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Abstract: After nerve injury, Schwann cells proliferate and revert to a phenotype that supports nerve regeneration. This phenotype-changing process can be viewed as Schwann cell dedifferentiation. Here, we investigated the role of extracellular ATP in Schwann cell dedifferentiation and proliferation during Wallerian degeneration. Using several markers of Schwann cell dedifferentiation and proliferation in sciatic explants, we found that extracellular ATP inhibits Schwann cell dedifferentiation and proliferation during Wallerian degeneration. Furthermore, the blockage of lysosomal exocytosis in ATP-treated sciatic explants is sufficient to induce Schwann cell dedifferentiation. Together, these findings suggest that ATP-induced lysosomal exocytosis may be involved in Schwann cell dedifferentiation. [Copyright &y& Elsevier]

Abstract: The present study demonstrates that adenosine triphosphate (ATP) is released from Schwann cells through lysosomal exocytosis during Wallerian degeneration and in response to stimulation. In primary Schwann cell cultures, ATP was stored in lysosomal vesicles. ATP could then induce Ca2+-dependent lysosomal exocytosis. Among three stimulants of lysosomal exocytosis (glutamate, NH4Cl and zymosan), only NH4Cl was sufficient to induce ATP release from ex vivo sciatic nerve explants at 3days in vitro. Lysosomal exocytosis inhibitors (metformin, chlorpromazine and vacuolin-1) reversed the effect of NH4Cl-enhanced ATP release, replicating the state of explants treated with NH4Cl in the absence of lysosomal exocytosis inhibitors. Furthermore, we observed ATP release through lysosomal exocytosis during Wallerian degeneration in sciatic explant cultures using the recently identified vesicular nucleotide transporter (VNUT). From these experiments, we conclude that the exocytosis of lysosomes in Schwann cells during Wallerian degeneration is Ca2+-dependent, and that it induces ATP release from Schwann cells. [Copyright &y& Elsevier]

In addition to inhibiting matrix metalloproteinases, tissue inhibitor of metalloproteinase-1 (TIMP-1) is involved in the regulation of cell growth and survival. To determine its mechanism of action, we investigated effects of TIMP-1 on cell proliferation and survival and signaling pathways induced by TIMP-1 in the human breast carcinoma T-47D cell line. Treatment of T-47D cells with TIMP-1 strongly inhibited apoptosis induced by serum deprivation, but did not affect cell proliferation. TIMP-1 induced phosphorylation of Akt and extracellular signal-regulated protein kinases (ERKs), but pertussis toxin and specific inhibitors of Src family tyrosine kinases, protein tyrosine kinases, and phosphatidylinositol-3 kinase (PI3 kinase) blocked the ability of TIMP-1 to activate Akt and ERKs as well as the anti-apoptotic effect of TIMP-1. We found that TIMP-1 enhanced the kinase activities of c-Src and PI3 kinase and that this enhancement was inhibited by pertussis toxin. Inhibition of ERK activation, however, resulted in a slight decrease of the TIMP-1-induced anti-apoptotic effect. These findings demonstrate that the ability of TIMP-1 to inhibit apoptosis in T-47D cells is mediated by the sequential activation of pertussis toxin-sensitive G protein, c-Src, PI3 kinase, and Akt. [Copyright &y& Elsevier]

Orthohantaviruses are negative-sense, single-stranded RNA viruses harbored by rodents, shrews, moles, and bats. Of the shrew-borne orthohantaviruses in the Republic of Korea (ROK), Jeju orthohantavirus (Jeju virus, JJUV) was found on Jeju Island. This small-scale epidemiologic survey investigated the geographic distribution and molecular phylogeny of JJUV in the ROK. In 32 trapping sites, tissues of 84 Crocidura shantungensis were analyzed for JJUV RNA. JJUV RNA was detected in seven (8.3%) shrews captured on the Korean peninsula. The molecular epidemiologic survey demonstrated the prevalence of JJUV by geographic distribution. The RNA loads of JJUV were evaluated in various tissues. Entire coding sequences of tripartite genomes were recovered from two JJUV strains on the mainland. Phylogenetic relationships of the JJUV revealed a distinct geographic lineage of mainland strains from the strains on Jeju Island. This study sheds light on the molecular epidemiology, phylogeographic diversity, and virus-host co-divergence of JJUV, ROK. • Discovery of Jeju virus (JJUV) strains in the Korean peninsula. • High JJUV RNA load in various tissues of the reservoir host (Crocidura shantungensis). • Distinct lineage of JJUV on the mainland of the Republic of Korea. [ABSTRACT FROM AUTHOR]

Abstract: The adenosine triphosphate (ATP) plays important roles under physiological and pathological conditions such as traumatic brain injury, neuroinflammation and neuropathic pain. In the present study, we set out to study the role of lysosomal vesicles on ATP release from the dorsal root ganglion neurons. We found that the lysosomal vesicles, which contain the quinacrine-positive fluorescence and express the vesicular nucleotide transporter (VNUT), were localized within the soma and growth cone of the cultured dorsal root ganglion neurons. In addition, the number of the quinacrine staining was decreased by application of lysosomal exocytosis activators, and this decrease was suppressed by the metformin and vacuolin-1, which suppressed lysosomal exocytosis. Thus, these findings suggest that ATP release via the lysosomal exocytosis may be one of the pathways for ATP release in response to stimulation. [Copyright &y& Elsevier]