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Article ; Online: Ceruloplasmin Deamidation in Neurodegeneration: From Loss to Gain of Function.

Zanardi, Alan / Alessio, Massimo

International journal of molecular sciences

2021 Volume 22, Issue 2

Abstract: Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the ... ...

Abstract	Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the oxidation induced by the pathological environment and are usually associated with activity loss. Together with oxidation, deamidation of Cp was found in the CSF from Alzheimer's and Parkinson's disease patients. Protein deamidation is a process characterized by asparagine residues conversion in either aspartate or isoaspartate, depending on protein sequence/structure and cellular environment. Cp deamidation occurs at two Asparagine-Glycine-Arginine (NGR)-motifs which, once deamidated to isoAspartate-Glycine-Arginine (isoDGR), bind integrins, a family of receptors mediating cell adhesion. Therefore, on the one hand, Cp modifications lead to loss of enzymatic activity, while on the other hand, these alterations confer gain of function to Cp. In fact, deamidated Cp binds to integrins and triggers intracellular signaling on choroid plexus epithelial cells, changing cell functioning. Working in concert with the oxidative environment, Cp deamidation could reach different target cells in the brain, altering their physiology and causing detrimental effects, which might contribute to the pathological mechanism.
MeSH term(s)	Amino Acid Motifs ; Amino Acids/metabolism ; Animals ; Brain/metabolism ; Ceruloplasmin/chemistry ; Ceruloplasmin/genetics ; Ceruloplasmin/metabolism ; Disease Susceptibility ; Gain of Function Mutation ; Genetic Predisposition to Disease ; Humans ; Integrins/metabolism ; Loss of Function Mutation ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Oligopeptides/chemistry
Chemical Substances	Amino Acids ; Integrins ; Oligopeptides ; asparagine-glycine-arginine ; Ceruloplasmin (EC 1.16.3.1)
Language	English
Publishing date	2021-01-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22020663
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Article: Serological proteome analysis identifies crustacean myosin heavy chain type 1 protein and house dust mite Der p 14 as cross-reacting allergens.

Conti, Antonio / Alqassir, Noor / Breda, Daniela / Zanardi, Alan / Alessio, Massimo / Burastero, Samuele E

Advances in clinical and experimental medicine : official organ Wroclaw Medical University

2023 Volume 32, Issue 1, Page(s) 107–112

Abstract: Background: Allergies to house dust mite (HDM) and to crustaceans are clinically and pathogenically linked. Several homologous allergenic proteins have been identified, among which tropomyosin is the prototype, expressing epitopes endowed with variable ... ...

Abstract	Background: Allergies to house dust mite (HDM) and to crustaceans are clinically and pathogenically linked. Several homologous allergenic proteins have been identified, among which tropomyosin is the prototype, expressing epitopes endowed with variable levels of immunoglobulin E (IgE) cross-reactivity. Component-resolved diagnosis (CRD) does not allow a thorough characterization of all relevant IgE reactivities to these allergen sources. Objectives: We studied 1 patient allergic to shrimp with positive skin prick test to HDM and negative scores for IgE to HDM allergen components routinely used in CRD (group 1 and 2 allergens, Der p 23 and tropomyosin). Material and methods: In order to identify the allergen(s) involved in IgE reactivity, we used serological proteome analysis (SERPA), which utilizes two-dimensional gel electrophoresis (2DE), immunoblotting and mass spectrometry (MS). The identified allergenic proteins were tested with sera from 20 crustacean-allergic patients and 19 grass-allergic patients serving as controls. Results: Der p 14 and myosin heavy chain type 1 (MHC1) were identified as the components recognized by patient's IgE in the proteome of Dermatophagoides pteronyssinus and Penaeus monodon, respectively. The MHC1 protein shows about 30% sequence identity with Der p 14 in specific domains, and cross-reactivity against epitopes shared by the 2 proteins was demonstrated by reduced reactivity to shrimp extract following pre-incubation with Der p 14. Serum IgE from 5 out of 20 patients allergic to crustaceans reacted with MHC1, compared to none among 19 controls (p < 0.05). Conclusion: We identified MHC1 as a relevant allergic component in the proteome of Penaeus monodon, the prototypic allergen source used in diagnosis of allergy to crustaceans. Our data demonstrate MHC1 cross-reactivity between MHC1 and Der p 14 from Dermatophagoides pteronyssinus.
MeSH term(s)	Animals ; Humans ; Allergens ; Epitopes/chemistry ; Hypersensitivity ; Immunoglobulin E ; Myosin Heavy Chains ; Proteome ; Pyroglyphidae ; Tropomyosin/chemistry ; Shellfish Hypersensitivity ; Cross Reactions
Chemical Substances	Allergens ; Epitopes ; Immunoglobulin E (37341-29-0) ; Myosin Heavy Chains (EC 3.6.4.1) ; Proteome ; Tropomyosin
Language	English
Publishing date	2023-01-07
Publishing country	Poland
Document type	Journal Article
ZDB-ID	2270257-X
ISSN	1899-5276 ; 1230-025X
ISSN	1899-5276 ; 1230-025X
DOI	10.17219/acem/158773
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Article ; Online: Ceruloplasmin-Deficient Mice Show Dysregulation of Lipid Metabolism in Liver and Adipose Tissue Reduced by a Protein Replacement.

Raia, Sara / Conti, Antonio / Zanardi, Alan / Ferrini, Barbara / Scotti, Giulia Maria / Gilberti, Enrica / De Palma, Giuseppe / David, Samuel / Alessio, Massimo

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: Ceruloplasmin is a ferroxidase that plays a role in iron homeostasis; its deficiency fosters inter alia iron accumulation in the liver, which expresses the soluble form of the protein secreted into the bloodstream. Ceruloplasmin is also secreted by the ... ...

Abstract	Ceruloplasmin is a ferroxidase that plays a role in iron homeostasis; its deficiency fosters inter alia iron accumulation in the liver, which expresses the soluble form of the protein secreted into the bloodstream. Ceruloplasmin is also secreted by the adipose tissue, but its role in adipocytes has been poorly investigated. We hypothesized that ceruloplasmin might have a role in iron/lipid interplay. We investigated iron/lipid dysmetabolism in the liver and adipose tissue of the ceruloplasmin-deficient mouse (CpKO) model of aceruloplasminemia and evaluated the effectiveness of ceruloplasmin replacement. We found that CpKO mice were overweight, showing adipose tissue accumulation, liver iron deposition and steatosis. In the adipose tissue of CpKO mice, iron homeostasis was not altered. Conversely, the levels of adiponectin and leptin adipokines behaved opposite to the wild-type. Increased macrophage infiltration was observed in adipose tissue and liver of CpKO mice, indicating tissue inflammation. The treatment of CpKO mice with ceruloplasmin limited liver iron accumulation and steatosis without normalizing the expression of iron homeostasis-related proteins. In the CpKO mice, the protein replacement limited macrophage infiltration in both adipose and hepatic tissues reduced the level of serum triglycerides, and partially recovered adipokines levels in the adipose tissue. These results underline the link between iron and lipid dysmetabolism in ceruloplasmin-deficient mice, suggesting that ceruloplasmin in adipose tissue has an anti-inflammatory role rather than a role in iron homeostasis. Furthermore, these data also indicate that ceruloplasmin replacement therapy may be effective at a systemic level.
MeSH term(s)	Mice ; Animals ; Ceruloplasmin/metabolism ; Lipid Metabolism ; Liver/metabolism ; Iron/metabolism ; Adipose Tissue/metabolism ; Adipokines/metabolism ; Fatty Liver/metabolism ; Lipids
Chemical Substances	Ceruloplasmin (EC 1.16.3.1) ; Iron (E1UOL152H7) ; Adipokines ; Lipids
Language	English
Publishing date	2023-01-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24021150
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Article ; Online: Lipid dysmetabolism in ceruloplasmin-deficient mice revealed both in vivo and ex vivo by MRI, MRS and NMR analyses.

Mannella, Valeria / Chaabane, Linda / Canu, Tamara / Zanardi, Alan / Raia, Sara / Conti, Antonio / Ferrini, Barbara / Caricasole, Andrea / Musco, Giovanna / Alessio, Massimo

FEBS open bio

2023 Volume 14, Issue 2, Page(s) 258–275

Abstract: Ceruloplasmin (Cp) is a ferroxidase that plays a role in cellular iron homeostasis and is mainly expressed in the liver and secreted into the blood. Cp is also produced by adipose tissue, which releases it as an adipokine. Although a dysfunctional ... ...

Abstract	Ceruloplasmin (Cp) is a ferroxidase that plays a role in cellular iron homeostasis and is mainly expressed in the liver and secreted into the blood. Cp is also produced by adipose tissue, which releases it as an adipokine. Although a dysfunctional interaction of iron with the metabolism of lipids has been associated with several metabolic diseases, the role of Cp in adipose tissue metabolism and in the interplay between hepatocytes and adipocytes has been poorly investigated. We previously found that Cp-deficient (CpKO) mice become overweight and demonstrate adipose tissue accumulation together with liver steatosis during aging, suggestive of lipid dysmetabolism. In the present study, we investigated the lipid alterations which occur during aging in adipose tissue and liver of CpKO and wild-type mice both in vivo and ex vivo. During aging of CpKO mice, we observed adipose tissue accumulation and liver lipid deposition, both of which are associated with macrophage infiltration. Liver lipid deposition was characterized by accumulation of triglycerides, fatty acids and ω-3 fatty acids, as well as by a switch from unsaturated to saturated fatty acids, which is characteristic of lipid storage. Liver steatosis was preceded by iron deposition and macrophage infiltration, and this was observed to be already occurring in younger CpKO mice. The accumulation of ω-3 fatty acids, which can only be acquired through diet, was associated with body weight increase in CpKO mice despite food intake being equal to that of wild-type mice, thus underlining the alterations in lipid metabolism/catabolism in Cp-deficient animals.
MeSH term(s)	Mice ; Animals ; Ceruloplasmin/genetics ; Ceruloplasmin/metabolism ; Fatty Liver ; Magnetic Resonance Imaging ; Triglycerides ; Iron/metabolism ; Fatty Acids ; Fatty Acids, Omega-3
Chemical Substances	Ceruloplasmin (EC 1.16.3.1) ; Triglycerides ; Iron (E1UOL152H7) ; Fatty Acids ; Fatty Acids, Omega-3
Language	English
Publishing date	2023-12-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2651702-4
ISSN	2211-5463 ; 2211-5463
ISSN (online)	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.13740
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Article ; Online: Oxidized/deamidated-ceruloplasmin dysregulates choroid plexus epithelial cells functionality and barrier properties via RGD-recognizing integrin binding.

Zanardi, Alan / Barbariga, Marco / Conti, Antonio / Vegliani, Franco / Curnis, Flavio / Alessio, Massimo

Neurobiology of disease

2021 Volume 158, Page(s) 105474

Abstract: Choroid plexus epithelial cells (CPEpiCs) determine the composition of cerebrospinal fluid (CSF) and constitute the blood-CSF barrier (BCSFB), functions that are altered in neurodegenerative diseases. In Parkinson's disease (PD) the pathological ... ...

Abstract	Choroid plexus epithelial cells (CPEpiCs) determine the composition of cerebrospinal fluid (CSF) and constitute the blood-CSF barrier (BCSFB), functions that are altered in neurodegenerative diseases. In Parkinson's disease (PD) the pathological environment oxidizes and deamidates the ceruloplasmin, a CSF-resident ferroxidase, which undergoes a gain of RGD-recognizing integrin binding property, that may result in signal transduction. We investigated the effects that oxidized/deamidated ceruloplasmin (Cp-ox/de) may exert on CPEpiCs functions. Through RGD-recognizing integrins binding, Cp-ox/de mediates CPEpiCs adhesion and intracellular signaling, resulting in cell proliferation inhibition and alteration of the secretome profile in terms of proteins related to cell-extracellular matrix interaction. Oxidative conditions, comparable to those found in the CSF of PD patients, induced CPEpiCs barrier leakage, allowing Cp-ox/de to cross it, transducing integrins-mediated signal that further worsens BCSFB integrity. This mechanism might contribute to PD pathological processes altering CSF composition and aggravating the already compromised BCSFB function.
MeSH term(s)	Amides ; Blood-Brain Barrier/physiology ; Cell Adhesion ; Cell Proliferation ; Ceruloplasmin/physiology ; Choroid Plexus/cytology ; Choroid Plexus/physiology ; Epithelial Cells/physiology ; Extracellular Matrix ; Humans ; Integrins/metabolism ; Oligopeptides/metabolism ; Oxidation-Reduction ; Secretome/physiology ; Signal Transduction/physiology
Chemical Substances	Amides ; Integrins ; Oligopeptides ; arginyl-glycyl-aspartic acid (78VO7F77PN) ; Ceruloplasmin (EC 1.16.3.1)
Language	English
Publishing date	2021-08-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2021.105474
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Article ; Online: Ceruloplasmin oxidized and deamidated by Parkinson's disease cerebrospinal fluid induces epithelial cells proliferation arrest and apoptosis.

Barbariga, Marco / Zanardi, Alan / Curnis, Flavio / Conti, Antonio / Boselli, Daniela / Di Terlizzi, Simona / Alessio, Massimo

Scientific reports

2020 Volume 10, Issue 1, Page(s) 15507

Abstract: In Parkinson's disease, the ferroxidase ceruloplasmin (Cp) is oxidized and deamidated by the pathological cerebrospinal fluid (CSF) environment. These modifications promote the gain of integrin binding properties, fostered by the deamidation of two NGR- ... ...

Abstract	In Parkinson's disease, the ferroxidase ceruloplasmin (Cp) is oxidized and deamidated by the pathological cerebrospinal fluid (CSF) environment. These modifications promote the gain of integrin binding properties, fostered by the deamidation of two NGR-motifs present in the Cp sequence that convert into the isoDGR-motif. Through isoDGR/integrin binding, the oxidized/deamidated-Cp (Cp-ox/de) mediates cell adhesion and transduces an intracellular signal in epithelial cells that seems to be addressed to regulate cell cycle, proliferation and cytoskeletal re-arrangement. However, the effect fostered on cells by integrins engagement via Cp-ox/de is not known. We found that in HaCaT epithelial cells, the incubation with Cp-ox/de resulted in proliferation inhibition mediated by isoDGR, cell cycle arrest and apoptosis induction. Similar proliferation inhibition was induced by treatment with purified Cp previously incubated in the CSF from Parkinson's disease patients, but not by Cp incubated in the CSF from healthy subjects. In human primary choroid plexus epithelial cells, a possible in vivo target of Cp-ox/de generated in pathological CSFs, we found that Cp-ox/de mediated cell adhesion via isoDGR/integrins binding and transduced an intracellular signal, which resulted in cell proliferation inhibition. Thus, the generation of Cp-ox/de in pathological CSFs and the consequent apoptosis induction of epithelial cells facing the liquor, might represent a novel mechanism that contributes to neurodegeneration.
MeSH term(s)	Apoptosis ; Cell Cycle ; Cell Proliferation ; Ceruloplasmin/cerebrospinal fluid ; Ceruloplasmin/metabolism ; Deamination ; Epithelial Cells/metabolism ; Epithelial Cells/physiology ; HaCaT Cells ; Humans ; Oxidation-Reduction ; Parkinson Disease/cerebrospinal fluid ; Parkinson Disease/metabolism
Chemical Substances	Ceruloplasmin (EC 1.16.3.1)
Language	English
Publishing date	2020-09-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-72447-z
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Article ; Online: New orphan disease therapies from the proteome of industrial plasma processing waste- a treatment for aceruloplasminemia.

Zanardi, Alan / Nardini, Ilaria / Raia, Sara / Conti, Antonio / Ferrini, Barbara / D'Adamo, Patrizia / Gilberti, Enrica / DePalma, Giuseppe / Belloli, Sara / Monterisi, Cristina / Coliva, Angela / Rainone, Paolo / Moresco, Rosa Maria / Mori, Filippo / Zurlo, Giada / Scali, Carla / Natali, Letizia / Pancanti, Annalisa / Giovacchini, Pierangelo /

Magherini, Giulio / Tovani, Greta / Salvini, Laura / Cicaloni, Vittoria / Tinti, Cristina / Tinti, Laura / Lana, Daniele / Magni, Giada / Giovannini, Maria Grazia / Gringeri, Alessandro / Caricasole, Andrea / Alessio, Massimo

Communications biology

2024 Volume 7, Issue 1, Page(s) 140

Abstract: Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited ... ...

Abstract	Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.
MeSH term(s)	Adult ; Humans ; Animals ; Mice ; Ceruloplasmin/genetics ; Ceruloplasmin/metabolism ; Proteome/metabolism ; Rare Diseases ; Industrial Waste ; Iron Metabolism Disorders ; Neurodegenerative Diseases
Chemical Substances	Ceruloplasmin (EC 1.16.3.1) ; Proteome ; Industrial Waste
Language	English
Publishing date	2024-01-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05820-7
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Article ; Online: Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia.

Zanardi, Alan / Conti, Antonio / Cremonesi, Marco / D'Adamo, Patrizia / Gilberti, Enrica / Apostoli, Pietro / Cannistraci, Carlo Vittorio / Piperno, Alberto / David, Samuel / Alessio, Massimo

EMBO molecular medicine

2017 Volume 10, Issue 1, Page(s) 91–106

Abstract: Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, ... ...

Abstract	Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin-treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin-treated CpKO mice share a similar pattern with wild-type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.
MeSH term(s)	Animals ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Ceruloplasmin/administration & dosage ; Ceruloplasmin/deficiency ; Ceruloplasmin/metabolism ; Ceruloplasmin/pharmacokinetics ; Ceruloplasmin/therapeutic use ; Enzyme Therapy ; Female ; Iron/metabolism ; Iron Metabolism Disorders/drug therapy ; Iron Metabolism Disorders/metabolism ; Iron Metabolism Disorders/pathology ; Male ; Mice, Inbred C57BL ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology
Chemical Substances	Iron (E1UOL152H7) ; Ceruloplasmin (EC 1.16.3.1)
Language	English
Publishing date	2017-11-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.201708361
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Article ; Online: Serological immune response against ADAM10 pro-domain is associated with favourable prognosis in stage III colorectal cancer patients.

Álvarez-Fernández, Sheila María / Barbariga, Marco / Cannizzaro, Luca / Cannistraci, Carlo Vittorio / Hurley, Laura / Zanardi, Alan / Conti, Antonio / Sanvito, Francesca / Innocenzi, Anna / Pecorelli, Nicolò / Braga, Marco / Alessio, Massimo

Oncotarget

2016 Volume 7, Issue 48, Page(s) 80059–80076

Abstract: A humoral immune response against aberrant tumor proteins can be elicited in cancer patients, resulting in the production of auto-antibodies (Abs). By serological proteome analysis we identified the surface membrane protein ADAM10, a metalloproteinase ... ...

Abstract	A humoral immune response against aberrant tumor proteins can be elicited in cancer patients, resulting in the production of auto-antibodies (Abs). By serological proteome analysis we identified the surface membrane protein ADAM10, a metalloproteinase that has a role in epithelial-tumor progression and invasion, as a target of the immune response in colorectal cancer (Crc). A screening carried out on the purified protein using testing cohorts of sera (Crc patients n = 57; control subjects n = 39) and validation cohorts of sera (Crc patients n = 49; control subjects n = 52) indicated that anti-ADAM10 auto-Abs were significantly induced in a large group (74%) of colon cancer patients, in particular in patients at stage II and III of the disease. Interestingly, in Crc patients classified as stage III disease, the presence of anti-ADAM10 auto-Abs in the sera was associated with a favourable follow-up with a significant shifting of the recurrence-free survival median time from 23 to 55 months. Even though the ADAM10 protein was expressed in Crc regardless the presence of auto-Abs, the immature/non-functional isoform of ADAM10 was highly expressed in the tumor of anti-ADAM10-positive patients and was the isoform targeted by the auto-Abs. In conclusion, the presence of anti-ADAM10 auto-Abs seems to reflect the increased tumor expression of the immunogenic immature-ADAM10 in a group of Crc patients, and is associated with a favourable prognosis in patients at stage III of the disease.
MeSH term(s)	ADAM10 Protein/chemistry ; ADAM10 Protein/immunology ; Adult ; Aged ; Aged, 80 and over ; Amyloid Precursor Protein Secretases/chemistry ; Amyloid Precursor Protein Secretases/immunology ; Antibody Formation/physiology ; Autoantibodies/blood ; Autoantibodies/metabolism ; Biomarkers, Tumor/blood ; Colorectal Neoplasms/blood ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/therapy ; Female ; Humans ; Male ; Membrane Proteins/chemistry ; Membrane Proteins/immunology ; Middle Aged ; Neoplasm Staging ; Prognosis ; Protein Domains/immunology ; Protein Precursors/chemistry ; Protein Precursors/immunology
Chemical Substances	Autoantibodies ; Biomarkers, Tumor ; Membrane Proteins ; Protein Precursors ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; ADAM10 Protein (EC 3.4.24.81) ; ADAM10 protein, human (EC 3.4.24.81)
Language	English
Publishing date	2016-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.11181
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Article ; Online: Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid.

Barbariga, Marco / Curnis, Flavio / Andolfo, Annapaola / Zanardi, Alan / Lazzaro, Massimo / Conti, Antonio / Magnani, Giuseppe / Volontè, Maria Antonietta / Ferrari, Laura / Comi, Giancarlo / Corti, Angelo / Alessio, Massimo

Molecular neurodegeneration

2015 Volume 10, Page(s) 59

Abstract: Background: Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson's disease (PD) contributing to the ... ...

Abstract	Background: Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson's disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function. Results: We have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the (962)NGR-motif which is usually hidden within the ceruloplasmin structure, and the gain of integrin-binding function. These effects occur owing to the presence of abnormal levels of hydrogen peroxide we detected in the CSF of PD patients. Interestingly, the pathological CSF's environment of PD patients promoted the same modifications in the exogenously added ceruloplasmin, which in turn resulted in loss of ferroxidase-activity and acquisition of integrin-binding properties. Conclusions: We show that in pathological oxidative environment of PD-CSF the endogenous ceruloplasmin, in addition to loss-of-ferroxidase function, is modified as to gain integrin-binding function. These findings, beside the known role of ceruloplasmin in iron homeostasis, might have important pathogenic implications due to the potential triggering of signals mediated by the unusual integrin binding in cells of central nervous system. Furthermore, there are pharmacological implications because, based on data obtained in murine models, the administration of ceruloplasmin has been proposed as potential therapeutic treatment of PD, however, the observed CSF's pro-oxidant properties raise the possibility that in human the ceruloplasmin-based therapeutic approach might not be efficacious.
MeSH term(s)	Aged ; Aged, 80 and over ; Central Nervous System/metabolism ; Ceruloplasmin/cerebrospinal fluid ; Female ; Humans ; Iron/cerebrospinal fluid ; Male ; Middle Aged ; Oxidation-Reduction ; Oxidative Stress ; Parkinson Disease/cerebrospinal fluid ; Reactive Oxygen Species/cerebrospinal fluid
Chemical Substances	Reactive Oxygen Species ; Iron (E1UOL152H7) ; Ceruloplasmin (EC 1.16.3.1)
Language	English
Publishing date	2015-11-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/s13024-015-0055-2
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Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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In stock of ZB MED Cologne/Königswinter

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Order via subito

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Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

Order via subito

Inter-library loan at ZB MED