Leptin attenuates BACE1 expression and amyloid-ß genesis via the activation of SIRT1 signaling pathway.

The aspartyl protease ß-site AßPP-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in Aß production, a peptide at the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce Aß production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in Aß levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor - kappa B (NF-κB) positively regulates BACE1 transcription. NF-κB activity is tightly regulated by the mammalian sirtuin SIRT1. Multiple studies have cogently evinced that leptin activates the metabolic master regulator SIRT1. In this study, we determined the extent to which SIRT1 expression and activity regulate the leptin-induced attenuation in BACE1 expression and Aß levels in cultured human neuroblastoma SH-SY5Y cells. This study also elucidated and delineated the signal transduction pathways involved in the leptin induced mitigation in BACE1 expression. Our results demonstrate for the first time that leptin attenuates the activation and transcriptional activity of NF-κB by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-κB-mediated transcription of BACE1 and consequently reduces Amyloid-ß genesis. Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-ß production and may help design potential therapeutic interventions.

Safety and initial efficacy of radiation segmentectomy for the treatment of hepatic metastases​.

BACKGROUND: Hepatic metastatectomy and ablation are associated with prolonged survival, but not all lesions are anatomically amenable to these therapies. We evaluated safety and initial efficacy of segmental ablative transarterial radioembolization, or radiation segmentectomy (RS), as a treatment for hepatic metastases. METHODS: A single institution retrospective analysis was performed of patients with hepatic metastases, determined unamenable to resection by a multidisciplinary tumor board, treated with RS from 2015-2017. Safety parameters evaluated were pre and post procedure liver chemistry, MELD score, ALBI grade, platelet count, and adverse events using both Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 and Clavien Dindo (CD) classifications. Initial efficacy was evaluated using RECIST, mRECIST, and PERCIST criteria. RESULTS: Ten patients underwent between 1-3 RS treatments. There was no clinical treatment toxicity or significant post-treatment change in liver chemistry, MELD, or ALBI score. One patient had a CTCAE Grade 1/CD Grade 1 adverse event. All patients showed partial or complete imaging response at initial assessment (1-3 months). Seven patients demonstrated disease control at a mean of 7.1 months post treatment. Three patients developed out of field disease progression. One RS was technically unsuccessful. CONCLUSIONS: Early evaluation of segmental radioembolization suggests a safe treatment option for select patients with hepatic metastases. Initial efficacy as definitive radiotherapy with minimal toxicity is promising in anatomic locations unamenable to resection or alternative means of ablation.

Cerebral Granulomatous Inflammation Secondary to Hydrophilic Polymer Embolization Following Thrombectomy.

BACKGROUND Given the recent completion of multiple trials demonstrating the benefit of endovascular mechanical thrombectomy for select patients with proximal large artery occlusive ischemic strokes, there has been a large increase in the performance of these procedures. In the context of increased thrombectomy performance, there have also been increased reports of rare occurrences of granulomatous inflammatory response to the hydrophilic polymer which coat many of these interventional devices. CASE REPORT A 59-year-old female presented with a complete occlusion of her right proximal middle cerebral artery (MCA) and imaging showed a large area of penumbra. Cerebral angiogram and mechanical thrombectomy were successfully performed with reversal of clinical symptoms. Eight months following her stroke, she developed progressive recurrence of left-sided neurological deficits. After extensive workup culminating in tissue sampling, she was found to have developed granulomatous inflammation surrounding microscopic embolization of hydrophilic polymer, which is used to coat many interventional devices such as wires and catheters. The patient responded both clinically and radiographically to anti-inflammatory steroid therapy. CONCLUSIONS Recognizing the significant potential morbidity of a large vessel ischemic stroke and the expanded use of endovascular interventions aimed at staving off this disability, there are emerging and at times indolent complications from the use of hydrophilic polymer coated wires and catheters. This rare and potentially under-recognized complication should be considered in the differential for any patient with new neurological findings following cerebral intervention, especially given the consideration that this appears to a treatable complication.

Differential effects of the estrogen receptor agonist estradiol on toxicity induced by enzymatically-derived or autoxidation-derived oxysterols in human ARPE-19 cells.

PURPOSE/AIM OF THE STUDY: Disturbances in cholesterol metabolism and increased levels of cholesterol oxidation products (oxysterols) in retina may contribute to age-related macular degeneration (AMD). The role of oxysterols or of their target receptors liver X receptors (LXRs) and estrogen receptors (ERs) in the pathogenesis of MD is ill-known. The purpose of this study is to determine the extent to which the oxysterols 27-hydroxycholesterol (27-OHC), 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-KC) affect the transcriptional activity of LXR and ER. MATERIALS AND METHODS: ARPE-19 cells, untreated or incubated with 27-OHC, 25-OHC or 7-KC for 24 h were harvested. We used Western blot analyses for detecting ERs and LXRs expression, dual luciferase assays for measuring LXRs and ERs transcriptional activity, cytotox-ONE homogeneous membrane integrity assay for measuring cytotoxicity, JC-1 method for measuring mitochondrial membrane potential changes and ELISA for measuring cytokine levels. RESULTS: Both LXRs and ERs are expressed and are transcriptionally active in ARPE-19 cells. 27-OHC, 25-OHC and 7-KC inhibited ER-mediated transcriptional activity, whereas 27-OHC and 25-OHC increased LXR-mediated transcription. E2 reduced 25-OHC and 27-OHC-induced cytotoxicity, mitochondrial permeability potential decline, and cytokine secretion. The LXR agonist GW3965 or the LXR antagonist 5α-6α-epoxycholesterol-3-sulfate (ECHS) did not offer protection against either 27-OHC and 25-OHC or 7-KC. CONCLUSIONS: Increased levels of oxysterols can decrease ER and increase LXR signaling. ER agonists can offer protection against cytotoxic effects of 27-OHC and 25-OHC, two oxysterols derived by enzymatic reactions. Although they exert similar toxicity, the cellular mechanisms involved in the toxic effects of oxysterols whether derived by enzymatic or autoxidation reactions appear to be different.