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Development of modified siRNA molecules incorporating 5-fluoro-2'-deoxyuridine residues to enhance cytotoxicity
Therapeutic small interfering RNAs (siRNAs) are composed of chemically modified nucleotides, which enhance RNA stability and increase affinity in Watson–Crick base pairing. However, the precise fate of such modified nucleotides once the siRNA is degraded within the cell is unknown. Previously, we demonstrated that deoxythymidine release from degraded siRNAs reversed the cytotoxicity of thymidylate synthase (TS)-targeted siRNAs and other TS inhibitor compounds. We hypothesized that siRNAs could be designed with specific nucleoside analogues that, once released, would enhance siRNA cytotoxicity. TS-targeted siRNAs were...
Source: Nucleic Acids Research - April 22, 2013 Category: Research Authors: Wu, S.-y., Chen, T.-m., Gmeiner, W. H., Chu, E., Schmitz, J. C. Tags: RNA Source Type: research

Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains.
In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by C...
Source: American Journal of Translational Research - November 14, 2014 Category: Research Tags: Am J Transl Res Source Type: research

Knockdown of the KINDLIN-2 Gene and Reduced Expression of Kindlin-2 Affects Vascular Permeability in Angiogenesis in a Mouse Model of Wound Healing.
CONCLUSIONS In a mouse model of wound healing, KINDLIN-2 gene knockdown inhibited wound healing, and increased neovascular permeability in vivo. PMID: 30070977 [PubMed - in process]
Source: Medical Science Monitor - August 6, 2018 Category: Research Tags: Med Sci Monit Source Type: research

Id: 140: klotho, an anti-aging molecule, regulates alveolar epithelial cell mtdna damage and apoptosis
Conclusions Our data demonstrate a crucial role for AEC AKT signaling in mediating the mtDNA damage protective effects of Klotho. Given the importance of AEC aging and apoptosis in pulmonary fibrosis, we reason that Klotho/AKT axis is an innovative therapeutic target for preventing common lung diseases of aging (i.e. IPF, COPD, lung cancer, etc.) for which more effective management regimens are clearly needed. Funding NIH-RO1 ES020357-01A1 (DK) and VA Merit (DK).
Source: Journal of Investigative Medicine - March 21, 2016 Category: Research Authors: Kim, S., Cheresh, P., Jablonski, R., Kamp, D., Eren, M., Vaughan, D. Tags: Pulmonary/Critical Care Source Type: research

DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance.
CONCLUSIONS ERCC1 and BRCA1 were overexpressed in NSCLC drug-resistant cells, and they regulated lung cancer occurrence and development through the phosphorylating PI3K/AKT signaling pathway. PMID: 27289442 [PubMed - as supplied by publisher]
Source: Medical Science Monitor - June 13, 2016 Category: Research Tags: Med Sci Monit Source Type: research

Homology directed repair is unaffected by the absence of siRNAs in Drosophila melanogaster
Small interfering RNAs (siRNAs) defend the organism against harmful transcripts from exogenous (e.g. viral) or endogenous (e.g. transposons) sources. Recent publications describe the production of siRNAs induced by DNA double-strand breaks (DSB) in Neurospora crassa, Arabidopsis thaliana, Drosophila melanogaster and human cells, which suggests a conserved function. A current hypothesis is that break-induced small RNAs ensure efficient homologous recombination (HR). However, biogenesis of siRNAs is often intertwined with other small RNA species, such as microRNAs (miRNAs), which complicates interpretation of experimental re...
Source: Nucleic Acids Research - September 28, 2016 Category: Research Authors: Schmidts, I., Böttcher, R., Mirkovic-Hösle, M., Förstemann, K. Tags: Genome Integrity, Repair and Replication Source Type: research

Enhanced SOCS3 in osteoarthiritis may limit both proliferation and inflammation.
Abstract Osteoarthritis (OA) is a degenerative joint disease that is characterized by localized inflammatory and secondary proliferative changes. Suppressor of cytokine signaling 3 (SOCS3) is elevated during OA development. We investigated the effects of this protein on human chondrocyte survival in OA and the inflammatory response together with the mechanisms of these effects. Small interfering RNA (siRNA) was used to knock down the expression of SOCS3 in interleukin(IL)-1β-induced primary human osteoarthritic chondrocytes. We found that siRNA-mediated SOCS3 knock-down in human osteoarthritic chondrocytes increa...
Source: Biotechnic and Histochemistry - March 19, 2017 Category: Research Authors: Gui T, He BS, Gan Q, Yang C Tags: Biotech Histochem Source Type: research

Exogenous MSCs ameliorate hypoxia/reoxygenation injury in renal tubular epithelial cells through JAK/STAT signaling pathway-mediated regulation of HMGB1.
This study was conducted to investigate the repair mechanism of hypoxia/reoxygenation injury (HRI) in renal tubular epithelial cells (HK-2) by exogenous mesenchymal stem cells (MSCs). The activation of the JAK/STAT pathway in HK-2 cells after HRI and treatment of MSCs, JAK inhibitor WP1066 and STAT inhibitor SOCS3 was investigated using Western blot analysis. HK-2 cells were transfected with siRNA STAT3 and analyzed for expression of STAT3, JAK2 and HMGB1 using fluorescence quantitative PCR and Western blot. Cell viability and apoptosis were analyzed using the MTT assay and flow cytometry. After HRI, the JAK/STAT pathway i...
Source: American Journal of Translational Research - June 2, 2017 Category: Research Tags: Am J Transl Res Source Type: research

The forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in malignant rhabdoid tumor.
CONCLUSION: This study demonstrates that FOXM1 may serve as a promising therapeutic target for MRT. PMID: 33221995 [PubMed - as supplied by publisher]
Source: Clin Med Res - November 21, 2020 Category: Research Authors: Shibui Y, Kohashi K, Tamaki A, Kinoshita I, Yamada Y, Yamamoto H, Taguchi T, Oda Y Tags: J Cancer Res Clin Oncol Source Type: research

DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase
The triazine derivative 12459 is a potent G-quadruplex ligand that triggers apoptosis or delayed growth arrest, telomere shortening and G-overhang degradation, as a function of its concentration and time exposure to the cells. We have investigated here the DNA damage response induced by 12459 in A549 cells. Submicromolar concentrations of 12459 triggers a delayed Chk1-ATR–mediated DNA damage response associated with a telomeric dysfunction and a G2/M arrest. Surprisingly, increasing concentrations of 12459 leading to cell apoptosis induced a mechanism that bypasses the DNA damage signaling and leads to the dephosphor...
Source: Nucleic Acids Research - March 31, 2013 Category: Research Authors: Douarre, C., Mergui, X., Sidibe, A., Gomez, D., Alberti, P., Mailliet, P., Trentesaux, C., Riou, J.-F. Tags: Genome Integrity, Repair and Replication Source Type: research

Non-erythroid alpha spectrin prevents telomere dysfunction after DNA interstrand cross-link damage
Telomere integrity is critical for telomere function and genomic stability. We previously demonstrated that non-erythroid α-spectrin (αIISp) is present in mammalian cell nuclei where it is important in repair of DNA interstrand cross-links (ICLs) and chromosome stability. We now demonstrate that αIISp is also important for telomere maintenance after ICL damage. It localizes to telomeres in S phase after ICL damage where it has enhanced association with TRF1 and TRF2 and is required for recruitment of the ICL repair protein, XPF, to damage-induced foci at telomeres. In telomerase-positive normal cells depl...
Source: Nucleic Acids Research - May 27, 2013 Category: Research Authors: Zhang, P., Herbig, U., Coffman, F., Lambert, M. W. Tags: Genome Integrity, Repair and Replication Source Type: research

The 26S proteasome drives trinucleotide repeat expansions
This study reports that the multi-functional protein Sem1 is a novel driver of TNR expansions in budding yeast. Mutants of SEM1 suppress up to 90% of expansions. Subsequent analysis showed that Sem1 facilitates expansions via its function in the 26S proteasome, a highly conserved multi-subunit complex with both proteolytic and non-proteolytic functions. The proteolytic function of the 26S proteasome is relevant to expansions, as mutation of additional proteasome components or treatment of yeast with a proteasome inhibitor suppressed CTG•CAG expansions. The 26S proteasome also drives expansions in human cells. In a hum...
Source: Nucleic Acids Research - June 26, 2013 Category: Research Authors: Concannon, C., Lahue, R. S. Tags: Genome Integrity, Repair and Replication Source Type: research

DHX9 helicase is involved in preventing genomic instability induced by alternatively structured DNA in human cells
Sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures in the human genome have been implicated in stimulating genomic instability. Previously, we found that a naturally occurring intra-molecular triplex (H-DNA) caused genetic instability in mammals largely in the form of DNA double-strand breaks. Thus, it is of interest to determine the mechanism(s) involved in processing H-DNA. Recently, we demonstrated that human DHX9 helicase preferentially unwinds inter-molecular triplex DNA in vitro. Herein, we used a mutation-reporter system containing H-DNA to examine the relevance of DHX9 activity on nat...
Source: Nucleic Acids Research - December 5, 2013 Category: Research Authors: Jain, A., Bacolla, A., del Mundo, I. M., Zhao, J., Wang, G., Vasquez, K. M. Tags: Genome Integrity, Repair and Replication Source Type: research

Lysophosphatidic acid stimulates cell migration of satellite cells: a role for sphingosine kinase/sphingosine 1‐phosphate axis
This study provides new compelling information on the regulatory mechanisms of satellite cell motility and reinforces the notion that SK/S1P signaling pathway plays a crucial role in the control of skeletal muscle precursor cell biology. This article is protected by copyright. All rights reserved.
Source: FEBS Journal - August 5, 2014 Category: Research Authors: Francesca Cencetti, Gennaro Bruno, Sabrina Blescia, Caterina Bernacchioni, Paola Bruni, Chiara Donati Tags: Original Article Source Type: research

A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation
MicroRNAs (miRNAs) have been implicated in DNA repair pathways through transcriptional responses to DNA damaging agents or through predicted miRNA regulation of DNA repair genes. We hypothesized that additional DNA damage regulating miRNAs could be identified by screening a library of 810 miRNA mimetics for the ability to alter cellular sensitivity to ionizing radiation (IR). A prostate cancer Metridia luciferase cell model was applied to examine the effects of individual miRNAs on IR sensitivity. A large percentage of miRNA mimetics were found to increase cellular sensitivity to IR, while a smaller percentage were protect...
Source: Nucleic Acids Research - May 2, 2015 Category: Research Authors: Hatano, K., Kumar, B., Zhang, Y., Coulter, J. B., Hedayati, M., Mears, B., Ni, X., Kudrolli, T. A., Chowdhury, W. H., Rodriguez, R., DeWeese, T. L., Lupold, S. E. Tags: Genome integrity, repair and replication Source Type: research

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