Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1 Cre/+; Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in GluCreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; Rosa26-eYFP mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2 ; ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells

Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1 Cre/+; Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2 ; ROSA26-eYFP and Ins1 Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in GluCreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; Rosa26-eYFP mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2 ; ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells

TASK-3, two-pore potassium channels, contribute to circadian rhythms in the electrical properties of the suprachiasmatic nucleus and play a role in driving stable behavioural photic entrainment

Stable and entrainable physiological circadian rhythms are crucial for overall health and well-being. The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, consists of diverse neuron types that collectively generate a circadian profile of electrical activity. However, the mechanisms underlying the regulation of endogenous neuronal excitability in the SCN remain unclear. Two-pore domain potassium channels (K2P), including TASK-3, are known to play a significant role in maintaining SCN diurnal homeostasis by inhibiting neuronal activity at night. In this study, we investigated the role of TASK-3 in SCN circadian neuronal regulation and behavioural photoentrainment using a TASK-3 global knockout mouse model. Our findings demonstrate the importance of TASK-3 in maintaining SCN hyperpolarization during the night and establishing SCN sensitivity to glutamate. Specifically, we observed that TASK-3 knockout mice lacked diurnal variation in resting membrane potential and exhibited altered glutamate sensitivity both in vivo and in vitro. Interestingly, despite these changes, the mice lacking TASK-3 were still able to maintain relatively normal circadian behaviour

A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus (EBV) target antigens:a phase I trial in UK patients with EBV-positive cancer

Purpose: Epstein–Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Experimental Design: Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 107 and 5 × 108 plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Results: Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively. Conclusions: MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 108 pfu) is recommended for investigation in current phase IB and II trials. Clin Cancer Res; 20(19); 5009–22. ©2014 AACR

Hubungan Antara Persepsi Ibu Menurut Teori Health Belief Model dengan Pemberian Asi Eksklusif di Kota Malang

ASI eksklusif telah terbukti menyediakan nutrisi dan cairan yang cukup dan sesuai dengan kebutuhan bayi untuk mencapai tumbuh kembang yang optimal. Sejak tahun 2014, cakupan ASI eksklusif di Indonesia telah ditargetkan mencapai angka 80%, sedangkan cakupan ASI eksklusif di Kota Malang masih sebesar 74,75%. Sebagai kota dengan prevalensi stunting tertinggi di Jawa Timur (51.7%), seharusnya dapat menggalakkan permberian ASI eksklusif sebagai upaya pencegahan stunting sedini mungkin. Tujuan dari penelitian ini adalah mengetahui hubungan antara persepsi ibu menurut teori health belief model dengan pemberian ASI eksklusif di kota Malang. Penelitian ini menggunakan jenis studi observasional analitik dengan pendekatan cross sectional. Responden penelitian ini adalah ibu yang memiliki anak usia 6-24 bulan di kota Malang, sebanyak 215 responden yang telah memenuhi kriteria inlusi dan eksklusi terlibat dalam penelitian. Pengambilan data dilakukan dengan pembagian kuesioner mengenai ASI eksklusif dan persepsi ibu. Hasil penelitian ini didapatkan 60,5% responden memberikan ASI secara eksklusif. Hasil analisis bivariat dengan uji Chi-Square didapatkan variabel yang berhubungan secara signifikan dengan pemberian ASI eksklusif adalah persepsi kerentanan (p= 0,001, OR= 2,980 | 95% CI 1,567-5,667), persepsi keparahan (p=0,046, OR= 1,785 | 95% CI 1,007-3,164), persepsi manfaat (p= 0,008, OR= 3,268 | 95% CI 1,319 - 8,094) dan persepsi hambatan (p= 0,003, OR= 5,178| 95% CI 1,611 – 16,646). Penelitian ini menyimpulkan bahwa keempat persepsi ibu pada teori health belief model memiliki hubungan yang signifikan dengan pemberian ASI eksklusif di kota Malang

Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic GluCreERT2;ROSA26-eYFP mice

Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P<0.05 to P<0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P<0.05 and P<0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P<0.05) apoptosis and increased (P<0.05 to P<0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P<0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P<0.01 and P<0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P<0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues