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The COVID-19 pandemic is still raging in most countries. Although the recent mass vaccination campaign has opened a new chapter in the battle against SARS-CoV-2, the world is still far from herd immunity. There is an urgent need to identify healthy people at high risk of contracting COVID-19, as well as supplements and nutraceuticals that can reduce the risk of infection or mitigate symptoms. In the present study, a metabolic phenotype that could protect individuals from SARS-CoV-2 infection or predispose them to developing COVID-19 was investigated. Untargeted metabolomics was performed on serum samples collected from 51 healthcare workers who were in good health at the beginning of the COVID-19 outbreak in Italy, and who were later exposed to the same risk of developing COVID-19. Half of them developed COVID-19 within three weeks of the blood collection. Our results demonstrate the presence of a specific signature associated with protection from SARS-CoV-2. Circulating monolaurin, which has well-known antiviral and antibacterial properties, was higher in protected subjects, suggesting a potential defensive role against SARS-CoV-2 infection; thus, dietary supplements could boost the immune system against this infection. In addition, our data demonstrate that people with higher levels of cholesterol are at higher risk of developing COVID-19. The present study demonstrates that metabolomics can be of great help for developing personalized medicine and for supporting public healthcare strategies. Studies with larger cohorts of subjects are necessary to confirm our findings.

Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a high burden of morbidity and mortality. Despite being triggered by different causative factors, fibrogenesis follows common pathways, the knowledge of which is, however, still unsatisfactory. This represents a significant limit for the development of effective antifibrotic drugs. In the present paper, we aimed to review the current evidence regarding the potential role played in fibrogenesis by growth arrest-specific 6 (Gas6) and its receptors Tyro3 protein tyrosine kinase (Tyro3), Axl receptor tyrosine kinase (Axl), and Mer tyrosine kinase protooncogene (MerTK) (TAM). Moreover, we aimed to review data about the pathogenetic role of this system in the development of different human diseases characterized by fibrosis. Finally, we aimed to explore the potential implications of these findings in diagnosis and treatment.

New roles for immune cells, overcoming the classical cytotoxic response, have been highlighted by growing evidence. The immune cells, such as neutrophils, monocytes/macrophages, and eosinophils, are versatile cells involved in the release of web-like DNA structures called extracellular traps (ETs) which represent a relevant mechanism by which these cells prevent microbes’ dissemination. In this process, many enzymes, such as elastase, myeloperoxidase (MPO), and microbicidal nuclear and granule proteins, which contribute to the clearance of entrapped microorganisms after DNA binding, are involved. However, an overproduction and release of ETs can cause unwanted and dangerous effects in the host, resulting in several pathological manifestations, among which are chronic inflammatory disorders, autoimmune diseases, cancer, and diabetes. In this review, we discuss the release mechanisms and the double-edged sword role of ETs both in physiological and in pathological contexts. In addition, we evaluated some possible strategies to target ETs aimed at either preventing their formation or degrading existing ones.

Photobiomodulation is a widely used tool in regenerative medicine thanks to its ability to modulate a plethora of physiological responses. Wound re-epithelialization is strictly regulated by locally produced chemical mediators, such as nitric oxide (NO), a highly reactive free radical generated by the nitric oxide synthase (NOS) enzymatic family. In this study, it has been hypothesized that a 980-nm low-level laser stimulation could increase NO production in human keratinocytes and that such event might be directly related to the re-epithelialization process. Human keratinocytes were irradiated with increasing energy outputs (10–75 J) in the absence or presence of L-NAME, a NOS inhibitor. Laser stimulation induced an increase in NO production, resulting in an energy-dependent increase in both keratinocytes proliferation and re-epithelialization ability. The direct link between increased NO production and the observed physiological responses was confirmed by their inhibition in L-NAME pre-treated samples. Since NO production increase is a quick event, it is conceivable that it is due to an increase in existing NOS activity rather than to a de novo protein synthesis. For this reason, it could be hypothesized that photobiomodulation-derived NO positive effects on keratinocytes behavior might rely on a near infrared mediated increase in NOS conformational stability and cofactors as well as substrate binding ability, finally resulting in an increased enzymatic activity.

The protein growth arrest-specific 6 (Gas6) and its tyrosine kinase receptors Tyro-3, Axl, and Mer (TAM) are ubiquitous proteins involved in regulating inflammation and apoptotic body clearance. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system leading to progressive and irreversible disability if not diagnosed and treated promptly. Gas6 and TAM receptors have been associated with neuronal remyelination and stimulation of oligodendrocyte survival. However, few data are available regarding clinical correlation in MS patients. We aimed to evaluate soluble levels of these molecules in the cerebrospinal fluid (CSF) and serum at MS diagnosis and correlate them with short-term disease severity. In a prospective cohort study, we enrolled 64 patients with a diagnosis of clinical isolated syndrome (CIS), radiological isolated syndrome (RIS) and relapsing-remitting (RR) MS according to the McDonald 2017 Criteria. Before any treatment initiation, we sampled the serum and CSF, and collected clinical data: disease course, presence of gadolinium-enhancing lesions, and expanded disability status score (EDSS). At the last clinical follow-up, we assessed EDSS and calculated MS severity score (MSSS) and age-related MS severity (ARMSS). Gas6 and TAM receptors were determined using an ELISA kit (R&D Systems) and compared to neurofilament (NFLs) levels evaluated with SimplePlex™ fluorescence-based immunoassay. At diagnosis, serum sAxl was higher in patients receiving none or low-efficacy disease-modifying treatments (DMTs) patients with high-efficacy DMTs ( = 0.04). Higher CSF Gas6 and serum sAXL were associated with an EDSS <3 at diagnosis ( = 0.04; = 0.037). Serum Gas6 correlates to a lower MSSS (r = -0.32, = 0.01). Serum and CSF NFLs were confirmed as disability biomarkers in our cohort according to EDSS ( = 0.005; = 0.002) and MSSS (r  = 0.27, = 0.03; r = 0.39, = 0.001). Results were corroborated using multivariate analysis. Our data suggest a protective role of Gas6 and its receptors in patients with MS and suitable severity disease biomarkers.

Hempseeds, from the Cannabis sativa plant, and its derivates are a versatile food option for various dietary preferences. Due to their aminoacidic profile, researchers have studied the presence of bioactive peptides in hempseed proteins. In this study, the water-soluble fraction of hempseed protein was extracted, and the derived peptides were analyzed. The investigation focused on their biological function, particularly their antioxidant activity. Several biological functions have arisen, such as angiotensin-converting enzyme inhibition activity, dipeptidyl-peptidase IV, dipeptidyl-peptidase III inhibition, and ubiquitin-mediated proteolysis activation. The hydrolysates show greater 2,2-azinobis-[3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical scavenging activity compared to the proteins (97.95 ± 4.48 versus 81.04 ± 10.63). Furthermore, the impact of these proteins and peptides on the U937 cell line was evaluated to assess cell viability and their potential role in modulating inflammation associated with gastrointestinal autoimmune diseases. Protein treatment resulted in a significant reduction in cell viability, as opposed to hydrolysates, which did not affect it.

NETosis is a novel immune defense strategy in which neutrophil activation results in the formation of extracellular DNA/protein network which is able to kill microbial populations. NETosis can be induced in vitro by lipopolysaccharide (LPS) or phorbol myristate acetate (PMA). Due to the importance of NETosis in different physiological and pathological processes, photobiostimulation effect on this neutrophil activation mechanism has been investigated. Human granulocytes, isolated from venous blood of healthy donors, were stimulated with a diode laser emitting at 980 nm with an energy intensity ranging from 0 to 75 joules. After 3 h of laser stimulation, granulocytes were fixed and colored with crystal violet in order to assess the NETosis morphology while extracellular DNA produced has been quantified using Sytox Green fluorescent dye. To evaluate ROS production and autophagy role in photobiostimulation-induced NETosis, granulocytes were pre-treated with ROS scavengers (vitamin C, sodium pyruvate, l-NAME, sodium azide), and an autophagy inhibitor (wortmannin). Laser stimulation induced an energy-dependent neutrophil extracellular trap (NET) production in human granulocytes starting from 50-J laser intensity. ROS scavengers and the autophagy inhibitor were able to abrogate both morphological features of NETosis and extracellular DNA production without modifying the basal level of NETosis. Photobiostimulation induced an increase in NET production due to an increase in ROS levels and autophagy activation.

Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.

A relevant proportion of immunocompromised patients did not reach a detectable seroconversion after a full primary vaccination cycle against SARS-CoV-2. The effect of different immunosuppressants and the potential risks for SARS-CoV-2 infection in these subjects is largely unknown. Patients from the Rivalsa prospective, observational cohort study with planned anti SARS-CoV-2 third dose mRNA vaccination between October and December 2021 were asked to participate to this follow-up study. Patients were asked about eventual confirmed positivity to SARS-CoV-2 infection within 6 months from the third dose and to undergo a blood draw to evaluate seroconversion status after the additional vaccine shot. 19 out of 114 patients taking part in the survey developed a confirmed SARS-CoV-2 infection; we identified mycophenolate treatment as an independent predictor of an increased risk of infection even after the third vaccine dose (OR: 5.20, 95% CI: 1.70-20.00, p=0.0053). This result is in agreement with the evidence that MMF impairs both B and T lymphocytes driven immune responses (reduction both in memory B cells producing anti-spike antibodies and in proliferating CD4+ and CD8+ T cells). Immunocompromised patients need an additional vaccine administration to reach a detectable seroconversion, thus fostering a more personalized approach to their clinical management. Moreover, patients undergoing mycophenolate treatment show a specific increased infection risk, with respect to other immunosuppressants thus supporting a closer monitoring of their health status.

Introduction: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are severe complications of patients with systemic sclerosis (SSc). Currently, there are a few tests for early identification of these conditions, although they are invasive and time-consuming. Extracellular vesicles (EVs) offer a promising possibility for gathering information on tissue health. This study aims to characterize EVs in cases of systemic sclerosis complicated by pulmonary hypertension and pulmonary fibrosis. Methods: A cohort of 58 patients with SSc was evaluated, including 14 with pulmonary hypertension, 17 with pulmonary fibrosis, and 27 without complications. Additionally, 11 healthy subjects, matched for sex and age, served as a control group. EVs were characterized by using a MACSplex kit to analyze the expression of 37 membrane markers. Results: After the overall analysis, we show that EVs from SSc patients had higher expression of CD146, CD42a, and CD29 (p = 0.03, p = 0.02 and p = 0.05) but lower expression of HLA-ABC with respect to the control patients (p = 0.02). Multivariate analyses demonstrated that only CD42a has a significant association with the disease (p = 0.0478). In group comparative analyses (PAH, ILD, uncomplicated systemic sclerosis (named SSc no PAH no ILD), and controls), CD3 and CD56 were higher in PAH patients, with respect to the controls, ILD, and the group SSc no PAH no ILD (CD3: p = 0.01, p = 0.003, p = 0.0005; CD56: p = 0.002, p < 0.0001, p = 0.0002). HLA-DR showed higher expression in PAH patients with respect to ILD patients (p = 0.02), CD25 showed higher expression in PAH patients with respect uncomplicated SSc (p = 0.02), and CD42a showed higher expression in PAH patients with respect to the controls (p = 0.03); nevertheless, multivariate analyses demonstrated that only CD3 retained its association with PAH. Conclusions: The expression of CD42a, a platelet-derived marker indicating endothelial damage, suggests its potential to provide information on the state of the microcirculation in systemic sclerosis. The higher expression of CD3 on the surface of the EVs in PAH patients might indicate increased T-cell activity in tissues, with a possible association with the development of pulmonary hypertension.