Browsing by Subject "Growth factor"

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  • DIABIMMUNE Study Grp; Miettinen, Maija E.; Honkanen, Jarno; Niinistö, Sari; Vaarala, Outi; Virtanen, Suvi M.; Knip, Mikael (2022)
    Aims/hypothesis Our aim was to study the association between duration of breastfeeding and circulating immunological markers during the first 3 years of life in children with HLA-conferred susceptibility to type 1 diabetes. Methods We performed a longitudinal analysis of 38 circulating immunological markers (cytokines, chemokines and growth factors) in serum samples from Finnish (56 individuals, 147 samples), Estonian (56 individuals 148 samples) and Russian Karelian children (62 individuals, 149 samples) at 3, 6, 12, 18, 24 and 36 months of age. We also analysed gut inflammation markers (calprotectin and human beta defensin-2) at 3 (n = 96) and 6 months (n = 153) of age. Comparisons of immunological marker medians were performed between children who were breastfed for 6 months or longer vs children who were breastfed for less than 6 months. Results Breastfeeding for 6 months or longer vs less than 6 months was associated with lower median of serum immunological markers at 6 months (granulocyte-macrophage colony-stimulating factor [GMCSF], macrophage inflammatory protein [MIP-3 alpha]), 12 months (IFN-alpha 2, vascular endothelial growth factor, GMCSF, IFN-gamma, IL-21), 18 months (FGF-2, IFN-alpha 2) and 24 months of age (CCL11 [eotaxin], monocyte chemoattractant protein-1, TGF alpha, soluble CD40 ligand, IL-13, IL-21, IL-5, MIP-1 alpha) (all p < 0.01) but not at 36 months of age. Breastfeeding was not associated with gut inflammation markers at 3 and 6 months of age. Conclusions/interpretation Children who were breastfed for 6 months or longer had lower medians for 14 immunological markers at one or more age points during the first 2 years of life compared with children who were breastfed for less than 6 months. The clinical meaning of the findings is not clear. However, the present study contributes to the understanding of immunological differences in children that have been breastfed longer, and thus provides a mechanistic suggestion for the previously observed associations between breastfeeding and risk of type 1 diabetes.
  • Runeberg-Roos, Pia; Piccinini, Elisa; Penttinen, Anna-Maija; Matlik, Kert; Heikkinen, Hanna; Kuure, Satu; Bespalov, Maxim M.; Peranen, Johan; Garea-Rodriguez, Enrique; Fuchs, Eberhard; Airavaara, Mikko; Kalkkinen, Nisse; Penn, Richard; Saarma, Mart (2016)
    In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in patients. As growth factors do not pass the blood-brain barrier, they have to be delivered intracranially. Therefore their efficient diffusion in brain tissue is of crucial importance. To improve the diffusion of the growth factor neurturin (NRTN), we modified its capacity to attach to heparan sulfates in the extracellular matrix. We present four new, biologically fully active variants with reduced heparin binding. Two of these variants are more stable than WT NRTN in vitro and diffuse better in rat brains. We also show that one of the NRTN variants diffuses better than its close homolog GDNF in monkey brains. The variant with the highest stability and widest diffusion regenerates dopamine fibers and improves the conditions of rats in a 6-hydroxydopamine model of Parkinson's disease more potently than GDNF, which previously showed modest efficacy in clinical trials. The new NRTN variants may help solve the major problem of inadequate distribution of NRTN in human brain tissue. (C) 2016 Elsevier Inc. All rights reserved.
  • Roussa, Eleni; Speer, Jan Manuel; Chudotvorova, Ilona; Khakipoor, Shokoufeh; Smirnov, Sergei; Rivera Baeza, Claudio; Krieglstein, Kerstin (2016)
    Functional activation of the neuronal K+-Cl- co-transporter KCC2 (also known as SLC12A5) is a prerequisite for shifting GABAA responses from depolarizing to hyperpolarizing during development. Here, we introduce transforming growth factor beta 2 (TGF-beta 2) as a new regulator of KCC2 membrane trafficking and functional activation. TGF-beta 2 controls membrane trafficking, surface expression and activity of KCC2 in developing and mature mouse primary hippocampal neurons, as determined by immunoblotting, immunofluorescence, biotinylation of surface proteins and KCC2-mediated Cl- extrusion. We also identify the signaling pathway from TGF-beta 2 to cAMP-response-element-binding protein (CREB) and Ras-associated binding protein 11b (Rab11b) as the underlying mechanism for TGF-beta 2-mediated KCC2 trafficking and functional activation. TGF-beta 2 increases colocalization and interaction of KCC2 with Rab11b, as determined by 3D stimulated emission depletion (STED) microscopy and co-immunoprecipitation, respectively, induces CREB phosphorylation, and enhances Rab11b gene expression. Loss of function of either CREB1 or Rab11b suppressed TGF-beta 2-dependent KCC2 trafficking, surface expression and functionality. Thus, TGF-beta 2 is a new regulatory factor for KCC2 functional activation and membrane trafficking, and a putative indispensable molecular determinant for the developmental shift of GABAergic transmission.