380 research outputs found
Insulin-like growth factor-I (IGF-I) : role and application in intestinal disease / Gordon Stanley Howarth.
No full text"November 2001."Author's previously published articles appended.Bibliography: leaves 80-106.xii, 139 leaves : ill, charts ; 30 cm.Describes studies which extended the understanding of growth factors, particularly of IGF-I in gut growth and repair in addition to the physiological role and hence, therapeutic potential, of a range of growth factors in gastrointestinal disease. It is suggested that future evaluation of the application of growth factors to combat gastrointestinal disorders could focus on functional outcomes such as effects on intestinal absorption. In addition, the efficacy of growth factor analogues with increased bioactivity, possibly incorporated into enterally-administered growth factor formulations, either enriched in, or depleted of, certain specific growth factors, could be investigated as a novel treatment strategy for diseases of the gastrointestinal tract.Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 200
Increased latencies to respond in a judgment bias test are not associated with pessimistic biases in rats
No full textExtinction of learning is a common, yet under-reported limitation of judgment bias testing methods. Repeated exposure to the ambiguous probe of a judgment bias paradigm encourages the animal to cease display of the required behaviours. However, there remains a need to repeatedly test animals to achieve statistical power. A delicate balance therefore needs to be struck between over- and under-exposure of the animals to the test conditions. This study presents the data of rats, a common animal subject of judgment bias testing. Rats were exposed to the ambiguous probe of a common, active-choice judgment bias test for 11 consecutive days. There was a significant increase in the latency to respond to the ambiguous probe following day 8, with no significant increase experienced for either the positive or less-positive probes. Following day 8 there was a significant increase in both optimistic and pessimistic latencies in response to the ambiguous probe. Therefore, repeated exposure to the ambiguous probe caused an increased latency in response even though optimistic interpretations were recorded. This implies that the use of response latency alone as a measure in judgment bias testing can falsely identify pessimism. Researchers should modify experimental design to include both choice and latency measures.Timothy Hugh Barker, Gordon Stanley Howarth, Alexandra Louise Whittake
Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease?
No full textCopyright © 2009 Elsevier Ltd. All rights reserved.
Data source: Figures & tables, https://doi.org/10.1016/j.tips.2009.08.003Dipeptidyl peptidase (DPP)-4 is a member of the S9b serine protease family, which also includes DPP8 and DPP9. DPP4 cleaves a number of regulatory factors, including chemokines and growth factors. DPP4 inhibitors have recently emerged as an effective treatment option for type 2 diabetes. Early in vitro studies demonstrated that DPP4 inhibitors inhibit T-cell proliferation and cytokine production, leading to their investigation in numerous pre-clinical models of inflammatory diseases, including arthritis, multiple sclerosis and inflammatory bowel disease. Recent data suggest that the early DPP4- specific inhibitors might also bind DPP8 and DPP9, thus exerting their effects through non-specific binding. This review highlights recent insights into the applicability of DPP inhibitors as novel pharmacological agents for inflammatory disease.Roger Yazbeck, Gordon S. Howarth and Catherine A. Abbot
Growth factor based therapies and intestinal disease: Is glucagon-like peptide-2 the new way forward?
No full textCopyright © 2009 Published by Elsevier Ltd.Inflammatory bowel disease (IBD) is a chronic, debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor that is demonstrating therapeutic potential for the prevention or treatment of an expanding number of intestinal diseases, including short bowel syndrome (SBS), small bowel enteritis and IBD. The biological activity of GLP-2 is limited due to proteolytic inactivation by the protease dipeptidyl peptidase (DP)IV. Inhibitors of DPIV activity may represent a novel strategy to prolong the growth promoting actions of GLP-2. This review outlines evidence for the clinical application of GLP-2, its degradation resistant analogue, Teduglutide, and novel DPIV inhibitors in efficacy studies utilizing pre-clinical models of intestinal damage, in particular IBD.Roger Yazbeck, Gordon S. Howarth and Catherine A. Abbotthttp://www.elsevier.com/wps/find/journaldescription.cws_home/868/description#descriptio
Assessment of housing density, space allocation and social hierarchy of laboratory rats on behavioural measures of welfare
No full textMinimum space allowances for laboratory rats are legislated based on weight and stocking rates, with the understanding that increased housing density encourages crowding stress. However, there is little evidence for these recommendations, especially when considering positive welfare outcomes. This study consisted of two experiments which investigated the effects of housing density (rats per cage), space allocation (surface area per rat) and social rank (dominance hierarchy) on the ability to perform simple behavioural tests. Male Sprague Dawley (SD) rats (n = 64) were allocated to either high-density (n = 8) or low-density (n = 8) cages. The second experiment investigated the effects of surface area. SD rats (n = 40) were housed in dyads in either the large (n = 10) or small (n = 10) cage. In both experiments, animals were tested on a judgment bias paradigm, with their responses to an ambiguous stimulus being ascribed as optimistic or pessimistic. Animals were also tested on open-field, novel-object recognition and social-interaction tests. Recordings were taken from 1700-2100h daily for rat observation and social rank establishment. Dominant animals responded with significantly more optimistic decisions compared to subordinates for both the housing density (p<0.001) and space allocation (p = 0.0015) experiment. Dominant animals responded with increased social affiliative behaviours in the social-interaction test, and spent more time in the centre of the open-field test for both experiments. No significance was detected between housing density or space allocation treatments. These findings suggest that social rank is a significantly greater modifier of affective state than either housing density or space allocation. This finding has not yet been reported and suggests that future drafts of housing guidelines should consider animal social status in addition to floor space requirements.Timothy Hugh Barker, Rebecca Peta George, Gordon Stanley Howarth, Alexandra Louise Whittake
Identification of differential duodenal gene expression levels and microbiota abundance correlated with differences in energy utilisation in chickens
No full textData source: Supplementary material, http://www.publish.csiro.au.access.library.unisa.edu.au/?act=view_file&file_id=AN12426_AC.zipAmong the terrestrial production animals, chickens are the most efficient users of energy. Apparent metabolisable energy (AME) is a measure of energy utilisation efficiency representing the difference between energy consumed and energy lost via the excreta. There are significant differences in the energy utilisation capability of individual birds that have a similar genetic background and are raised under identical conditions. It would be of benefit to poultry producers if the basis of these differences could be understood and the differences minimised. We analysed duodenal gene expression and microbiota differences in birds with different energy utilisation efficiencies. Using microarray analysis, significant differences were found in duodenal gene expression between high-and low-AME birds, indicating that level of cell turnover may distinguish different groups of birds. High-throughput sequencing of bacterial 16S rRNA genes indicated that duodenal microbiota was dominated by Lactobacillus species and two operational taxonomic units, identified as lactobacilli species, were found to be more abundant (P 0.05) in low-AME birds. The present study has identified gene expression and microbiota properties that correlate with differences in AME; further studies will be required to investigate the causal relationships.Barbara M. Konsak, Dragana Stanley, Volker R. Haring, Mark S. Geier, Robert J. Hughes, Gordon S. Howarth, Tamsyn M. Crowley and Robert J. Moor
Emu oil promotes intestinal repair in rat models of enteric inflammation.
No full textSeveral disorders of the gastrointestinal (GI) tract including ulcerative colitis, chemotherapy-induced mucositis and non-steroidal anti-inflammatory drug (NSAID)- induced enteropathy, are characterised by inflammation, ulceration, mucosal damage and malabsorption. Treatment options are variably effective, highlighting the need to broaden therapeutic approaches, including adjunctive strategies. Emu Oil, derived from subcutaneous and retroperitoneal Emu adipose tissue, is a rich source of fatty acids (FA). Despite limited rigorous scientific studies, topically applied Emu Oil has demonstrated potent anti-inflammatory properties in vivo. Previously, orally administered Emu Oil improved intestinal architecture in a rat model of mucositis, with early indications of enhanced intestinal repair. Accordingly, this thesis investigated the effects of orally administered Emu Oil in rat models of colitis (colonic damage), NSAID-enteropathy (small intestinal [SI] damage) and on the time course of SI repair in chemotherapy-induced mucositis. In the current study, Emu Oil improved colonic tissue damage associated with dextran sulphate sodium-induced colitis in Sprague Dawley rats and facilitated the repair process (Chapter 2). Improvements were indicated histologically by reduced intestinal damage severity scores and enhanced crypt compensatory elongation in the colon. These findings suggested the potential for Emu Oil to augment conventional treatment approaches for colitis. The effectiveness of Emu Oil in the colon provided impetus to further investigate Emu Oil action proximally, in the SI. In a rat model of chemotherapy (5-Fluorouracil; 5- FU)-induced mucositis, Emu Oil maintained SI villus height and crypt depth during the phase of maximal damage (Chapter 3). This was followed by an enhanced compensatory mucosal thickening, suggesting an acceleration of the repair process. Furthermore, Emu Oil significantly decreased myeloperoxidase (MPO) activity, indicative of acute inflammation, in the jejunum and ileum of 5-FU-injected rats. Potent anti-inflammatory properties of Emu Oil were reaffirmed in NSAID (Indomethacin)-induced enteropathy, whereby MPO activity in the jejunum and ileum of Indomethacin-treated rats was markedly decreased following Emu Oil administration (Chapter 4). Treatments for diseases such as coronary artery disease and GI disorders seek to minimise oxidative damage by free radicals through the use of antioxidants. Oils derived from ratites (flightless birds) predominantly comprise FA varying in composition between ratite species. The influence of farm location, rendering method, duration and storage mode was investigated for free radical scavenging activity (RSA) against 2,2-diphenyl-1-picryl hydracyl and primary oxidation status of Ratite Oils (Chapter 5). Emu Oil conferred the greatest RSA compared to Ostrich and Rhea Oil, potentially attributed to its high unsaturated FA: saturated FA ratio and non-triglyceride fraction minor constituents. Rendering and storage variables impacted on Emu Oil RSA and primary oxidation. This thesis identified Emu Oil as a safe, renewable and economical means to augment pharmaceutical options for GI disorders. A new mechanism of action for Emu Oil could represent a promotion of repair from injury together with decreased SI inflammation. This suggests potential for Emu Oil as an adjunct to conventional treatment approaches for colitis, cancer management and long-term NSAID usage.Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 201
Effects of GSE (mg/kg) on histological severity scores in the jejunum 72 h after either saline or 5-FU injection.
No full text<p>The severity scores were rated based on 11 parameters on different layers of intestinal tissues based on previously described protocol Howarth <i>et al. </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085184#pone.0085184-Howarth1" target="_blank">[19]</a> The box plots represent the range of disease severity score and the horizontal lines represent the median disease severity score. ** indicates <i>P</i><0.01 compared to Water+Saline. ## indicates <i>P</i><0.01 compared to Water+5-FU.</p
Inhibiting dipeptidyl peptidase activity partially ameliorates colitis in mice
No full textLink to a related website: https://www.imrpress.com/journal/FBL/13/18/10.2741/3193/pdfNew treatment strategies are required for the debilitating inflammatory bowel diseases (lBO), Crohn 's Disease and Ulcerative Colitis. DP inhibitors can prolong the bioactivity of the potent intestinotrophic growth factor glucagon-like peptide-2 (GLP-21•33). We investigated whether novel inhibitors of DP activity could modify the course of disease activity in the dextran sulfate sodium (DSS) model of colitis. C57BL/6 mice consumed 2% DSS in drinking water for 6 days. Mice were orally gavaged twice daily with 0.9% saline, I Omglkg isoleucyl-cyanopyrrolidine (P59/99) or isoleucyl-thiazolidine (P32/98). Assessment of disease severity incorporated a disease activity index (DAl), together with histological assessment of crypt area and depth in the distal colon. DP activity was significantly inhibited at all time points. The DAl was significantly lower in the P59/99 and P32/98 treatment groups compared to saline treatment in all three time courses. Crypt hyperplasia (p<0.05) was observed in the saline group compared to P32/98 treatment at day 9. This preliminary study shows that novel inhibitors ofDP activity may provide a new treatment strategy for lBD.Roger Yazbeck, Gordon S. Howarth, Mark S. Geier, Hans-Ulrich Demuth, Catherine A. Abbot
Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells
No full textOBJECTIVE: Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells. DESIGN: Female Dark Agouti rats were gavaged with grape seed extract (400-1000 mg/kg) or water (day 3-11) and were injected intraperitoneally with 5-Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5-Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) assay. RESULTS: Compared with 5-Fluorouracil controls, grape seed extract (400-1000 mg/kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. Grape seed extract was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum. Grape seed extract (10-25 ug/mL) significantly enhanced the growth-inhibitory effects of 5-Fluorouracil by 26% (P<0.05) in Caco-2 cells and was more potent than 5-Fluorouracil at 50-100 µg/mL. CONCLUSION: Grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells.Ker Yeaw Cheah, Gordon Stanley Howarth, Susan Elaine Putnam Bastia
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