Roles of endothelin-1 in beta-amyloid-induced neurotoxicity in hippocampus: an implication for Alzheimer’s pathology

Poster F - Nervous System Disorders: abstract no. P3-F-012The British Neuroscience Association’s Festival of NeuroscienceAlzheimer’s disease (AD) is an incurable neurodegenerative disorder. Abnormal levels of endothelin-1 (ET-1) have been demonstrated in parietal white matter(1), cerebral cortex and vessels of the AD brain(2). Neuronal death and accumulation of beta-amyloid (Aβ) are prominent pathological features of AD. Significant neuronal death is found in Aβ-treated primary neurons and Aβ-overexpressing mouse models(3,4). ET-1 is a known vasoconstrictor and neuro-active peptide. ET-1 induces apoptosis in primary retinal neurons(5). In contrary, ET-receptor (ETR) type B agonist can rescue neurons from Aβ-induced apoptosis(6). These findings suggest ET-1 plays dual roles in neurodegeneration and neuroprotection, respectively. This study aims to investigate the effect of ET-1 on Aβ-induced cell death in hippocampal neurons. Primary hippocampal neurons were pretreated with or without ETR antagonists prior to the treatment of oligomeric form of Aβ1-42, ET-1 or both on 14 DIV. Cell viability was measured by MTT assay. Changes in protein expression in apoptotic and ET-1 signaling pathways were assessed by western-blot analysis. This study shed light on the roles of ET-1 in Aβ1-42-neurotoxicity, building upon which the ET-1 signaling pathway as a potential therapeutic target for AD can be further investigated.published_or_final_versio

Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency

OBJECTIVE: β cell dedifferentiation may underlie the reversible reduction in pancreatic β cell mass and function in type 2 diabetes (T2D). We previously reported that β cell-specific Sirt3 knockout (Sirt3f/f;Cre/+) mice developed impaired glucose tolerance and glucose-stimulated insulin secretion after feeding with high fat diet (HFD). RNA sequencing showed that Sirt3-deficient islets had enhanced expression of Enpp2 (Autotaxin, or ATX), a secreted lysophospholipase which produces lysophosphatidic acid (LPA). Here, we hypothesized that activation of the ATX/LPA pathway contributed to pancreatic β cell dedifferentiation in Sirt3-deficient β cells. METHODS: We applied LPA, or lysophosphatidylcoline (LPC), the substrate of ATX for producing LPA, to MIN6 cell line and mouse islets with altered Sirt3 expression to investigate the effect of LPA on β cell dedifferentiation and its underlying mechanisms. To examine the pathological effects of ATX/LPA pathway, we injected the β cell selective adeno-associated virus (AAV-Atx-shRNA) or negative control AAV-scramble in Sirt3f/f and Sirt3f/f;Cre/+ mice followed by 6-week of HFD feeding. RESULTS: In Sirt3f/f;Cre/+ mouse islets and Sirt3 knockdown MIN6 cells, ATX upregulation led to increased LPC with increased production of LPA. The latter not only induced reversible dedifferentiation in MIN6 cells and mouse islets, but also reduced glucose-stimulated insulin secretion from islets. In MIN6 cells, LPA induced phosphorylation of JNK/p38 MAPK which was accompanied by β cell dedifferentiation. The latter was suppressed by inhibitors of LPA receptor, JNK, and p38 MAPK. Importantly, inhibiting ATX in vivo improved insulin secretion and reduced β cell dedifferentiation in HFD-fed Sirt3f/f;Cre/+ mice. CONCLUSIONS: Sirt3 prevents β cell dedifferentiation by inhibiting ATX expression and upregulation of LPA. These findings support a long-range signaling effect of Sirt3 which modulates the ATX-LPA pathway to reverse β cell dysfunction associated with glucolipotoxicity

Serum levels of WNT1-inducible signaling pathway protein-1 (WISP-1): a noninvasive biomarker of renal fibrosis in subjects with chronic kidney disease

WNT1-inducible signaling pathway protein-1 (WISP-1) is an extracellular matrix-related protein that plays multiple roles in cellular physiology and pathology. Accumulating evidence shows that WISP-1 is involved in the process underlying fibrotic diseases. However, the correlation between WISP-1 and renal fibrosis is unknown. In this study, we hypothesized that WISP-1 levels might be correlated with renal fibrosis and could be used as a noninvasive biomarker to screen for renal fibrosis in patients with chronic kidney disease (CKD). We first measured the WISP-1 expression levels using a transforming growth factor-β (TGF-β)-induced renal fibrosis tubular epithelial cell (TEC) model and a mouse model of obstructive nephropathy. We then evaluated the correlation between serum WISP-1 levels and fibrosis scores in biopsy-proven renal fibrosis of patients with CKD. Based on the findings from both in vivo and in vitro studies, the levels of WISP-1 and fibrotic parameters (collagen I, fibronectin and α-smooth muscle actin) were significantly increased in the fibrotic models. Consistently, patients with focal proliferative IgA nephropathy, focal segmental glomerular sclerosis and diabetic nephropathy displayed markedly elevated serum WISP-1 levels and fibrosis scores of renal biopsies compared with normal subjects and patients with minimal change disease (P<0.05). Importantly, the serum WISP-1 levels were positively correlated with fibrosis scores in the renal biopsies of these patients (r=0.475, P=0.0001). Thus, serum WISP-1 levels may be used as a potential noninvasive biomarker of renal fibrosis in patients with CKD.published_or_final_versio

Mysid crustaceans as standard models for the screening and testing of endocrine-disrupting chemicals

Author Posting. © Springer, 2007. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Ecotoxicology 16 (2007): 205-219, doi:10.1007/s10646-006-0122-0.Investigative efforts into the potential endocrine-disrupting effects of chemicals have mainly concentrated on vertebrates, with significantly less attention paid to understanding potential endocrine disruption in the invertebrates. Given that invertebrates account for at least 95% of all known animal species and are critical to ecosystem structure and function, it remains essential to close this gap in knowledge and research. The lack of progress regarding endocrine disruption in invertebrates is still largely due to: (1) our ignorance of mode-of-action, physiological control, and hormone structure and function in invertebrates; (2) lack of a standardized invertebrate assay; (3) the irrelevance to most invertebrates of the proposed activity-based biological indicators for endocrine disruptor exposure (androgen, estrogen and thyroid); (4) limited field studies. Past and ongoing research efforts using the standard invertebrate toxicity test model, the mysid shrimp, have aimed at addressing some of these issues. The present review serves as an update to a previous publication on the use of mysid shrimp for the evaluation of endocrine disruptors (Verslycke et al., 2004a). It summarizes recent investigative efforts that have significantly advanced our understanding of invertebrate-specific endocrine toxicity, population modeling, field studies, and transgeneration standard test development using the mysid model.Supported by a Fellowship of the Belgian American Educational Foundation

Perceived level of knowledge and difficulty in applying family assessment among senior undergraduate nursing students

Because the structure, development, and functioning of a family plays an important role in health and illness, preparing nursing students to assess families in health care settings is of critical importance. A quasi-experimental design using a pre- and postcourse questionnaire was used to examine students' perceived knowledge about family assessment and perceived difficulty applying family assessment in the clinical setting. The Calgary Family Assessment Model (CFAM) was taught in an elective nursing course, "Families in Health and Illness," offered at the University of Hong Kong. At the completion of the course, 46 senior baccalaureate nursing students showed a significant increase in their perceived understanding of all subcategories in CFAM compared with the control group of 43 senior baccalaureate nursing students who completed an elective nursing course in women's health. Teaching family nursing assessment in undergraduate programs may be useful in ensuring that nurses attend to families in practice. © The Author(s) 2010.link_to_subscribed_fulltex

Electroacupuncture for primary insomnia: A randomized controlled trial

Study Objectives: To evaluate the short-term efficacy and safety of electroacupuncture for the treatment of primary insomnia. Design: Randomized, single-blind, placebo-controlled, parallel-group. Setting: A university-based sleep clinic. Participants: Community sample of 60 Chinese adult volunteers who report having insomnia 3 or more nights per week, whose symptoms meet the DSM-IV criteria for primary insomnia for at least 3 months, and who have an Insomnia Severity Index total score of at least 15. Participants were screened with polysomnography and the Structured Clinical Interview for the DSM-IV prior to randomization. Intervention: Electroacupuncture at Yintang (EX-HN3), Baihui (GV20), bilateral ear Shenmen, Sishencong (EX-HN1), and Anmian (EX) 3 times per week for 3 weeks or placebo acupuncture using Streitberger needles at the same points. Measurements and Results: Self-reported questionnaires, 1-week sleep diaries, and 3-day actigraphy were collected at baseline and 1 week after treatment. The Insomnia Severity Index was used as the primary outcome measure. Both groups showed significant improvement compared with the pretreatment baseline. One-way analysis of covariance adjusted for baseline scores showed that there were significantly greater improvements in sleep efficiency by sleep diary and actigraphy in the electroacupuncture group. However, no significant between-group differences were observed in the Insomnia Severity Index and other outcome measures. The proportions of subjects having less than 30 minutes of wake after sleep onset and a sleep efficiency of at least 85% at the posttreatment visit were significantly higher in the electroacupuncture group. All adverse events were mild in severity. Conclusion: We found a slight advantage of electroacupuncture over placebo acupuncture in the short-term treatment of primary insomnia. Because of some limitations of the current study, further studies are necessary to verify the effectiveness of acupuncture for insomnia.link_to_OA_fulltex