Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50% of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While over-expression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene.

The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines such as interleukin-1β (IL-1β), which in turn activate a well-described myeloid differentiation factor 88 (MYD88) -mediated, nuclear factor-κB (NF-κB) -dependent transcriptional pathway that results in inflammatory cell activation and recruitment1–4. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response5,6. Paradoxically, the same cytokines vital to a successful immune defense also have disruptive effects on endothelial cell-cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture7–9. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remains ill defined. Here we show that the direct, immediate, and disruptive effects of IL-1β on endothelial stability are NF-κB independent and are instead the result of signaling via the small GTPase, ADP-ribosylation factor 6 (ARF6), and its activator, ARF nucleotide binding site opener (ARNO). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, and thus propose MYD88-ARNO-ARF6 as a proximal IL-1β signaling pathway distinct from that mediated by NF-κB (Supplementary Fig. 1). Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors (GEFs) such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.

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Objective The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability. Methods Utilizing Pmp22+/− mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. Results We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain–containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. Interpretation Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.

Colorectal cancer (CRC) is a major cause of cancer-related mortality in the world. Recently, a number of studies have demonstrated that cancer stem cells (CSCs) present in colorectal cancer tissues, are responsible for resistance to conventional therapies. Therefore, effective recognition of CSCs is of great importance. In the present study, to explore the potential characterizations of CSCs by the expression of specific cell surface markers such as CD133 and CD44, we screened six CRC cell lines using western blotting, immunofluorescence and flow cytometry. SW620, one of the six cell lines analyzed, was sorted into four subpopulations by fluorescence activated cell sorting (FACS). The capability of colony formation, proliferation rate, apoptosis, drug resistance, as well as their migratory and invasion potential were detected. The results revealed that the combination of CD44 and CD133 correlates with the features of CSCs in SW620 cells. CD44 positive cells showed more robust colony formation, higher proliferation, less spontaneous apoptosis, a higher resistance to drug-induced cell death, and were enriched after drug treatment. Among CD44 positive SW620 cells, the CD133 negative subpopulation was more migratory and invasive, which means that CD44+CD133− correlates with most of features proposed for CSCs. Overall, the data presented herein showed that CRCs have a wide range of expression for CD44 and CD133; it is unlikely the CSCs can be characterized by any single marker or the same set of markers for all colon cancer cells. For SW620 cells, the CSCs are likely represented by the CD44+CD133− surface marker. This finding of CSC markers represented by one positive and one negative is in line with CSCs in other tumors, such as CD34+CD38− for acute myeloid leukemia; CD44+CD24− for breast and pancreatic tumors. The absence of surface molecule(s) on CSCs will make it even more difficult to track and target this group of minority cells.

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Study design: An animal model of transected spinal cord injury (SCI) was used to test the hypothesis that cografted neural stem cells (NSCs) and NT-3-SCs promote morphologic and functional recoveries of injured spinal cord. Objective: To explore whether cotransplant of NSCs and NT-3-SCs could promote the injured spinal cord repair. Setting: Zhongshan Medical College, Sun Yat-sen University, PR China. Methods: Female Sprague-Dawley (SD) rats weighing on 200-220 g were used to prepare SCI models. The spinal cord was transected between T 9 and T 10 , then NSCs, SCs þ NSCs, LacZSCs þ NSCs, or NT-3-SCs þ NSCs were grafted into the transected site. Results: (1) Part of NSCs could differentiate to neuron-like cells in the transected site and the percentage of differentiation was NT-3-SCs þ NSCs group4SCs þ NSCs group4NSCs group. (2) In the grafted groups, there were 5-HT, CGRP, and SP positive nerve fibres within the transected site. Some fluorogold (FG)-labeled cells were found in the spinal cord rostral to the transected site, the red nuclei and the inner pyramidal layer of sensorimotor cortex. (3) The cells grafted could enhance the injured neurons survival in inner pyramidal layer of sensorimotor cortex, red nuclei of midbrain, and Clark's nuclei of spinal cord's L1 segment, could decrease the latency and increase the amplitude of cortical somatosensory evoked potential (CSEP) and cortical motor evoked potential (CMEP), and could promote partly structural and functional recovery of the SCI rats.Conclusion: These results demonstrate that cografted NT-3-SCs and NSCs is a potential therapy for SCI.