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Oxysterols, resulting from the oxidation of cholesterol, are formed either by autoxidation, enzymatically, or by both processes. These molecules, which are provided in more or less important quantities depending on the type of diet, are also formed in the body and their presence is associated with a normal physiological activity. Their increase and decrease at the cellular level and in biological fluids can have significant consequences on health due or not to the interaction of some of these molecules with different types of receptors but also because oxysterols are involved in the regulation of RedOx balance, cytokinic and non-cytokinic inflammation, lipid metabolism, and induction of cell death. Currently, various pathologies such as age-related diseases, inflammatory and infectious diseases, and several cancers are associated with abnormal levels of oxysterols. Due to the important biological activities of oxysterols, their interaction with several receptors and their very likely implications in several diseases, this review focuses on these molecules and on oxysterol derivatives, which are often more efficient, in a therapeutic context. Currently, several oxysterol derivatives are developed and are attracting a lot of interest.

Introduction: Prevalence of cardiac and vascular fibrosis in patients with Idiopathic Pulmonary Fibrosis (IPF) has not been extensively evaluated. Aim: In this study, we aimed to evaluate the heart and vessels functional and structural properties in patients with IPF compared to healthy controls. An exploratory analysis regarding disease severity in IPF patients has been done. Methods: We enrolled 50 patients with IPF (at disease diagnosis before antifibrotic therapy initiation) and 50 controls matched for age and gender. Heart was evaluated through echocardiography and plasmatic NT-pro-brain natriuretic peptide that, together with patients' symptoms, allow to define the presence of Heart Failure (HF) and diastolic dysfunction. Vessels were evaluated through Flow Mediated Dilation (FMD - endothelial function) and Pulse Wave Velocity (PWV-arterial stiffness) RESULTS: Patients with IPF had a prevalence of diastolic disfunction of 83.8%, HF of 37.8% and vascular fibrosis of 76.6%. No statistically significant difference was observed in comparison to the control group who showed prevalence of diastolic disfunction, HF and vascular fibrosis of 67.3%, 24.5% and 84.8%, respectively. Disease severity seems not to affect PWV, FMD, diastolic dysfunction and HF. Conclusions: Patients with IPF early in the disease course do not present a significant CV fibrotic involvement when compared with age- and sex-matched controls. Bigger and adequately powered studies are needed to confirm our preliminary data and longitudinal studies are required in order to understand the time of appearance and progression rate of heart and vascular involvement in IPF subjects.

Cholesterol regulates fluidity and structure of cellular membranes. The brain is involved in signal transduction, synaptogenesis, and membrane trafficking. An impairment of its metabolism was observed in different neurodegenerative diseases, such as Multiple Sclerosis, Alzheimer, and Huntington diseases. Because of the blood–brain barrier, cholesterol cannot be uptaken from the circulation and all the cholesterol is locally synthetized. The excess cholesterol in neurons is converted into 24S-hydroxycholesterol (24OHC) by the cholesterol 24-hydroxylase (CYP46A1). The plasmatic concentration of 24OHC results in the balance between cerebral production and liver elimination. It is related to the number of metabolically active neurons in the brain. Several factors that affect the brain cholesterol turnover and the liver elimination of oxysterols, the genetic background, nutrition, and lifestyle habits were found to significantly affect plasma levels of 24OHC. Reduced levels of 24OHC were found related to the loss of metabolically active cells and the degree of brain atrophy. The dysfunction of the blood–brain barrier, inflammation, and increased cholesterol turnover might overlap with this progressive reduction giving temporary increased levels of 24OHC. The study of plasma 24OHC is likely to offer an insight into brain cholesterol turnover with a limited diagnostic power.

We retrospectively analyzed the antimicrobial data of Enterobacter spp. strains isolated from hospitalized subjects and outpatients over 20 years (2000–2019). A total of 2277 non-duplicate Enterobacter spp. isolates, 1037 from outpatients (45%) and 1240 from hospitalized subjects (55%), were retrieved. Most of samples are infections of the urinary tract. Considering Enterobacter aerogenes, now classified as Klebsiella aerogenes, and Enterobacter cloacae, representing more than 90% of all isolates, except for aminoglycosides and fluroquinolones, which showed significant antibiotic decreasing trends (p < 0.01), none of the other antimicrobial agents tested showed significant changes in both groups (p > 0.05). Conversely, there was a significant increasing resistance trend for fosfomycin (p < 0.01), among both community and hospital-related subjects, most probably owing to uncontrolled and improper usage. Surveillance studies on antibiotic resistance at the local and regional level are required to detect new resistance mechanisms, reduce inappropriate antimicrobial consumption, and increase the focus on antimicrobial stewardship.

Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing (“early treatment”) or reversing (“late treatment”) HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic (“early treatment”) or symptomatic (“late treatment”) stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments (“2 cycle treatment”) lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. Data availability: This study does not include data deposit

Non-enzymatic cholesterol oxidation products (COPs) are nowadays receiving increasing attention in food technology for their potential use as biomarkers of freshness and safety in raw materials and complex food matrices, as well as markers of cholesterol oxidation during the production and shelf-life of end products. Here reported is the investigation of how long three prototype milk chocolates containing whole milk powders (WMPs) of increasing shelf-lives (i.e. 20, 120, and 180 days), could be safely stored in the market by adopting the non-enzymatic COPs as a quality markers. In addition, the protective effect of two different primary packaging, sealed and unsealed ones, in mitigating the generation of non-enzymatic COPs in three prototype milk chocolates after 3, 6, 9, 12 months of shelf-life was assessed to simulate two real storage conditions. Quantifying oxysterols’ levels by mass spectrometry, the oxygen impermeable packaging (PLUS) resulted to significantly quench the non-enzymatic COPs production up to 34% as to that found in the same product but with unsealed standard packaging (STD). This study represents one practical application of non-enzymatic COPs as a reliable tool for corrective strategies to prevent food oxidation.

Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process. We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal beta-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation. In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature. We highlighted cholesterol accumulation in plasma membranes and observed autophagy patterns in the cell mutants. We confirmed the upregulation or downregulation at the protein level for a few selected genes that mostly corroborated our observations and clearly demonstrated increased expression and secretion of DAM proteins in the BV-2 mutant cells. In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders.

The perception of social exclusion among patients with opioid use disorder (OUD) could be affected by long-term opioid use. This study explores the emotional and cardiac autonomic responses to an experience of ostracism in a sample of participants with OUD on opioid agonist treatment (OAT).Twenty patients with OUD and twenty healthy controls (HC) performed a ball-tossing game (Cyberball) with two conditions: Inclusion and Ostracism. We measured self-reported ratings of perceived threat towards one's fundamental needs and respiratory sinus arrhythmia (RSA) immediately after the game and 10 min after Ostracism (Reflective stage).Following ostracism, participants with OUD self-reported blunted feelings of threat to the fundamental need to belong. RSA levels were significantly suppressed immediately after ostracism and during the Reflective stage in comparison with HC, indicating an autonomic alteration in response to threatening social situations. Finally, only among HC higher perceived threats towards fundamental needs predicted increases in RSA levels, suggesting an adaptive vagal regulation in response to a perceived threat. Conversely, among patients with OUD the subjective response to ostracism was not associated with the autonomic reaction.OAT may have a protective effect against negative feelings of ostracism. However patients with OUD on OAT present poor autonomic regulation in response to social threats, which could reflect their trait hypersensitivity to social rejection.

Cholesterol oxidation products (COPs) of non-enzymatic origin are mainly found in meat, fish, eggs and milk, mostly originating from the type of feeding, processing and storage. To verify the significance of COPs as biomarkers of cholesterol autoxidation and milk freshness, we quantified them in chocolates containing whole milk powders (WMPs) of increasing shelf-lives (i.e. 20, 120, and 180 days). Non-enzymatic total COPs (both free and esterified) ranged from 256.57 ± 11.97 to 445.82 ± 11.88 ng/g, increasing proportionally to the shelf-life of the WMPs, thus reflecting the ingredients' freshness. Based on the expected theoretical COPs, the effect of processing was quantitatively less significant in the generation of oxysterols (41-44%) than the contribution of the autoxidation of the WMPs over time (56-59%), pointing to the shelf-life as the primary determinant of COPs. Lastly, we quantified COPs of major commercial milk chocolates on the Italian market, which followed a similar distribution (from 240.79 ± 11.74 to 475.12 ± 12.58 ng/g). Although further replications of this work are needed, this study reports preliminary results and a practical example of a first application of non-enzymatic COPs as markers to further quantify and characterize the nutritional quality and freshness, not only of ingredients but also of composite products.

Cholesterol is a lipid of high nutritional value that easily undergoes oxidation through enzymatic and non-enzymatic pathways, leading to a wide variety of cholesterol oxidation products (COPs), more commonly named oxysterols. The major oxysterols found in animal products are 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, 7-ketocholesterol, 5 alpha,6 alpha-epoxycholesterol, 5 beta,6 beta-epoxycholesterol, cholestan-3 beta,5 alpha,6 beta-triol, and 25-hydroxycholesterol. They are all produced by cholesterol autoxidation, thus belonging to the non-enzymatic oxysterol subfamily, even if 7 alpha-hydroxycholesterol and 25-hydroxycholesterol are, in part, generated enzymatically as well. A further oxysterol of the full enzymatic origin has recently been detected for the first time in milk of both human and bovine origin, namely 27-hydroxycholesterol. Nowadays, gas or liquid chromatography combined to mass spectrometry allows to measure all these oxysterols accurately in raw and in industrially processed food. While non-enzymatic oxysterols often exhibited in vitro relevant cytotoxicity, above all 7 beta-hydroxycholesterol and 7-ketocholesterol, 27-hydroxycholesterol, as well as 25-hydroxycholesterol, shows a broad spectrum in vitro antiviral activity, inhibition of SARS-CoV-2 included, and might contribute to innate immunity. Quantification of oxysterols was afforded over the years, almost always focused on a few family's compounds. More comprehensive COPs measurements, also including oxysterols of enzymatic origin, are, nowadays, available, which better display the many advantages of systematically adopting this family of compounds as markers of quality, safety, and nutritional value in the selection of ingredients in processing and storage. Regarding foodstuff shelf life, COPs monitoring already provided useful hints for more suitable packaging. The identification of a subset of non-enzymatic and enzymatic oxysterols to be routinely assessed in food production a

Coronavirus illness (COVID-19) is an infectious pathology generated by intense severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This infectious disease has emerged in 2019. The COVID-19-associated pandemic has considerably affected the way of life and the economy in the world. It is consequently crucial to find solutions allowing remedying or alleviating the effects of this infectious disease. Natural products have been in perpetual application from immemorial time given that they are attested to be efficient towards several illnesses without major side effects. Various studies have shown that plant extracts or purified molecules have a promising inhibiting impact towards coronavirus. In addition, it is substantial to understand the characteristics, susceptibility and impact of diet on patients infected with COVID-19. In this review, we recapitulate the influence of extracts or pure molecules from medicinal plants on COVID-19. We approach the possibilities of plant treatment/co-treatment and feeding applied to COVID-19. We also show coronavirus susceptibility and complications associated with nutrient deficiencies and then discuss the major food groups efficient on COVID-19 pathogenesis. Then, we covered emerging technologies using plant-based SARS-CoV-2 vaccine. We conclude by giving nutrient and plants curative therapy recommendations which are of potential interest in the COVID-19 infection and could pave the way for pharmacological treatments or co-treatments of COVID-19.

Background: Vulvovaginal candidiasis (VVC) is the second most common infection of the genital tract affecting millions of women worldwide. Data concerning the distribution and antifungal resistance of Candida species responsible of VVC vary among countries and population studied. Objectives: The aim of this work was to determine the prevalence, species distribution and antifungal susceptibility patterns of Candida species among symptomatic women over a 20-year period. Methods: A total of 5,820 unique samples were retrospectively identified. Out of them, 1,046 (18%) were diagnosed with VVC. Results: Women between 18 and 30 years had the highest prevalence rate of VVC (21%). Women aged less than 18 years and greater than 51 years had the highest prevalence rates of vaginal bacterial infections. Thirty-five (3.3%) women presented recurrent VVC. The most common yeast isolated was C. albicans, followed by C. glabrata, C. krusei, and C. parapsilosis. Non-Candida albicans species (NAC) were more significantly isolated among women aged 51 or above, than in women included in other groups (p < 0.01). Resistance to fluconazole and amphotericin B was infrequent in C. albicans strains. Resistance to fluconazole and amphotericin B was infrequent in C. albicans strains. NAC species presented higher resistance rates against fluconazole (30%) and voriconazole (25%). C. krusei and C. glabrata isolates showed lower MICs than most of the strains against amphotericin B (1 mg/L) and flucytosine (1 mg/L). Conclusions: Our findings indicated that continued surveillance on Candida species distribution and non-susceptibility rates to antifungals should be routinely reported to help the selection of the most appropriate drug, to avoid the emergence of resistant strains, and to improve the patient's outcomes.

Direct translation of findings achieved in experimental cell or animal models to humans is quite a difficult task. We focused here only on the epidemiological and ex vivo human studies so far available about the role of 27-hydroxycholesterol (27OHC) and related metabolism in cancer development. Some studies point to an adverse effect of 27OHC in breast cancer, based on the oxysterol's recognized ability to bind to and modulate estrogen receptors. The detrimental role of this side chain oxysterol would be evident in cancer progression, mainly in post-menopausal women and in an advanced stage of the disease. Other human researches, however, would rather correlate 27OHC intra-tumoral levels to a better prognosis. The analyses on human prostate cancer specimens performed to date are all against a detrimental contribution of 27OHC, rather suggesting interesting anti-prostate cancer effects exerted by this oxysterol. Finally, an increased 27OHC synthesis on the contrary seems to favour progression of late stage cancers in colon, brain and thyroid tissues, as found for breast cancer, possibly due to pro-inflammatory and pro-survival signalling triggered by disproportionate amounts of this oxysterol.

Background: Cefiderocol is a siderophore cephalosporin that exhibits antimicrobial activity against most multi-drug resistant Gram-negative bacteria, including Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. Methods: A total of 20 multidrug-resistant A. baumannii strains were isolated from 2020 to 2021, molecularly characterized and tested to assess the in vitro antibacterial activity of cefiderocol. Thirteen strains were carbapenem-hydrolysing oxacillinase OXA-23-like producers, while seven were non-OXA-23-like producers. Minimum in-hibitory concentrations (MICs) were determined by broth microdilution, considered as the gold standard method. Disk diffusion test was also carried out using iron-depleted CAMHB plates for cefiderocol. Results: Cefiderocol MICs ranged from 0.5 to 1 mg/L for OXA-23-like non-producing A. baumannii strains and from 0.25 to >32 mg/L for OXA-23-like producers, using the broth microdi-lution method. Cefiderocol MIC90 was 8 mg/L. Diameter of inhibition zone of cefiderocol ranged from 18 to 25 mm for OXA-23-like non-producers and from 15 to 36 mm for OXA-23-like producers, using the diffusion disk method. A large variability and a low reproducibility were observed during the determination of diameter inhibition zone. Molecular characterization showed that all isolates presented the ISAba1 genetic element upstream the blaOXA-51. Among OXA-23-like non-producers, four were blaOXA-58 positive and two were negative for all the resistance determinants analyzed. Conclusions: Cefiderocol showed in vitro antimicrobial activity against both carbapenem-susceptible and non-susceptible A. baumannii strains, although some OXA-23-like producers were resistant. Further clinical studies are needed to consolidate the role of cefiderocol as an antibiotic against MDR A. baumannii.

The correlation of clinical, radiological and laboratory findings of patients at admission in the Emergency Department (ED) with clinical severity and risk of mortality was investigated. Adult coronavirus disease 2019 (COVID-19) patients hospitalized in March 2020 in Desio Hospital, Lombardy, were retrospectively included in the study, and categorized in terms of disease severity and adverse outcome. Out of the 175 patients enrolled, 79% presented one or more comorbidities, with cardiovascular disease being the most frequent (62%). More than half of the patients showed lymphocytopenia and 20% thrombocytopenia. The patients in the severe group presented higher absolute neutrophil count (ANC), C-reactive protein (CRP), AST, LDH, procalcitonin (PCT) and BUN values compared to the non-severe group (p <.05). Increased odds of mortality associated with older age (OR = 22.43; 95% CI 5.22–96.27), partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FIO2) ratio < 200 (OR = 4.97; 95% CI 1.55–15.84), clinical severity (OR = 21.32; 95% CI 2.27–200.13), creatinine > 106.08 µmol/L (OR = 2.87; 95% CI 1.04–7.92) and creatine kinase > 2.90 µkat/L (OR = 3.80; 95% CI 1.31–10.9) were observed on admission (p <.05). The above findings may contribute to identify early risk factors of poor prognosis, and to select the most appropriate management for patients.

Introduction: The aim of the paper is to present the results from the process of external validation of a number of machine learning (ML) models that had been previously developed to detect SARS-CoV-2 virus positivity on both symptomatic and asymptomatic patients on the basis of the complete blood count (CBC) test. Methods: Briefly, models were trained using a dataset of 816 COVID-19 positive and 920 negative cases collected at the emergency departments of IRCCS Hospital San Raffaele and IRCCS Istituto Ortopedico Galeazzi. 21 parameters, including the results of the CBC analysis, age [60.9 (0.9) years], gender (57% males) and the presence of COVID-19 related symptoms were used. The validation regarded the evaluation of the error rate (through different metrics, including accuracy, sensitivity, specificity and the area under the curve (AUC)) of the models considered. This external validation was conducted on two well balanced datasets coming from two different hospitals in Northern Italy: Desio hospital and Bergamo Papa Giovanni XXIII hospital. 163 positive and 174 true negative patients from Desio, and 104 positive and 145 true negative from Bergamo were included in the validation. Results: The performance of the predictive models is satisfactory as we can report an average AUC of 95% for both external datasets. Conclusion: ML models have been applied to hematological parameters for a more rapid and cost-effective detection of the COVID-19 disease. We make the point that validated models may be useful in the management and early detection of potential COVID-19 patients.

Background: In two patients under treatment with various antibiotics, spheroplasts were detected with an automated urine sediment analyzer. Methods: Urinalysis was performed by an AutionMAX AX 4030-sediMAX platform. Results: Spheroplasts can be easily misclassified as yeasts or erythrocytes, but when automated urine sediment analyzers are used by well-trained, and experienced operators they can be correctly identified and classified. Conclusion: Appropriate training of urine laboratory professionals in spheroplast detection and association with UTI, together with timely communication with the microbiologist and caring clinician, will provide prompt targeted treatment.

7-Ketocholesterol, which is one of the earliest cholesterol oxidization products identified, is essentially formed by the auto-oxidation of cholesterol. In the body, 7-ketocholesterol is both provided by food and produced endogenously. This pro-oxidant and pro-inflammatory molecule, which can activate apoptosis and autophagy at high concentrations, is an abundant component of oxidized Low Density Lipoproteins. 7-Ketocholesterol appears to significantly contribute to the development of age-related diseases (cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease), chronic inflammatory bowel diseases and to certain cancers. Recent studies have also shown that 7-ketocholesterol has anti-viral activities, including on SARS-CoV-2, which are, however, lower than those of oxysterols resulting from the oxidation of cholesterol on the side chain. Furthermore, 7-ketocholesterol is increased in the serum of moderately and severely affected COVID-19 patients. In the case of COVID-19, it can be assumed that the antiviral activity of 7-ketocholesterol could be counterbalanced by its toxic effects, including pro-oxidant, pro-inflammatory and pro-coagulant activities that might promote the induction of cell death in alveolar cells. It is therefore suggested that this oxysterol might be involved in the pathophysiology of COVID-19 by contributing to the acute respiratory distress syndrome and promoting a deleterious, even fatal outcome. Thus, 7-ketocholesterol could possibly constitute a lipid biomarker of COVID-19 outcome and counteracting its toxic effects with adjuvant therapies might have beneficial effects in COVID-19 patients.

The detection and quantification of immunoglobulin free light chains in serum and urine is recommended for the diagnosis and monitoring of monoclonal gammopathies according to the guidelines of the International Myeloma Working Group (IMWG). Several tests are currently available in the clinical laboratory to detect and quantify free light chains but although quality, efficiency, and effectiveness have been improved, the results are still variable and poorly harmonized and standardized. The present review article wants to analyze these aspects, with a keen eye on techniques, such as mass spectrometry, that could replace in the practical clinical laboratory the current methods including Bence-Jones protein assay and free light chain immunoassays.

Multiple sclerosis is an autoimmune disease that affects the central nervous system. Dysfunction of the immune system leads to lesions that cause motor, sensory, cognitive, visual and/or sphincter disturbances. In the long term, these disorders can progress towards an irreversible handicap. The diagnosis takes time because there are no specific criteria to diagnose multiple sclerosis. To realize the diagnosis, a combination of clinical, biological, and radiological arguments is therefore required. Hence, there is a need to identify multiple sclerosis biomarkers. Some biomarkers target immunity through the detection of oligoclonal bands, the measurement of the IgG index and cytokines. During the physiopathological process, the blood-brain barrier can be broken, and this event can be identified by measuring metalloproteinase activity and diffusion of gadolinium in the brain by magnetic resonance imaging. Markers of demyelination and of astrocyte and microglial activity may also be of interest as well as markers of neuronal damage and mitochondrial status. The measurement of different lipids in the plasma and cerebrospinal fluid can also provide suitable information. These different lipids include fatty acids, fatty acid peroxidation products, phospholipids as well as oxidized derivatives of cholesterol (oxysterols). Oxysterols could constitute new biomarkers providing information on the form of multiple sclerosis, the outcome of the disease and the answer to treatment.

Supplementing brain cholesterol is emerging as a potential treatment for Huntington's disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the blood-brain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses. Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction. In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

Physiological cholesterol metabolism implies the generation of a series of oxidized derivatives, whose oxysterols are by far the most investigated ones for their potential multifaceted involvement in human pathophysiology. In this regard, noteworthy is the broad antiviral activity displayed by defined side chain oxysterols, in particular 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC). Although their antiviral mechanism(s) may vary depending on virus/host interaction, these oxysterols share the common feature to hamper viral replication by interacting with cellular proteins. Here reported is the first analysis of the modulation of a cell proteome by these two oxysterols, that, besides yielding additional clues about their potential involvement in the regulation of sterol metabolism, provides novelinsights about the mechanism underlying the inhibition of virus entry and trafficking within infected cells. We show here that both 25HC and 27HC can down-regulate the junction adhesion molecule-A (JAM-A) and the cation independent isoform of mannose-6-phosphate receptor (MPRci), two crucial molecules for the replication of all those viruses that exploit adhesion molecules and the endosomal pathway to enter and diffuse within target cells

Background: Surfactant protein-D (SP-D) is a lung-resident protein that has emerged as a potential biomarker for COVID-19. Previous investigations on acute respiratory distress syndrome patients demonstrated a significant increment of SP-D serum levels in pathological conditions. Since SP-D is not physiologically permeable to alveoli-capillary membrane and poorly expressed by other tissues, this enhancement is likely due to an impairment of the pulmonary barrier caused by prolonged inflammation. Methods: A retrospective study on a relatively large cohort of patients of Hospital Pio XI of Desio was conducted to assess differences of the hematic SP-D concentrations among COVID-19 patients and healthy donors and if SP-D levels resulted a risk factor for disease severity and mortality. Results: The first analysis, using an ANOVA-model, showed a significant difference in the mean of log SP-D levels between COVID-19 patients and healthy donors. Significant variations were also found between dead vs survived patients. Results confirm that SP-D concentrations were significantly higher for both hospitalized COVID-19 and dead patients, with threshold values of 150 and 250 ng/mL, respectively. Further analysis conducted with Logistic Mixed models, highlighted that higher SP-D levels at admission and increasing differences among follow-up and admission values resulted the strongest significant risk factors of mortality (model predictive accuracy, AUC = 0.844). Conclusions: The results indicate that SP-D can be a predictive marker of COVID-19 disease and its outcome. Considering its prognostic value in terms of mortality, the early detection of SP-D levels and its follow-up in hospitalized patients should be considered to direct the therapeutic intervention.