The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets ...remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.
Cognitive impairment (CI) is a frequent and disabling symptom in Multiple Sclerosis (MS). Axonal damage may contribute to CI development from early stages. Nevertheless, no biomarkers are at the ...moment available to track CI in MS patients. We aimed to explore the correlation of cerebrospinal fluid (CSF) axonal biomarkers, in particular: light-chain neurofilaments (NFL), Tau, and Beta-amyloid protein (Abeta) in MS patients with CI at the diagnosis. 62 newly diagnosed MS patients were enrolled, and cognition was evaluated using the Brief International Cognitive Assessment for MS (BICAMS) battery. CSF NFL, Abeta, and Tau levels were determined with commercial ELISA. Patients with CI (45.1%) did not differ for demographic, clinical, and MRI characteristics (except for lower educational level), but they displayed greater neurodegeneration, exhibiting higher mean CSF Tau protein (162.1 ± 52.96 pg/ml versus 132.2 ± 63.86 pg/ml
p
:0.03). No differences were observed for Abeta and NFL. The number of impaired tests and Tau were significantly correlated (
r
:0.32
p
:0.01). Tau was higher in particular in patients with slowed information processing speed (IPS) (
p
:0.006) and a linear regression analysis accounting for EDSS, MRI, and MS subtype confirmed Tau as a weak predictor of IPS and cognitive impairment. In conclusion, CI has an important burden on the quality of life of MS patients and should be looked for even at diagnosis. Axonal damage biomarkers, and in particular Tau, seem to reflect cognition impairment in the early stages.
Knowledge of the host response to the novel coronavirus SARS-CoV-2 remains limited, hindering the understanding of COVID-19 pathogenesis and the development of therapeutic strategies. During the ...course of a viral infection, host cells release exosomes and other extracellular vesicles carrying viral and host components that can modulate the immune response. The present study used a shotgun proteomic approach to map the host circulating exosomes' response to SARS-CoV-2 infection. We investigated how SARS-CoV-2 infection modulates exosome content, exosomes' involvement in disease progression, and the potential use of plasma exosomes as biomarkers of disease severity. A proteomic analysis of patient-derived exosomes identified several molecules involved in the immune response, inflammation, and activation of the coagulation and complement pathways, which are the main mechanisms of COVID-19-associated tissue damage and multiple organ dysfunctions. In addition, several potential biomarkers-such as fibrinogen, fibronectin, complement C1r subcomponent and serum amyloid P-component-were shown to have a diagnostic feature presenting an area under the curve (AUC) of almost 1. Proteins correlating with disease severity were also detected. Moreover, for the first time, we identified the presence of SARS-CoV-2 RNA in the exosomal cargo, which suggests that the virus might use the endocytosis route to spread infection. Our findings indicate circulating exosomes' significant contribution to several processes-such as inflammation, coagulation, and immunomodulation-during SARS-CoV-2 infection. The study's data are available via ProteomeXchange with the identifier PXD021144.
Platelets, traditionally known for their roles in hemostasis and coagulation, are the most prevalent blood component after erythrocytes (150,000-400,000 platelets/μL in healthy humans). However, only ...10,000 platelets/μL are needed for vessel wall repair and wound healing. Increased knowledge of the platelet's role in hemostasis has led to many advances in understanding that they are crucial mediators in many other physiological processes, such as innate and adaptive immunity. Due to their multiple functions, platelet dysfunction is involved not only in thrombosis, mediating myocardial infarction, stroke, and venous thromboembolism, but also in several other disorders, such as tumors, autoimmune diseases, and neurodegenerative diseases. On the other hand, thanks to their multiple functions, nowadays platelets are therapeutic targets in different pathologies, in addition to atherothrombotic diseases; they can be used as an innovative drug delivery system, and their derivatives, such as platelet lysates and platelet extracellular vesicles (pEVs), can be useful in regenerative medicine and many other fields. The protean role of platelets, from the name of Proteus, a Greek mythological divinity who could take on different shapes or aspects, is precisely the focus of this review.
Sars-Cov-2 infection causes fever and cough that may rapidly lead to acute respiratory distress syndrome (ARDS). Few biomarkers have been identified but, unfortunately, these are individually poorly ...specific, and novel biomarkers are needed to better predict patient outcome. The aim of this study was to evaluate the diagnostic performance of circulating platelets (PLT)-derived extracellular vesicles (EVs) as biomarkers for Sars-Cov-2 infection, by setting a rapid and reliable test on unmanipulated blood samples. PLT-EVs were quantified by flow cytometry on two independent cohorts of Sars-CoV-2+ (n = 69), Sars-Cov-2- (n = 62) hospitalized patients, and healthy controls. Diagnostic performance of PLT-EVs was evaluated by receiver operating characteristic (ROC) curve. PLT-EVs count were higher in Sars-Cov-2+ compared to Sars-Cov-2- patients or HC. ROC analysis of the combined cohorts showed an AUC = 0.79 and an optimal cut-off value of 1472 EVs/μL, with 75% sensitivity and 74% specificity. These data suggest that PLT-EVs might be an interesting biomarker deserving further investigations to test their predictive power.
Background: ICOS and its ligand ICOSL are immune receptors whose interaction triggers bidirectional signals that modulate the immune response and tissue repair. Aim: The aim of this study was to ...assess the in vivo effects of ICOSL triggering by ICOS-Fc, a recombinant soluble form of ICOS, on skin wound healing. Methods: The effect of human ICOS-Fc on wound healing was assessed, in vitro, and, in vivo, by skin wound healing assay using ICOS−/− and ICOSL−/− knockout (KO) mice and NOD-SCID-IL2R null (NSG) mice. Results: We show that, in wild type mice, treatment with ICOS-Fc improves wound healing, promotes angiogenesis, preceded by upregulation of IL-6 and VEGF expression; increases the number of fibroblasts and T cells, whereas it reduces that of neutrophils; and increases the number of M2 vs. M1 macrophages. Fittingly, ICOS-Fc enhanced M2 macrophage migration, while it hampered that of M1 macrophages. ICOS−/− and ICOSL−/− KO, and NSG mice showed delayed wound healing, and treatment with ICOS-Fc improved wound closure in ICOS−/− and NSG mice. Conclusion: These data show that the ICOS/ICOSL network cooperates in tissue repair, and that triggering of ICOSL by ICOS-Fc improves cutaneous wound healing by increasing angiogenesis and recruitment of reparative macrophages.
Thrombosis is a multifaceted process involving various molecular components, including the coagulation cascade, platelet activation, platelet-endothelial interaction, anticoagulant signaling ...pathways, inflammatory mediators, genetic factors and the involvement of various cells such as endothelial cells, platelets and leukocytes. A comprehensive understanding of the molecular signaling pathways and cell interactions that play a role in thrombosis is essential for the development of precise therapeutic strategies for the treatment and prevention of thrombotic diseases. Ongoing research in this field is constantly uncovering new molecular players and pathways that offer opportunities for more precise interventions in the clinical setting. These molecular insights into thrombosis form the basis for the development of targeted therapeutic approaches for the treatment and prevention of thrombotic disease. The aim of this review is to provide an overview of the pathogenesis of thrombosis and to explore new therapeutic options.
The interest elicited by the large microbial population colonizing the human gut has ancient origins and has gone through a long evolution during history. However, it is only in the last decades that ...the introduction of high-throughput technologies has allowed to broaden this research field and to disentangle the numerous implications that gut microbiota has in health and disease. This comprehensive ecosystem, constituted mainly by bacteria but also by fungi, parasites, and viruses, is proven to be involved in several physiological and pathological processes that transcend the intestinal homeostasis and are deeply intertwined with apparently unrelated body systems, such as the immune and the nervous ones. In this regard, a novel speculation is the relationship between the intestinal microbial flora and the pathogenesis of some neurological and neurodevelopmental disorders, including the clinical entities defined under the umbrella term of autism spectrum disorders. The bidirectional interplay has led researchers to coin the term gut-brain-immune system axis, subverting the theory of the brain as an immune-privileged site and underscoring the importance of this reciprocal influence already from fetal life and especially during the pre- and post-natal neurodevelopmental process. This revolutionary theory has also unveiled the possibility to modify the gut microbiota as a way to treat and even to prevent different kinds of pathologies. In this sense, some attempts have been made, ranging from probiotic administration to fecal microbiota transplantation, with promising results that need further elaboration. This state-of-art report will describe the main aspects regarding the human gut microbiome and its specific role in the pathogenesis of autism and its related disorders, with a final discussion on the therapeutic and preventive strategies aiming at creating a healthy intestinal microbial environment, as well as their safety and ethical implications.
Activated T cells express the inducible T-cell co-stimulator (ICOS) that, upon binding to its ubiquitously expressed ligand (ICOSL), regulates the immune response and tissue repair. We sought to ...determine the effect of ICOS:ICOSL interaction on human M1 and M2 macrophages. M1 and M2 macrophages were polarized from monocyte-derived macrophages, and the effect of a soluble recombinant form of ICOS (ICOS-CH3) was assessed on cytokine production and cell migration. We show that ICOS-CH3 treatment increased the secretion of CCL3 and CCL4 in resting M1 and M2 cells. In LPS-treated M1 cells, ICOS-CH3 inhibited the secretion of TNF-α, IL-6, IL-10 and CCL4, while it increased that of IL-23. In contrast, M2 cells treated with LPS + IL4 displayed enhanced secretion of IL-6, IL-10, CCL3 and CCL4. In CCL7- or osteopontin-treated M1 cells, ICOS-CH3 boosted the migration rate of M1 cells while it decreased that of M2 cells. Finally, β-Pix expression was upregulated in M1 cells and downregulated in M2 cells by treatment with ICOS-CH3. These findings suggest that ICOSL activation modulates the activity of human M1 and M2 cells, thereby eliciting an overall anti-inflammatory effect consistent with its role in promoting tissue repair.
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.
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