Neuropathy target esterase (NTE) is a neuronal membrane protein originally identified for its property to be modified by organophosphates (OPs), which in humans cause neuropathy characterized by axonal degeneration. Drosophila mutants for the homolog gene of NTE, swisscheese (sws), indicated a possible involvement of sws in the regulation of axon-glial cell interaction during glial wrapping. However, the role of NTE͞sws in mammalian brain pathophysiology remains unknown. To investigate NTE function in vivo, we used the cre͞loxP site-specific recombination strategy to generate mice with a specific deletion of NTE in neuronal tissues. Here we show that loss of NTE leads to prominent neuronal pathology in the hippocampus and thalamus and also defects in the cerebellum. Absence of NTE resulted in disruption of the endoplasmic reticulum, vacuolation of nerve cell bodies, and abnormal reticular aggregates. Thus, these results identify a physiological role for NTE in the nervous system and indicate that a loss-of-function mechanism may contribute to neurodegenerative diseases characterized by vacuolation and neuronal loss.cre͞lox P ͉ vacuolation ͉ thalamus ͉ hippocampus ͉ Purkinje cells N europathy target esterase (NTE) is a 150-kDa transmembrane protein that is highly conserved among species including insects, nematodes, yeast, and bacteria (1). Mutations in the Drosophila homolog, swisscheese (sws), produced glial-axonal hyperwrapping, degeneration, and a shortened life span (2). Both neurons and glia underwent cell death, accompanied by extensive vacuolation in the nervous system of Drosophila sws mutants. The NTE protein represents the mammalian homolog of the Drosophila swisscheese gene (3). The swisscheese and NTE proteins share a number of motifs including several hydrophobic transmembrane sequences, a serine esterase domain, and a sequence similar to the regulatory subunit of protein kinase A. A variety of pharmacological experiments have established the involvement of NTE in organophosphate (OP)-induced delayed neuropathy in humans and in animal models (3, 4), presumably through inactivation of the serine esterase activity. The protein NTE was initially identified as a target of OPs, found in pesticides and chemical warfare agents that cause peripheral neuropathy in humans (5, 6). OP-induced neuropathy has been implicated in Gulf War disease and other toxic neuropathies. However, the physiological functions of NTE, as well as the downstream events of NTE-induced neuropathy after OP exposure, remain unknown.We therefore sought to examine the physiological role of NTE in the central nervous system. Knockout of the NTE gene is embryonic lethal in mice at an early embryonic age (4, 19), thereby precluding the study of the role of NTE in the adult brain. We therefore constructed a conditional mutant NTE strain and deleted NTE specifically in neuronal tissues. We show here that neuron-specific deletion of NTE causes vacuolation of neuronal bodies and dendrites. The NTE protein was found to associate with the endopla...

Objectives: To unveil the role of SIRT1 in limiting oxidative stress in psoriasis and to further discuss the therapeutic prospects of salidroside in psoriasis. Methods: Literature from 2002 to 2019 was searched with "psoriasis", "oxidative stress", "SIRT1", "salidroside" as the key words. Then, Oxidative stress in psoriasis and the role of SIRT1 were summarized and the potential role of salidroside in the disease was speculated. Results: Oxidative stress might contribute to the pathogenesis of psoriasis. High levels of ROS produced during oxidative stress lead to the release of inflammatory mediators, that, in turn, induce angiogenesis and excessive proliferation of keratinocytes. SIRT1 is a member of the sirtuin family, of which the activation lead to the inhibition of such oxidative stress signaling pathways MAPK, NF-κB, and STAT3, down-regulation of inflammatory factors, suppression of inflammation and keratinocyte hyperproliferation, and inhibition of angiogenesis. Salidroside, the main ingredient of Rhodiola, is known to exert antioxidant roles, which has been attributed to SIRT1 activation. Conclusion: Salidroside might inhibit oxidative stress singling pathways via SIRT1 activation, and could be as an ideal candidate for management of psoriasis.

Background Skin photodamage is associated with ultraviolet- (UV-) induced reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (Nrf2) inactivation. In our previous study, skin-derived precursors (SKPs) were shown to ameliorate a UV-induced damage in mice, probably through Nrf2 activation and ROS scavenging. Objective To clarify the mechanism underlying the photoprotective effect of SKPs against UV-induced damage in a three-dimensional (3D) skin model. Methods The Nrf2 gene in SKPs was modified using lentiviral infection, and 3D skin models were reconstructed with keratinocytes and fibroblasts on the basis of type I collagen. Subsequently, these models were divided into the following six groups: normal, model, overexpressed, control, silenced, and negative control groups. Prior to irradiation, respective SKPs were injected into the last four groups. Next, all groups except the normal group were exposed to UVA+UVB. Lastly, the pathological and molecular-biological techniques were employed to determine the parameters. Additionally, LY294002, a PI3K inhibitor, was used to investigate the roles of PI3K/Akt and Nrf2/hemeoxygenase-1 (HO-1) in SKP photoprotection. Results Normal 3D skin models appeared as milky-white analogs with a clear, well-arranged histological structure. After the skin was exposed to irradiation, it exhibited cell swelling and a disorganized structure and developed nuclear condensation with numerous apoptotic cells. The expressions of cellular protective genes and Nrf2/HO-1/PI3K/Akt proteins remarkably decreased, which were accompanied by increased oxidative stress and decreased antioxidants (P < 0.05). However, these phenomena were reversed by nrf2-overexpressing SKPs. The 3D skin in the overexpressed group showed mild swelling, neatly arranged cells, and few apoptotic cells. Cellular protective genes and Nrf2/HO-1/PI3K/Akt proteins were highly expressed, and the oxidative biomarkers were remarkably ameliorated (P < 0.05). Nevertheless, the expression of these proteins decreased after LY294002 pretreatment regardless of SKP treatment or not. Meanwhile, there were increases in both UV-induced apoptotic cells and ROS level accompanied with SOD and GPX decrease in the presence of LY294002. Conclusions Evidence from the 3D skin model demonstrates that the protection of SKPs against UV-mediated damage is primarily via the PI3K/Akt-mediated activation of the Nrf2/HO-1 pathway, indicating that SKPs may be a promising candidate for the treatment of photodermatoses.