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Article: Modular Nanotransporters Delivering Biologically Active Molecules to the Surface of Mitochondria.

Khramtsov, Yuri V / Ulasov, Alexey V / Slastnikova, Tatiana A / Rosenkranz, Andrey A / Lupanova, Tatiana N / Georgiev, Georgii P / Sobolev, Alexander S

Pharmaceutics

2023 Volume 15, Issue 12

Abstract: Treatment of various diseases, in particular cancer, usually requires the targeting of biologically active molecules at a selected subcellular compartment. We modified our previously developed modular nanotransporters (MNTs) for targeting mitochondria. ... ...

Abstract	Treatment of various diseases, in particular cancer, usually requires the targeting of biologically active molecules at a selected subcellular compartment. We modified our previously developed modular nanotransporters (MNTs) for targeting mitochondria. The new MNTs are capable of binding to the protein predominantly localized on the outer mitochondrial membrane, Keap1. These MNTs possessing antiKeap1 monobody co-localize with mitochondria upon addition to the cells. They efficiently interact with Keap1 both in solution and within living cells. A conjugate of the MNT with a photosensitizer, chlorin
Language	English
Publishing date	2023-11-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15122687
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Intracellular Degradation of SARS-CoV-2 N-Protein Caused by Modular Nanotransporters Containing Anti-N-Protein Monobody and a Sequence That Recruits the Keap1 E3 Ligase.

Khramtsov, Yuri V / Ulasov, Alexey V / Lupanova, Tatiana N / Slastnikova, Tatiana A / Rosenkranz, Andrey A / Bunin, Egor S / Georgiev, Georgii P / Sobolev, Alexander S

Pharmaceutics

2023 Volume 16, Issue 1

Abstract: The proper viral assembly relies on both nucleic acids and structural viral proteins. Thus a biologically active agent that provides the degradation of one of these key proteins and/or destroys the viral factory could suppress viral replication ... ...

Abstract	The proper viral assembly relies on both nucleic acids and structural viral proteins. Thus a biologically active agent that provides the degradation of one of these key proteins and/or destroys the viral factory could suppress viral replication efficiently. The nucleocapsid protein (N-protein) is a key protein for the SARS-CoV-2 virus. As a bioactive agent, we offer a modular nanotransporter (MNT) developed by us, which, in addition to an antibody mimetic to the N-protein, contains an amino acid sequence for the attraction of the Keap1 E3 ubiquitin ligase. This should lead to the subsequent degradation of the N-protein. We have shown that the functional properties of modules within the MNT permit its internalization into target cells, endosome escape into the cytosol, and binding to the N-protein. Using flow cytometry and western blotting, we demonstrated significant degradation of N-protein when A549 and A431 cells transfected with a plasmid coding for N-protein were incubated with the developed MNTs. The proposed MNTs open up a new approach for the treatment of viral diseases.
Language	English
Publishing date	2023-12-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics16010004
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Article: Nrf2/Keap1/ARE signaling: Towards specific regulation

Ulasov, Alexey V. / Rosenkranz, Andrey A. / Georgiev, Georgii P. / Sobolev, Alexander S.

Life sciences. 2022 Feb. 15, v. 291

2022

Abstract: The Nrf2 transcription factor governs the expression of hundreds genes involved in cell defense against oxidative stress, the hallmark of numerous diseases such as neurodegenerative, cardiovascular, some viral pathologies, diabetes and others. The main ... ...

Abstract	The Nrf2 transcription factor governs the expression of hundreds genes involved in cell defense against oxidative stress, the hallmark of numerous diseases such as neurodegenerative, cardiovascular, some viral pathologies, diabetes and others. The main route for Nrf2 activity regulation is via interactions with the Keap1 protein. Under the normoxia the Keap1 binds the Nrf2 and targets it to the proteasomal degradation, while the Keap1 is regenerated. Upon oxidative stress the interactions between Nrf2 and Keap1 are interrupted and the Nrf2 activates the transcription of the protective genes. Currently, the Nrf2 system activation is considered as a powerful cytoprotective strategy for treatment of different pathologies, which pathogenesis relies on oxidative stress including viral diseases of pivotal importance such as COVID-19. The implementation of this strategy is accomplished mainly through the inactivation of the Keap1 “guardian” function. Two approaches are now developing: the Keap1 modification via electrophilic agents, which leads to the Nrf2 release, and direct interruption of the Nrf2:Keap1 protein-protein interactions (PPI). Because of theirs chemical structure, the Nrf2 electrophilic inducers could non-specifically interact with others cellular proteins leading to undesired effects. Whereas the non-electrophilic inhibitors of the Nrf2:Keap1 PPI could be more specific, thereby widening the therapeutic window.
Keywords	COVID-19 infection ; Lewis acids ; chemical structure ; diabetes ; normoxia ; oxidative stress ; pathogenesis ; therapeutics ; transcription factors
Language	English
Dates of publication	2022-0215
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.2021.120111
Database	NAL-Catalogue (AGRICOLA)

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Article: An Approach to Evaluate the Effective Cytoplasmic Concentration of Bioactive Agents Interacting with a Selected Intracellular Target Protein.

Khramtsov, Yuri V / Ulasov, Alexey V / Rosenkranz, Andrey A / Slastnikova, Tatiana A / Lupanova, Tatiana N / Georgiev, Georgii P / Sobolev, Alexander S

Pharmaceutics

2023 Volume 15, Issue 2

Abstract: To compare the effectiveness of various bioactive agents reversibly acting within a cell on a target intracellular macromolecule, it is necessary to assess effective cytoplasmic concentrations of the delivered bioactive agents. In this work, based on a ... ...

Abstract	To compare the effectiveness of various bioactive agents reversibly acting within a cell on a target intracellular macromolecule, it is necessary to assess effective cytoplasmic concentrations of the delivered bioactive agents. In this work, based on a simple equilibrium model and the cellular thermal shift assay (CETSA), an approach is proposed to assess effective concentrations of both a delivered bioactive agent and a target protein. This approach was tested by evaluating the average concentrations of nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated-protein 1 (Keap1) proteins in the cytoplasm for five different cell lines (Hepa1, MEF, RAW264.7, 3LL, and AML12) and comparing the results with known literature data. The proposed approach makes it possible to analyze both binary interactions and ternary competition systems; thus, it can have a wide application for the analysis of protein-protein or molecule-protein interactions in the cell. The concentrations of Nrf2 and Keap1 in the cell can be useful not only in analyzing the conditions for the activation of the Nrf2 system, but also for comparing the effectiveness of various drug delivery systems, where the delivered molecule is able to interact with Keap1.
Language	English
Publishing date	2023-01-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15020324
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Article ; Online: Nrf2/Keap1/ARE signaling: Towards specific regulation.

Ulasov, Alexey V / Rosenkranz, Andrey A / Georgiev, Georgii P / Sobolev, Alexander S

Life sciences

2021 Volume 291, Page(s) 120111

Abstract	The Nrf2 transcription factor governs the expression of hundreds genes involved in cell defense against oxidative stress, the hallmark of numerous diseases such as neurodegenerative, cardiovascular, some viral pathologies, diabetes and others. The main route for Nrf2 activity regulation is via interactions with the Keap1 protein. Under the normoxia the Keap1 binds the Nrf2 and targets it to the proteasomal degradation, while the Keap1 is regenerated. Upon oxidative stress the interactions between Nrf2 and Keap1 are interrupted and the Nrf2 activates the transcription of the protective genes. Currently, the Nrf2 system activation is considered as a powerful cytoprotective strategy for treatment of different pathologies, which pathogenesis relies on oxidative stress including viral diseases of pivotal importance such as COVID-19. The implementation of this strategy is accomplished mainly through the inactivation of the Keap1 "guardian" function. Two approaches are now developing: the Keap1 modification via electrophilic agents, which leads to the Nrf2 release, and direct interruption of the Nrf2:Keap1 protein-protein interactions (PPI). Because of theirs chemical structure, the Nrf2 electrophilic inducers could non-specifically interact with others cellular proteins leading to undesired effects. Whereas the non-electrophilic inhibitors of the Nrf2:Keap1 PPI could be more specific, thereby widening the therapeutic window.
MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; Animals ; Antioxidant Response Elements/physiology ; COVID-19/metabolism ; Host-Pathogen Interactions/physiology ; Humans ; Kelch-Like ECH-Associated Protein 1/metabolism ; Molecular Targeted Therapy/methods ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Ozone/therapeutic use ; Protein Interaction Maps/drug effects ; Signal Transduction ; COVID-19 Drug Treatment
Chemical Substances	KEAP1 protein, human ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; Ozone (66H7ZZK23N) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-10-31
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2021.120111
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Article: Mouse Syngeneic Melanoma Model with Human Epidermal Growth Factor Receptor Expression.

Slastnikova, Tatiana A / Rosenkranz, Andrey A / Ulasov, Alexey V / Khramtsov, Yuri V / Lupanova, Tatiana N / Georgiev, Georgii P / Sobolev, Alexander S

Pharmaceutics

2022 Volume 14, Issue 11

Abstract: The development of epidermal growth factor receptor (EGFR)-targeting agents for the treatment of malignant melanoma requires cheap and easy animal tumor models for high-throughput in vivo screening. Thus, the aim of this study was to develop mouse ... ...

Abstract	The development of epidermal growth factor receptor (EGFR)-targeting agents for the treatment of malignant melanoma requires cheap and easy animal tumor models for high-throughput in vivo screening. Thus, the aim of this study was to develop mouse syngeneic melanoma model that expresses human EGFR. Cloudman S91 clone M3 mouse melanoma cells were transduced with lentiviral particles carrying the human EGFR gene followed by a multistep selection process. The resulting M3-EGFR has been tested for EGFR expression and functionality in vitro and in vivo. Radioligand assay confirmed the presence of 13,900 ± 1500 EGF binding sites per cell at a dissociation constant of 5.3 ± 1.4 nM. M3-EGFR demonstrated the ability to bind and internalize specifically and provide the anticipated intracellular nuclear import of three different EGFR-targeted modular nanotransporters designed for specific anti-cancer drug delivery. Introduction of the human EGFR gene did not alter the tumorigenicity of the offspring M3-EGFR cells in host immunocompetent DBA/2J mice. Preservation of the expression of EGFR in vivo was confirmed by immunohistochemistry. To sum up, we successfully developed the first mouse syngeneic melanoma model with preserved in vivo expression of human EGFR.
Language	English
Publishing date	2022-11-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14112448
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Article ; Online: Transcription factors: Time to deliver.

Ulasov, Alexey V / Rosenkranz, Andrey A / Sobolev, Alexander S

Journal of controlled release : official journal of the Controlled Release Society

2017 Volume 269, Page(s) 24–35

Abstract: Transcription factors (TFs) are at the center of the broad regulatory network orchestrating gene expression programs that elicit different biological responses. For a long time, TFs have been considered as potent drug targets due to their implications in ...

Abstract	Transcription factors (TFs) are at the center of the broad regulatory network orchestrating gene expression programs that elicit different biological responses. For a long time, TFs have been considered as potent drug targets due to their implications in the pathogenesis of a variety of diseases. At the same time, TFs, located at convergence points of cellular regulatory pathways, are powerful tools providing opportunities both for cell type change and for managing the state of cells. This task formulation requires the TF modulation problem to come to the fore. We review several ways to manage TF activity (small molecules, transfection, nanocarriers, protein-based approaches), analyzing their limitations and the possibilities to overcome them. Delivery of TFs could revolutionize the biomedical field. Whether this forecast comes true will depend on the ability to develop convenient technologies for targeted delivery of TFs.
MeSH term(s)	Animals ; Cell Transdifferentiation ; DNA ; Drug Delivery Systems ; Humans ; Pluripotent Stem Cells ; RNA ; Transcription Factors/administration & dosage ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors ; RNA (63231-63-0) ; DNA (9007-49-2)
Language	English
Publishing date	2017-11-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2017.11.004
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Article: Targeted Delivery of

Karyagina, Tatiana S / Ulasov, Alexey V / Slastnikova, Tatiana A / Rosenkranz, Andrey A / Lupanova, Tatiana N / Khramtsov, Yuri V / Georgiev, Georgii P / Sobolev, Alexander S

Frontiers in pharmacology

2020 Volume 11, Page(s) 176

Abstract: Since cell nucleus is one of the most vulnerable compartments, the maximum therapeutic effect from a variety of locally acting agents, such as photosensitizers, alfa-emitters, Auger electron emitters, will be expected when they get there. Therefore, the ... ...

Abstract	Since cell nucleus is one of the most vulnerable compartments, the maximum therapeutic effect from a variety of locally acting agents, such as photosensitizers, alfa-emitters, Auger electron emitters, will be expected when they get there. Therefore, the targeted delivery of these agents into the nuclei of target tumor cells is necessary for their anticancer effects and minimization of side effects. Modular nanotransporters (MNT) are artificial polypeptides comprising several predefined modules that recognize target cell, launching their subsequent internalization, escape from endosomes, and transport the drug load to the nucleus. This technology significantly enhances the cytotoxicity of locally acting drugs
Language	English
Publishing date	2020-03-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2020.00176
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Article: Transcription factors: Time to deliver

Ulasov, Alexey V / Alexander S. Sobolev / Andrey A. Rosenkranz

Journal of controlled release. 2018 Jan. 10, v. 269

2018

Abstract	Transcription factors (TFs) are at the center of the broad regulatory network orchestrating gene expression programs that elicit different biological responses. For a long time, TFs have been considered as potent drug targets due to their implications in the pathogenesis of a variety of diseases. At the same time, TFs, located at convergence points of cellular regulatory pathways, are powerful tools providing opportunities both for cell type change and for managing the state of cells. This task formulation requires the TF modulation problem to come to the fore. We review several ways to manage TF activity (small molecules, transfection, nanocarriers, protein-based approaches), analyzing their limitations and the possibilities to overcome them. Delivery of TFs could revolutionize the biomedical field. Whether this forecast comes true will depend on the ability to develop convenient technologies for targeted delivery of TFs.
Keywords	drugs ; gene expression ; nanocarriers ; pathogenesis ; transcription (genetics) ; transcription factors ; transfection
Language	English
Dates of publication	2018-0110
Size	p. 24-35.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2017.11.004
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Article ; Online: Low-resolution structures of modular nanotransporters shed light on their functional activity.

Khramtsov, Yuri V / Vlasova, Anastasiia D / Vlasov, Alexey V / Rosenkranz, Andrey A / Ulasov, Alexey V / Ryzhykau, Yury L / Kuklin, Alexander I / Orekhov, Anton S / Eydlin, Ilia B / Georgiev, Georgii P / Gordeliy, Valentin I / Sobolev, Alexander S

Acta crystallographica. Section D, Structural biology

2020 Volume 76, Issue Pt 12, Page(s) 1270–1279

Abstract: Modular nanotransporters (MNTs) are multifunctional chimeric polypeptides for the multistep transport of locally acting cytotoxic agents into the nuclei of cancer target cells. MNTs consist of several polypeptide domains (functional modules) for the ... ...

Abstract	Modular nanotransporters (MNTs) are multifunctional chimeric polypeptides for the multistep transport of locally acting cytotoxic agents into the nuclei of cancer target cells. MNTs consist of several polypeptide domains (functional modules) for the recognition of a cell-surface internalizable receptor, pH-dependent endosomal escape and subsequent transport into the nucleus through the nuclear pores. MNTs are a promising means for cancer treatment. As has been shown previously, all of the modules of MNTs retain their functionalities. Despite their importance, there is no structural information available about these chimeric polypeptides, which hampers the creation of new MNT variants. Here, a low-resolution 3D structure of an MNT is presented which was obtained by atomic force microscopy, transmission electron microscopy and small-angle X-ray scattering coupled to size-exclusion chromatography. The data suggest that the MNT can adopt two main conformations, but in both conformations the protein N- and C-termini are distanced and do not influence each other. The change in the MNT conformation during acidification of the medium was also studied. It was shown that the fraction of the elongated conformation increases upon acidification. The results of this work will be useful for the development of MNTs that are suitable for clinical trials and possible therapeutic applications.
MeSH term(s)	Cell Nucleus/metabolism ; Humans ; Nanostructures/chemistry ; Peptides/chemistry
Chemical Substances	Peptides
Language	English
Publishing date	2020-11-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S2059798320013765
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