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Article ; Online: Improving Efficiency of Direct Pro-Neural Reprogramming: Much-Needed Aid for Neuroregeneration in Spinal Cord Injury.

Chudakova, Daria A / Samoilova, Ekaterina M / Chekhonin, Vladimir P / Baklaushev, Vladimir P

2023 Volume 12, Issue 20

Abstract: Spinal cord injury (SCI) is a medical condition affecting ~2.5-4 million people worldwide. The conventional therapy for SCI fails to restore the lost spinal cord functions; thus, novel therapies are needed. Recent breakthroughs in stem cell biology and ... ...

Abstract	Spinal cord injury (SCI) is a medical condition affecting ~2.5-4 million people worldwide. The conventional therapy for SCI fails to restore the lost spinal cord functions; thus, novel therapies are needed. Recent breakthroughs in stem cell biology and cell reprogramming revolutionized the field. Of them, the use of neural progenitor cells (NPCs) directly reprogrammed from non-neuronal somatic cells without transitioning through a pluripotent state is a particularly attractive strategy. This allows to "scale up" NPCs in vitro and, via their transplantation to the lesion area, partially compensate for the limited regenerative plasticity of the adult spinal cord in humans. As recently demonstrated in non-human primates, implanted NPCs contribute to the functional improvement of the spinal cord after injury, and works in other animal models of SCI also confirm their therapeutic value. However, direct reprogramming still remains a challenge in many aspects; one of them is low efficiency, which prevents it from finding its place in clinics yet. In this review, we describe new insights that recent works brought to the field, such as novel targets (mitochondria, nucleoli, G-quadruplexes, and others), tools, and approaches (mechanotransduction and electrical stimulation) for direct pro-neural reprogramming, including potential ones yet to be tested.
MeSH term(s)	Adult ; Animals ; Humans ; Mechanotransduction, Cellular ; Neural Stem Cells/pathology ; Spinal Cord Injuries/pathology ; Nerve Regeneration
Language	English
Publishing date	2023-10-20
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12202499
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The growth hormone receptor interacts with transcriptional regulator HMGN1 upon GH-induced nuclear translocation.

Jain, Lekha / Vickers, Mark H / Jacob, Bincy / Middleditch, Martin J / Chudakova, Daria A / Ganley, Austen R D / O'Sullivan, Justin M / Perry, Jo K

Journal of cell communication and signaling

2023 Volume 17, Issue 3, Page(s) 925–937

Abstract: Growth hormone (GH) actions are mediated through binding to its cell-surface receptor, the GH receptor (GHR), with consequent activation of downstream signalling. However, nuclear GHR localisation has also been observed and is associated with increased ... ...

Abstract	Growth hormone (GH) actions are mediated through binding to its cell-surface receptor, the GH receptor (GHR), with consequent activation of downstream signalling. However, nuclear GHR localisation has also been observed and is associated with increased cancer cell proliferation. Here we investigated the functional implications of nuclear translocation of the GHR in the human endometrial cancer cell-line, RL95-2, and human mammary epithelial cell-line, MCF-10A. We found that following GH treatment, the GHR rapidly translocates to the nucleus, with maximal localisation at 5-10 min. Combined immunoprecipitation-mass spectrometry analysis of RL95-2 whole cell lysates identified 40 novel GHR binding partners, including the transcriptional regulator, HMGN1. Moreover, microarray analysis demonstrated that the gene targets of HMGN1 were differentially expressed following GH treatment, and co-immunoprecipitation showed that HMGN1 associates with the GHR in the nucleus. Therefore, our results suggest that GHR nuclear translocation might mediate GH actions via interaction with chromatin factors that then drive changes in specific downstream transcriptional programs.
Language	English
Publishing date	2023-04-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2299380-0
ISSN	1873-961X ; 1873-9601
ISSN (online)	1873-961X
ISSN	1873-9601
DOI	10.1007/s12079-023-00741-2
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Article: The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors.

Petersen, Elena V / Chudakova, Daria A / Skorova, Ekaterina Yu / Anikin, Vladimir / Reshetov, Igor V / Mynbaev, Ospan A

Frontiers in oncology

2020 Volume 10, Page(s) 575569

Abstract: The tumor biomarkers already have proven clinical value and have become an integral part in cancer management and modern translational oncology. The tumor tissue microenvironment (TME), which includes extracellular matrix (ECM), signaling molecules, ... ...

Abstract	The tumor biomarkers already have proven clinical value and have become an integral part in cancer management and modern translational oncology. The tumor tissue microenvironment (TME), which includes extracellular matrix (ECM), signaling molecules, immune and stromal cells, and adjacent non-tumorous tissue, contributes to cancer pathogenesis. Thus, TME-derived biomarkers have many clinical applications. This review is predominately based on the most recent publications (manuscripts published in a last 5 years, or seminal publications published earlier) and fills a gap in the current literature on the cancer biomarkers derived from the TME, with particular attention given to the ECM and products of its processing and degradation, ECM-associated extracellular vesicles (EVs), biomechanical characteristics of ECM, and ECM-derived biomarkers predicting response to the immunotherapy. We discuss the clinical utility of the TME-incorporating three-dimensional
Language	English
Publishing date	2020-12-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.575569
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Article: Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.

Nikitin, Aleksey G / Chudakova, Daria A / Enikeev, Rafael F / Sakaeva, Dina / Druzhkov, Maxim / Shigapova, Leyla H / Brovkina, Olga I / Shagimardanova, Elena I / Gusev, Oleg A / Gordiev, Marat G

Frontiers in oncology

2020 Volume 10, Page(s) 666

Abstract: Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. ... ...

Abstract	Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome. We proposed that Lynch Syndrome-related germline mutations (LS-mutations) are associated with breast cancer (BC). In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes
Language	English
Publishing date	2020-05-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.00666
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Article: Expression of Cathepsins B, D, and G in Infantile Hemangioma.

Itinteang, Tinte / Chudakova, Daria A / Dunne, Jonathan C / Davis, Paul F / Tan, Swee T

Frontiers in surgery

2015 Volume 2, Page(s) 26

Abstract: Aims: The role of the renin-angiotensin system (RAS) in the biology of infantile hemangioma (IH) represents an emerging paradigm, particularly the involvement of renin, angiotensin converting enzyme, and angiotensin II. This study investigated the ... ...

Abstract	Aims: The role of the renin-angiotensin system (RAS) in the biology of infantile hemangioma (IH) represents an emerging paradigm, particularly the involvement of renin, angiotensin converting enzyme, and angiotensin II. This study investigated the expression of cathepsins B, D, and G, enzymes that may modulate the RAS, in IH. Materials and methods: The expression of cathepsins B, D, and G was examined using immunohistochemistry, enzyme activity assays, mass spectrometry, and NanoString gene expression assay in IH samples at different phases of development. Results: Immunohistochemical staining showed the expression of cathepsins B, D, and G in proliferating and involuted IH samples. This was confirmed at the transcriptional level using NanoString gene expression assays. Mass spectrometry confirmed the identification of cathepsins D and G in all three phases of IH development, whereas cathepsin B was detected in 2/2 proliferating and 1/2 involuting lesions. Enzyme activity assays demonstrated the activity of cathepsins B and D, but not G, in all phases of IH development. Conclusion: Our data demonstrated the presence of cathepsins B, D, and G in IH. Their role in modulating the RAS and the biology of IH offers potential novel targets for the management of this tumor.
Language	English
Publishing date	2015-06-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2773823-1
ISSN	2296-875X
ISSN	2296-875X
DOI	10.3389/fsurg.2015.00026
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Article ; Online: Expression of embryonic stem cell markers in keloid-associated lymphoid tissue.

Grant, Chelsea / Chudakova, Daria A / Itinteang, Tinte / Chibnall, Alice M / Brasch, Helen D / Davis, Paul F / Tan, Swee T

Journal of clinical pathology

2016 Volume 69, Issue 7, Page(s) 643–646

Abstract: Aims: To identify, characterise and localise the population of primitive cells in keloid scars (KS).: Methods: 5-µm-thick formalin-fixed paraffin-embedded sections of KS samples from 10 patients underwent immunohistochemical (IHC) staining for the ... ...

Abstract	Aims: To identify, characterise and localise the population of primitive cells in keloid scars (KS). Methods: 5-µm-thick formalin-fixed paraffin-embedded sections of KS samples from 10 patients underwent immunohistochemical (IHC) staining for the embryonic stem cell (ESC) markers OCT4, SOX2, pSTAT3 and NANOG, and keloid-associated lymphoid tissue (KALT) markers CD4 and CD20. NanoString gene expression analysis and in situ hybridisation (ISH) were used to determine the abundance and localisation of the mRNA for these ESC markers. Results: IHC staining revealed the expression of the ESC markers OCT4, SOX2, pSTAT3 and NANOG by a population of cells within KS tissue. These are localised to the endothelium of the microvessels within the KALTs. NanoString gene expression analysis confirmed the abundance of the transcriptional expression of the same ESC markers. ISH localised the expression of the ESC transcripts to the primitive endothelium in KS tissue. Conclusions: This report demonstrates the expression of ESC markers OCT4, SOX2, pSTAT3 and NANOG by the endothelium of the microvessels within the KALTs. These findings show a unique niche of primitive cells within KS, expressing ESC markers, revealing a potential therapeutic target in the treatment of KS.
MeSH term(s)	Embryonic Stem Cells/metabolism ; Female ; Humans ; Immunohistochemistry ; Keloid/metabolism ; Keloid/pathology ; Lymphoid Tissue/metabolism ; Lymphoid Tissue/pathology ; Male ; Nanog Homeobox Protein/metabolism ; Octamer Transcription Factor-3/metabolism ; Phosphorylation ; SOXB1 Transcription Factors/metabolism ; STAT3 Transcription Factor/metabolism
Chemical Substances	Nanog Homeobox Protein ; Octamer Transcription Factor-3 ; POU5F1 protein, human ; SOX2 protein, human ; SOXB1 Transcription Factors ; STAT3 Transcription Factor
Language	English
Publishing date	2016-07
Publishing country	England
Document type	Journal Article
ZDB-ID	80261-x
ISSN	1472-4146 ; 0021-9746
ISSN (online)	1472-4146
ISSN	0021-9746
DOI	10.1136/jclinpath-2015-203483
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Article: The Ethnic-Specific Spectrum of Germline Nucleotide Variants in DNA Damage Response and Repair Genes in Hereditary Breast and Ovarian Cancer Patients of Tatar Descent.

Brovkina, Olga I / Shigapova, Leila / Chudakova, Daria A / Gordiev, Marat G / Enikeev, Rafael F / Druzhkov, Maxim O / Khodyrev, Dmitriy S / Shagimardanova, Elena I / Nikitin, Alexey G / Gusev, Oleg A

Frontiers in oncology

2018 Volume 8, Page(s) 421

Abstract: The Russian population consists of more than 100 ethnic groups, presenting a unique opportunity for the identification of hereditary pathogenic mutations. To gain insight into the landscape of heredity pathogenic variants, we employed targeted next- ... ...

Abstract	The Russian population consists of more than 100 ethnic groups, presenting a unique opportunity for the identification of hereditary pathogenic mutations. To gain insight into the landscape of heredity pathogenic variants, we employed targeted next-generation sequencing to analyze the germline mutation load in the DNA damage response and repair genes of hereditary breast and ovary cancer syndrome (HBOCS) patients of Tatar ethnicity, which represents ~4% of the total Russian population. Several pathogenic mutations were identified in DNA double-strand break repair genes, and the spectrum of these markers in Tatar patients varied from that previously reported for patients of Slavic ancestry. The CDK12 gene encodes cyclin-dependent kinase 12, the key transcriptional regulator of the genes involved in DNA damage response and repair. C
Language	English
Publishing date	2018-10-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2018.00421
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Article ; Online: Characterisation of subpopulations of myeloid cells in infantile haemangioma.

Tan, Elysia M S / Chudakova, Daria A / Davis, Paul F / Brasch, Helen D / Itinteang, Tinte / Tan, Swee T

Journal of clinical pathology

2015 Volume 68, Issue 7, Page(s) 571–574

Abstract: Aims: Cells expressing markers of mast cells, macrophages and dendritic cells have previously been demonstrated within the interstitium of infantile haemangioma (IH). This study characterised these myeloid cellular subpopulations within IH.: Methods: ...

Abstract	Aims: Cells expressing markers of mast cells, macrophages and dendritic cells have previously been demonstrated within the interstitium of infantile haemangioma (IH). This study characterised these myeloid cellular subpopulations within IH. Methods: Immunohistochemical staining was performed on proliferating and involuted IHs for the expression of Nanog, tryptase, CD163, DC-SIGN and CD45. The presence of mRNA corresponding to Nanog, tryptase α/β-1, tryptase β-2, CD163 and DC-SIGN was confirmed by NanoString and RT-PCR in snap-frozen IH tissues. Results: Immunohistochemical staining showed expression of Nanog by interstitial phenotypical mast cells within proliferating IH, which were separate from the interstitial M2-polarised macrophages that also expressed DC-SIGN, a dendritic cell marker. These two myeloid cellular subpopulations in IH did not express the pan-haematopoietic marker, CD45. Conclusions: There are two interstitial subpopulations of myeloid cells within IH: phenotypical mast cells which also express Nanog, indicating a primitive phenotype; and M2-polarised macrophages which also express DC-SIGN.
MeSH term(s)	Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; Cell Proliferation ; Child ; Gene Expression Regulation, Neoplastic ; Hemangioma/chemistry ; Hemangioma/pathology ; Humans ; Immunohistochemistry ; Infant ; Macrophages/chemistry ; Macrophages/classification ; Macrophages/pathology ; Mast Cells/chemistry ; Mast Cells/classification ; Mast Cells/pathology ; Phenotype ; RNA, Messenger/analysis ; Real-Time Polymerase Chain Reaction
Chemical Substances	Biomarkers, Tumor ; RNA, Messenger
Language	English
Publishing date	2015-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80261-x
ISSN	1472-4146 ; 0021-9746
ISSN (online)	1472-4146
ISSN	0021-9746
DOI	10.1136/jclinpath-2014-202846
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Article ; Online: Characterisation of lymphocyte subpopulations in infantile haemangioma.

Tan, Elysia M S / Itinteang, Tinte / Chudakova, Daria A / Dunne, Jonathan C / Marsh, Reginald / Brasch, Helen D / Davis, Paul F / Tan, Swee T

Journal of clinical pathology

2015 Volume 68, Issue 10, Page(s) 812–818

Abstract: Aims: Interstitial CD45+ cells and T lymphocytes have previously been demonstrated within infantile haemangioma (IH). This study investigated the expression of B and T lymphocyte markers by the CD45+ population, and the expression of Thy-1, a marker of ... ...

Abstract	Aims: Interstitial CD45+ cells and T lymphocytes have previously been demonstrated within infantile haemangioma (IH). This study investigated the expression of B and T lymphocyte markers by the CD45+ population, and the expression of Thy-1, a marker of thymocyte progenitors, which have the ability to give rise to both B and T cells. Methods: Immunohistochemical (IHC) staining was performed on proliferating and involuted IHs for the expression of CD45, CD3, CD20, CD79a, Thy-1 and CD34. The presence of mRNA corresponding to CD45, CD3G, CD20 and Thy-1 was confirmed by reverse transcriptase-polymerase chain reaction in snap-frozen IH tissues. Cell counting of 3,3-diaminobenzidine IHC-stained slides was performed on CD45+ only cells and dually stained CD45+/CD3+ cells or CD45+/CD20+ cells and analysed statistically. In situ hybridisation and mass spectrometry were also performed to confirm the presence and abundance of Thy-1, respectively. Results: IHC staining showed a subpopulation of CD45+ interstitial cells that expressed the T lymphocyte marker, CD3, and another subpopulation that expressed the B lymphocyte marker, CD20, in proliferating and diminished in involuted IHs. The abundant expression of Thy-1 on the endothelium of proliferating, but not involuted IH, was demonstrated by IHC staining and confirmed by in situ hybridisation and mass spectrometry. Conclusions: Both B and T lymphocytes are present within the interstitium of proliferating and involuted IH. The expression of Thy-1 by the endothelium suggests that B and T cells in IH may have originated from within the lesion, rather than migrating from the peripheral circulation.
MeSH term(s)	Antigens, CD20/analysis ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/pathology ; Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; CD3 Complex/analysis ; Cell Lineage ; Cell Proliferation ; Endothelial Cells/immunology ; Endothelial Cells/pathology ; Hemangioma/genetics ; Hemangioma/immunology ; Hemangioma/pathology ; Humans ; Immunohistochemistry ; Immunophenotyping ; In Situ Hybridization ; Infant ; Leukocyte Common Antigens/analysis ; Leukocyte Common Antigens/genetics ; Phenotype ; RNA, Messenger/analysis ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/pathology ; Tandem Mass Spectrometry ; Thy-1 Antigens/analysis ; Thy-1 Antigens/genetics
Chemical Substances	Antigens, CD20 ; Biomarkers, Tumor ; CD3 Complex ; RNA, Messenger ; Thy-1 Antigens ; Leukocyte Common Antigens (EC 3.1.3.48) ; PTPRC protein, human (EC 3.1.3.48)
Language	English
Publishing date	2015-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80261-x
ISSN	1472-4146 ; 0021-9746
ISSN (online)	1472-4146
ISSN	0021-9746
DOI	10.1136/jclinpath-2015-203073
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Article: Developmentally Regulated Ceramide Synthase 6 Increases Mitochondrial Ca²⁺ Loading Capacity and Promotes Apoptosis

Novgorodov, Sergei A / Chudakova, Daria A / Wheeler, Brian W / Bielawski, Jacek / Kindy, Mark S / Obeid, Lina M / Gudz, Tatyana I

Journal of biological chemistry. 2011 Feb. 11, v. 286, no. 6

2011

Abstract: Ceramides, which are membrane sphingolipids and key mediators of cell-stress responses, are generated by a family of (dihydro) ceramide synthases (Lass1-6/CerS1-6). Here, we report that brain development features significant increases in sphingomyelin, ... ...

Abstract	Ceramides, which are membrane sphingolipids and key mediators of cell-stress responses, are generated by a family of (dihydro) ceramide synthases (Lass1-6/CerS1-6). Here, we report that brain development features significant increases in sphingomyelin, sphingosine, and most ceramide species. In contrast, C₁₆:₀-ceramide was gradually reduced and CerS6 was down-regulated in mitochondria, thereby implicating CerS6 as a primary ceramide synthase generating C₁₆:₀-ceramide. Investigations into the role of CerS6 in mitochondria revealed that ceramide synthase down-regulation is associated with dramatically decreased mitochondrial Ca²⁺-loading capacity, which could be rescued by addition of ceramide. Selective CerS6 complexing with the inner membrane component of the mitochondrial permeability transition pore was detected by immunoprecipitation. This suggests that CerS6-generated ceramide could prevent mitochondrial permeability transition pore opening, leading to increased Ca²⁺ accumulation in the mitochondrial matrix. We examined the effect of high CerS6 expression on cell survival in primary oligodendrocyte (OL) precursor cells, which undergo apoptotic cell death during early postnatal brain development. Exposure of OLs to glutamate resulted in apoptosis that was prevented by inhibitors of de novo ceramide biosynthesis, myriocin and fumonisin B1. Knockdown of CerS6 with siRNA reduced glutamate-triggered OL apoptosis, whereas knockdown of CerS5 had no effect: the pro-apoptotic role of CerS6 was not stimulus-specific. Knockdown of CerS6 with siRNA improved cell survival in response to nerve growth factor-induced OL apoptosis. Also, blocking mitochondrial Ca²⁺ uptake or decreasing Ca²⁺-dependent protease calpain activity with specific inhibitors prevented OL apoptosis. Finally, knocking down CerS6 decreased calpain activation. Thus, our data suggest a novel role for CerS6 in the regulation of both mitochondrial Ca²⁺ homeostasis and calpain, which appears to be important in OL apoptosis during brain development.
Language	English
Dates of publication	2011-0211
Size	p. 4644-4658.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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