64 research outputs found
Angiogenesis and Multiple Sclerosis Pathogenesis: A Glance at New Pharmaceutical Approaches
Multiple sclerosis is a chronic disease of the central nervous system characterized by demyelination and destruction of axons. The most common form of the disease is the relapsing-remitting multiple sclerosis in which episodic attacks with typical neurological symptoms are followed by episodes of partial or complete recovery. One of the underestimated factors that contribute to the pathogenesis of multiple sclerosis is excessive angiogenesis. Here, we review the role of angiogenesis in the onset and in the development of the disease, the molecular mechanisms underlying angiogenesis, the current therapeutic approaches, and the potential therapeutic strategies with a look at natural compounds as multi-target drugs with both neuroprotective and anti-angiogenic properties
Genetic ablation of soluble TNF does not affect lesion size and functional recovery after moderate spinal cord injury in mice
Traumatic spinal cord injury (SCI) is followed by an instant increase in expression of the microglial-derived proinflammatory cytokine tumor necrosis factor (TNF) within the lesioned cord. TNF exists both as membrane-anchored TNF (mTNF) and as cleaved soluble TNF (solTNF). We previously demonstrated that epidural administration of a dominant-negative inhibitor of solTNF, XPro1595, to the contused spinal cord resulted in changes in Iba1 protein expression in microglia/macrophages, decreased lesion volume, and improved locomotor function. Here, we extend our studies using mice expressing mTNF, but no solTNF (mTNFΔ/Δ), to study the effect of genetic ablation of solTNF on SCI. We demonstrate that TNF levels were significantly decreased within the lesioned spinal cord 3 days after SCI in mTNFΔ/Δ mice compared to littermates. This decrease did, however, not translate into significant changes in other pro- and anti-inflammatory cytokines (IL-10, IL-1β, IL-6, IL-5, IL-2, CXCL1, CCL2, or CCL5), despite a tendency towards increased IL-10 and decreased IL-1β, TNFR1, and TNFR2 levels in mTNFΔ/Δ mice. In addition, microglial and leukocyte infiltration, activation state (Iba1, CD11b, CD11c, CD45, and MHCII), lesion size, and functional outcome after moderate SCI were comparable between genotypes. Collectively, our data demonstrate that genetic ablation of solTNF does not significantly modulate postlesion outcome after SCI
Opioid precursor protein isoform is targeted to the cell nuclei in the human brain
Background: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the kappa-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms. We here searched for novel PDYN mRNA and their protein product in the human brain. Methods: Novel PDYN transcripts were identified using nested PCR amplification of oligo(dT) selected full-length capped mRNA. Gene expression was analyzed by qRT-PCR, PDYN protein by western blotting and confocal imaging, dynorphin peptides by radioimmunoassay. Neuronal nuclei were isolated using fluorescence activated nuclei sorting (FANS) from postmortem human striatal tissue. lmmunofluorescence staining and con focal microscopy was performed for human caudate nucleus. Results: Two novel human PDYN mRNA splicing variants were identified. Expression of one of them was confined to the striatum where its levels constituted up to 30% of total PDYN mRNA. This transcript may be translated into ASP-PDYN protein lacking 13 N-terminal amino acids, a fragment of signal peptide (SP). Delta SP-PDYN was not processed to mature dynorphins and surprisingly, was targeted to the cell nuclei in a model cellular system. The endogenous PDYN protein was identified in the cell nuclei in human striatum by western blotting of isolated neuronal nuclei, and by confocal imaging. Conclusions and general significance: High levels of alternatively spliced Delta SP-PDYN mRNA and nuclear localization of PDYN protein suggests a nuclear function for this isoform of the opioid peptide precursor in human striatum. (C) 2016 Elsevier B.V. All rights reserved
Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice
Traumatic spinal cord injury (SCI) is followed by an instant increase in expression of the microglial-derived proinflammatory cytokine tumor necrosis factor (TNF) within the lesioned cord. TNF exists both as membrane-anchored TNF (mTNF) and as cleaved soluble TNF (solTNF). We previously demonstrated that epidural administration of a dominant-negative inhibitor of solTNF, XPro1595, to the contused spinal cord resulted in changes in Iba1 protein expression in microglia/macrophages, decreased lesion volume, and improved locomotor function. Here, we extend our studies using mice expressing mTNF, but no solTNF (mTNF Δ/Δ ), to study the effect of genetic ablation of solTNF on SCI. We demonstrate that TNF levels were significantly decreased within the lesioned spinal cord 3 days after SCI in mTNF Δ/Δ mice compared to littermates. This decrease did, however, not translate into significant changes in other pro-and anti-inflammatory cytokines (IL-10, IL-1 , IL-6, IL-5, IL-2, CXCL1, CCL2, or CCL5), despite a tendency towards increased IL-10 and decreased IL-1 , TNFR1, and TNFR2 levels in mTNF Δ/Δ mice. In addition, microglial and leukocyte infiltration, activation state (Iba1, CD11b, CD11c, CD45, and MHCII), lesion size, and functional outcome after moderate SCI were comparable between genotypes. Collectively, our data demonstrate that genetic ablation of solTNF does not significantly modulate postlesion outcome after SCI
Substrate Micropatterning as a New in Vitro Cell Culture System to Study Myelination
ArtÃculo de publicación ISIMyelination is a highly regulated developmental
process whereby oligodendrocytes in the central nervous system
and Schwann cells in the peripheral nervous system ensheathe axons
with a multilayered concentric membrane. Axonal myelination
increases the velocity of nerve impulse propagation. In this work,
we present a novel in vitro system for coculturing primary dorsal root
ganglia neurons along with myelinating cells on a highly restrictive
and micropatterned substrate. In this new coculture system, neurons
survive for several weeks, extending long axons on defined Matrigel
tracks. On these axons, myelinating cells can achieve robust myelination, as demonstrated by the distribution of compact myelin
and nodal markers. Under these conditions, neurites and associated myelinating cells are easily accessible for studies on the
mechanisms of myelin formation and on the effects of axonal damage on the myelin sheath.Regenerative Medicine and Nanomedicine Initiative of the Canadian Institutes of Health Research (CIHR)
RMF-7028
FONDECYT
1080252
CIHR
Ministry of Industry of Canada
Rio Tinto Alcan
Molson Foundatio
Insulin and the insulin-like growth factors I and II are mitogenic to cultured rat sciatic nerve segments and stimulate [3H]thymidine incorporation through their respective receptors
Effects of insulin and insulin-like growth factor-2 on the in vitro regeneration of the frog sciatic nerve
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