1,720,985 research outputs found
PGC1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity
Get PDFDue to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1αin vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1α expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1α expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies.Open Acces
Histone Acetylation and Chemoresistance in Colorectal Cancer: an Opportunity for Effective Personalized Treatment
Get PDFColorectal cancer (CRC) is the most common cause of deaths in the West. Despite many therapeutic opportunities, drug resistance or recurrence has significant rates among patients. Nearly 50% of CRC patients develop metastases. Therefore, sensitive biomarker and effective treatments with minimal toxicity are needed. Genetic and epigenetic alterations play major roles in initiation, development, and chemoresistance of CRC. Histone deacetylase2 (HDAC2) over-expression is well-known in CRC. Many studies have associated HDAC2 over-expression and TP53 mutations with late stages of metastatic CRC (mCRC). However, the relationship between HDAC2 expression level and TP53 status and mCRC drug resistance is unclear. Here, I have investigated HDAC2 role in drug resistance and assessed the synergistic effects of DNA chemotherapeutics agents and HDAC inhibitors (HDACIs) on TP53 status in mCRC cell lines. I have shown for the first time that in mutated p53 mCRC cells (Sw480 and HT-29) the steady-state level of HDAC2 is low compared to wild-type p53 cells (HCT116 p53+/+). I have also found that increase in HDAC2 expression level in the highly resistant cell line HT-29 enhances drug resistance and its depletion by shRNA sensitises HT-29 to 5Fluorouracil (5FU) or Oxaliplatin (Oxa). The combined treatment of suberoylanilide hydroxamic acid (SAHA)/5FU and SAHA/Oxa was able to reduced HDAC2 expression level and induced mitotic cell death. However, SAHA/Doxorubicin combined treatment induced cell death in wild-type p53 (HCT116 p53+/+), null p53 (HCT116 p53-/-), and SW480 cell lines. This cell death associated with decrease in HDAC2 level. I have shown the association between sensitivity to treatment and reduction of HDAC2 level via bioluminescence imaging in combination with liposomal-encapsulated SAHA/Doxorubicin delivery to monitor tumour growth. I have observed a significant decrease in tumour growth and HADC2 level. Therefore, I suggest that unlike mutated p53, HDAC2 could be an epigenetic prognostic biomarker to predict therapeutic response in mCRC
Molecular mechanisms and outcomes of arsenic-induced histone acetylation and microRNA regulation in cellular transformation
Get PDFChronic exposure to arsenic causes negative health outcomes, particularly malignant neoplasms of the skin, lung and bladder. Although epidemiological data has associated arsenic exposure to cancer, a clear molecular mechanism has remained elusive. This thesis studied the impact of arsenic trioxide (ATO) exposure on histone acetylation and microRNA expression at both tolerated and toxic levels in vitro to determine an epigenetic-based mechanism of carcinogenesis.
This thesis outlines a framework for identifying tolerated and toxic ATO exposures, as a prerequisite to epigenetic characterisation. Tolerated ATO exposure increased cellular survival, anchorage-independent colony formation, cell-cycle progression and proliferation in HEK293T cells. HEK293T and UROtsa cells treated with tolerated ATO exhibited global H3K9 hyperacetylation at 3 hours and global H3K9 hypoacetylation at 72 hours. This was mediated by an imbalance in the intracellular HDAC2 to PCAF mRNA expression ratio. Global H3K9 hypoacetylation occurred for both tolerated and toxic exposures, giving poor mechanistic differentiation between these separated cellular outcomes. Chromatin immunoprecipitation identified PCAF recruitment, E2F1 binding and H3K9 acetylation at the FOS proto-oncogenic promoter leading to an elevation in FOS mRNA levels at the tolerated concentration only. This thesis also reports ATO-induced chromatin relaxation in HEK293T cells followed by a return to nominal levels for the tolerated concentration. This is in contrast to the toxic exposure, which leads to clear chromatin condensation and apoptosis. This thesis postulates that arsenic-induced global H3K9 hypoacetylation is caused by a miR-372 -mediated attenuation mechanism targeting PCAF mRNA, as predicted through bioinformatic analysis.
In summary, tolerated ATO exposure resulted in measurable perturbations in both global and promoter-specific histone acetylation in addition to the aberrant expression of microRNAs, which led to cellular transformation over toxicity.Open Acces
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Pharmacological Effect of Histone Deacetylase Inhibitors on Pulmonary Arterial Hypertension
Get PDFPulmonary hypertension (PH) is characterized by structural remodelling of pulmonary
arteries and arterioles, the result, at least in part, of excessive cell proliferation, resistance
to cell death and hyperactive inflammatory reactions. Currently available treatments
targeting the hyper-proliferative and pro-inflammatory pathology are limited. Epigenetic
programming, dynamically regulated by histone acetylation, is an important mechanism
for cell proliferation and survival. Aberrant changes of histone acetylation, modulated by
histone deacetylase (HDAC), are shown in many proliferative and inflammatory disorders,
especially cancer, and may contribute to the phenotypical changes in remodelling and
overall to the development of PH. Hypothetically, HDAC inhibitors have therapeutic
potential by reversing the imbalance of acetylation.
I examined the correlations between HDAC expression and PH development, followed by
evaluation of the pharmacological effects and possible mechanisms of two HDAC
inhibitors, class I inhibitor valproic acid (VPA) and pan-HDAC inhibitor suberoylanilide
hydroxamic acid (SAHA), on animal models and cellular systems.
Altered HDAC expression, specifically increased HDAC1 and HDAC5 along with
elevation of anti-apoptotic marker Bcl-2, were found in lungs from patients with
idiopathic pulmonary arterial hypertension and chronically hypoxic rats. In in vivo studies,
VPA and SAHA ameliorated the established PH in both hypoxia- and monocrotalineinduced
PH rat models, by reducing pulmonary arterial pressure, right ventricular
hypertrophy and pulmonary vascular muscularization, in parallel with increasing histone
acetylation. In in vitro studies, VPA and SAHA inhibited stimulated cell growth of
pulmonary artery smooth muscle cells and cytokine release from endothelial cells.
Biochemical analysis indicated these two inhibitors exert anti-proliferative effects
comprising cell cycle arrest by upregulation of p21 and apoptotic induction by
downregulation of Bcl-2.
Collectively, this study shows the contribution of abnormal HDAC activity to vascular
pathology of PH and provides a preclinical basis to further explore the therapeutic
potential of HDAC inhibitors in human PH
Design, synthesis and biological evaluation of novel lipid-based nanoparticle delivery system for metabolic re-engineering
Get PDFDietary supplementation with fibre has been shown to ameliorate features of the metabolic
syndrome and inhibit malignant growth in certain types of cancer. These effects have been
linked to short-chain fatty acids (SCFA), mostly acetate. However, the ubiquitous role of
SCFAs in metabolism, combined with a short tissue half-life and the non-targeted nature of
oral and peripheral administrations make achieving phenotypically relevant levels of SCFA
by standard delivery techniques challenging and limit their therapeutic potential. Liposomal
encapsulation of a therapeutic agent overcomes these issues by protecting against
degradation, increasing circulation time and passively targeting both the liver and tumour
tissue.
In this research project, I have designed a bifunctional liposome formulation to transport
SCFA, monitored their distribution and uptake utilising visualisation by MRI, PET/CT and
fluorescence microscopy. These bifunctional liposomes were useful for effectively
encapsulating small molecules within their aqueous core, which in this case was acetate,
and capable of acetate delivery into cells while also being amenable to cellular imaging. I
have shown that preferential delivery of liposome encapsulated acetate (LITA) nanoparticles
to key sites of metabolic control provide beneficial therapeutic effects in animal models of
both obesity and cancer. Chronic administration of LITA nanoparticles in an obeseogenic
model led to a significant reduction in adiposity, intrahepatocellular lipid, inflammatory tone
and genetic indication of a decrease fatty acid synthesis in the liver. Application of LITA in a
murine xenograft model caused an inhibition of tumour growth in three colorectal cancer cell
lines: HT-29, HCT116 p53+/+ and HCT116 p53-/-. The mechanisms for these two outcomes
are not fully defined; however cellular energy homeostasis of both scenarios was restored.
These results indicate that LITA nanoparticles can be used to improve multiple metabolic
pathways, in vivo.Open Acces
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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