The involvement and the in vivo relevance of endoplasmic reticulum (ER) stress in the atherosclerotic process are well established, but the mechanisms have been only partly elucidated. Emerging evidence indicates that ER protein folding pathways are sensitive to nitric oxide (NO) fluctuations and therefore heavily vulnerable under conditions of nitrosative stress. Recent research indicates that protein S-nitrosylation (S-NO), a key redox-mediated modification involved in several disorders, affects neuronal function by altering ER stress sensor proteins. However, the mechanisms by which ER protein S-NO impacts vascular diseases remain unclear. Here, we provide evidence that secosterol-B (SEC-B), an oxysterol found in atherosclerotic plaques, induces nitrosative stress and protein S-NO in vascular endothelium, leading to ER stress. In detail, our findings demonstrate that SEC-B triggers activation of the inositol-requiring enzyme-X-box binding protein 1 signaling pathway and causes ER-membrane expansion and the accumulation of misfolded proteins in human umbilical vein endothelial cells. In parallel, increased NO levels with upregulation of inducible nitric oxide synthase protein expression and alterations in the nitrosylation levels of various proteins, including protein disulfide isomerase and glucose regulatory protein 78, were observed. Interestingly, pretreatment with NG-nitro-L-arginine methyl ester strongly reduced ER swelling and aggresome formation. Collectively, our findings demonstrate that NO and protein S-NO play a critical role in SEC-B-induced ER dysfunction, providing new insights into the mechanisms underlying vascular dysfunction observed in atherosclerosis and highlighting potential therapeutic targets to preserve endothelial integrity.

A 42-year-old man with severe chronic schizophrenia who was on no medications presented to the internal medicine ward with a 2-week history of vomiting and 10-kg weight loss in the past 3 months. He was known to ingest small objects, which passed the gastrointestinal tract without requiring

In this context, our study aimed to ascertain whether the esterification of 24-hydroxycholesterol, a process heavily affected by oxidative stress, is altered in ALS.The study examined the level of 24-hydroxycholesteryl esters in cerebrospinal fluid and plasma of 18 ALS patients by spectroscopic technique as Ultra-high performance liquid chromatography mass spectrometry (UPLC-MS).The level of 24-hydroxycholesteryl esters in cerebrospinal fluid was found to be lower as the brain-blood barrier was damaged. Such a level was positively correlated with the level of esters in plasma. Both cerebrospinal fluid (CSF) level and plasma level were lower in ALS patients (60.05 ± 4.24 % and 54.07 ± 20.37 % respectively) than in controls (79.51 ± 2.47 % and 80.07 ± 10.02 % respectively).The data suggest that the level 24-hydroxycholesteryl esters might be a new biomarker of ALS and can be measured for monitoring the disease progression.

Oxidized LDL (oxLDL) and oxysterols are known to play a crucial role in endothelial dysfunction (ED) by inducing endoplasmic reticulum stress (ERS), inflammation, and apoptosis. However, the precise molecular mechanisms underlying these pathophysiological processes remain incompletely understood. Emerging evidence strongly implicates excessive nitric oxide (NO) production in the progression of various pathological conditions. The accumulation of reactive nitrogen species (RNS) leading to nitrosative stress (NSS) and aberrant protein S-nitrosylation contribute to NO toxicity. Studies have highlighted the involvement of NSS and S-nitrosylation in perturbing ER signaling through the modification of ER sensors and resident isomerases in neurons. This review focuses on the existing evidence that strongly associates NO with ERS and the possible implications in the context of ED induced by oxLDL and oxysterols. The potential effects of perturbed NO synthesis on signaling effectors linking NSS with ERS in endothelial cells are discussed to provide a conceptual framework for further investigations and the development of novel therapeutic strategies targeting ED.

Oxysterols are a family of 27-carbon cholesterol oxidation derivatives found in low-density lipoproteins (LDLs) and atherosclerotic plaques where they trigger several biological responses involved in the initiation and progression of atherosclerosis. Several pieces of evidence suggest that oxysterols contribute to endothelial dysfunction (ED) due to their ability to alter membrane fluidity and cell permeability leading to inflammation, oxidative stress and apoptosis. The present study aimed to investigate the molecular events occurring in human microvascular endothelial cells (HMEC-1) in response to autoxidation-generated 3β-hydroxy-5β-hydroxy-B-norcholestane-6β-carboxaldehyde (SEC-B) exposure. Our results highlight that SEC-B rapidly activates HMEC-1 by inducing oxidative stress, nitric oxide (NO) production and pro-inflammatory cytokine release. Exposure to SEC-B up to 24 h results in persistent accumulation of the vasodilator NO paralleled by an upregulation of the endothelial nitric oxide synthase (eNOS) enzyme and downregulation of Caveolin-1 (Cav-1) protein levels. Moreover, reduced expression and extracellular release of the vasoconstrictor factor endothelin-1 (ET-1) are observed. Furthermore, SEC-B stimulates the expression of the cytokines interleukin-6 (IL-6) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). This proinflammatory state leads to increased monocyte recruitment on activated HMEC-1 cells. Our findings add new knowledge on the role of SEC-B in ED and further support its potential implication in atherosclerosis.

Abstract:Reel syndrome is a rare cause of pacemaker lead displacement. This case report shows a rare presentation of Reel syndrome highlighting the importance of an early diagnosis and discussing the underlying mechanism, management and prevention.

•There is the need to better understand the humoral immunity response to mRNA vaccines against SARS-CoV-2 in a real world setting.•In response to BNT162b2 we observed that at peak immunity anti-SP IgG titer range was wide, spanning more than two orders of magnitude.•Anti-spike IgG declined over time to reach a residual value of about 18% at 28 weeks.•Our results support the use of booster doses.

INTRODUCTION:Normal-pressure hydrocephalus (NPH) is a common condition associated with a cognitive deterioration and possibly involving up to 9%-14% of all nursing home residents older than 65 years old. The purpose of the present paper is to introduce an inclusive study protocol aimed at increasing the diagnostic precision and follow-up accuracy. METHODS:A total of 28 patients were operated on for NPH in our institution in the period ranging between January 2015 and December 2019. All the patients underwent magnetic resonance imaging of the brain with standard sequences, calculation of the Evans index and corpus callosum angle, and evaluations by means of Montreal Cognitive Assessment (MOCA), Mini-Mental State Examination, and Frontal Assessment Battery (FAB) neuropsychological tests preoperatively and at 1 and 6 months. A preoperative lumbar test infusion (LIT) with fine measurement of the intrathecal pressures at the beginning and at the end of the procedures was performed. RESULTS:MOCA and FAB proved an overall improvement of the neurocognitive conditions at 1 month postoperatively. The mean pressure at the beginning of the LIT, was negatively associated with the neuropsychological outcome variables (Mini-Mental State Examination, FAB, and MOCA) in the 3 different evaluations, with FAB and MOCA at 6 months. We found a strong positive correlation between the Evans index as measured on the first magnetic resonance imaging scan both with the diastolic and systolic pressure at the beginning of the test. CONCLUSIONS:Neuropsychological assessment, combined with LIT with intrathecal pressure managements aids the diagnostic process in patients affected by NPH. It allows standardizing in a rigorous fashion the follow-up evaluation of patients undergoing surgery for a ventriculoperitoneal shunt.

As the population ages and the healthcare improves, the incidence of diseases associated with aging is rising. Longevity is not necessarily synonymous with healthy aging and cognitive decline represents one of the most common and unwanted consequences of aging. Therefore maintaining optimal cognitive health in the elderly has become a priority. Given the extensive evidence in support of an association between diet and cognitive performance, in recent years, a growing number of studies have been investigating the impact of nutrition on brain health and memory. In particular, the Mediterranean diet and consumption of its main component, the extra-virgin olive oils (EVOOs) have been linked to better visual memory, verbal fluency, and decreased risk of developing dementia and Alzheimer's disease (AD). Besides the well-documented antioxidative and antiinflammatory properties, numerous in vitro and in vivo studies have revealed the potent beneficial effect of EVOO and its phenolic compounds in terms of synaptic function and integrity. Interestingly, recent reports have shed new lights into the possible mechanisms responsible for EVOO neuroprotective effect on memory, suggesting that it could be also mediated by an increase in adenosine triphosphate, the main source of energy in eukaryotic cells and by modulation of basal synaptic activity and short-term plasticity. This chapter summarizes the evidence in support of EVOO as a therapeutic agent for promoting brain health, delaying cognitive decline, and the onset of dementia and AD.

The ongoing SARS-CoV-2 pandemic, which is dramatically spreading worldwide, is well known for its respiratory sequelae. Besides cases of Guillain-Barré Syndrome, encephalitis, hyposmia, the whole range of neurological complications due to SARSCoV-2 is still not well known. Herein, we report a new case of COVID-19, associated with mononeuropathy with reversible conduction block (CB). After SARS-CoV-2 infection, the patient developed acute weakness of left peroneal muscles. He underwent an endovenous immunoglobulin treatment, and symptoms improved. Two electroneurographic exam (before and after treatment), showed a reversible CB on left peroneal nerve. Dosage of serum antiganglioside antibodies showed anti-GM1 IgM positivity. The present case gives new informations about reversible CB neuropathy as an acute presentation of SARS-CoV-2. Besides, antiganglioside antibodies evaluation could be useful to understand etiology of the increasing number of neurological manifestations related to SARS-CoV-2.

A 42-year-old male presented with weight loss and progressively increasing pain and swelling in joints over the past 3 months. Contrast-enhanced computed tomography (CT) demonstrated pleuropulmonary opacities and supra/infradiaphragmatic lymph nodes enlargement. Positron emission tomography (PET/CT) with 18F-fluorodeoxyglucose showed intensely increased tracer uptake in joints, in pulmonary opacities, as well as in thoracic, iliac, and inguinal nodes. On suspicion of lymphoma with synovial involvement, he was submitted to lymph node and synovial biopsy, which revealed reactive follicular lymphadenopathy and synovium inflammatory changes, respectively. Rheumatoid factor resulted increased, and thus, diagnosis of rheumatoid arthritis with related lung and lymph node involvement was made.

Insulinoma is an insulin-producing pancreatic neuroendocrine tumor that can be malignant in about 10% of cases. Locoregional invasion, lymph node metastases, or remote metastases are the main criteria of malignant insulinoma. Its incidence in patients with pre-existing diabetes mellitus (DM) is exceptionally rare. In this report, we describe a 66-year-old man with long-standing type 2 DM who presented with recurrent episodes of diaphoresis due to severe hypoglycemia despite the withdrawal of insulin therapy, hypercalcitoninemia, and biochemical and radiological findings suggestive of metastatic malignant insulinoma. Unfortunately, after few days of diazoxide treatment, edema, hypotension, oliguria, and water retention were observed, patient's clinical status deteriorated rapidly, and he died in our department from acute renal failure.

You have accessJournal of UrologyInfertility: Basic Research & Pathophysiology (MP38)1 Apr 2020MP38-17 THE PROFILE OF HUMAN SPERM OXYSTEROLS IN NORMAL AND SUBFERTILE PATIENTS: RESULTS FROM A PROSPECTIVE MULTICENTRE STUDY Antonio Luigi Pastore*, Andrea Fuschi, Yazan Al Salhi, Gennaro Velotti, Lorenzo Capone, Alessia Martoccia, Pietro Paolo Suraci, Chiara Zerbinati, Luigi Iuliano, and Antonio Carbone Antonio Luigi Pastore*Antonio Luigi Pastore* More articles by this author , Andrea FuschiAndrea Fuschi More articles by this author , Yazan Al SalhiYazan Al Salhi More articles by this author , Gennaro VelottiGennaro Velotti More articles by this author , Lorenzo CaponeLorenzo Capone More articles by this author , Alessia MartocciaAlessia Martoccia More articles by this author , Pietro Paolo SuraciPietro Paolo Suraci More articles by this author , Chiara ZerbinatiChiara Zerbinati More articles by this author , Luigi IulianoLuigi Iuliano More articles by this author , and Antonio CarboneAntonio Carbone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000887.017AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cholesterol is the main lipid component of sperm cell that is essential for sperm membrane fluidity, capacitation, and acrosomal reaction. Recent data obtained in bovine sperm showed that sperm capacitation is associated with the formation of oxysterols, oxidized products of cholesterol. The main objective of the present study was to identify and quantify, for the first time, the different species of oxysterols in human semen from normozoospermic, oligoasthenoteratozoospermic and asthenozoospermic patients. The secondary aim was to investigate the potential role of oxysterols in sperm pathophysiology. METHODS: To investigate the profile of human sperm oxysterols in subjects with normal and altered sperm characteristics, we recruited 150 consecutive subjects referring at the Centre of Andrology of Department of Urology for analysis of seminal fluid between March 2017 and June 2018. In order to investigate the possible correlation to oxidative stress and semen oxysterols profile, we included a group of patients with varicocele given the demonstrated relationship between varicocele and oxidative stress. Semen analysis was assessed by light microscope according to World Health Organization guidelines (WHO, 2010). Oxysterols were determined by GC–MS using deuterium-labelled internal standards as described by Dzeletovic et al. RESULTS: Complete oxysterol profile was obtained in 134 human semen of normozoospermic, oligoasthenoteratozoospermic, asthenozoospermic and varicocele patients. Oxysterols analyzed included seven autoxidation- and five enzymatically-generated oxysterols. Among the 12 oxysterols analyzed, 25-hydroxycholesterol (25-HC) resulted the most abundant oxysterol in normozoospermic subjects, and turned out to be the only one that differed significantly (p<0.0001) among the 4 groups. It was higher in the normozoospermic group (21.63±18.47 ng/mL, mean±SD) than oligoasthenoteratozoospermic (2.59±2.93, ng/mL, mean±SD), asthenozoospermic (5.59±3.17) and varicocele (13.48±11.81, ng/mL, mean±SD) groups. Furthermore, 25-HC positively correlated with the spermatozoa number (r=0.72, p<0.0001). CONCLUSIONS: In conclusion, to the best of our knowledge, this is the first study providing evidence for the feasibility of detection and quantification of oxysterols in human semen samples. We found in spermatozoa the presence of cholesterol 25-hydroxylase and its preferential accumulation in the neck and the post acrosomal area. 25-HC was able to induce calcium ions and cholesterol depletion in the acrosomal region, in an extent comparable to that of a capacitating medium. This finding offers the opportunity to identify a new molecular player involved in pre-fertilization processes. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e575-e576 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Antonio Luigi Pastore* More articles by this author Andrea Fuschi More articles by this author Yazan Al Salhi More articles by this author Gennaro Velotti More articles by this author Lorenzo Capone More articles by this author Alessia Martoccia More articles by this author Pietro Paolo Suraci More articles by this author Chiara Zerbinati More articles by this author Luigi Iuliano More articles by this author Antonio Carbone More articles by this author Expand All Advertisement PDF downloadLoading ...

Oxidized LDLs (oxLDLs) and oxysterols play a key role in endothelial dysfunction and the development of atherosclerosis. The loss of vascular endothelium function negatively impacts vasomotion, cell growth, adhesiveness and barrier functions. While for some of these disturbances, a reasonable explanation can be provided from a mechanistic standpoint, for many others, the molecular mediators that are involved are unknown. Caveolae, specific plasma membrane domains, have recently emerged as targets and mediators of oxLDL‐induced endothelial dysfunction. Caveolae and their associated protein caveolin‐1 (Cav‐1) are involved in oxLDLs/LDLs transcytosis, mainly through the scavenger receptor class B type 1 (SR‐B1 or SCARB1). In contrast, oxLDLs endocytosis is mediated by the lectin‐like oxidized LDL receptor 1 (LOX‐1), whose activity depends on an intact caveolae system. In addition, LOX‐1 regulates the expression of Cav‐1 and vice versa. On the other hand, oxLDLs may affect cholesterol plasma membrane content/distribution thus influencing caveolae architecture, Cav‐1 localization and the associated signalling. Overall, the evidence indicate that caveolae have both active and passive roles in oxLDL‐induced endothelial cell dysfunction. First, as mediators of lipid uptake and transfer in the subendothelial space and, later, as targets of changes in composition/dynamics of plasma membrane lipids resulting from increased levels of circulating oxLDLs. Gaining a better understanding of how oxLDLs interact with endothelial cells and modulate caveolae‐mediated signalling pathways, leading to endothelial dysfunction, is crucial to find new targets for intervention to tackle atherosclerosis and the related clinical entities.LINKED ARTICLESThis article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc

In spite of the significant progress of estrogen-dependent breast cancer (BC) treatment, aromatase inhibitor resistance is a major problem limiting the clinical benefit of this frontier endocrine-therapy. The aim of this study was to determine the differential expression of steroid-converting enzymes between tumor and adjacent normal tissues, as well as their correlation in modulating intratumoral steroid-hormone levels in post-menopausal estrogen-dependent BC. RNA sequencing dataset (n = 1097) of The-Cancer-Genome-Atlas (Breast Invasive Carcinoma) retrieved through the data portal of Genomic Data Commons was used for differential expressions and expression correlation analyses by Mann–Whitney U and Spearman’s rank test, respectively. The results showed significant up-regulation of 17β-HSD7 (2.50-fold, p < 0.0001) in BC, supporting its effect in sex-hormone control. Besides, suppression of 11β-HSD1 expression (-8.29-fold, p < 0.0001) and elevation of 11β-HSD2 expression (2.04-fold, p < 0.0001) provide a low glucocorticoid environment diminishing BC anti-proliferation. Furthermore, 3α-HSDs were down-regulated (−1.59-fold, p < 0.01; −8.18-fold, p < 0.0001; −33.96-fold, p < 0.0001; −31.85-fold, p < 0.0001 for type 1–4, respectively), while 5α-reductases were up-regulated (1.41-fold, p < 0.0001; 2.85-fold, p < 0.0001; 1.70-fold, p < 0.0001 for type 1–3, respectively) in BC, reducing cell proliferation suppressers 4-pregnenes, increasing cell proliferation stimulators 5α-pregnanes. Expression analysis indicates significant correlations between 11β-HSD1 with 3α-HSD4 (r = 0.605, p < 0.0001) and 3α-HSD3 (r = 0.537, p < 0.0001). Significant expression correlations between 3α-HSDs were also observed. Our results systematically present the regulation of steroid-converting enzymes and their roles in modulating the intratumoral steroid-hormone levels in BC with a vivid 3D-schema, supporting novel therapy targeting the reductive 17β-HSD7 and proposing a new combined therapy targeting 11β-HSD2 and 17β-HSD7.