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Article ; Online: Compensational role between cathepsins.

Pečar Fonović, Urša / Kos, Janko / Mitrović, Ana

2024

Abstract: Cathepsins, a family of lysosomal peptidases, play a crucial role in maintaining cellular homeostasis by regulating protein turnover and degradation as well as many specific regulatory actions that are important for proper cell function and human health. ...

Abstract	Cathepsins, a family of lysosomal peptidases, play a crucial role in maintaining cellular homeostasis by regulating protein turnover and degradation as well as many specific regulatory actions that are important for proper cell function and human health. Alterations in the activity and expression of cathepsins have been observed in many diseases such as cancer, inflammation, neurodegenerative disorders, bone remodelling-related conditions and others. These changes are not exclusively harmful, but rather appear to be a compensatory response on the lack of one cathepsin in order to maintain tissue integrity. The upregulation of specific cathepsins in response to the inhibition or dysfunction of other cathepsins suggests a fine-tuned system of proteolytic balance and understanding the compensatory role of cathepsins may improve therapeutic potential of cathepsin's inhibitors. Selectively targeting one cathepsin or modulating their activity could offer new treatment strategies for a number of diseases. This review emphasises the need for comprehensive research into cathepsin biology in the context of disease. The identification of the specific cathepsins involved in compensatory responses, the elucidation of the underlying molecular mechanisms and the development of targeted interventions could lead to innovative therapeutic approaches.
Language	English
Publishing date	2024-04-23
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	120345-9
ISSN	1638-6183 ; 0300-9084
ISSN (online)	1638-6183
ISSN	0300-9084
DOI	10.1016/j.biochi.2024.04.010
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Article: Editorial: Peptidases as a therapeutic target in anti-cancer management.

Mitrović, Ana / Burden, Roberta E / Softič, Adaleta / Kavčič, Nežka

Frontiers in pharmacology

2024 Volume 15, Page(s) 1394018

Language	English
Publishing date	2024-04-11
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2024.1394018
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Article ; Online: Lysosomal peptidases-intriguing roles in cancer progression and neurodegeneration.

Kos, Janko / Mitrović, Ana / Perišić Nanut, Milica / Pišlar, Anja

FEBS open bio

2022 Volume 12, Issue 4, Page(s) 708–738

Abstract: Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and ... ...

Abstract	Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.
MeSH term(s)	Apoptosis/physiology ; Humans ; Lysosomes/metabolism ; Neoplasms ; Neoplastic Processes ; Peptide Hydrolases/metabolism
Chemical Substances	Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2022-02-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2651702-4
ISSN	2211-5463 ; 2211-5463
ISSN (online)	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.13372
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Article ; Online: Nitroxoline: repurposing its antimicrobial to antitumor application.

Mitrović, Ana / Kos, Janko

Acta biochimica Polonica

2019 Volume 66, Issue 4, Page(s) 521–531

Abstract: Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to ... ...

Abstract	Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to improve therapy, prolong survival of cancer patients and improve their quality of life. The high cost of development and clinical evaluation of new drugs limits the number that actually enter clinical use. To overcome this problem, repurposing of established drugs for new indications has gained a lot of interest, especially in the field of oncology. The well-established antimicrobial agent nitroxoline has been identified as a promising candidate to be repurposed for cancer treatment in several independent studies. Here we have reviewed a wide range of molecular mechanisms and tumor models involving nitroxoline in impairment of tumor progression. Furthermore, nitroxoline was used as a lead compound for structure-based chemical synthesis of new derivatives in order to improve its potency as well as selectivity for various targets. The potent antitumor activity of nitroxoline points strongly in the direction of its repurposing for cancer treatment and to the benefits of this strategy for patients and healthcare system.
MeSH term(s)	Anti-Infective Agents/therapeutic use ; Carcinogenesis/drug effects ; Cell Proliferation/drug effects ; Drug Repositioning ; Humans ; Neoplasms/drug therapy ; Nitroquinolines/therapeutic use
Chemical Substances	Anti-Infective Agents ; Nitroquinolines ; nitroxoline (A8M33244M6)
Language	English
Publishing date	2019-12-13
Publishing country	Poland
Document type	Journal Article ; Review
ZDB-ID	595762-x
ISSN	1734-154X ; 0001-527X
ISSN (online)	1734-154X
ISSN	0001-527X
DOI	10.18388/abp.2019_2904
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Article: Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

Kos, Janko / Mitrović, Ana / Perišić Nanut, Milica / Pišlar, Anja

FEBS Open Bio. 2022 Apr., v. 12, no. 4

2022

Abstract	Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.
Keywords	apoptosis ; autophagy ; cell communication ; endocytosis ; extracellular space ; lysosomes ; metastasis ; mitochondria ; neoplasm progression ; neoplasms ; neurodegenerative diseases ; neurons ; oxidative stress ; peptidases ; plasma membrane ; protein metabolism ; secretion
Language	English
Dates of publication	2022-04
Size	p. 708-738.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	2651702-4
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.13372
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Article ; Online: Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection.

Milan Bonotto, Rafaela / Mitrović, Ana / Sosič, Izidor / Martínez-Orellana, Pamela / Dattola, Federica / Gobec, Stanislav / Kos, Janko / Marcello, Alessandro

Antiviral research

2023 Volume 216, Page(s) 105655

Abstract: The severity of the SARS-CoV-2 pandemic and the recurring (re)emergence of viruses prompted the development of new therapeutic approaches that target viral and host factors crucial for viral infection. Among them, host peptidases cathepsins B and L have ... ...

Abstract	The severity of the SARS-CoV-2 pandemic and the recurring (re)emergence of viruses prompted the development of new therapeutic approaches that target viral and host factors crucial for viral infection. Among them, host peptidases cathepsins B and L have been described as essential enzymes during SARS-CoV-2 entry. In this study, we evaluated the effect of potent selective cathepsin inhibitors as antiviral agents. We demonstrated that selective cathepsin B inhibitors, such as the antimicrobial agent nitroxoline and its derivatives, impair SARS-CoV-2 infection in vitro. Antiviral activity observed at early stage of virus entry was cell-type dependent and correlated well with the intracellular content and enzymatic function of cathepsins B or L. Furthermore, tested inhibitors were effective against the ancestral SARS-CoV-2 D614 as well as against the more recent BA.1_4 (Omicron). Taken together, our results highlight the important role of host cysteine cathepsin B in SARS-CoV-2 virus entry and show that cathepsin-specific inhibitors, such as nitroxoline and its derivatives, could be used to treat COVID-19. Finally, these results also suggest that nitroxoline has potential to be further explored as repurposed drug in antiviral therapy.
MeSH term(s)	Humans ; COVID-19 ; Cathepsin B/pharmacology ; SARS-CoV-2 ; Antiviral Agents/pharmacology ; Virus Internalization
Chemical Substances	Cathepsin B (EC 3.4.22.1) ; nitroxoline (A8M33244M6) ; Antiviral Agents
Language	English
Publishing date	2023-06-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2023.105655
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Article ; Online: Targeting of fluorescent Lactococcus lactis to colorectal cancer cells through surface display of tumour-antigen binding proteins.

Plavec, Tina Vida / Mitrović, Ana / Perišić Nanut, Milica / Štrukelj, Borut / Kos, Janko / Berlec, Aleš

Microbial biotechnology

2021 Volume 14, Issue 5, Page(s) 2227–2240

Abstract: Development of targeted treatment for colorectal cancer is crucial to avoid side effects. To harness the possibilities offered by microbiome engineering, we prepared safe multifunctional cancer cell-targeting bacteria Lactococcus lactis. They displayed, ... ...

Abstract	Development of targeted treatment for colorectal cancer is crucial to avoid side effects. To harness the possibilities offered by microbiome engineering, we prepared safe multifunctional cancer cell-targeting bacteria Lactococcus lactis. They displayed, on their surface, binding proteins for cancer-associated transmembrane receptors epithelial cell adhesion molecule (EpCAM) and human epidermal growth factor receptor 2 (HER2) and co-expressed an infrared fluorescent protein for imaging. Binding of engineered L. lactis to tumour antigens EpCAM and HER2 was confirmed and characterised in vitro using soluble receptors. The proof-of-principle of targeting was demonstrated on human cell lines HEK293, HT-29 and Caco-2 with fluorescent microscopy and flow cytometry. The highest L. lactis adhesion was seen for the HEK293 cells with the overexpressed tumour antigens, where colocalisation with their tumour antigens was seen for 39% and 67% of EpCAM-targeting and HER2-targeting bacteria, respectively. On the other hand, no binding was observed to HEK293 cells without tumour antigens, confirming the selectivity of the engineered L. lactis. Apart from cell targeting in static conditions, targeting ability of engineered L. lactis was also shown in conditions of constant flow of bacterial suspension over the HEK293 cells. Successful targeting by engineered L. lactis support the future use of these bacteria in biopharmaceutical delivery for the treatment of colorectal cancer.
MeSH term(s)	Antigens, Neoplasm/genetics ; Caco-2 Cells ; Carrier Proteins ; Colorectal Neoplasms/therapy ; HEK293 Cells ; Humans ; Lactococcus lactis/genetics
Chemical Substances	Antigens, Neoplasm ; Carrier Proteins
Language	English
Publishing date	2021-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2406063-X
ISSN	1751-7915 ; 1751-7915
ISSN (online)	1751-7915
ISSN	1751-7915
DOI	10.1111/1751-7915.13907
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Article: New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity.

Mitrović, Ana / Senjor, Emanuela / Jukić, Marko / Bolčina, Lara / Prunk, Mateja / Proj, Matic / Nanut, Milica Perišić / Gobec, Stanislav / Kos, Janko

Computational and structural biotechnology journal

2022 Volume 20, Page(s) 4667–4687

Abstract: Cathepsin V is a human lysosomal cysteine peptidase with specific functions during pathological processes and is as such a promising therapeutic target. Peptidase inhibitors represent powerful pharmacological tools for regulating excessive proteolytic ... ...

Abstract	Cathepsin V is a human lysosomal cysteine peptidase with specific functions during pathological processes and is as such a promising therapeutic target. Peptidase inhibitors represent powerful pharmacological tools for regulating excessive proteolytic activity in various diseases. Cathepsin V is highly related to cathepsin L but differs in tissue distribution, binding site morphology, substrate specificity, and function. To validate its therapeutic potential and extend the number of potent and selective cathepsin V inhibitors, we used virtual high-throughput screening of commercially available compound libraries followed by an evaluation of kinetic properties to identify novel potent and selective cathepsin V inhibitors. We identified the ureido methylpiperidine carboxylate derivative, compound
Language	English
Publishing date	2022-08-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.08.046
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Article: New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Mitrović, Ana / Senjor, Emanuela / Jukić, Marko / Bolčina, Lara / Prunk, Mateja / Proj, Matic / Nanut, Milica Perišić / Gobec, Stanislav / Kos, Janko

Computational and Structural Biotechnology Journal. 2022 Aug. 20,

2022

Abstract	Cathepsin V is a human lysosomal cysteine peptidase with specific functions during pathological processes and is as such a promising therapeutic target. Peptidase inhibitors represent powerful pharmacological tools for regulating excessive proteolytic activity in various diseases. Cathepsin V is highly related to cathepsin L but differs in tissue distribution, binding site morphology, substrate specificity, and function. To validate its therapeutic potential and extend the number of potent and selective cathepsin V inhibitors, we used virtual high-throughput screening of commercially available compound libraries followed by an evaluation of kinetic properties to identify novel potent and selective cathepsin V inhibitors. We identified the ureido methylpiperidine carboxylate derivative, compound 7, as a reversible, selective, and potent inhibitor of cathepsin V. It also exhibited the most preferable characteristics for further evaluation with in vitro functional assays that simulate the processes in which cathepsin V is known to play an important role. Compound 7 exerted significant effects on cell proliferation, elastin degradation, and immune cell cytotoxicity. The latter was increased because compound 7 impaired conversion of immunosuppressive factor cystatin F to its active monomeric form. Taken together, our results present novel potent inhibitors of cathepsin V and provide new hit compounds for detailed development and optimization. Further, we demonstrate that cathepsin V is a potential target for new approaches to cancer therapy.
Keywords	biotechnology ; cancer therapy ; cathepsin L ; cathepsin V ; cell proliferation ; cysteine ; cytotoxicity ; elastin ; humans ; immunosuppression ; neoplasm cells ; proteolysis ; substrate specificity ; tissue distribution
Language	English
Dates of publication	2022-0820
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.08.046
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy

Mitrović, Ana / Završnik, Janja / Mikhaylov, Georgy / Knez, Damijan / Pečar Fonović, Urša / Matjan Štefin, Petra / Butinar, Miha / Gobec, Stanislav / Turk, Boris / Kos, Janko

Cell. Mol. Life Sci.. 2022 Jan., v. 79, no. 1 p.34-34

2022

Abstract: New therapeutic targets that could improve current antitumor therapy and overcome cancer resistance are urgently needed. Promising candidates are lysosomal cysteine cathepsins, proteolytical enzymes involved in various critical steps during cancer ... ...

Abstract	New therapeutic targets that could improve current antitumor therapy and overcome cancer resistance are urgently needed. Promising candidates are lysosomal cysteine cathepsins, proteolytical enzymes involved in various critical steps during cancer progression. Among them, cathepsin X, which acts solely as a carboxypeptidase, has received much attention. Our results indicate that the triazole-based selective reversible inhibitor of cathepsin X named Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) significantly reduces tumor progression, both in vitro in cell-based functional assays and in vivo in two independent tumor mouse models: the FVB/PyMT transgenic and MMTV-PyMT orthotopic breast cancer mouse models. One of the mechanisms by which cathepsin X contributes to cancer progression is the compensation of cathepsin-B activity loss. Our results confirm that cathepsin-B inhibition is compensated by an increase in cathepsin X activity and protein levels. Furthermore, the simultaneous inhibition of both cathepsins B and X with potent, selective, reversible inhibitors exerted a synergistic effect in impairing processes of tumor progression in in vitro cell-based assays of tumor cell migration and spheroid growth. Taken together, our data demonstrate that Z9 impairs tumor progression both in vitro and in vivo and can be used in combination with other peptidase inhibitors as an innovative approach to overcome resistance to antipeptidase therapy.
Keywords	breast neoplasms ; cancer therapy ; cathepsin B ; cathepsin X ; cell movement ; cysteine ; genetically modified organisms ; mice ; neoplasm cells ; neoplasm progression ; synergism
Language	English
Dates of publication	2022-01
Size	p. 34.
Publishing place	Springer International Publishing
Document type	Article ; Online
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-021-04117-w
Database	NAL-Catalogue (AGRICOLA)

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