 in the brain during exercise are unknown. Here, we assessed the expressions of NT-4 and its receptor, trkB, following cerebral ischemia and hypothesized that exercise changes the expressions of NT-4 and trkB. Results showed that in a permanent middle cerebral artery occlusion rat model, ischemia decreased NT-4 and trkB expression. Immunohistochemistry showed their immunoreactivities around the region of the ischemic area. Treadmill exercise changed the expression of NT-4, which increased in the contralateral hemisphere in rats with ischemic injury. TrkB also showed similar patterns to its neurotophins. The change in NT-4 suggested that exercise might have primed NT4 production so that further injury causes slightly greater increases in NT4 compared with non-exercise controls. [ABSTRACT FROM AUTHOR]

Abstract: Moderate hypothermia (25–31°C) may have a significant influence on vascular tone. We investigated the cellular mechanisms by which moderate hypothermia alters α-adrenoceptor-mediated contraction in rat thoracic aortae. Cyclooxygenase inhibition by indomethacin; nitric oxide (NO) synthase inhibition by l-NAME; potassium channel and endothelium-derived hyperpolarizing factor (EDHF) inhibition by glibenclamide and TEA; G protein inhibition by pertussis toxin; α2-adrenergic inhibition by yohimbine; and β-adrenergic inhibition by propranolol were assessed for their effect on the contractile response to the α1-adrenoceptor agonist phenylephrine (Phe) in combination with moderate hypothermia (25°C). Moderate hypothermia produced a shift to the right for the Phe concentration–response curves in endothelium-intact (E+) and endothelium-denuded (E−) aortic rings. The maximal response to Phe in E+ rings was significantly decreased (P <0.05) at 25°C compared to 38°C, whereas there was no significant difference in E− rings. Hypothermia-induced vasorelaxation in E+ rings was attenuated (P <0.05) following combined pretreatment with l-NAME (10−4 M) and indomethacin (10−5 M), whereas other inhibitors had no significant effect. Importantly, the addition of TEA to rings that were pretreated with l-NAME and indomethacin exhibited no further attenuation (P >0.05) of hypothermia-induced vasorelaxation. The concentrations of cGMP and cAMP, as measured by radioimmunoassay, were significantly increased (P <0.05) in E+ rings at 25°C compared to those at 38°C, whereas there were no significant differences (P >0.05) in E− rings. The present study demonstrated that rat aortic endothelium is stimulated during moderate hypothermia and that the NO–cGMP and prostacyclin (PGI2)–cAMP pathways represent endothelium-dependent mechanisms of hypothermia-induced vasorelaxation. In contrast, EDHF may not be associated with hypothermia-induced vasorelaxation. [Copyright &y& Elsevier]

Abstract: Transplantation of adipose-derived stem cells (ASCs) is one of the possible therapeutic tools for ischemic damage. In this study, we observed the effects of ASCs against ischemic damage in the ventral horn of L5–6 levels in the rabbit spinal cord. ASCs were isolated from rabbits, and cell type was confirmed by flow cytometry analysis, labeling with CM-DiI dye and differentiation into adipocytes in adipogenesis differentiation medium. ASCs were administered intrathecally into recipient rabbits (2×105) immediately after reperfusion following a 15-min aortic artery occlusion in the subrenal region. Transplantation of ASCs significantly improved functions of the hindlimb and morphology of the ventral horn of spinal cord although CM-DiI-labeled ASCs were not observed in the spinal cord parenchyma. In addition, transplantation of ASCs significantly increased brain-derived neurotrophic factor (BDNF) levels at 72h after ischemia/reperfusion. These results suggest that transplantation of ASCs prevents motor neurons from spinal ischemic damage and reactive gliosis by increasing neurotrophic factors such as BDNF in the spinal cord. [Copyright &y& Elsevier]

Abstract: Given the mixed findings of extant research on the impact of low-cost carriers (hereafter LCC) on aviation markets (with some studies showing stimulation of new demand, other studies showing LCCs encroaching on the turf of full-service carriers), the emergence of LCCs in Korea raised an interesting question as to whether or not they actually contribute to overall growth in domestic air traffic. The literature has paid limited attention to this issue so far. Employing a multivariate regression analysis with monthly data from 2000 to 2009, the impact of LCCs on tourism demand to a popular destination in Korea, Jeju Island, is examined, focusing on two specific questions: Have LCCs generated new tourism demand and brought more tourism revenue into the island’s economy? Have LCCs mitigated tourism seasonality on the island? Controlling for the effects of a number of factors, results showed that LCCs have generated new demand in addition to existing tourist flows to the island. Korean LCCs accounted for 35% of total passengers in 2009, which indicates an average growth rate of 161.7% over the last 4years, compared to a −0.3% growth rate for all full-service carriers in Korea. However, LCCs seem to have had little impact on reducing seasonal fluctuations in passenger traffic to Jeju Island. The findings of this study will be of interest to researchers, policy makers, and a variety of stakeholders in the tourism industry interested in the relationship between no-frills airlines and island economies. [Copyright &y& Elsevier]

Abstract: Activation of the trkA pathway has been widely accepted as a crucial factor for neuronal survival during cerebral ischemia. Findings from earlier studies have suggested that exercise changed neurotrophic factors and trk family in an ischemic rat model. In this study, we investigated the question of whether or not treadmill exercise improves motor function in an ischemic rat model, and whether or not the result is associated with trkA, responding to NGF. Adult male Sprague–Dawley rats underwent surgery for permanent ischemia, followed by either 12days of treadmill exercise or non-exercise. We found that exercise increased the level of trkA and NGF proteins in the contralateral hemisphere and improved the motor behavior index. Our data indicate that treadmill exercise ameliorates motor performance via the elevation of trkA and NGF proteins in the contralateral hemisphere after permanent brain ischemia. [Copyright &y& Elsevier]

Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Interleukin 31 (IL-31), a novel cytokine in AD, causes pruritus, typically characteristic of AD patients. The transient receptor potential vanilloid type 1 (TRPV1) is a cation channel activated by diverse noxious stimuli that has been studied in a variety of pruritic skin diseases. In this study, the AD animal model was generated by administering the hapten, trinitrochlorobenzene (TNCB), to Nc/Nga mice, and the degree of expression of the IL-31 receptor alpha (IL-31RA) and TRPV1 in the skin of these atopic models was evaluated. The Nc/Nga mice were divided into 3 groups: control, TNCB 2-weeks treated, and TNCB 8-weeks treated. After inducing AD, the skin lesions in each group were scored and compared, and the histology of the skin lesions and the IL-31RA and TRPV1 expression for each group were evaluated by analyzing immunohistochemistry. The results show a significant difference in the skin lesion scores between the groups. The immunohistochemistry evaluation highlighted the remarkable expression of IL-31RA and TRPV1 in the nerve fibers of the TNCB 8-weeks-treated group. We thus confirmed that the long-term application of TNCB induced chronic atopic-like dermatitis and that IL-31RA and TRPV1 were overexpressed in the peripheral nerve fibers in this AD model. [ABSTRACT FROM AUTHOR]

Background: A common complication after rotator cuff repair is postoperative stiffness, which can be reduced by a simple application of an anti-adhesive agent. However, anti-adhesive agents may affect rotator cuff healing by preventing fibrosis. This experimental animal study evaluated the effect of the application of a poloxamer-based thermosensitive anti-adhesive gel and its influence on the healing of an acute rotator cuff repair in a rabbit model. Methods: Acute rotator cuff repair (supraspinatus tendon) was performed using a transosseous suturing method. One shoulder on a randomly selected side was treated with a local application of the anti-adhesive agent (applied side), and saline was applied to the contralateral side (control side). Biomechanical testing and histological analyses were performed at 4 and 8 weeks postoperatively. Eight rabbits were included for each testing and time point, for a total of 32 rabbits. Results: The failure load at 4 weeks was lower in the experimental group (95.2 ± 19.6 N vs. 110.0 ± 20.5 N; P = 0.017). Conversely, at 8 weeks, the failure load was higher in the experimental group (148.3 ± 16.2 N) than in the control group (122.4 ± 16.9 N; P = 0.002). Histological analyses revealed no statistically significant differences in the tendon maturing scores at 4 and 8 weeks between the two groups (all P > 0.05). The thickness of the fibrosis between the rotator cuff tendon and deltoid was thinner in the experimental group at both time points (0.50 ± 0.25 vs. 1.27 ± 0.47; P = 0.002 at 4 weeks, and 0.37 ± 0.35 vs. 1.39 ± 0.50; P = 0.003 at 8 weeks). Conclusions: Application of an anti-adhesive agent in this rotator cuff model confirmed the agent's effectiveness at reducing fibrosis in the subacromial space. The healing of the tendon showed interesting results, as the experimental group had poorer biomechanical strength at 4 weeks but superior strength at 8 weeks. [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) is one of the most devastating genetic neurodegenerative disorders with no effective medical therapy. β-Lapachone (βL) is a natural compound obtained from the bark of the Lapacho tree and has been reported to have beneficial effects on various diseases. Sirt1 is a deacetylase of the sirtuin family and deacetylates proteins including the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) which is associated with mitochondrial respiration and biogenesis. To examine the effectiveness of βL on HD, βL was orally applied to R6/2 HD mice and behavioral phenotypes associated with HD, such as impairment of rota-rod performance and increase of clasping behavior, as well as changes of Sirt1 expression, CREB phosphorylation and PGC-1α deacetylation were examined. Western blot results showed that Sirt1 and p-CREB levels were significantly increased in the brains of βL-treated R6/2 mice. An increase in deacetylation of PGC-1α, which is thought to increase its activity, was observed by oral administration of βL. In an in vitro HD model, βL treatment resulted in an attenuation of MitoSOX red fluorescence intensity, indicating an amelioration of mitochondrial reactive oxygen species by βL. Furthermore, improvements in the rota-rod performance and clasping score were observed in R6/2 HD mice after oral administration of βL compared to that of vehicle control-treated mice. Taken together, our data show that βL is a potential therapeutic candidate for the treatment of HD-associated phenotypes, and increases in Sirt1 level, CREB phosphorylation and PGC-103B1 deacetylation can be the possible underlying mechanism of the effects of βL. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. The gene encoding Cu/Zn superoxide dismutase (SOD1) is responsible for 20% of familial ALS cases. Growth hormone (GH) concentrations are low in the cerebrospinal fluid of patients with ALS; however, its association with motoneuronal death is not known. We tested the neuroprotective effects of GH on human SOD-1-expressing cultured motor neurons and SOD1G93A transgenic mice. Results: In cultured motor neurons, cytotoxicity was induced by A23187, GNSO, or homocysteine, and the effects of GH were determined by MTT, bax, PARP cleavage pattern, Hoechst nuclear staining, MAPK, and PI3K assay. In SOD-1 transgenic mice, rotarod motor performance was evaluated. Survival analysis of motoneuronal loss was done using cresyl violet, GFAP, and Bcl-2 staining. GH prevents motorneuronal death caused by GSNO and homocysteine, but not that by A23187. It activates MAPK and PI3K. GH-treated mice showed prolonged survival with improved motor performance and weight loss. GH decreased cresyl violet positive motoneuronal loss with strong Bcl-2 and less GFAP immunoreactivity. Conclusions: Our results demonstrate that GH has a protective effect on mutant SOD-1-expressing motor neurons. [ABSTRACT FROM AUTHOR]

Abstract: Blockade of the B7:CD28 costimulatory pathway has been shown to inhibit humoral immunity, graft rejection, graft versus host disease and ameliorate autoimmune diseases. A soluble chimeric fusion protein, CTLA4Ig, binds to B7 with greater affinity than CD28 and blocks the binding of CD28 to B7. We describe the cloning and expression of canine CTLA4Ig, a recombinant chimeric fusion protein composed of the extracellular domain of canine CTLA-4 and the CH2–CH3 domains of canine immunoglobulin alpha constant region (IGHA) genes, linked via an immunologically inert flexible peptide. The recombinant CTLA4Ig protein of approximately 45kDa molecular weight was expressed mainly as insoluble inclusion bodies in Escherichia coli. The protein was solubilized in denaturing buffer and purified using nickel-nitrilotriacetic acid (Ni-NTA) affinity column chromatography followed by refolding. The yield was about 6mg of recombinant CTLA4Ig per liter of culture. The purified protein was biologically active in one-way mixed lymphocyte reactions, demonstrating immunosuppressive activities in a dose-dependent manner. The findings suggest that recombinant canine CTLA4Ig protein could be valuable in assessing the function of CTLA-4 in the canine immune system and may be effective in autoimmune disease therapy. [Copyright &y& Elsevier]

Vascular endothelial growth factor (VEGF) is a key regulator for placental angiogenesis and vascular functions via activating two high affinity tyrosine–kinase receptors, VEGF receptor-1 (VEGFR-1) and -2 (VEGFR-2). Recently, a specific VEGF165 receptor, neuropilin-1 (NP-1), was also identified in endothelial cells and upon VEGF binding, NP-1, synergistically with VEGFR-2, enhances VEGF-induced cell proliferation and migration. To evaluate the role of VEGF and NP-1 in regulating fetoplacental angiogenesis and endothelial function, an ovine fetal placental artery endothelial (OFPAE) cell line was established. In this study, an OFPAE cell cDNA library was constructed. Two positive clones for VEGF and one for NP-1 were isolated from the OFPAE cell cDNA library, and their partial 3′ sequences were identified. The sequence of VEGF cDNA insert had 98% homology to the reported ovine VEGF (GenBank accesssion # X89506). The partial NP-1 cDNA sequence included a portion of the protein coding region and a complete 3′ untranslated region (UTR), and had 90% homology to human NP-1 (GenBank accession # AF016050). The predicted amino acid sequence of ovine NP-1 was 97–98% identical to human (GenBank accession # AAC12921.1), mouse (GenBank accession # NP_032763), and rat (GenBank accession # AAC53345.1) NP-1. Two CU-rich stabilizing and two consensus destabilizing elements 5′-AUUUA-3′ were identified in the 3′ UTR of ovine NP-1 cDNA sequence. These elements are the potential binding sites for mRNA-binding proteins which may regulate the stability of NP-1 mRNA. Expression of VEGF and NP-1 in OFPAE cells and fetal placentas was confirmed by Northern and Western blot analyses. Using PCR analysis, we also identified partial sequences of multiple VEGF isoforms (VEGF188, 183, 164, and 120) as well as VEGFR-1, VEGFR-2, and neuropilin-2 (NP-2) from the OFPAE cell cDNA library. These results indicate that multiple isoforms of VEGF are expressed in OFPAE cells. Moreover, we also identified, for the first time, a complete 3′ UTR of NP-1 cDNA in any species. Together with expression of VEGF and VEGF receptors in OFPAE cells, we propose that there is an autocrine mechanism by which VEGF regulates fetal placental angiogenesis and other functions of endothelial cells. [Copyright &y& Elsevier]

Background: Pyridoxine (PDX; vitamin B6), is an essential vitamin. PDX deficiency induces various symptoms, and when PDX is misused it acts as a neurotoxicant, inducing severe sensory neuropathy.Results: To assess the possibility of creating a reversible sensory neuropathy model using dogs, 150 mg/kg of PDX was injected subcutaneously into dogs for 7 days and body weight measurements, postural reaction assessments, and electrophysiological recordings were obtained. In addition, the morphology of dorsal root ganglia (DRG) and changes in glial fibrillary acidic protein (GFAP) immunoreactive satellite glial cells and ionized calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia/macrophages were assessed at 1 day, 1 week, and 4 weeks after the last PDX treatment. During the administration period, body weight and proprioceptive losses occurred. One day after the last PDX treatment, electrophysiological recordings showed the absence of the H-reflex in the treated dogs. These phenomena persisted over the four post-treatment weeks, with the exception of body weight which recovered to the pre-treatment level. Staining (CV and HE) results revealed significant losses of large-sized neurons in the DRG at 1 day and 1 week after PDX treatment cessation, but the losses were recovered at 4 weeks post-treatment. The Iba-1 and GFAP immunohistochemistry results showed pronounced increases in reactive microglia/macrophage and satellite glial cell at 1 day and 1 week, respectively, after the last PDX treatment, and thereafter, immunoreactivity decreased with increasing time after PDX treatment.Conclusions: The results suggest that PDX-induced neuropathy is reversible in dogs; thus, dogs can be considered a good experimental model for research on neuropathy. [ABSTRACT FROM AUTHOR]

Glutamate is a major excitatory neurotransmitter that is stored in vesicles located in the presynaptic terminal. Glutamate is transported into vesicles via the vesicular glutamate transporter (VGLUT). In the present study, the age‑associated changes of the major VGLUTs, VGLUT1 and VGLUT2, in the hippocampus were investigated, based on immunohistochemistry and western blot analysis at postnatal month 1 (PM1; adolescent), PM6, PM12 (adult group), PM18 and PM24 (the aged groups). VGLUT1 immunoreactivity was primarily detected in the mossy fibers, Schaffer collaterals and stratum lacunosum‑moleculare. By contrast, VGLUT2 immunoreactivity was observed in the granule cell layer and the outer molecular layer of the dentate gyrus, stratum pyramidale, Schaffer collaterals and stratum lacunosum‑moleculare in the hippocampal CA1‑3 regions. VGLUT1 immunoreactivity and protein levels remained constant across all age groups. However, VGLUT2 immunoreactivity and protein levels decreased in the PM3 group when compared with the PM1 group. VGLUT2 immunoreactivity and protein levels were not altered in the PM12 group; however, they increased in the PM18 group. In addition, in the PM18 group, highly immunoreactive VGLUT2 cells were also identified in the stratum radiatum and oriens of the hippocampal CA1 region. In the PM24 group, VGLUT2 immunoreactivity and protein levels were significantly decreased and were the lowest levels observed amongst the different groups. These results suggested that VGLUT1 may be less susceptible to the aging process; however, the increase of VGLUT2 in the non‑pyramidal cells in the PM18 group, and the consequent decrease in VGLUT2, may be closely linked to age‑associated memory impairment in the hippocampus. [ABSTRACT FROM AUTHOR]

The present study investigated the effects of hypothyroidism on cyclooxygenase‑2 (COX‑2) and pro‑inflammatory cytokines in the dentate gyrus to elucidate the roles of COX‑2 in the hypothyroid hippocampus. Hypothyroidism was induced in rats by treating with 0.03% 2‑mercapto‑1‑methyl‑imidazole dissolved in drinking water for 5 weeks. The animals were sacrificed at 12 weeks of age. Hypothyroidism rats exhibited decreased triiodothyronine and thyroxine levels in the serum, while the levels of thyroid‑stimulating hormone and the weight of thyroid glands were significantly higher in the hypothyroid rats compared with those in the vehicle‑treated group. COX‑2 immunoreactivity was significantly increased in the hippocampal CA2/3 region and the dentate gyrus compared with the vehicle‑treated group. Levels of pro‑inflammatory cytokines including interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α were significantly higher in the hippocampal homogenates of hypothyroid rats. Cell proliferation and neuroblast differentiation based on Ki67 and doublecortin immunohistochemistry were decreased in the dentate gyrus of hypothyroid rats compared with those in the vehicle‑treated group. These results suggested that hypothyroidism‑mediated COX‑2 expression affected hippocampal plasticity by upregulating the levels of pro‑inflammatory cytokines in the hippocampus. Therefore, COX‑2 may be suggested as a candidate molecule for preventing hypothyroidism‑induced neurological side effects. [ABSTRACT FROM AUTHOR]

Background In the present study, we investigated the effects of pyridoxine on hippocampal functions and changes in protein profiles based on the proteomic approach. Methods Eight-week-old mice received intraperitoneal injections of physiological saline (vehicle) or 350 mg/kg pyridoxine twice a day for 21 days. Results Phosphoglycerate mutase 1 was up-regulated, while CB1 cannabinoid receptor-interacting protein 1 (CRIP1) was down-regulated, in the pyridoxine-treated group. Additionally, the serotonin and tyrosine hydroxylase was increased in the hippocampus of the pyridoxine-treated group than in that of the vehicle-treated group. Furthermore, discrimination indices based on the novel object recognition test were significantly higher in the pyridoxine-treated group than in the vehicle-treated group. Administration of CRIP1a siRNA significantly increases the discrimination index as well as cell proliferation and neuroblast differentiation in the dentate gyrus. In addition, the administration of rimonabant, a CB1 cannabinoid receptor antagonist, for 3 weeks significantly decreased the novel object recognition memory, the tyrosine hydroxylase level, the amount of cell proliferation, and neuroblast differentiation in the dentate gyrus. Treatment with pyridoxine significantly increased novel object recognition memory, but slightly ameliorated rimonabant-induced reduction in serotonin, the tyrosine hydroxylase level, the amount of cell proliferation, and neuroblast differentiation in the dentate gyrus. Conclusion These results suggest that pyridoxine promotes hippocampal functions by increasing serotonin and tyrosine hydroylase immunoreactivity in the hippocampus. This positive effect may be associated with CRIP1a and CB1 cannabinoid receptor function. General significance Vitamin-B 6 enhances hippocampal functions and this is closely associated with CRIP1a and CB1 cannabinoid receptors. [ABSTRACT FROM AUTHOR]

Background: Nerve growth factor (NGF) is known not only as a major factor for neuronal plasticity but also as a pain stimulator. Although there have been several trials with NGF for its application in the regeneration or protection of the nervous system, the pain induced by NGF remains a challenge to be overcome. In this study, the pain induced by NGF gene therapy was evaluated.Results: Vehicle or recombinant dog NGF plasmid was administered into the intrathecal space of dogs. Twenty-four hours after the vehicle or NGF plasmid inoculation, dogs were subcutaneously treated with 150 mg/kg pyridoxine every day for 7 days. For pain assessment, physical examination and electrophysiological recording were performed. Only in the vehicle-treated group, weight loss occurred, while NGF plasmid inoculation significantly improved this physical abnormalities. In the vehicle-treated group, electrophysiological recordings showed that H-reflex disappeared at 24 h after the last pyridoxine treatment. However, in the NGF plasmid inoculated group, the H-reflex were normal. In the results of immunohistochemistry, the NGF plasmid administration efficiently expressed in the dorsal root ganglia and significantly increased the pyridoxine-induced reduction of calcitonin gene-related peptide (CGRP) immunoreactive neurons, but not in substance P immunoreactive neurons, in the dorsal root ganglia.Conclusions: Given these results, we reason that NGF gene therapy in pyridoxine induced neuropathic dogs does not induce neuropathic pain with this dosage, even with increasing the expression of CGRP. [ABSTRACT FROM AUTHOR]

Entacapone, a reversible inhibitor of catechol-O-methyl transferase, is used for patients in Parkinson's disease because it increases the bioavailability and effectiveness of levodopa. In the present study, we observed that entacapone increases novel object recognition and neuroblasts in the hippocampus. In the present study, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry were performed to compare the abundance profiles of proteins expressed in the hippocampus after entacapone treatment in mice. Results of 2-DE, MALDI-TOF mass spectrometry, and subsequent proteomic analysis revealed an altered protein expression profile in the hippocampus after entacapone treatment. Based on proteomic analysis, 556 spots were paired during the image analysis of 2-DE gels and 76 proteins were significantly changed more than two-fold among identified proteins. Proteomic analysis indicated that treatment with entacapone induced expressional changes in proteins involved in synaptic transmission, cellular processes, cellular signaling, the regulation of cytoskeletal structure, energy metabolism, and various subcellular enzymatic reactions. In particular, entacapone significantly increased proteins related to synaptic trafficking and plasticity, such as dynamin 1, synapsin I, and Munc18-1. Immunohistochemical staining showed the localization of the proteins, and western blot confirmed the significant increases in dynamin I (203.5% of control) in the hippocampus as well as synapsin I (254.0% of control) and Munc18-1 (167.1% of control) in the synaptic vesicle fraction of hippocampus after entacapone treatment. These results suggest that entacapone can enhance hippocampal synaptic trafficking and plasticity against various neurological diseases related to hippocampal dysfunction. [ABSTRACT FROM AUTHOR]

We investigated the effects of pyridoxine deficiency on ischemic neuronal death in the hippocampus of gerbil (n = 5 per group). Serum pyridoxal 5′-phosphate levels were significantly decreased in Pyridoxine-deficient diet (PDD)-fed gerbils, while homocysteine levels were significantly increased in sham- and ischemia-operated gerbils. PDD-fed gerbil showed a reduction in neuronal nuclei (NeuN)-immunoreactive neurons in the medial part of the hippocampal CA1 region three days after. Reactive astrocytosis and microgliosis were found in PDD-fed gerbils, and transient ischemia caused the aggregation of activated microglia in the stratum pyramidale three days after ischemia. Lipid peroxidation was prominently increased in the hippocampus and was significantly higher in PDD-fed gerbils than in Control diet (CD)-fed gerbils after ischemia. In contrast, pyridoxine deficiency decreased the proliferating cells and neuroblasts in the dentate gyrus in sham- and ischemia-operated gerbils. Nuclear factor erythroid-2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) levels also significantly decreased in PDD-fed gerbils sham 24 h after ischemia. These results suggest that pyridoxine deficiency accelerates neuronal death by increasing serum homocysteine levels and lipid peroxidation, and by decreasing Nrf2 levels in the hippocampus. Additionally, it reduces the regenerated potentials in hippocampus by decreasing BDNF levels. Collectively, pyridoxine is an essential element in modulating cell death and hippocampal neurogenesis after ischemia. [ABSTRACT FROM AUTHOR]

Pyridoxine, one of the vitamin B6 vitamers, plays a crucial role in amino acid metabolism and synthesis of monoamines as a cofactor. In the present study, we observed the effects of pyridoxine deficiency on novel object recognition memory. In addition, we examined the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenethylamine (DA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid and the number of proliferating cells and neuroblasts in the hippocampus. We also examined the effects of pyridoxine deficiency on protein profiles applying a proteomic study. Five-week-old mice fed pyridoxine-deficient diets for 8 weeks and showed a significant decrease in the serum and brain (cerebral cortex, hippocampus, and thalamus) levels of pyridoxal 5′-phosphate, a catalytically active form of vitamin-B6, and decline in 5-HT and DA levels in the hippocampus compared to controls fed a normal chow. In addition, pyridoxine deficiency significantly decreased Ki67-positive proliferating cells and differentiated neuroblasts in the dentate gyrus compared to controls. A proteomic study demonstrated that a total of 41 spots were increased or decreased more than two-fold. Among the detected proteins, V-type proton ATPase subunit B2 (ATP6V1B2) and heat shock cognate protein 70 (HSC70) showed coverage and matching peptide scores. Validation by Western blot analysis showed that ATP6V1B2 and HSC70 levels were significantly decreased and increased, respectively, in pyridoxine-deficient mice compared to controls. These results suggest that pyridoxine is an important element of novel object recognition memory, monoamine levels, and hippocampal neurogenesis. Pyridoxine deficiency causes cognitive impairments and reduction in 5-HT and DA levels, which may be associated with a reduction of ATP6V1B2 and elevation of HSC70 levels in the hippocampus. [ABSTRACT FROM AUTHOR]

Mutant huntingtin (mHtt) aggregation in the nucleus is the most readily apparent phenotype and cause of neuronal death in Huntington's disease (HD). Inhibiting mHtt aggregation reduces cell death in the brain and is thus a promising therapeutic approach. The results of the present study demonstrated that mHtt aggregation in the nucleus was altered by the activity of multidrug resistance protein 1 (MDR1), which was experimentally modulated by verapamil, siRNA and an expression vector. MDR1 detoxifies drugs and metabolites through its excretory functions in the membrane compartment, thereby protecting cells against death or senescence. When they were treated with verapamil, R6/2 mice showed a progressive decline in rotarod performance and increased mHtt aggregation in the brain. Using neuronal stem cells from R6/2 mice, we developed an in vitro HD model to test mHtt accumulation in the nuclei of neurons. When MDR1 activity in cells was decreased by verapamil or siRNA, mHtt aggregation in the nuclei increased, whereas the induction of MDR1 resulted in a decrease in mHtt aggregation. Thus, our data provide evidence that MDR1 plays an important role in the clearance of mHtt aggregation and may thus be a potential target for improving the survival of neurons in Huntington's disease. [ABSTRACT FROM AUTHOR]