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Article ; Online: Defining the timeline of periostin upregulation in cardiac fibrosis following acute myocardial infarction in mice.

Gil, Hadas / Goldshtein, Matan / Etzion, Sharon / Elyagon, Sigal / Hadad, Uzi / Etzion, Yoram / Cohen, Smadar

2022 Volume 12, Issue 1, Page(s) 21863

Abstract: After myocardial infarction (MI), the heart's reparative response to the ischemic insult and the related loss of cardiomyocytes involves cardiac fibrosis, in which the damaged tissue is replaced with a fibrous scar. Although the scar is essential to ... ...

Abstract	After myocardial infarction (MI), the heart's reparative response to the ischemic insult and the related loss of cardiomyocytes involves cardiac fibrosis, in which the damaged tissue is replaced with a fibrous scar. Although the scar is essential to prevent ventricular wall rupture in the infarction zone, it expands over time to remote, non-infarct areas, significantly increasing the extent of fibrosis and markedly altering cardiac structure. Cardiac function in this scenario deteriorates, thereby increasing the probability of heart failure and the risk of death. Recent works have suggested that the matricellular protein periostin, known to be involved in fibrosis, is a candidate therapeutic target for the regulation of MI-induced fibrosis and remodeling. Different strategies for the genetic manipulation of periostin have been proposed previously, yet those works did not properly address the time dependency between periostin activity and cardiac fibrosis. Our study aimed to fill that gap in knowledge and fully elucidate the explicit timing of cellular periostin upregulation in the infarcted heart to enable the safer and more effective post-MI targeting of periostin-producing cells. Surgical MI was performed in C57BL/6J and BALB/c mice by ligation of the left anterior descending coronary artery. Flow cytometry analyses of cells derived from the infarcted hearts and quantitative real-time PCR of the total cellular RNA revealed that periostin expression increased during days 2-7 and peaked on day 7 post-infarct, regardless of mouse strain. The established timeline for cellular periostin expression in the post-MI heart is a significant milestone toward the development of optimal periostin-targeted gene therapy.
MeSH term(s)	Animals ; Mice ; Cicatrix/pathology ; Disease Models, Animal ; Fibrosis ; Mice, Inbred C57BL ; Myocardial Infarction/metabolism ; Myocardium/metabolism ; Myocytes, Cardiac/metabolism ; Up-Regulation ; Ventricular Remodeling/genetics
Chemical Substances	Postn protein, mouse
Language	English
Publishing date	2022-12-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-26035-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Specificity-Determining DNA Triplet Code for Positioning of Human Preinitiation Complex.

Goldshtein, Matan / Lukatsky, David B

Biophysical journal

2017 Volume 112, Issue 10, Page(s) 2047–2050

Abstract: The notion that transcription factors bind DNA only through specific, consensus binding sites has been recently questioned. No specific consensus motif for the positioning of the human preinitiation complex (PIC) has been identified. Here, we reveal that ...

Abstract	The notion that transcription factors bind DNA only through specific, consensus binding sites has been recently questioned. No specific consensus motif for the positioning of the human preinitiation complex (PIC) has been identified. Here, we reveal that nonconsensus, statistical, DNA triplet code provides specificity for the positioning of the human PIC. In particular, we reveal a highly nonrandom, statistical pattern of repetitive nucleotide triplets that correlates with the genomewide binding preferences of PIC measured by Chip-exo. We analyze the triplet enrichment and depletion near the transcription start site and identify triplets that have the strongest effect on PIC-DNA nonconsensus binding. Using statistical mechanics, a random-binder model without fitting parameters, with genomic DNA sequence being the only input, we further validate that the nonconsensus nucleotide triplet code constitutes a key signature providing PIC binding specificity in the human genome. Our results constitute a proof-of-concept for, to our knowledge, a new design principle for protein-DNA recognition in the human genome, which can lead to a better mechanistic understanding of transcriptional regulation.
MeSH term(s)	DNA/metabolism ; DNA-Binding Proteins/metabolism ; Genetic Code ; Humans ; Models, Genetic ; Models, Statistical ; Protein Binding ; Transcription Factor TFIIB/metabolism ; Transcription Initiation, Genetic ; Trinucleotide Repeats
Chemical Substances	DNA-Binding Proteins ; Transcription Factor TFIIB ; DNA (9007-49-2)
Language	English
Publishing date	2017-05-23
Publishing country	United States
Document type	Journal Article ; Validation Studies
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2017.04.023
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: A Synthetic SOD/Catalase Mimic Compound for the Treatment of ALS.

Soll, Matan / Goldshtein, Hagit / Rotkopf, Ron / Russek-Blum, Niva / Gross, Zeev

Antioxidants (Basel, Switzerland)

2021 Volume 10, Issue 6

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis perturbation, protein misfolding and protein aggregation as key players in the pathology of the disease. Twenty percent of familial ALS and two percent of sporadic ALS instances are due to a mutation in Cu/Zn superoxide dismutase (SOD1). Sporadic and familial ALS affects the same neurons with similar pathology; therefore, the underlying hypothesis is that therapies effective in mutant SOD1 models could be translated to sporadic ALS. Corrole metal complexes have lately been identified as strong and potent catalytic antioxidants with beneficial effects in oxidative stress-related diseases such as Parkinson's disease, Alzheimer's disease, atherosclerosis, diabetes and its complications. One of the most promising candidates is the iron complex of an amphiphilic corrole,
Language	English
Publishing date	2021-05-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10060827
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Article: Co-assembled Ca

Goldshtein, Matan / Shamir, Stav / Vinogradov, Ekaterina / Monsonego, Alon / Cohen, Smadar

Molecular therapy. Nucleic acids

2019 Volume 16, Page(s) 378–390

Abstract: Successful gene therapy requires the development of suitable carriers for the selective and efficient delivery of genes to specific target cells, with minimal toxicity. In this work, we present a non-viral vector for gene delivery composed of ... ...

Abstract	Successful gene therapy requires the development of suitable carriers for the selective and efficient delivery of genes to specific target cells, with minimal toxicity. In this work, we present a non-viral vector for gene delivery composed of biocompatible materials, CaCl
Language	English
Publishing date	2019-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2019.03.006
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Article ; Online: Intratumoral Administration of High-Concentration Nitric Oxide and Anti-mPD-1 Treatment Improves Tumor Regression Rates and Survival in CT26 Tumor-Bearing Mice.

Confino, Hila / Sela, Yogev / Epshtein, Yana / Malka, Lidor / Goldshtein, Matan / Chaisson, Selena / Lisi, Steve / Avniel, Amir / Monson, Jedidiah Mercer / Dirbas, Frederick M

Cells

2023 Volume 12, Issue 20

Abstract: Background: Immune checkpoint inhibitors have transformed clinical oncology. However, their use is limited as response is observed in only ~20-50% of patients. Previously, we demonstrated that treating CT26 tumor-bearing mice with ultra-high- ... ...

Abstract	Background: Immune checkpoint inhibitors have transformed clinical oncology. However, their use is limited as response is observed in only ~20-50% of patients. Previously, we demonstrated that treating CT26 tumor-bearing mice with ultra-high-concentration gaseous nitric oxide (UNO) followed by tumor resection stimulated antitumor immune responses. Accordingly, UNO may improve tumor response to immune checkpoint inhibitors. Here, we investigated the ability of UNO to improve the efficacy of a programmed cell death protein-1 (PD-1) antibody in vitro and in treating CT26 tumor-bearing mice. Methods: CT26 cells were injected into the flank of Balb/c mice ( Results: (1) Short exposure to 25,000-100,000 parts per million (ppm) UNO in vitro resulted in significant upregulation of PD-L1 expression on CT26 cells. (2) UNO treatment in vivo consistently reduced cell viability in CT26 tumors. (3) Treatment reduced regulatory T-cell (Treg) levels in the tumor and increased levels of systemic M1 macrophages. UNO responders had increased CD8+ T-cell tumor infiltration. (4) Nine days after treatment, primary tumor growth was significantly lower in the combination arm vs. anti-mPD-1 alone ( Conclusion: Combining high-concentration NO and immune checkpoint inhibitors warrants further assessment especially in tumors resistant to checkpoint inhibitor therapy.
MeSH term(s)	Humans ; Mice ; Animals ; Nitric Oxide/metabolism ; Immune Checkpoint Inhibitors ; Cell Line, Tumor ; CD8-Positive T-Lymphocytes
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; Immune Checkpoint Inhibitors
Language	English
Publishing date	2023-10-11
Publishing country	Switzerland
Document type	Journal Article ; 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/cells12202439
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Article: A Synthetic SOD/Catalase Mimic Compound for the Treatment of ALS

Soll, Matan / Goldshtein, Hagit / Rotkopf, Ron / Russek-Blum, Niva / Gross, Zeev

Antioxidants. 2021 May 22, v. 10, no. 6

2021

Abstract	Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis perturbation, protein misfolding and protein aggregation as key players in the pathology of the disease. Twenty percent of familial ALS and two percent of sporadic ALS instances are due to a mutation in Cu/Zn superoxide dismutase (SOD1). Sporadic and familial ALS affects the same neurons with similar pathology; therefore, the underlying hypothesis is that therapies effective in mutant SOD1 models could be translated to sporadic ALS. Corrole metal complexes have lately been identified as strong and potent catalytic antioxidants with beneficial effects in oxidative stress-related diseases such as Parkinson’s disease, Alzheimer’s disease, atherosclerosis, diabetes and its complications. One of the most promising candidates is the iron complex of an amphiphilic corrole, 1-Fe. In this study we used the SOD1 G93R mutant zebrafish ALS model to assess whether 1-Fe, as a potent catalytic antioxidant, displays any therapeutic merits in vivo. Our results show that 1-Fe caused a substantial increase in mutant zebrafish locomotor activity (up to 30%), bringing the locomotive abilities of the mutant treated group close to that of the wild type untreated group (50% more than the mutated untreated group). Furthermore, 1-Fe did not affect WT larvae locomotor activity, suggesting that 1-Fe enhances locomotor ability by targeting mechanisms underlying SOD1 ALS specifically. These results may pave the way for future development of 1-Fe as a viable treatment for ALS.
Keywords	Danio rerio ; amyotrophic lateral sclerosis ; atherosclerosis ; catalase ; diabetes ; etiology ; homeostasis ; locomotion ; mitochondria ; models ; mutants ; mutation ; protein folding ; reactive oxygen species ; superoxide dismutase ; therapeutics
Language	English
Dates of publication	2021-0522
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10060827
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Mechanisms of cellular uptake and endosomal escape of calcium-siRNA nanocomplexes.

Goldshtein, Matan / Forti, Efrat / Ruvinov, Emil / Cohen, Smadar

International journal of pharmaceutics

2016 Volume 515, Issue 1-2, Page(s) 46–56

Abstract: ... ...

Abstract	Ca
MeSH term(s)	Animals ; Calcium/metabolism ; Cations/metabolism ; Caveolins/metabolism ; Cell Line, Tumor ; Clathrin/metabolism ; Dynamins/metabolism ; Endocytosis/physiology ; Endosomes/metabolism ; Gene Silencing/physiology ; Mice ; Nanoparticles/metabolism ; RNA Interference/physiology ; RNA, Small Interfering/metabolism
Chemical Substances	Cations ; Caveolins ; Clathrin ; RNA, Small Interfering ; Dynamins (EC 3.6.5.5) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2016-12-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2016.10.009
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Zs.A 1409: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Transcription Factor Binding in Embryonic Stem Cells Is Constrained by DNA Sequence Repeat Symmetry.

Goldshtein, Matan / Mellul, Meir / Deutch, Gai / Imashimizu, Masahiko / Takeuchi, Koh / Meshorer, Eran / Ram, Oren / Lukatsky, David B

Biophysical journal

2020 Volume 118, Issue 8, Page(s) 2015–2026

Abstract: Transcription factor (TF) recognition is dictated by the underlying DNA motif sequence specific for each TF. Here, we reveal that DNA sequence repeat symmetry plays a central role in defining TF-DNA-binding preferences. In particular, we find that ... ...

Abstract	Transcription factor (TF) recognition is dictated by the underlying DNA motif sequence specific for each TF. Here, we reveal that DNA sequence repeat symmetry plays a central role in defining TF-DNA-binding preferences. In particular, we find that different TFs bind similar symmetry patterns in the context of different developmental layers. Most TFs possess dominant preferences for similar DNA repeat symmetry types. However, in some cases, preferences of specific TFs are changed during differentiation, suggesting the importance of information encoded outside of known motif regions. Histone modifications also exhibit strong preferences for similar DNA repeat symmetry patterns unique to each type of modification. Next, using an in vivo reporter assay, we show that gene expression in embryonic stem cells can be positively modulated by the presence of genomic and computationally designed DNA oligonucleotides containing identified nonconsensus-repetitive sequence elements. This supports the hypothesis that certain nonconsensus-repetitive patterns possess a functional ability to regulate gene expression. We also performed a solution NMR experiment to probe the stability of double-stranded DNA via imino proton resonances for several double-stranded DNA sequences characterized by different repetitive patterns. We suggest that such local stability might play a key role in determining TF-DNA binding preferences. Overall, our findings show that despite the enormous sequence complexity of the TF-DNA binding landscape in differentiating embryonic stem cells, this landscape can be quantitatively characterized in simple terms using the notion of DNA sequence repeat symmetry.
MeSH term(s)	Base Sequence ; Binding Sites ; Embryonic Stem Cells/metabolism ; Protein Binding ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors
Language	English
Publishing date	2020-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2020.02.009
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Gaseous nitric oxide tumor ablation induces an anti-tumor abscopal effect.

Confino, Hila / Dirbas, Frederick M / Goldshtein, Matan / Yarkoni, Shay / Kalaora, Rinat / Hatan, Meital / Puyesky, Shani / Levi, Yakir / Malka, Lidor / Johnson, Matt / Chaisson, Selena / Monson, Jedidiah M / Avniel, Amir / Lisi, Steve / Greenberg, David / Wolf, Ido

Cancer cell international

2022 Volume 22, Issue 1, Page(s) 405

Abstract: Background: In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by delivering exogenous ultra-high concentration (> 10, ...

Abstract	Background: In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by delivering exogenous ultra-high concentration (> 10,000 ppm) gaseous nitric oxide (UHCgNO) intratumorally. Methods: The capability of UHCgNO to induce apoptosis was tested in vitro in mouse colon (CT26), breast (4T1) and Lewis lung carcinoma (LLC-1) cancer cell lines. In vivo, UHCgNO was studied by treating CT26 tumor-bearing mice in-situ and assessing the immune response using a Challenge assay. Results: Exposing CT26, 4T1 and LLC-1 cell lines to UHCgNO for 10 s-2.5 min induced cellular apoptosis 24 h after exposure. Treating CT26 tumors in-situ with UHCgNO followed by surgical resection 14 days later resulted in a significant secondary anti-tumor effect in vivo. 100% of tumor-bearing mice treated with 50,000 ppm UHCgNO and 64% of mice treated with 20,000 ppm UHCgNO rejected a second tumor inoculation, compared to 0% in the naive control for 70 days. Additionally, more dendrocytes infiltrated the tumor 14 days post UHCgNO treatment versus the nitrogen control. Moreover, T-cell penetration into the primary tumor was observed in a dose-dependent manner. Systemic increases in T- and B-cells were seen in UHCgNO-treated mice compared to nitrogen control. Furthermore, polymorphonuclear-myeloid-derived suppressor cells were downregulated in the spleen in the UHCgNO-treated groups. Conclusions: Taken together, our data demonstrate that UHCgNO followed by the surgical removal of the primary tumor 14 days later induces a strong and potent anti-tumor response.
Language	English
Publishing date	2022-12-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2091573-1
ISSN	1475-2867
ISSN	1475-2867
DOI	10.1186/s12935-022-02828-z
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Article ; Online: NITRIC OXIDE IS A POWERFUL ANTI-CORONAVIRUS-INHALED AGENT THAT ACTS WITHIN HOURS

Goldshtein, Matan / Lerner, Omer / Kalaora, Rinat / Yarkoni, Shay / Dekel, Elya / Confino, Hila / Golden, Pam / Greenberg, David / Lisi, Steve / Avniel, Amir / Shemer-Avni, Yonat

Chest

Keywords	covid19
Publisher	Elsevier; PMC
Document type	Article ; Online
DOI	10.1016/j.chest.2020.09.031
Database	COVID19

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