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Article ; Online: Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation.

Monticelli, Maria / Hay Mele, Bruno / Wright, Demi Marie / Guerriero, Simone / Andreotti, Giuseppina / Cubellis, Maria Vittoria

Biochimie

2024 Volume 222, Page(s) 123–131

Abstract: PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of ...

Abstract	PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.
Language	English
Publishing date	2024-03-06
Publishing country	France
Document type	Journal Article
ZDB-ID	120345-9
ISSN	1638-6183 ; 0300-9084
ISSN (online)	1638-6183
ISSN	0300-9084
DOI	10.1016/j.biochi.2024.02.011
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Article ; Online: Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat.

Hay Mele, Bruno / Rossetti, Federica / Cubellis, Maria Vittoria / Monticelli, Maria / Andreotti, Giuseppina

Genes

2024 Volume 15, Issue 3

Abstract: Rare diseases, or orphan diseases, are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), a cluster of rare metabolic diseases characterized by enzyme ... ...

Abstract	Rare diseases, or orphan diseases, are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), a cluster of rare metabolic diseases characterized by enzyme mutations causing abnormal glycolipid storage. Drug repositioning involves repurposing existing approved drugs for new therapeutic applications, offering advantages in cost, time savings, and a lower risk of failure. We present a comprehensive analysis of existing drugs, their repurposing potential, and their clinical implications in the context of LSDs, highlighting the necessity of mutation-specific approaches. Our review systematically explores the landscape of drug repositioning as a means to enhance LSDs therapies. The findings advocate for the strategic repositioning of drugs, accentuating its role in expediting the discovery of effective treatments. We conclude that drug repurposing represents a viable pathway for accelerating therapeutic discovery for LSDs, emphasizing the need for the careful evaluation of drug efficacy and toxicity in disease-specific contexts.
MeSH term(s)	Humans ; Drug Repositioning ; Lysosomal Storage Diseases/drug therapy ; Lysosomal Storage Diseases/genetics ; Mutation ; Lysosomes/metabolism
Language	English
Publishing date	2024-02-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes15030290
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Article ; Online: ReBaTSA: A simplified CeTSA protocol for studying recombinant mutant proteins in bacterial extracts.

Monticelli, Maria / Wright, Demi Marie / Cubellis, Maria Vittoria / Andreotti, Giuseppina

Biochimica et biophysica acta. General subjects

2023 Volume 1868, Issue 2, Page(s) 130526

Abstract: Introduction: The study of protein stability is crucial to biochemistry and relies on different methodologies. Recently, the Cellular Thermal Shift Assay has been introduced to study protein stability in whole cells.: Methods: We report a novel ... ...

Abstract	Introduction: The study of protein stability is crucial to biochemistry and relies on different methodologies. Recently, the Cellular Thermal Shift Assay has been introduced to study protein stability in whole cells. Methods: We report a novel application of CeTSA named ReBaTSA. This Recombinant Bacterial TSA was performed using clear extracts from bacteria expressing a recombinant protein, incubated at different temperatures, centrifuged and analyzed via SDS-PAGE. Results and conclusions: We demonstrated the feasibility and reliability of this simplified approach. We validated the method using the protein phosphomannomutase-2 and its common mutants, which were compared in the presence or the absence of a known ligand.
MeSH term(s)	Bacterial Lysates ; Mutant Proteins ; Reproducibility of Results ; Protein Stability ; Recombinant Proteins/genetics
Chemical Substances	Bacterial Lysates ; Mutant Proteins ; Recombinant Proteins
Language	English
Publishing date	2023-12-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagen.2023.130526
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Article ; Online: Congenital disorders of glycosylation: narration of a story through its patents.

Monticelli, Maria / D'Onofrio, Tania / Jaeken, Jaak / Morava, Eva / Andreotti, Giuseppina / Cubellis, Maria Vittoria

Orphanet journal of rare diseases

2023 Volume 18, Issue 1, Page(s) 247

Abstract: Congenital disorders of glycosylation are a group of more than 160 rare genetic defects in protein and lipid glycosylation. Since the first clinical report in 1980 of PMM2-CDG, the most common CDG worldwide, research made great strides, but nearly all of ...

Abstract	Congenital disorders of glycosylation are a group of more than 160 rare genetic defects in protein and lipid glycosylation. Since the first clinical report in 1980 of PMM2-CDG, the most common CDG worldwide, research made great strides, but nearly all of them are still missing a cure. CDG diagnosis has been at a rapid pace since the introduction of whole-exome/whole-genome sequencing as a diagnostic tool. Here, we retrace the history of CDG by analyzing all the patents associated with the topic. To this end, we explored the Espacenet database, extracted a list of patents, and then divided them into three major groups: (1) Drugs/therapeutic approaches for CDG, (2) Drug delivery tools for CDG, (3) Diagnostic tools for CDG. Despite the enormous scientific progress experienced in the last 30 years, diagnostic tools, drugs, and biomarkers are still urgently needed.
MeSH term(s)	Humans ; Glycosylation ; Narration ; Congenital Disorders of Glycosylation/diagnosis ; Congenital Disorders of Glycosylation/genetics ; Databases, Factual ; Exome
Language	English
Publishing date	2023-08-29
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/s13023-023-02852-w
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Article ; Online: Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease.

Monticelli, Maria / Hay Mele, Bruno / Allocca, Mariateresa / Liguori, Ludovica / Lukas, Jan / Monti, Maria Chiara / Morretta, Elva / Cubellis, Maria Vittoria / Andreotti, Giuseppina

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: Fabry disease is a lysosomal storage disease caused by mutations in ... ...

Abstract	Fabry disease is a lysosomal storage disease caused by mutations in the
MeSH term(s)	Humans ; Fabry Disease/drug therapy ; Fabry Disease/genetics ; alpha-Galactosidase/metabolism ; Curcumin/pharmacology ; Curcumin/therapeutic use ; Curcumin/metabolism ; Galactose/metabolism ; Mutation ; Lysosomes/metabolism ; 1-Deoxynojirimycin/pharmacology ; 1-Deoxynojirimycin/therapeutic use
Chemical Substances	alpha-Galactosidase (EC 3.2.1.22) ; Curcumin (IT942ZTH98) ; Galactose (X2RN3Q8DNE) ; 1-Deoxynojirimycin (19130-96-2)
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/ijms24021095
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Article ; Online: Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy.

Iacobucci, Ilaria / Hay Mele, Bruno / Cozzolino, Flora / Monaco, Vittoria / Cimmaruta, Chiara / Monti, Maria / Andreotti, Giuseppina / Monticelli, Maria

International journal of molecular sciences

2023 Volume 24, Issue 5

Abstract: Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its ... ...

Abstract	Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy.
MeSH term(s)	Humans ; Fabry Disease/metabolism ; alpha-Galactosidase/metabolism ; Enzyme Replacement Therapy/methods ; Isoenzymes/therapeutic use ; Recombinant Proteins/therapeutic use
Chemical Substances	alpha-Galactosidase (EC 3.2.1.22) ; Isoenzymes ; Recombinant Proteins
Language	English
Publishing date	2023-02-25
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/ijms24054548
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Article ; Online: Enzyme Replacement Therapy for FABRY Disease

Ilaria Iacobucci / Bruno Hay Mele / Flora Cozzolino / Vittoria Monaco / Chiara Cimmaruta / Maria Monti / Giuseppina Andreotti / Maria Monticelli

International Journal of Molecular Sciences, Vol 24, Iss 4548, p

Possible Strategies to Improve Its Efficacy

2023 Volume 4548

Abstract	Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy.
Keywords	Fabry disease ; drug repositioning ; interactome ; GLA ; Fabrazyme ; Replagal ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Why does SARS-CoV-2 hit in different ways? Host genetic factors can influence the acquisition or the course of COVID-19.

Monticelli, Maria / Mele, Bruno Hay / Andreotti, Giuseppina / Cubellis, Maria Vittoria / Riccio, Guglielmo

European journal of medical genetics

2021 Volume 64, Issue 6, Page(s) 104227

Abstract: The identification of high-risk factors for the infection by SARS-CoV-2 and the negative outcome of COVID-19 is crucial. The genetic background of the host might account for individual responses to SARS-CoV-2 infection besides age and comorbidities. A ... ...

Abstract	The identification of high-risk factors for the infection by SARS-CoV-2 and the negative outcome of COVID-19 is crucial. The genetic background of the host might account for individual responses to SARS-CoV-2 infection besides age and comorbidities. A list of candidate polymorphisms is needed to drive targeted screens, given the existence of frequent polymorphisms in the general population. We carried out text mining in the scientific literature to draw up a list of genes referable to the term "SARS-CoV*". We looked for frequent mutations that are likely to affect protein function in these genes. Ten genes, mostly involved in innate immunity, and thirteen common variants were identified, for some of these the involvement in COVID-19 is supported by publicly available epidemiological data. We looked for available data on the population distribution of these variants and we demonstrated that the prevalence of five of them, Arg52Cys (rs5030737), Gly54Asp (rs1800450) and Gly57Glu (rs1800451) in MBL2, Ala59Thr (rs25680) in CD27, and Val197Met (rs12329760) in TMPRSS2, correlates with the number of cases and/or deaths of COVID-19 observed in different countries. The association of the TMPRSS2 variant provides epidemiological evidence of the usefulness of transmembrane protease serine 2 inhibitors for the cure of COVID-19. The identified genetic variants represent a basis for the design of a cost-effective assay for population screening of genetic risk factors in the COVID-19 pandemic.
MeSH term(s)	COVID-19/genetics ; COVID-19/immunology ; Data Mining ; Gene Frequency ; Genetic Predisposition to Disease ; Genetic Variation ; Host Microbial Interactions ; Humans ; Immunity, Innate ; Mannose-Binding Lectin/genetics ; Mannose-Binding Lectin/immunology ; Polymorphism, Single Nucleotide ; Risk Factors ; SARS-CoV-2/pathogenicity ; Serine Endopeptidases/genetics ; Serine Endopeptidases/immunology ; Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics ; Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
Chemical Substances	MBL2 protein, human ; Mannose-Binding Lectin ; Tumor Necrosis Factor Receptor Superfamily, Member 7 ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2021-04-16
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2184135-4
ISSN	1878-0849 ; 1769-7212
ISSN (online)	1878-0849
ISSN	1769-7212
DOI	10.1016/j.ejmg.2021.104227
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Article ; Online: Evolutionary rescue of phosphomannomutase deficiency in yeast models of human disease.

Vignogna, Ryan C / Allocca, Mariateresa / Monticelli, Maria / Norris, Joy W / Steet, Richard / Perlstein, Ethan O / Andreotti, Giuseppina / Lang, Gregory I

eLife

2022 Volume 11

Abstract: The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene ... PMM2, ... which affect protein ... N ... -linked glycosylation. The yeast gene ... SEC53 ... encodes a homolog of human ... PMM2 ... ... ...

Abstract	The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease-associated alleles.
MeSH term(s)	Humans ; Saccharomyces cerevisiae/genetics ; Congenital Disorders of Glycosylation/genetics ; Congenital Disorders of Glycosylation/metabolism ; Phosphoglucomutase/genetics ; Mutant Proteins ; Saccharomyces cerevisiae Proteins/genetics
Chemical Substances	phosphomannomutase (EC 5.4.2.8) ; Phosphoglucomutase (EC 5.4.2.2) ; Mutant Proteins ; SEC53 protein, S cerevisiae (EC 5.4.2.8) ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2022-10-10
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.79346
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Article ; Online: Drug Repositioning for Fabry Disease: Acetylsalicylic Acid Potentiates the Stabilization of Lysosomal Alpha-Galactosidase by Pharmacological Chaperones.

Monticelli, Maria / Liguori, Ludovica / Allocca, Mariateresa / Bosso, Andrea / Andreotti, Giuseppina / Lukas, Jan / Monti, Maria Chiara / Morretta, Elva / Cubellis, Maria Vittoria / Hay Mele, Bruno

International journal of molecular sciences

2022 Volume 23, Issue 9

Abstract: Fabry disease is caused by a deficiency of lysosomal alpha galactosidase and has a very large genotypic and phenotypic spectrum. Some patients who carry hypomorphic mutations can benefit from oral therapy with a pharmacological chaperone. The drug ... ...

Abstract	Fabry disease is caused by a deficiency of lysosomal alpha galactosidase and has a very large genotypic and phenotypic spectrum. Some patients who carry hypomorphic mutations can benefit from oral therapy with a pharmacological chaperone. The drug requires a very precise regimen because it is a reversible inhibitor of alpha-galactosidase. We looked for molecules that can potentiate this pharmacological chaperone, among drugs that have already been approved for other diseases. We tested candidate molecules in fibroblasts derived from a patient carrying a large deletion in the gene
MeSH term(s)	1-Deoxynojirimycin/pharmacology ; 1-Deoxynojirimycin/therapeutic use ; Aspirin/pharmacology ; Aspirin/therapeutic use ; Drug Repositioning ; Fabry Disease/drug therapy ; Fabry Disease/genetics ; Humans ; Lysosomes ; Molecular Chaperones/genetics ; Mutation ; alpha-Galactosidase/genetics ; alpha-Galactosidase/therapeutic use
Chemical Substances	Molecular Chaperones ; 1-Deoxynojirimycin (19130-96-2) ; alpha-Galactosidase (EC 3.2.1.22) ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	2022-05-04
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/ijms23095105
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