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Article ; Online: Novel mechanisms of thrombo-inflammation during infection: the harmful impact of circulating histones.

Ligi, Daniela / Della Franca, Chiara / Mannello, Ferdinando

Research and practice in thrombosis and haemostasis

2023 Volume 7, Issue 3, Page(s) 100141

Language	English
Publishing date	2023-03-30
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1016/j.rpth.2023.100141
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Article: Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?

Ligi, Daniela / Maniscalco, Rosanna / Plebani, Mario / Lippi, Giuseppe / Mannello, Ferdinando

Journal of clinical medicine

2022 Volume 11, Issue 7

Abstract: Several studies shed light on the interplay among inflammation, thrombosis, multi-organ failures and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Increasing levels of both free and/or circulating histones have been associated ... ...

Abstract	Several studies shed light on the interplay among inflammation, thrombosis, multi-organ failures and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Increasing levels of both free and/or circulating histones have been associated to coronavirus disease 2019 (COVID-19), enhancing the risk of heart attack and stroke with coagulopathy and systemic hyperinflammation. In this view, by considering both the biological and clinical rationale, circulating histones may be relevant as diagnostic biomarkers for stratifying COVID-19 patients at higher risk for viral sepsis, and as predictive laboratory medicine tool for targeted therapies.
Language	English
Publishing date	2022-03-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm11071800
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Article ; Online: New Frontiers for an Old Drug: What Is New on the Pleiotropic Effect of Sulodexide in Chronic Venous Disease.

Ligi, Daniela / Maniscalco, Rosanna / Mannello, Ferdinando

Journal of cardiovascular pharmacology

2020 Volume 75, Issue 3, Page(s) 208–210

MeSH term(s)	Chronic Disease ; Glycosaminoglycans ; Humans ; Vascular Diseases
Chemical Substances	Glycosaminoglycans ; glucuronyl glucosamine glycan sulfate (75HGV0062C)
Language	English
Publishing date	2020-02-10
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	391970-5
ISSN	1533-4023 ; 0160-2446
ISSN (online)	1533-4023
ISSN	0160-2446
DOI	10.1097/FJC.0000000000000799
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Article ; Online: Thrombocytopenia and hyperinflammation are induced by extracellular histones circulating in blood.

Giglio, Rosaria Vincenza / Ligi, Daniela / Della Franca, Chiara / Lo Sasso, Bruna / Rivas, Julia Zulema / Agnello, Luisa / Mannello, Ferdinando / Ciaccio, Marcello

Clinical chemistry and laboratory medicine

2023 Volume 61, Issue 12, Page(s) e239–e243

MeSH term(s)	Humans ; Histones/pharmacology ; Thrombocytopenia ; Blood Coagulation ; Anemia ; Sepsis
Chemical Substances	Histones
Language	English
Publishing date	2023-06-21
Publishing country	Germany
Document type	Letter
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2023-0590
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Zs.A 121: Show issues

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Article ; Online: Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?

Daniela Ligi / Rosanna Maniscalco / Mario Plebani / Giuseppe Lippi / Ferdinando Mannello

Journal of Clinical Medicine, Vol 11, Iss 1800, p

2022 Volume 1800

Abstract	Several studies shed light on the interplay among inflammation, thrombosis, multi-organ failures and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Increasing levels of both free and/or circulating histones have been associated to coronavirus disease 2019 (COVID-19), enhancing the risk of heart attack and stroke with coagulopathy and systemic hyperinflammation. In this view, by considering both the biological and clinical rationale, circulating histones may be relevant as diagnostic biomarkers for stratifying COVID-19 patients at higher risk for viral sepsis, and as predictive laboratory medicine tool for targeted therapies.
Keywords	histone ; COVID-19 ; coagulopathy ; cytokine storm ; inflammation ; multiorgan injury ; Medicine ; R
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Deciphering the role of monocyte and monocyte distribution width (MDW) in COVID-19: an updated systematic review and meta-analysis.

Ligi, Daniela / Lo Sasso, Bruna / Henry, Brandon M / Ciaccio, Marcello / Lippi, Giuseppe / Plebani, Mario / Mannello, Ferdinando

Clinical chemistry and laboratory medicine

2023 Volume 61, Issue 6, Page(s) 960–973

Abstract: The SARS-CoV-2 infection is characterized by both systemic and organ hyper-thromboinflammation, with a clinical course ranging from mild up-to critical systemic dysfunction and death. In patients with coronavirus disease 2019 (COVID-19) the monocyte/ ... ...

Abstract	The SARS-CoV-2 infection is characterized by both systemic and organ hyper-thromboinflammation, with a clinical course ranging from mild up-to critical systemic dysfunction and death. In patients with coronavirus disease 2019 (COVID-19) the monocyte/macrophage population is deeply involved as both trigger and target, assuming the value of useful diagnostic/prognostic marker of innate cellular immunity. Several studies correlated morphological and immunophenotypic alterations of circulating monocytes with clinical outcomes in COVID-19 patients, concluding that monocyte distribution width (MDW) may retain clinical value in stratifying the risk of disease worsening. Through an electronic search in Medline and Scopus we performed an updated literature review and meta-analysis aimed to explore the association between increased MDW levels and illness severity in COVID-19 patients, deciphering role(s) and function(s) of monocytes in the harmful network underlining SARS-CoV-2 infection. We found that significantly elevated MDW values were frequently present in COVID-19 patients who developed unfavorable clinical outcomes, compounded by a significant association between monocyte anisocytosis and SARS-CoV-2 outcomes. These findings suggest that blood MDW index and its scatter plot could represent useful routine laboratory tools for early identification of patients at higher risk of unfavorable COVID-19 and for monitoring the progression of viral infection, clinical outcomes, and therapeutic efficacy throughout hospitalization. According to this evidence, therapeutic decisions in patients with SARS-CoV-2 infection could benefit from monitoring MDW value, with administration of drugs limiting thrombo-inflammation due to monocyte hyper-activation in patients with severe/critical COVID-19 disease.
MeSH term(s)	Humans ; COVID-19 ; Monocytes ; SARS-CoV-2 ; Inflammation ; Thrombosis
Language	English
Publishing date	2023-01-11
Publishing country	Germany
Document type	Meta-Analysis ; Systematic Review ; Journal Article ; Review
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2022-0936
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Zs.A 121: Show issues

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Article ; Online: Platelet distribution width (PDW) as a significant correlate of COVID-19 infection severity and mortality.

Ligi, Daniela / Della Franca, Chiara / Notarte, Kin Israel / Goldrich, Nathaniel / Kavteladze, David / Henry, Brandon Michael / Mannello, Ferdinando

Clinical chemistry and laboratory medicine

2023 Volume 62, Issue 3, Page(s) 385–395

Abstract: SARS-CoV-2 infection may cause a wide spectrum of symptoms, from asymptomatic, to mild respiratory symptoms and life-threatening sepsis. Among the clinical laboratory biomarkers analyzed during COVID-19 pandemic, platelet indices have raised great ... ...

Abstract	SARS-CoV-2 infection may cause a wide spectrum of symptoms, from asymptomatic, to mild respiratory symptoms and life-threatening sepsis. Among the clinical laboratory biomarkers analyzed during COVID-19 pandemic, platelet indices have raised great interest, due to the critical involvement of platelets in COVID-19-related thromboinflammation. Through an electronic literature search on MEDLINE, CINAHL, PubMed, EMBASE, Web of Science, and preprint servers we performed and updated a systematic review aimed at providing a detailed analysis of studies addressing the potential clinical utility of platelet distribution width, platelet distribution width (PDW), in laboratory medicine, exploring the possible association between increased PDW levels, disease severity, and mortality in COVID-19. Our systematic review revealed a wide heterogeneity of COVID-19 cohorts examined and a lack of homogenous expression of platelet indices. We found that 75 % of studies reported significantly elevated PDW values in COVID-19 infected cohorts compared to healthy/non-COVID-19 controls, and 40 % of studies reported that patients with severe COVID-19 showed increased PDW values than those with less-than-severe illness. Interestingly, 71.4 % of studies demonstrated significant increased PDW values in non survivors vs. survivors. Overall, these results suggest that platelets are critically involved as major players in the process of immunothrombosis in COVID-19, and platelet reactivity and morphofunctional alterations are mirrored by PDW, as indicator of platelet heterogeneity. Our results confirm that the use of PDW as prognostic biomarkers of COVID-19 sepsis still remains debated due to the limited number of studies to draw a conclusion, but new opportunities to investigate the crucial role of platelets in thrombo-inflammation are warranted.
MeSH term(s)	Humans ; Biomarkers ; Blood Platelets ; COVID-19 ; Inflammation ; Mean Platelet Volume ; Pandemics ; SARS-CoV-2 ; Sepsis ; Thrombosis
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-09-20
Publishing country	Germany
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2023-0625
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Zs.A 121: Show issues

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Article ; Online: Monocyte distribution width alterations and cytokine storm are modulated by circulating histones.

Ligi, Daniela / Lo Sasso, Bruna / Della Franca, Chiara / Giglio, Rosaria Vincenza / Agnello, Luisa / Ciaccio, Marcello / Mannello, Ferdinando

Clinical chemistry and laboratory medicine

2023 Volume 61, Issue 8, Page(s) 1525–1535

Abstract: Objectives: Extracellular histone levels are associated with the severity of many human pathologies, including sepsis and COVID-19. This study aimed to investigate the role of extracellular histones on monocyte distribution width (MDW), and their effect ...

Abstract	Objectives: Extracellular histone levels are associated with the severity of many human pathologies, including sepsis and COVID-19. This study aimed to investigate the role of extracellular histones on monocyte distribution width (MDW), and their effect on the release of cytokines by blood cells. Methods: Peripheral venous blood was collected from healthy subjects and treated with different doses of a histone mixture (range 0-200 μg/mL) to analyze MDW modifications up-to 3 h and digital microscopy of blood smears. Plasma obtained after 3 h of histone treatment were assayed to evaluate a panel of 24 inflammatory cytokines. Results: MDW values significantly increased in a time- and dose-dependent manner. These findings are associated with the histone-induced modifications of cell volume, cytoplasmic granularity, vacuolization, and nuclear structure of monocytes, promoting their heterogeneity without affecting their count. After 3 h of treatment almost all cytokines significantly increased in a dose-dependent manner. The most relevant response was shown by the significantly increased G-CSF levels, and by the increase of IL-1β, IL-6, MIP-1β, and IL-8 at the histone doses of 50, 100, and 200 µg/mL. VEGF, IP-10, GM-CSF, TNF-α, Eotaxin, and IL-2 were also up-regulated, and a lower but significant increase was observed for IL-15, IL-5, IL-17, bFGF, IL-10, IFN-γ, MCP-1, and IL-9. Conclusions: Circulating histones critically induce functional alterations of monocytes mirrored by MDW, monocyte anisocytosis, and hyperinflammation/cytokine storm in sepsis and COVID-19. MDW and circulating histones may be useful tools to predict higher risks of worst outcomes.
MeSH term(s)	Humans ; Histones ; Monocytes/metabolism ; Cytokine Release Syndrome ; COVID-19 ; Cytokines ; Sepsis
Chemical Substances	Histones ; Cytokines
Language	English
Publishing date	2023-02-28
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2023-0093
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Zs.A 121: Show issues

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Article ; Online: Transcriptional signatures in human macrophage-like cells infected by Leishmania infantum, Leishmania major and Leishmania tropica.

Diotallevi, Aurora / Bruno, Federica / Castelli, Germano / Persico, Giuseppe / Buffi, Gloria / Ceccarelli, Marcello / Ligi, Daniela / Mannello, Ferdinando / Vitale, Fabrizio / Magnani, Mauro / Galluzzi, Luca

PLoS neglected tropical diseases

2024 Volume 18, Issue 4, Page(s) e0012085

Abstract: Background: In the Mediterranean basin, three Leishmania species have been identified: L. infantum, L. major and L. tropica, causing zoonotic visceral leishmaniasis (VL), zoonotic cutaneous leishmaniasis (CL) and anthroponotic CL, respectively. Despite ... ...

Abstract	Background: In the Mediterranean basin, three Leishmania species have been identified: L. infantum, L. major and L. tropica, causing zoonotic visceral leishmaniasis (VL), zoonotic cutaneous leishmaniasis (CL) and anthroponotic CL, respectively. Despite animal models and genomic/transcriptomic studies provided important insights, the pathogenic determinants modulating the development of VL and CL are still poorly understood. This work aimed to identify host transcriptional signatures shared by cells infected with L. infantum, L. major, and L. tropica, as well as specific transcriptional signatures elicited by parasites causing VL (i.e., L. infantum) and parasites involved in CL (i.e., L. major, L. tropica). Methodology/principal findings: U937 cells differentiated into macrophage-like cells were infected with L. infantum, L. major and L. tropica for 24h and 48h, and total RNA was extracted. RNA sequencing, performed on an Illumina NovaSeq 6000 platform, was used to evaluate the transcriptional signatures of infected cells with respect to non-infected cells at both time points. The EdgeR package was used to identify differentially expressed genes (fold change > 2 and FDR-adjusted p-values < 0.05). Then, functional enrichment analysis was employed to identify the enriched ontology terms in which these genes are involved. At 24h post-infection, a common signature of 463 dysregulated genes shared among all infection conditions was recognized, while at 48h post-infection the common signature was reduced to 120 genes. Aside from a common transcriptional response, we evidenced different upregulated functional pathways characterizing L. infantum-infected cells, such as VEGFA-VEGFR2 and NFE2L2-related pathways, indicating vascular remodeling and reduction of oxidative stress as potentially important factors for visceralization. Conclusions: The identification of pathways elicited by parasites causing VL or CL could lead to new therapeutic strategies for leishmaniasis, combining the canonical anti-leishmania compounds with host-directed therapy.
MeSH term(s)	Animals ; Humans ; Leishmania tropica/genetics ; Leishmania infantum/genetics ; Leishmania major ; Leishmaniasis, Cutaneous/parasitology ; Leishmaniasis, Visceral/parasitology ; Macrophages
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0012085
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Article ; Online: MMP-2 and MMP-9 in Human Peripheral Blood: Optimizing Gelatinase Calibrator for Degradome Research and Discovering a Novel Gelatinolytic Enzyme.

Ligi, Daniela / Maniscalco, Rosanna / Mannello, Ferdinando

Journal of proteome research

2019 Volume 19, Issue 1, Page(s) 525–536

Abstract: Matrix metalloprotease-2 and -9 (gelatinase A and B, respectively) are enzymes crucially involved in a plethora of physiopathological conditions. Gelatin zymography is considered one of the major qualitative/semiquantitative assays for simultaneously ... ...

Abstract	Matrix metalloprotease-2 and -9 (gelatinase A and B, respectively) are enzymes crucially involved in a plethora of physiopathological conditions. Gelatin zymography is considered one of the major qualitative/semiquantitative assays for simultaneously determining zymogenic, active, and complexed forms of gelatinases. Critical steps are represented by variations in sample collection methods, molecular weight standard calibrators, and different zymography assay protocols. A normalization of these aspects is required for reducing discrepancies in technical procedures and interpreting results among different laboratories. In this study, we describe a novel protocol for gelatin zymography with increased pore size, which improves the separation of gelatinases with different molecular weights. A new method for obtaining gelatinase calibrator for gelatin zymography, by extracting MMP-2 and MMP-9 from peripheral blood, is also reported. Our method provides a gelatinase calibrator with enhanced stability both at room temperature and during multiple freeze-thaw cycles. This calibrator preparation is also suitable for in vitro post-translational modifications. For the first time, the improved zymography protocol allowed us to reveal in human peripheral blood samples new gelatinolytic bands resolved at very high molecular weight, likely complexes of MMP-9, undetectable with classical zymography protocols.
MeSH term(s)	Blood Specimen Collection/methods ; Calibration ; Cross-Linking Reagents/chemistry ; Electrophoresis, Polyacrylamide Gel/methods ; Enzyme Activation ; Freezing ; Humans ; Matrix Metalloproteinase 2/blood ; Matrix Metalloproteinase 9/blood ; Matrix Metalloproteinase Inhibitors/pharmacology ; Molecular Weight ; Time Factors
Chemical Substances	Cross-Linking Reagents ; Matrix Metalloproteinase Inhibitors ; MMP2 protein, human (EC 3.4.24.24) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; MMP9 protein, human (EC 3.4.24.35) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2019-10-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.9b00261
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