60 research outputs found
Amyloid-Associated Nucleic Acid Hybridisation
Nucleic acids promote amyloid formation in diseases including Alzheimer's
and Creutzfeldt-Jakob disease. However, it remains unclear whether the close
interactions between amyloid and nucleic acid allow nucleic acid secondary
structure to play a role in modulating amyloid structure and function. Here we
have used a simplified system of short basic peptides with alternating
hydrophobic and hydrophilic amino acid residues to study nucleic acid - amyloid
interactions. Employing biophysical techniques including X-ray fibre
diffraction, circular dichroism spectroscopy and electron microscopy we show
that the polymerized charges of nucleic acids concentrate and enhance the
formation of amyloid from short basic peptides, many of which would not
otherwise form fibres. In turn, the amyloid component binds nucleic acids and
promotes their hybridisation at concentrations below their solution
Kd, as shown by time-resolved FRET studies. The
self-reinforcing interactions between peptides and nucleic acids lead to the
formation of amyloid nucleic acid (ANA) fibres whose properties are distinct
from their component polymers. In addition to their importance in disease and
potential in engineering, ANA fibres formed from prebiotically-produced peptides
and nucleic acids may have played a role in early evolution, constituting the
first entities subject to Darwinian evolution
Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres
<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs), some of which function as oncogenes or tumor suppressor genes, are involved in carcinogenesis via regulating cell proliferation and/or cell death. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor. miR-34 targets Notch, HMGA2, and Bcl-2, genes involved in the self-renewal and survival of cancer stem cells. The role of miR-34 in gastric cancer has not been reported previously. In this study, we examined the effects of miR-34 restoration on p53-mutant human gastric cancer cells and potential target gene expression.</p> <p>Methods</p> <p>Human gastric cancer cells were transfected with miR-34 mimics or infected with the lentiviral miR-34-MIF expression system, and validated by miR-34 reporter assay using Bcl-2 3'UTR reporter. Potential target gene expression was assessed by Western blot for proteins, and by quantitative real-time RT-PCR for mRNAs. The effects of miR-34 restoration were assessed by cell growth assay, cell cycle analysis, caspase-3 activation, and cytotoxicity assay, as well as by tumorsphere formation and growth.</p> <p>Results</p> <p>Human gastric cancer Kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. Bcl-2 3'UTR reporter assay showed that the transfected miR-34s were functional and confirmed that Bcl-2 is a direct target of miR-34. Restoration of miR-34 chemosensitized Kato III cells with a high level of Bcl-2, but not MKN-45 cells with a low level of Bcl-2. miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth.</p> <p>Conclusion</p> <p>Our results demonstrate that in p53-deficient human gastric cancer cells, restoration of functional miR-34 inhibits cell growth and induces chemosensitization and apoptosis, indicating that miR-34 may restore p53 function. Restoration of miR-34 inhibits tumorsphere formation and growth, which is reported to be correlated to the self-renewal of cancer stem cells. The mechanism of miR-34-mediated suppression of self-renewal appears to be related to the direct modulation of downstream targets Bcl-2, Notch, and HMGA2, indicating that miR-34 may be involved in gastric cancer stem cell self-renewal/differentiation decision-making. Our study suggests that restoration of the tumor suppressor miR-34 may provide a novel molecular therapy for p53-mutant gastric cancer.</p
The relation between total cerebral small vessel disease burden and gait impairment in patients with minor stroke
Acknowledgements We thank the patients and their families, and the staff of the Brain Research Imaging Centre, Edinburgh, where MRI scanning was performed. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Mild Stroke Study-2 follow up study at three years was funded by Chest Heart Stroke Scotland. The original MSS-2 study was funded by the Wellcome Trust (ref. 088134/Z/09/A) and Row Fogo Charitable Trust. The imaging was performed at the Brain Research Imaging Centre Edinburgh, which is supported by the SINAPSE collaboration and the Chief Scientist Office of the Scottish Government (http://www.bric.ed.ac.uk/). The work was supported by European Union Horizon 2020 (EU H2020), PHC03-15, project No 666881, ’SVDs@Target’, and the Fondation Leducq Transatlantic Network of Excellence for Study of Perivascular Spaces in Small Vessel Disease, ref no. 16 CVD 05. The work reflects the views of the authors and not of the funders. CMJL was supported by the Dutch Alzheimer Foundation and VC holds a NHS Research Scotland Fellowship. The work was performed in the Edinburgh Dementia Research Centre in the UK DementiaResearch InitiativePeer reviewedPublisher PD
- …