histone deacetylase inhibitors Though the physiological role

Though the physiological roles of microglia-derived elastases in the CNS are not well understood, their involvement in the metabolism of cholecystokinin [41] and in the processing of plasminogen to produce a low molecular weight plasminogen that enhances neurite outgrowth has been reported [38]. Expression of elastase activity on the cell surface of monocytes was also suggested by the activation of human coagulation factor V [42]. Our results show that elastases within the microglial histone deacetylase inhibitors that surround Aβ plaques are responsible for ApoE degradation in the brains of patients with AD, thus suggesting a new physiological role of microglial elastases in the CNS. Control of the proteases with specific inhibitors may affect Aβ clearance via ApoE metabolism in brains with AD. Further studies aimed at developing therapeutic approaches that utilize elastase-specific inhibitors are required.
Conflict of interest
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Acknowledgements This study was supported by a Grant-in-Aid (No. 23590697, Alzheimer\'s disease) from the Ministry of Education, Science, Sport, and Culture of Japan. The authors are grateful to Editage for providing excellent editorial assistance.
Introduction Schistosomiasis is a disease caused by the blood flukes of Schistosoma spp., which has widespread prevalence in many mammalian hosts, including humans. The disease remains a major global health problem, affecting over 200 million people in 76 countries in tropical and subtropical regions (McKerrow and Salter, 2002; Ross et al., 2001). Three main schistosome species infect humans are Schistosoma japonicum, S. mansoni and S. haematobium, of them S. japonicum is endemic in China, Indonesia and the Philippines. S. japonicum exhibits a distinct infection process compared to the other schistosome species, as its larval cercariae penetrate through mammalian host skin quicker and migrates to the lungs much more rapidly (Gui et al., 1995; Rheinberg et al., 1998; Wang et al., 2005). Although the molecular mechanisms for this rapid migration of S. japonicum have not been clearly defined, the proteolytic role of cercarial proteases is strongly assumed to be involved in the invasion process (Bahgat et al., 2001; Chlichlia et al., 2005; Dvorak et al., 2008; Ruppel et al., 2004). Cercarial elastase is a member of Clan PA family S1 serine protease, and is able to effectively cleave insoluble elastin in mammalian skin (Pierrot et al., 1995). As a key enzyme in schistosome lifecycle, cercarial elastase is synthesized during the sporocyst stage, stored in the acetabular glands of infective cercarial stage and released upon penetration to degrade mammalian host skin layer facilitating invasion (McKerrow and Doenhoff, 1988; Salter et al., 2000). In addition, elastase also appears to modulate the host immunological and haemostatic defence mechanisms to better protect the invading larvae (Aslam et al., 2008; Doenhoff et al., 1990; Hansell et al., 2008; Marikovsky et al., 1988). Cercarial elastase (CE) was first described in S. mansoni (Landsperger et al., 1982), composing two proteases, “chymotrypsin-like” protease and “trypsin-like” protease, which were found in cercarial secretions. Further characterization of these proteins revealed that the “chymotrypsin-like” protease, designated cercarial elastase, had a strong preference for proteins with large hydrophobic side chains at P1 position and was the primary contributor to the invasive process of cercariae (Salter et al., 2000). The CE is a composite of multiple isoforms comprising nine orthologous genes (SmCE-1a, SmCE-1b, SmCE-1c, SmCE-2a, SmCE-2b, SdCE-1a, SdCE-1b, ShCE-1a, ShCE-1b) identified in three schistosome species, S. mansoni, S. haematobium and Schistosomatium douthitti (Salter et al., 2002). Given the fact that S. japonicum penetrates and migrates much more rapidly, it was speculated that S. japonicum cercariae might present some enzymatic differences with respect to other schistosome spp. (Ruppel et al., 2004). It was reported that the homolog of SmCE-1a, the major SmCE isoform in S. mansoni cercariae, was not immunologically detectable in S. japonicum cercaria in either developing or mature stage parasites, when using the sera of mice immunized with SmCE-1a DNA construct (Chlichlia et al., 2005). The result is in line with the findings that the fluorescence reaction with antisera raised against purified CE was found only inside the heads of cercariae from S. mansoni or S. haematobium (Bahgat et al., 2001). To fill in the unknowns, our previous work provided new insights into S. japonicum CE. We have previously indentified SjCE-2b, an ortholog gene to SmCE-2b, in S. japonicum, and found the protein present in sporocysts, cercariae and infected mouse skin by immunobloting and immunofluorescence assays, indicating its invasive role (Huang et al., 2007; ). Most recently, a proteomic study demonstrated the presence of two abundant proteases, SjCE2b and SjCB2, in S. japonicum cercaria, but not in schistosomula transformed right after skin penetration, inferring the two enzymes might be consumed in skin migration (Liu et al., 2015). Nevertheless, the enzyme activity of SjCE has not been reported. In this study, we successfully purified and refolded the recombinant SjCE-2b protein from inclusion bodies, and demonstrated its enzymatic activity biochemically. Additionally we report on the immunoprotective response in immunized mice.