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Article ; Online: Extracellular Vesicles

Martina Schiavello / Barbara Vizio / Ornella Bosco / Emanuele Pivetta / Filippo Mariano / Giuseppe Montrucchio / Enrico Lupia

International Journal of Molecular Sciences, Vol 24, Iss 1920, p

New Players in the Mechanisms of Sepsis- and COVID-19-Related Thromboinflammation

2023 Volume 1920

Abstract: Sepsis and COVID-19 patients often manifest an imbalance in inflammation and coagulation, a complex pathological mechanism also named thromboinflammation, which strongly affects patient prognosis. Extracellular vesicles (EVs) are nanoparticles released ... ...

Abstract	Sepsis and COVID-19 patients often manifest an imbalance in inflammation and coagulation, a complex pathological mechanism also named thromboinflammation, which strongly affects patient prognosis. Extracellular vesicles (EVs) are nanoparticles released by cells into extracellular space that have a relevant role in cell-to-cell communication. Recently, EVs have been shown to act as important players in a variety of pathologies, including cancer and cardiovascular disease. The biological properties of EVs in the mechanisms of thromboinflammation during sepsis and COVID-19 are still only partially known. Herein, we summarize the current experimental evidence on the role of EVs in thromboinflammation, both in bacterial sepsis and in COVID-19. A better understanding of EV involvement in these processes could be useful in describing novel diagnostic and therapeutic applications of EVs in these diseases.
Keywords	extracellular vesicles ; sepsis ; COVID-19 ; thromboinflammation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Thrombopoietin Contributes to Enhanced Platelet Activation in Patients with Type 1 Diabetes Mellitus

Ornella Bosco / Barbara Vizio / Gabriella Gruden / Martina Schiavello / Bartolomeo Lorenzati / Paolo Cavallo-Perin / Isabella Russo / Giuseppe Montrucchio / Enrico Lupia

International Journal of Molecular Sciences, Vol 22, Iss 13, p

2021 Volume 7032

Abstract: Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic ... ...

Abstract	Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to stimulate megakaryocyte proliferation and differentiation, also modulates the response of mature platelets by enhancing both activation and binding to leukocytes in response to different agonists. Increased THPO levels have been reported in different clinical conditions characterized by a generalized pro-thrombotic state, from acute coronary syndromes to sepsis/septic shock, and associated with elevated indices of platelet activation. To investigate the potential contribution of elevated THPO levels in platelet activation in T1DM patients, we studied 28 T1DM patients and 28 healthy subjects. We measured plasma levels of THPO, as well as platelet-leukocyte binding, P-selectin, and THPO receptor (THPOR) platelet expression. The priming activity of plasma from diabetic patients or healthy subjects on platelet–leukocyte binding and the role of THPO on this effect was also studied in vitro. T1DM patients had higher circulating THPO levels and increased platelet–monocyte and platelet–granulocyte binding, as well as platelet P-selectin expression, compared to healthy subjects, whereas platelet expression of THPOR did not differ between the two groups. THPO concentrations correlated with platelet–leukocyte binding, as well as with fasting glucose and Hb1Ac. In vitro, plasma from diabetic patients, but not from healthy subjects, primed platelet–leukocyte binding and platelet P-selectin expression. Blocking THPO biological activity using a specific inhibitor prevented the priming effect induced by plasma from diabetic patients. In conclusion, augmented THPO may enhance platelet activation in patients with T1DM, potentially participating in increasing atherosclerotic risk.
Keywords	type 1 diabetes mellitus ; platelet–leukocyte adhesion ; platelet activation markers ; thrombopoietin ; atherosclerotic cardiovascular diseases ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Platelets and Multi-Organ Failure in Sepsis

Elisabetta Greco / Enrico Lupia / Ornella Bosco / Barbara Vizio / Giuseppe Montrucchio

International Journal of Molecular Sciences, Vol 18, Iss 10, p

2017 Volume 2200

Abstract: Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused ... ...

Abstract	Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models.
Keywords	platelet ; sepsis ; multi-organ failure ; thrombocytopenia ; septic shock ; antiplatelets ; ARDS ; AKI ; DIC ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2017-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Thrombopoietin participates in platelet activation in COVID-19 patients

Enrico Lupia / Marialessia Capuano / Barbara Vizio / Martina Schiavello / Ornella Bosco / Maria Gelardi / Edoardo Favale / Emanuele Pivetta / Fulvio Morello / Shahid Husain / Shaf Keshavjee / Lorenzo Del Sorbo / Giuseppe Montrucchio

EBioMedicine, Vol 85, Iss , Pp 104305- (2022)

2022

Abstract: Summary: Background: The pathogenesis of coronavirus disease 2019 (COVID-19) is characterized by enhanced platelet activation and diffuse hemostatic alterations, which may contribute to immunothrombosis/thromboinflammation and subsequent development of ... ...

Abstract	Summary: Background: The pathogenesis of coronavirus disease 2019 (COVID-19) is characterized by enhanced platelet activation and diffuse hemostatic alterations, which may contribute to immunothrombosis/thromboinflammation and subsequent development of target-organ damage.Thrombopoietin (THPO), a growth factor essential to megakariocyte proliferation, is known to prime platelet activation and leukocyte-platelet interaction. In addition, THPO concentrations increase in several critical diseases, such as acute cardiac ischemia and sepsis, thus representing a potential diagnostic and prognostic biomarker. Furthermore, several data suggest that interleukin (IL)-6 is one of the most important inflammatory mediators involved in these phenomena, which led to explore the potential therapeutic role of IL-6 inhibitors.In this prospective cohort study, we aimed to study THPO and IL-6 concentrations in COVID-19 patients at the time of first clinical evaluation in the Emergency Department (ED), and to investigate their potential use as diagnostic and prognostic biomarkers. In addition, we sought to explore the role of THPO contained in plasma samples obtained from COVID-19 patients in priming in vitro platelet activation and leukocyte-platelet interaction. Methods: We enrolled 66 patients presenting to the ED with symptoms suggestive of COVID-19, including 47 with confirmed COVID-19 and 19 in whom COVID-19 was excluded (Non-COVID-19 patients). As controls, we also recruited 18 healthy subjects.In vitro, we reproduced the effects of increased circulating THPO on platelet function by adding plasma from COVID-19 patients or controls to platelet-rich plasma or whole blood obtained by healthy donors, and we indirectly studied the effect of THPO on platelet activation by blocking its biological activity. Findings: THPO levels were higher in COVID-19 patients than in both Non-COVID-19 patients and healthy subjects. Studying THPO as diagnostic marker for the diagnosis of COVID-19 by receiver-operating-characteristic (ROC) ...
Keywords	COVID-19 ; Thrombopoietin ; Interleukin-6 ; Platelet activation ; Biomarker ; Thromboinflammation ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cooperative Role of Thrombopoietin and Vascular Endothelial Growth Factor-A in the Progression of Liver Cirrhosis to Hepatocellular Carcinoma

Barbara Vizio / Ornella Bosco / Ezio David / Gian Paolo Caviglia / Maria Lorena Abate / Martina Schiavello / Angela Pucci / Antonina Smedile / Gianluca Paraluppi / Renato Romagnoli / Enrico Lupia / Graziella Bellone / Giuseppe Montrucchio

International Journal of Molecular Sciences, Vol 22, Iss 4, p

2021 Volume 1818

Abstract: Primary thrombopoietic mediator thrombopoietin (THPO) is mainly produced by the liver; it may act as a growth factor for hepatic progenitors. Principal angiogenesis inducer vascular endothelial growth factor-A (VEGF-A) is critical for the complex ... ...

Abstract	Primary thrombopoietic mediator thrombopoietin (THPO) is mainly produced by the liver; it may act as a growth factor for hepatic progenitors. Principal angiogenesis inducer vascular endothelial growth factor-A (VEGF-A) is critical for the complex vascular network within the liver architecture. As a cross-regulatory loop between THPO and VEGF-A has been demonstrated in the hematopoietic system, the two growth factors were hypothesized to cooperatively contribute to the progression from liver cirrhosis (LC) to hepatocellular carcinoma (HCC). The mRNA and protein expression levels of THPO, VEGF-A, and their receptors were examined, compared, and correlated in paired cancerous and LC tissues from 26 cirrhosis-related HCC patients, using qRT-PCR and immunohistochemistry. THPO and VEGF-A were alternatively silenced by small interfering RNA (siRNA) in human liver cancer cell lines Huh7 and HepG2. THPO and VEGF-A expressions significantly increased in tumor versus LC tissues. HCC and paired LC cells expressed similar levels of THPO receptor (R), whereas vascular endothelial growth factor receptor (VEGFR) -1 and VEGFR-2 levels were higher in HCC than in corresponding LC tissue samples. A significant linear correlation emerged between THPO and VEGF-A transcripts in HCC and, at the protein level, THPO and THPOR were significantly correlated with VEGF-A in tumor tissues. Both HCC and LC expressed similar levels of gene and protein hypoxia inducible factor (HIF)-1α. Positive cross-regulation occurred with the alternative administration of siRNAs targeting THPO and those targeting VEGF-A in hypoxic liver cancer cell lines. These results suggest THPO and VEGF-A might act as interdependently regulated autocrine and/or paracrine systems for cellular growth in HCC. This might be clinically interesting, since new classes of THPOR agonistic/antagonistic drugs may provide novel therapeutic options to correct the frequent hemostatic abnormality seen in HCC patients.
Keywords	angiogenesis ; hepatocellular carcinoma ; thrombopoietin ; tumor microenvironment ; vascular endothelial growth factor-A ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Thrombopoietin as Biomarker and Mediator of Cardiovascular Damage in Critical Diseases

Ornella Bosco / Giuseppe Montrucchio / Alberto Goffi / Enrico Lupia

Mediators of Inflammation, Vol

2012 Volume 2012

Keywords	Pathology ; RB1-214 ; Medicine ; R ; DOAJ:Pathology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Fibulin-1 interacts with Sex Hormone Binding Globulin and is linked to less aggressive estrogen-dependent breast cancers

Marano, Francesca / Emanuela Arvat / Isabella Castellano / Maria Graziella Catalano / Nicoletta Fortunati / Ornella Bosco / Roberto Frairia / Valentina Zunino

Life sciences. 2018 Aug. 15, v. 207

2018

Abstract: Interaction of Sex Hormone-Binding Globulin (SHBG) with estrogen-sensitive breast cancer cells has a protective role against estrogen exposure. No specific membrane receptor for SHBG had been identified by now, but a putative interaction of SHBG with ... ...

Abstract	Interaction of Sex Hormone-Binding Globulin (SHBG) with estrogen-sensitive breast cancer cells has a protective role against estrogen exposure. No specific membrane receptor for SHBG had been identified by now, but a putative interaction of SHBG with extracellular matrix associated-proteins (e.g. fibulins) was suggested. In this study we investigated the expression of fibulins, their functional relationship with SHBG and involvement in behavior of estrogen-sensitive breast cancer.Gene expression of fibulins was performed by Real time-PCR on two estrogen-sensitive breast cancer cell lines, MCF-7 and T47D. Fibulin-1 protein expression and localization were determined by Western blot and immunofluorescence. SHBG interaction with-fibulin-1 was assessed by GST-pull down assay. MCF-7 cell growth and gene expression, after fibulin-1 silencing by siRNA, were evaluated. Finally, the expression of fibulin-1 was correlated to clinical and pathological data of 21 breast cancer tissue samples.Fibulin-1 was expressed in both cell lines and it was increased by estradiol. SHBG interacted with fibulin-1C; proteins co-localized at MCF-7 cell membranes and SHBG localization at membranes disappeared after silencing fibulin-1. Fibulin-1 silencing, moreover, generated MCF-7 cells unresponsive to estradiol and SHBG and characterized by increased proliferation. Finally, in breast cancer tissue samples expressing fibulin-1 the proliferation index was significantly lower than in fibulin-1 negative samples.Fibulin-1 interacts with SHBG, it is associated with a less aggressive behavior of breast cancer cells and correlates to a better prognosis of the tumor.
Keywords	aggression ; breast neoplasms ; breasts ; cell growth ; cell lines ; cell membranes ; estradiol ; extracellular matrix ; fluorescent antibody technique ; gene expression ; neoplasm cells ; prognosis ; protective effect ; protein synthesis ; quantitative polymerase chain reaction ; sex hormone-binding globulin ; small interfering RNA ; Western blotting
Language	English
Dates of publication	2018-0815
Size	p. 372-380.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2018.06.024
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Blockade of Thrombopoietin Reduces Organ Damage in Experimental Endotoxemia and Polymicrobial Sepsis.

Alessandra Cuccurullo / Elisabetta Greco / Enrico Lupia / Paolo De Giuli / Ornella Bosco / Erica Martin-Conte / Tiziana Spatola / Emilia Turco / Giuseppe Montrucchio

PLoS ONE, Vol 11, Iss 3, p e

2016 Volume 0151088

Abstract: BACKGROUND AND PURPOSE:Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the ... ...

Abstract	BACKGROUND AND PURPOSE:Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions. METHODS:We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP) model. RESULTS:In both models, TPO levels markedly increased, from 289.80±27.87 pg/mL to 465.60±45.92 pg/mL at 3 hours in the LPS model (P<0.01), and from 265.00±26.02 pg/mL to 373.70±26.20 pg/mL in the CLP model (P<0.05), respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86±2.48% to 46.13±1.39% at 3 hours in the LPS model (P<0.01), and from 43.68±1.69% to 56.52±4.66% in the CLP model (P<0.05). Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86±0.34 to 0.60±0.27 (P<0.01) and from 1.43±0.37 to 0.40±0.16 (P<0.05), respectively, in the LPS model at 3 hours, and from a score of 1.75±0.37 to 0.38±0.18 (P<0.01) and from 1.25±0.31 to 0.13±0.13 (P<0.001), respectively, in the ...
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Targeting Taxanes to Castration-Resistant Prostate Cancer Cells by Nanobubbles and Extracorporeal Shock Waves.

Francesca Marano / Letizia Rinella / Monica Argenziano / Roberta Cavalli / Francesca Sassi / Patrizia D'Amelio / Antonino Battaglia / Paolo Gontero / Ornella Bosco / Rossella Peluso / Nicoletta Fortunati / Roberto Frairia / Maria Graziella Catalano

PLoS ONE, Vol 11, Iss 12, p e

2016 Volume 0168553

Abstract: To target taxanes to castration-resistant prostate cancer cells, glycol-chitosan nanobubbles loaded with paclitaxel and docetaxel were constructed. The loaded nanobubbles were then combined with Extracorporeal Shock Waves, acoustic waves widely used in ... ...

Abstract	To target taxanes to castration-resistant prostate cancer cells, glycol-chitosan nanobubbles loaded with paclitaxel and docetaxel were constructed. The loaded nanobubbles were then combined with Extracorporeal Shock Waves, acoustic waves widely used in urology and orthopedics, with no side effects. Nanobubbles, with an average diameter of 353.3 ± 15.5 nm, entered two different castration-resistant prostate cancer cells (PC3 and DU145) as demonstrated by flow cytometry and immunofluorescence. The shock waves applied increased the amount of intracellular nanobubbles. Loading nanobubbles with paclitaxel and docetaxel and combining them with shock waves generated the highest cytotoxic effects, resulting in a paclitaxel GI50 reduction of about 55% and in a docetaxel GI50 reduction of about 45% respectively. Combined treatment also affected cell migration. Paclitaxel-loaded nanobubbles and shock waves reduced cell migration by more than 85% with respect to paclitaxel alone; whereas docetaxel-loaded nanobubbles and shock waves reduced cell migration by more than 82% with respect to docetaxel alone. The present data suggest that nanobubbles can act as a stable taxane reservoir in castration-resistant prostate cancer cells and shock waves can further increase drug release from nanobubbles leading to higher cytotoxic and anti-migration effect.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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