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Sullivan, Mark Edward. "Investigations into the pathogenesis of diabetic erectile dysfunction : an experimental animal model." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391611.
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Malik, Rayaz Ahmed. "The pathology, pathogenesis and treatment of diabetic neuropathy : studies in diabetic patients and animal models." Thesis, University of Manchester, 1997. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488257.
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Chan, Wai-ho, and 陳韋豪. "Study on the role of osmotic stress, oxidative stress and poly(ADP-ribose) polymerase in the pathogenesis of diabetic cataract." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B36371725.
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Todd, Derrick James. "Role of the Intestinal Immune System in the Pathogenesis of Autoimmune Diabetes in the BB Rat Model of Type 1 Diabetes Mellitus." eScholarship@UMMS, 2001. https://escholarship.umassmed.edu/gsbs_diss/138.
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The intestine is the largest lymphoid organ in the body, challenged constantly by an enonnous quantity and diversity of antigens. Distinct from peripheral lymphocytes, intestinal lymphocytes have evolved unique mechanisms of tolerance and appear to govern mucosal processes such as "chronic physiologic inflammation" and oral tolerance. Failure of mucosal tolerance has been implicated in the pathogenesis of several diseases, including inflammatory bowel disease, celiac disease, and even autoimmune diabetes. One population of intestinal lymphocytes, intraepithelial lymphocytes (IELs), exists within the intestinal epithelium itself and remains poorly characterized. IELs respond to unique activation signals and appear to be in part responsible for the maintenance of epithelial integrity and mucosal tolerance.
Type 1 diabetes is one of the most common chronic childhood illnesses and causes significant morbidity and mortality. Type 1 diabetes mellitus is an autoimmune disease that results from immune-mediated destruction of insulin-producing pancreatic beta cells and is characterized by an absolute insulin deficiency. Several animal models are used to study the immunopathogenesis of type 1 diabetes, including the BB rat and NOD mouse. BBDP rats spontaneously develop autoimmune diabetes mellitus and are severely deficient in peripheral T cells. BBDR rats do not spontaneously develop autoimmune diabetes, have nonnal numbers of peripheral T cells, and can be induced to become diabetic by injections of a cytotoxic anti-ART2a mAb and low doses of poly I:C. The cause of autoimmune diabetes in BB rats and humans is still unknown, but both genetic and environmental factors appear to participate. I hypothesize that one important class of environmental factors--diet and enteromicrobial agents--participates in this pathogenic process through the mediation of the gut immune system.
In this dissertation, I report a new method for the isolation of rat IELs that is based on the selective removal of intestinal epithelial cells under conditions that leave the basement membrane undisturbed. The yield of rat IELs using this method is 5-10 fold greater than that reported for other methods. Morphological and phenotypic analyses demonstrate that the purified cell population is comprised of IELs and is not contaminated with lamina propria or Peyer's patch lymphocytes. Phenotypic analysis reveals 5 major subsets of IELs, including populations of γδ T and natural killer (NK) cells present at levels not previously detected.
I also report that rat intraepithelial NK (IENK) and peripheral NK cells are similar in morphology, in their ability to lyse NK-sensitive targets, and in their ability to suppress a one-way mixed lymphocyte culture. In contrast, IENK cells differ from splenic NK cells phenotypically, and a substantial fraction of IENK cells appear to spontaneously secrete IL-4 and/or IFN-γ. I conclude that rat IELs harbor a large population of NKR-P1A+ CD3-cells that function as NK cells but display an activated phenotype and unusual cytokine profile that clearly distinguish them from splenic NK cells. Their phenotypic and functional characteristics suggest that these distinctive intraepithelial NK cells may participate in the regulation of mucosal immunity.
I next demonstrate that, prior to diabetes, both BBDP and ART2a-depleted BBDR rats have a reduced total number of IELs and exhibit a selective deficiency of IENK cell number and function as compared to control BBDR rats. The deficiency of BBDP rat IELs can be corrected by engraftment of bone marrow from histocompatible WF donors. These results suggest 1) that the peripheral lymphopenia in BBDP rats extends to the IEL compartment, particularly to IENK cells, 2) that in BBDR rats the diabetes-inducing treatment depletes IELs, particularly IENK cells, and 3) that the defect in BBDP rat IELs is intrinsic to hematopoietic cells, not intestinal stromal cells.
I also establish that, unlike BBDR and WF rats, BBDP rats are also deficient in γδTCR+IELs, a population of T cells that may play a role in normal mucosal tolerance. In addition, I report preliminary data supporting the hypothesis that systemic autoreactivity may be initiated in the intestine; peripheral autoreactive lymphocyte populations appear to emanate first from mesenteric lymph nodes that drain the intestine, and such cells may initiate a type 2 autoimmune phenomenon driven by IL-4.
Collectively, my findings support the hypothesis that a failure of mucosal tolerance in BBDP rats, perhaps secondary to deficiencies in one or more IEL subpopulations, participates in the pathogenesis of autoimmune diabetes in these animals by activating peripheral autoreactive T cells. The nature of the autoimmune response in BB rats (driven by IL-4) appears to be distinct from that of NOD mice. Despite the differences between these two well-accepted animal models of autoimmune diabetes, until more is known about the pathogenesis of type 1 DM in humans, lessons learned from both the BB rat and NOD mouse continue to be of tremendous benefit to our understanding of human disease.
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Chen, Yuk-shan, and 陳玉珊. "Role of aldose reductase in pathogenesis of diabetic neuropathy by making use of Thy1-YFP transgenic mice with aldose reductase-mutation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B36371191.
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Klingström, Jonas. "Hantaviruses : animal models, immunology and pathogenesis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-071-0/.
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Hitchen, Barry. "Behavioural evaluation of animal models of diabetes." Thesis, Ulster University, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744769.
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Diabetes is considered as a prominent threat to the worldwide population, and if left untreated may result in a number of severe complications, cognitive deterioration, and death. For the most prevalent form of the disease, type 2 diabetes, the main contributing factors to the development of the disease is being overweight and obese. There are a number of mediating factors regarding the relationship between excessive weight gain and subsequent development of diabetes, the most widely supported of which is the typical eating behaviours of the individual. While the physiological characteristics of diabetes are well-known, much less is understood in relation to the behavioural consequences. Animal models may aid our understanding of a disease, but the animal model used should not only replicate the physiological symptoms but also the behavioural characteristics. The studies discussed within this thesis encompass a thorough behavioural evaluation of two of the most commonly used diet-induced and chemically-induced animal models of diabetes; the high-fat diet model of obesity induced diabetes and Streptozotocin induced diabetes. The main focus of investigation was on the impact of the disease regarding the food preferences and motivations of mice to obtain food, using a classical method for assessing preference (T-maze) and motivation to respond for different appetitive stimuli on an operant conditioning schedule of food reinforcement (progressive ratio schedule, PR). During the latter phase of experiments, a range of behavioural processes (e.g. food deprivation alterations, prefeeding with or without satiation, and extinction) were also assessed in relation to how these may be affected by the presence of diabetes. In the final study, a new model of PR performance was applied to the results, with the intention of addressing issues relating to the accurate measurement of motivation under a PR schedule. Orderly behavioural data were obtained but neither model of diabetes showed clear effects on food motivation. Results are presented and discussed in relation to the limitations and implications of the research.
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Thudi, Nanda Kumar. "Pathogenesis of Osteoblastic metastasis in Prostate Cancer: Role of Animal Models." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1244042766.
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Cartón, García Fernando. "Myosin VB in intestinal pathogenesis." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458251.
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Miosina VB es una proteína que actúa como un motor molecular usando la energía del ATP para moverse a lo largo de filamentos de actina. Participa en el trafico intracelular de endosomas de reciclaje en la parte subapical de células polarizadas y no polarizadas. Su expresión es muy abundante en el intestino donde participa en el establecimiento y mantenimiento de la polaridad de los enterocitos. Mutaciones en MYO5B causan la enfermedad de inclusión de microvellosidades, in raro trastorno congénito que afecta a las células epiteliales del intestino cursando con diarrea acuosa persistente que suele ser fatal. Esta enfermedad se caracteriza por la presencia de alteraciones morfológicas en los enterocitos, atrofia de las vellosidades y deslocalización de proteínas del polo apical y basolateral del enterocito. Su patología molecular no se conoce, principalmente por la falta de modelos animales. En el presente estudio, describimos un versátil modelo murino con inactivación constitutiva de Myo5b e inactivación condicional en las células epiteliales intestinales inducida por tamoxifeno. En ambos casos, los animales muestras un cuadro clínico muy semejantes al de los pacientes con enfermedad de inclusión de microvellosidades, presentado diarrea y deshidratación que causan la muerte del animal. A nivel histológico, el intestino muestra las mismas alteraciones en los enterocitos que las presentes en pacientes humanos, incluyendo atrofia de vellosidades y deslocalización de marcadores proteicos. Además, la inactivación de Myo5b también provocó hiperproliferación de las criptas intestinales. Por lo tanto, el modelo animal presentado constituye una herramienta muy útil para investigar las causas moleculares de la enfermedad y ensayar de manera preclínica fármacos u otras opciones terapéuticas. Por otro lado, la pérdida de polaridad y diferenciación es también una de las señas de identidad de los carcinomas metastásicos avanzados y correlaciona con un mal pronóstico de los pacientes. En concreto, para el cáncer colorrectal, investigaciones previas llevadas a cabo en nuestro laboratorio ya han demostrado que la pérdida de miosina IA promueve la progresión la enfermedad y tiene actividad supresora de tumores. Dicha proteína es abundante en el borde en cepillo de los enterocitos, y participa en el mantenimiento de la estructura polarizada. Otros estudios han señalado la relación entre la inactivación de MYO5B con un incremento en la motilidad e invasión de células de cáncer gástrico, aunque todavía no se conoce nada de su relación con en el cáncer colorrectal. Para resolver esta cuestión, hemos diseñado modelos in vitro inducibles por doxiciclina para sobre expresar y reducir la expresión de dicha proteína en líneas celulares de cáncer de colon. Además, se ha empleado la tecnología CRISPR/Cas9 para inactivar la expresión de MYO5B en la línea de cáncer de colon Caco2-BBE. Los resultados muestran cambios en la polarización y diferenciación de dichas líneas celulares, de acuerdo con observaciones previas. También se ha observado una posible relación entre MYO5B y la capacidad de movilidad e invasión de las líneas de cáncer de colon. Sin embargo, la hiperproliferación observada en el intestino de los ratones no se reproduce en las líneas de cáncer de colon empleadas tras reducir o sobre expresar MYO5B, o en modelos xenograft subcutáneos in vivo de dichas líneas. Por otro lado, usando un microarray de tejidos con 155 muestras de tumores primarios de pacientes con cáncer colorrectal en estadio Dukes C se ha comprobado que una reducción en la expresión de MYO5B se asocia con una disminución en el tiempo de recaída y en la supervivencia total de los pacientes de cáncer de colon. Además, tumores con un grado de diferenciación bajo también expresan niveles de MYO5B significativamente reducidos. Finalmente, todos estos resultados indican que MYO5B juega un papel importante en la diferenciación del intestino normal y de las líneas de cáncer de colon. De la misma manera, MYO5B también podría desempeñar un papel en la progresión del cáncer colorrectal promoviendo movilidad e invasión de las células tumorales.<br>Myosin VB is a molecular motor protein that uses the energy of ATP to move along actin filaments. It participates in the recycling endosomes trafficking in the subapical cytoplasmic region of non-polarized and polarized cells. It is highly expressed in the small and large intestine, where its role in the establishment of polarized function in enterocytes is also well known. Inactivating mutations of MYO5B have been associated with microvillus inclusion disease (MVID), a rare congenital disorder of the intestinal epithelial cells that presents with persistent life-threatening watery diarrhea. It is characterized by morphological enterocyte abnormalities such as microvillus atrophy and mislocalization of apical and basolateral protein transporters. The molecular pathology of the disease is not well known mainly due to the lack of animal models. In the present study, we report a versatile murine model with targeted inactivation of Myo5b. This model allowed us to generate and characterized a constitutive Myo5b knockout mice and a tamoxifen-inducible intestinal-epithelium-specific Myo5b knockout. In both cases, the mice closely resemble the phenotype of MVID patients, developing watery diarrhea and dehydration causing the death of the animal. Histological study of the intestine showed all the characteristic enterocyte defects observed in MVID patients, including microvillus atrophy and mislocalization of protein markers. Moreover, the inactivation of MYO5B also originated hyperproliferation of the intestinal crypts. Therefore, our mice constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches. In addition, hyperproliferation as well as loss of cell polarity, differentiation, and tissue architecture are hallmarks of advanced metastatic carcinomas and strongly correlate with poor patient prognosis. Specifically, for colorectal cancer, the third most common type of cancer worldwide, we have previously demonstrated that the loss of brush border MYO1A, also involved in cell polarity, promotes cancer progression and has tumor suppressor activity. Other studies have indicated a relationship between MYO5B inactivation and gastric cancer, promoting invasion and motility, but little is known regarding its role in colorectal cancer. To address this question, we have developed novel doxycycline-inducible in vitro models of MYO5B overexpression and downregulation. Moreover, we have generated MYO5B knockout Caco2-BBE cells using CRISPR/Cas9 technology. Our results showed changes in the polarization and differentiation of colon cancer cells, in agreement with previous observations in the normal intestine. Moreover, we have observed a relationship between MYO5B and the motility and invasion capacity of colon cancer cells, indicating a possible role of MYO5B in colon cancer progression. However, the effect of MYO5B loss in cell proliferation observed in our Myo5b knockout mice could not be confirmed in our models in vitro and in vivo, employing cell line-derived xenografts. In addition, using a tissue microarray containing triplicate samples from 155 primary Dukes C colorectal tumors, reduced MYO5B expression was found to be associated with shorter disease-free and overall survival of the patients. Moreover, poorly differentiated tumors showed significantly reduced expression of MYO5B. Collectively, our results indicate that MYO5B plays an important role in the differentiation of the normal intestinal epithelium and colon cancer cells, as well as a possible role in cancer progression promoting cell motility and invasion.
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Wiskur, Brandt Justin. "Pathogenesis of Klebsiella pneumoniae endophthalmitis." Oklahoma City : [s.n.], 2008.
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Graham, Suzanne. "Intestinal immunity and pathology in animal models of type 1 diabetes." Thesis, University of Glasgow, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402005.
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Watson, Edmund M. "Modelling endocrine regulation of glycaemic control in animal models of diabetes." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/69356/.
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This thesis is concerned with mathematical modelling of the glucose-insulin homeostatic system, with the specific aim of mathematically modelling diabetes and diabetes-like conditions in animals. Existing models were examined and critiqued in this thesis. Additionally, structural identifiability analysis of the most widely-used model in the field, the Minimal Model, was performed using Taylor series and similarity transformation approaches. It was shown under certain assumptions that it was theoretically possible to obtain a unique set of parameters for the model from only measuring glucose. C-peptide deconvolution was performed using the WinNonLin algorithm and Maximum Entropy technique implemented in MATLAB. This was used to calculate insulin secretion, the percentage of insulin appearing in the periphery and insulin clearance rate. This was then further developed to model insulin appearance and clearance based on hepatic blood flow changes. A short-term model of the glucose-insulin and C-peptide system was initially formulated using a PID controller concept and later refined to reduce the number of model parameters. Structural identifiability analysis was performed using the Lie symmetries approach, followed by parameter estimation on rat and mice data from IVGTTs, OGTTs and hyperglycaemic clamps and sensitivity analysis. This short-term model was integrated into a long-term model to analyse Zucker and ZDF rat data to create a single model to cater for both short- and long-term dynamics. Finally, a software tool was developed to allow non-mathematical scientists to use and access the benefits of the model.
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Wong, Ching-keung, and 黃靜強. "The effects of streptozotocin-diabetes on adrenomedullin gene expression and peptide levels in the gastrointestinal system of therat." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B45011503.
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Vingsbo, Lundberg Carina. "Chronic autoimmune arthritis in rats pathogenesis and genetic factors /." Lund : Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945081.html.
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Wilder, Steven P. "Computational analysis of susceptibility genes for diabetes and cardiovascular diseases in animal models." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670109.
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Tsang, Kwok-yeung, and 曾國揚. "Molecular pathogenesis of abnormal chondrocyte differentiation in a transgenic mouse model." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B4501551X.
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Tam, Chung-nga, and 談頌雅. "Pathogenesis of congenital cataract in a gamma-crystallin mutant mousemodel." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B4786994X.
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Congenital cataract is a leading cause of visual disability among children worldwide.
It has a heterogeneous genetic basis; the cellular and molecular mechanisms for
cataractogenesis remain elusive. A spontaneously occurred autosomal dominant
mouse mutant named Secc, which displays small eye, cataract and closed eyelid, has
been obtained in our laboratory. By gene mapping and DNA sequencing, we identified
a single nucleotide deletion at position 273 of the Cryga gene, leading to a frame-shift
from the 3rd Greek Key motif of the A-crystallin (Cryga). The aim of this study is to
investigate the pathogenic mechanisms underlying the development of cataract in the
Secc mutant, as a disease model for understanding human congenital cataract. Initial
phenotype analysis showed that cataract was initiated in E14.5 CrygaSecc mutant
embryos, the nuclei of the primary lens fibres were scattered and failed to align in the
equatorial region. By E16.5, the secondary lens fibre cells were abnormally arranged
with poor lens suture formation. Apoptotic cells were found in the centre of the lens as
shown by TUNEL assay, cytoskeleton and cell adhesion in the lens centre were
disturbed as shown in immunohistochemistry analysis.
Previously by western blotting it was found that mutant -crystallins were enriched in
the insoluble fraction. I hypothesized that mutant A-crystallins might be misfolded
and protein aggregates were then formed. In this study, aggregation was observed in
semi-thin sections stained with toluidine blue. By co-staining using custom-made
anti-Secc antibody, CrygaSecc protein was found to be ubiquitinated and was wrapped
around by vimentin. Clearly, in the Secc mutant lens, aggresomes were formed for the
disposal of the misfolded proteins and to maintain cell survival. However, ultimately
cell death would occur in the mutant lens and contributed to cataract formation.
It is known that misfolded proteins would trigger unfolded protein response (UPR)
and heat shock protein (HSP) responses to facilitate folding and to prevent misfolded
proteins from intoxicating the cell. In order to determine which stress response
pathway was triggered, gene expression analysis by qRT-PCR was performed. The
expression of genes involved in the UPR pathways including BiP, CHOP and spliced
variant of XBP-1 were all up-regulated significantly in E14.5 and 16.5 mutant lenses.
In addition, among different ER stress related genes, cytosolic chaperones and
autophagy related genes, Hsp70 and BiP were upregulated, while Hsp40 and Hsp90aa
were downregulated in the homozygotes. The results suggested that both UPR and
HSP response pathways were triggered during cataractogenesis in the Secc mutant.
In conclusion, mutant A-crystallin appeared to trigger UPR, HSPs and cell death in
the fibre cells, while autophagy was not triggered. In the lens fibre cells, the
ubiquitin-proteasomal pathway was utilized for the removal of misfolded CrygaSecc
proteins. However, the stress perpetuated as the lens grew and produced more mutant
proteins. The mutant cells lost their normal cell adhesion, failed to maintain the
proper lens architecture, leading to cataract formation. Similar cellular mechanisms
could be implicated in human congenital cataract or age-related cataract development.<br>published_or_final_version<br>Biochemistry<br>Doctoral<br>Doctor of Philosophy
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Talbot, Nicola A. "Obesity, inflammation and insulin resistance in skeletal muscle." Thesis, Royal Veterinary College (University of London), 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618327.
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Kharroubi, Ilham. "Molecular pathways underlying beta-cell loss in vitro models of type 2 diabetes mellitus." Doctoral thesis, Universite Libre de Bruxelles, 2006. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210746.
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Foster, Jayne Louise Clinical School Prince of Wales Hospital Faculty of Medicine UNSW. "The microencapsulation and transplantation of fetal pig islet-like cell clusters: a potential therapy for type 1 diabetes." Awarded by:University of New South Wales. Clinical School - Prince of Wales Hospital, 2007. http://handle.unsw.edu.au/1959.4/40715.
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Diabetes can be considered to be one of the main health epidemics of the 21st century. Studies conducted by the World Health Organisation (WHO) indicate that the number of people with diabetes in the year 2000 was 171 million and this is projected to increase to 366 million by 2030 (Wild et al. 2004). The increasing incidence of both Type 1 and Type 2 diabetes is due to population growth, aging, urbanisation, obesity and physical inactivity. The current treatment by insulin injections for individuals with Type 1 diabetes fails to overcome the long term microvascular and macrovascular complications associated with the disease. A major challenge in the treatment of diabetes is to provide patients with an insulin source that is capable of regulating blood glucose levels (BGL) on a minute to minute basis. Advances in medical research have enabled the investigation of a variety of potential alternative therapies that may provide Type 1 diabetic patients with a more superior control of BGL and consequently minimise complications. The utilisation of pancreases obtained from fetal pigs offers potential therapeutic value in the treatment of Type 1 diabetes. Islet-like cell clusters (ICCs) are obtained from such tissue following partial mechanical and enzymatic digestive procedures. ICCs are primarily composed of immature duct cells which, when transplanted, will mainly differentiate into insulin producing ?? cells. Such cells are able to normalise BGL in immunodeficient diabetic recipients and in immunocompetent recipients when anti-rejection drugs are administered. This study investigates microencapsulation as an immunoprotective strategy that has the potential to remove the need for immunosuppression when such cells are transplanted. A review of the literature related to current medical research in the field of diabetes is presented in Chapter 1. In order to achieve the aims of the study, an understanding of how fetal pig ICCs behave when placed within a barium alginate microcapsule both in vitro and in vivo is essential and this data is presented in Chapter 3. This chapter demonstrates that ICCs will survive and differentiate in their typical manner when enclosed within microcapsules and transplanted. Such encapsulated cells will function to normalise BGL when transplanted into diabetic immunodeficent mice for at least 25 weeks and the animals exhibit increased bodyweight. Microcapsules retrieved at this time point were observed to be intact with no breakages or evidence of cellular overgrowth. Transplantation of encapsulated insulin-producing cells into immunocompetent mice are described in Chapter 4. Allotransplantation of a microencapsulated mouse insulin-producing cell line into these diabetic mice also exhibited graft function, resulting in normal BGL in recipients. Large animal experiments are described in Chapter 5. Allotransplantation of microencapsulated fetal pig ICCs into diabetic pig recipients displayed evidence of transient graft function in terms of lower BGL and reduced exogenous insulin requirements. The xenotransplantion of encapsulated fetal pIg ICCs into diabetic immunocompetent mice described in Chapter 4 proved to be more challenging. The transplantation of such cells in this environment did not yield particularly positive results. BGL remained elevated in these recipients and the animals lost bodyweight post transplantation. This area of research warrants further investigation as it is likely that further measures such as transient immunosuppression in combination with microencapsulation will allow fetal pig ICCs to function in a xenograft setting.
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Wang, Yan-Jiang, and yanjiang_wang@tmmu edu cn. "Clearance of amyloid-beta in Alzheimer's disease: To understand the pathogenesis and develop potential therapies in animal models." Flinders University. School of Medicine, 2010. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20100419.124325.
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Alzheimer's disease (AD) is the most common cause of dementia. No strong disease-modifying treatments are currently available. Amyloid-beta peptide (Abeta) appears to play a pivotal role in the pathogenesis of AD. We focused our interest on revealing the pathogenesis of the disease and developing novel therapeutic modalities. The thesis consists of three projects:
1. Prevention of AD by intramuscular delivery of an anti-Abeta single chain antibody (scFv) gene:
Immunotherapy is effective in removing brain Abetazbut was associated with detrimental effects. In the present study, the gene of an anti-Abeta scFv was delivered in the hind leg muscles of APPSwe/PS1dE9 mice with adeno-associated virus at three months of age. Six months later, we found that brain Abeta accumulation, AD-type pathologies and cognitive impairment were significantly attenuated in scFv-treated mice relative to enhanced green fluorescence protein (EGFP)-treated mice. Intramuscular delivery of scFv gene was well tolerated by the animals. These findings suggest that peripheral application of scFv is effective and safe in preventing the development of AD, and would be a promising non-inflammatory immunological modality for prevention and treatment of AD.
2. Prevention of AD with grape seed derived polyphenols: Polyphenols extracted from grape seeds are able to inhibit Abetanaggregation, reduce Abeta production and protect against Abeta neurotoxicity in vitro. We investigated the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in vivo. APPSwe/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.07% curcumin, or diet with 2% GSE beginning at 3 months of age for 9 months. Total phenolic content of GSE was 592.5 mg/g dry weight, including gallic acid, catechin, epicatechin and proanthocyanidins. Long-term feeding of GSE diet was well tolerated. The Abetanlevels in the brain and serum of the mice fed with GSE were reduced by 33% and 44% respectively compared with the mice fed with the control diet. Amyloid plaques and microgliosis in the brain of mice fed with GSE were also reduced by 49% and 70% respectively. In conclusion, polyphenol-rich GSE is promising to be a safe and effective drug to prevent the development of AD.
3. Roles of p75NTR in the development of AD: P75NTR has been suggested to mediate Abeta induced neurotoxicity. However, its role in the development of AD is undetermined. APPSwe/PS1dE9 transgenic mice were crossed with p75NTR knockout mice to generate APPSwe/PS1dE9 mice with p75NTR gene deleted. P75NTR mainly expressed in the basal forebrain neurons and degenerative neurites in neocortex and hippocampus. Genetic deletion of p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Abeta levels, but increased the insoluble Abeta accumulation and Abeta plaque formation in the brain. P75NTR deletion decreased Abeta production of cortical neurons in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Abeta42 peptide in vitro, and reduced local Abeta plaques after hippocampus injection in vivo. Our data suggest that p75NTR plays an important role in AD development and may be a valid therapeutic target for the treatment of AD.
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Black, Shawn Clive. "Studies on the effect of experimental insulin-dependent diabetes mellitus and hypothyroidism on rat cardiac and saroplasmic reticulum function." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/30597.
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The objective of these studies was to investigate mechanisms whereby cardiac sarcoplasmic reticulum (SR) calcium transport activity may be influenced by changes in the lipid environment of the SR membrane in the experimental endocrine disease states hypothyroidism and insulin-dependent diabetes mellitus. These endocrine disease states were studied to determine, respectively, if SR function is influenced by endogenous acylcarnitine associated with the SR membrane and if SR phospholipid acyl composition plays a role in diabetes-induced cardiomyopathy.
The effects of endogenous acylcarnitines on SR calcium transport in hypothyroidism were of interest since it has previously been implicated that acyl carnitines play a regulatory role in SR function. SR calcium transport was not affected at two weeks, but was significantly reduced at four, six and eight weeks following thyroidectomy. Endogenous acyl carnitines were detectable in the SR membrane fraction isolated from both euthyroid control and thyroidectomized animals. The level of acyl carnitine associated with the SR did not correlate with calcium transport activity. Since acylcarnitine did not appear to play a role in the reduced SR calcium transport, SR calcium pump protein was quantified. The reduced SR calcium transport of thyroidectomized animals, manifest at four weeks, was shown to correlate with a reduction in SR acylphosphoprotein level. Therefore the reduced SR calcium transport activity of hypothyroidism is not related to the level of SR acyl carnitine, but rather a hypothyroid-induced reduction in SR calcium pump sites.
Since omega-3 fatty acids affect parameters relevant to diabetes-induced cardiomyopathy, it was of interest to determine the cardiac effects
of omega-3 fatty acid treatment of streptozocin (STZ)-induced diabetic animals. Omega-3 fatty acid treatment significantly reduced the development of diabetic cardiomyopathy and improved isolated cardiac SR calcium transport activity of STZ-induced diabetic animals. To determine if the cardiac and SR changes were related to membrane changes induced by omega-3 fatty acids, the fatty acyl composition of phospholipid was determined. Phospholipid analysis of cardiac phosphatidylcholine and phosphatidylethanolamine, and total SR phospholipid indicated modest changes in the omega-3 fatty acid component. Omega-3 fatty acid treatment produced slight (statistically insignificant) changes in SR cholesterol levels. Therefore a change in membrane phospholipid acyl composition may not account for the observed cardiac and SR functional changes.<br>Pharmaceutical Sciences, Faculty of<br>Graduate
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Haeser, Alexsandro da Silva. "O Estresse oxidativo e a depressão no diabetes em modelo animal : o efeito do clonazepam." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2006. http://hdl.handle.net/10183/10451.
Full textAbstract:
Objetivo: o presente estudo teve como objetivo avaliar o estresse oxidativo em animais diabéticos e não diabéticos submetidos ao modelo experimental de depressão, o nado forçado, e os efeitos do clonazepam, um modulador positivo GABAA, correlacionado os efeitos comportamentais com as alterações bioquímicas. Metodologia: ratos Wistar machos com 30 dias de idade, foram induzidos ao Diabetes por estreptozotocina e submetidos ao teste de natação forçada 21 dias após a indução. Após uma ambientação, o clonazepam foi administrado na dose 0,5 mg/Kg, bem como solução salina nos controles, 24, 5 e 1 hora antes do teste. A freqüência e a duração dos comportamentos neste teste foi registrada em vídeo cassete para avaliação etológica dos comportamentos por pesquisador treinado. Trinta minutos após o teste, os animais foram sacrificados por decapitação e foram separados o plasma e os eritrócitos, bem como os tecidos cerebrais córtex pré-frontal, estriado e hipocampo. Foram avaliadas as espécies reativas ao ácido tiobarbitúrico (TBARS) e a reatividade antioxidante total (TAR), bem como a atividade das enzimas antioxidantes catalase (CAT) e superóxido dismutase (SOD). Resultados e discussão: os resultados mostraram um aumento significativo do TBARS e uma diminuição significativa do TAR no plasma de animais diabéticos, efeitos estes revertidos pelo clonazepam. Não houve alteração na atividade da SOD e da CAT em eritrócitos. No hipocampo observou-se um aumento significativo no TBARS nos diabéticos, também revertido pelo clonazepam, sendo que nenhuma alteração foi verificada na medida do TAR. O aumento significativo do TBARS no córtex de ratos diabéticos, um indicador de lipoperoxidação, e a diminuição significativa do TAR no córtex dos animais diabéticos, um indicador da capacidade de modulação da ação dos radicais livres produzidos, não foram revertidos pela administração do clonazepam neste tecido cerebral. Ainda, não houve alteração do TBARS e do TAR no estriado dos grupos testados. O clonazepam foi capaz de reverter a imobilidade dos animais diabéticos submetidos ao teste de natação forçada. Não foi verificada correlação significativa entre a imobilidade e as medidas de TBARS e TAR. Conclusão: considerando a conhecida ação ansiolítica e antidepressiva do clonazepam, sugere-se que ele possa ser uma alternativa terapêutica na depressão em pacientes diabéticos, uma vez que ele não altera a glicemia e, pelos resultados aqui apresentados, teria uma ação protetora contra os radicais livres, os quais sabidamente contribuem para o desenvolvimento das complicações secundárias de Diabete Mellitus.<br>Objective: the present study had as objective to evaluate the oxidative stress from diabetic animals submitted to an experimental model of depression (forced swimming) and the effects of clonazepan, a GABA agonist, correlating behavioral with biochemical effects. Methodology: male Wistar rats, 30 days years old, were induced to diabetes with streptozotocin and submitted to forced swimming test 21 days after induction. After to be accustomed with the environment, clonazepan was administered to rats in a dose of 0,5 mg/kg, as well as saline solution to control rats, 24, 5 and 1 hours before test. The frequency and duration of behaviour in the test were filmed for ethologic evaluation by a trained pearson. Thirty minutes after test, the animals were sacrified by decapitation, and plasma and erythrocytes were separated, as well as hippocamp, cortex and striatum. Reactive species of tiobarbituric acid (TBARS) and total antioxidant reactivity (TAR), as well as antioxidant enzyme activities catalase (CAT) and superoxide dismutase (SOD) were evaluated. Results and discussion: results showed a significant increase of TBARS and a significant decrease of TAR in plasma from diabetic animals, which was altered by clonazepan. There were no effect of CAT and SOD activities in erytrocytes from tested animals. The results observed in hippocamp showed a significative increase of TBARS from diabetics rats, inverted by clonazepan, and no one alteration was verified in TAR. The significant increase of TBARS in cortex from diabetic rats, an indicator of lipoperoxidation, and the significant decrease of TAR in cortex from diabetic rats, an indicator of modulation capability against free radicals, were not altered by clonazepan administration. Besides, there were no alteration of TBARS and TAR in striatum from tested animals. Clonazepan was capable to alter the immobility from diabetic animals submitted to forced swimming. There was no significative correlation between immobility and TBARS neither TAR measurements. Conclusion: considering the ansiolitic and antidepressive action of clonazepan, it’s suggested that it could be an alternative therapeutic for depression to diabetic patients, once clonazepan do not alter glycemia and, by the results here presented, could give a protection against free radicals, which are known to contribute to the development of complications in Mellitus Diabetes.
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Pringle, Nadine Alex. "Characterization of a glycated gelatin model to explore the therapeutic properties of macrofungi in diabetic wound healing: an in vitro study." Thesis, Nelson Mandela Metropolitan University, 2017. http://hdl.handle.net/10948/11992.
Full textAbstract:
Diabetic wounds frequently undergo impaired and prolonged wound healing due to a multitude of factors including hypoxia, impaired angiogenesis, hyperglycaemia, formation of ROS and AGEs, and infection - all of which may lead to cellular dysfunction. To date, however, treatment options for individuals suffering from impaired diabetic wound healing are limited, non-specific, and generally unsuccessful. The search for new and effective treatment strategies is severely hampered by the availability of adequately characterized screening models which comprehensively mimic the complexity of the diabetic wound healing process. In order to explore natural products as potential therapeutics to treat diabetic wounds and to encourage more research on this topic, this study sought out to develop and characterize a more convenient and cost effective in vitro screening assay which mimics the effects of protein glycation on the healing process of diabetic wounds. As proof of principal, this model was subsequently used to screen the potential of five wild mushroom species (P. tinctorius, R. capensis, B. badius, P. ostreatus and G. lucidum) as suitable diabetic wound healing therapies. The glycated gelatin model developed during this study was found to suitably mimic the diabetic state as it successfully simulated the major cellular dysfunctions in macrophages (NO production, phagocytosis, macrophage polarization, NF-ĸB translocation and COX-2 expression) and fibroblasts (proliferation and migration) documented during diabetic wound healing. Together these findings provide confidence that the model may serve as a valuable tool to study the poorly understood mechanisms which characterize cellular dysfunction in response to AGE accumulation and also to aid the identification of novel therapeutic agents to treat this pathology. Screening a number of mushroom extracts revealed that the ethanol extracts of R. capensis and P. ostreatus had the greatest potential for attenuating chronic inflammation due to their ability to promote macrophage phagocytosis, increased M2 activation (R. capensis) and decreased M1 activation (P. ostreatus) as well as reduced COX-2 expression while the water extract of G. lucidum proved to be the most promising candidate for stimulating fibroplasia as it was the most successful at promoting both fibroblast proliferation and migration. Different mushroom species were thus shown to promote different stages of the wound healing process providing sufficient evidence to support further studies related to the use of macrofungi as therapeutic agents in the search for more cost-effective and efficient treatment strategies for impaired diabetic wound healing.
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Young, James L. "Innate Immunity in Type 2 Diabetes Pathogenesis: Role of the Lipopolysaccharide Signaling Cascade: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/400.
Full textAbstract:
Once seen as a disease of wealthy nations, type 2 diabetes mellitus is now showing unprecedented growth throughout the world, fueling increases in microvascular and macrovascular complications. A compelling and growing body of evidence suggests that glucose intolerance and insulin resistance, hallmarks of the diabetic patient, may be driven by chronic inflammation. In particular, a predominance of visceral fat has been associated with enhanced inflammatory cytokine secretion that may contribute to enhanced risk of diabetes and comorbid cardiovascular disease in these individuals. As a function of its potency and wide environmental and biological distribution, we hypothesized that bacterial lipopolysaccharide (LPS, also known as endotoxin) may promote adipose inflammation and concomitant metabolic dysfunction.
Indeed, expression of the LPS receptor CD14 is enhanced on visceral adipocytes of ob/ob mice, paralleling enhanced IL-6 secretion ex vivo. Furthermore, rosiglitazonefed ob/obmice demonstrated a reduction in CD14 that coordinated with diminished IL-6 secretion, suggesting a basis for the touted anti-inflammatory effects of this commonly employed type 2 diabetes medication. Mice deficient in components of the LPS signaling cascade, namely CD14, TLR4, and MyD88, yielded adipocytes with markedly attenuated IL-6 secretion, corroborating the central importance of LPS in adipocyte inflammation and supporting the role of this signaling pathway in depot-specific inflammation.
Despite the prominent role of LPS signaling in adipocyte inflammation, CD14-, TLR4-, and MyD88-deficient mice failed to show resistance to diet induced obesity. Surprisingly, cd14-/- and tlr4-/- mice had marked glucose intolerance without alteration in total weight or adipose accumulation. In contrast, myd88-/- mice revealed minor glucose intolerance only with high fat diet challenge at an advanced age despite being overtly obese. In cd14-/- and tlr4-/-, but not myd88-/-, mice, an exaggerated rebound to hypoglycemia was associated with enhanced norepinephrine secretion, which could be abrogated by the adrenergic β-blocker propranolol. The overlay of these mouse models reveals a divergence of phenotypes that demonstrate LPS signaling disruption may lead to glucose intolerance and insulin resistance in part due to enhanced sympathoadrenal tone, uncovering an essential role of innate immunity in physiological stress and its impact upon glucose homeostasis.
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Rudrich, Horst R. "The reduction of the diabetic syndrome in the C57Bl/KsJ (db/db) diabetic mouse by diet-restriction and exercise." CSUSB ScholarWorks, 1985. https://scholarworks.lib.csusb.edu/etd-project/425.
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Zhang, Qing, and 張清. "Comparison of mycophenolate mofetil and cyclophosphamide on inflammatory and fibrotic processes in the pathogenesis of lupusnephritis: animal and in vitro studies." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085222.
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Kalousek, A. Kay. "The effect of intraperitoneally administered thyroxine, thiidothyronine and iopanoic acid on the in vivo and in vitro oxygen consumption rates of normal (C57BL/KsJ DB/M) and diabetic (C57BL/KsJ DB/DB) mice." CSUSB ScholarWorks, 1986. https://scholarworks.lib.csusb.edu/etd-project/363.
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Schenk, Johannes. "Examination of cardiovascular function in conscious hypertensive diabetic rats." Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30318.
Full textAbstract:
This investigation was concerned with measuring aspects of cardiac function in conscious control, diabetic, hypertensive control, and hypertensive diabetic rats.
Preliminary studies were conducted to determine catheter suitability and acute responses to atropine and angiotensin II in conscious animals. The catheter-manometer was tested using a square wave impact and was shown to accurately reproduce a left ventricular pressure pulse. Intravenous atropine caused both heart rate and left ventricular +dP/dt to rise. Intravenously administered angiotensin II caused systolic blood pressure to increase dramatically. In this case heart rate fell and +dP/dt was elevated.
Hypertension was induced with deoxycorticosterone acetate (DOCA) and saline drinking water. Rats were first made diabetic with streptozotocin (60 mg/kg; i.v.). One week following this, subcutaneous DOCA (25 mg/kg) was administered twice weekly and all animals received saline drinking water. Following 2 and 5 weeks of DOCA treatment rats were catheterized and resting cardiovascular function was measured.
DOCA treatment caused increased systolic and diastolic blood pressures to occur in control and diabetic rats at 2 and 5 weeks. Bradycardia was also observed in DOCA-diabetic and DOCA-control rats at 2 and 5 weeks of treatment. Two and 5 week hypertensive diabetic and control rats exhibited elevated -dP/dt and +dP/dt. The rate of contraction was shown to be proportional to the magnitude of systolic blood pressure in all treatment groups. It is concluded that diabetic rats and control rats did not differ in their response to hypertension after 5 weeks of DOCA treatment.<br>Medicine, Faculty of<br>Anesthesiology, Pharmacology and Therapeutics, Department of<br>Graduate
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Clark, Catherine Renee. "Thyroid hormone influence on oxygen consumption rates, body mass, and lipid metabolism in mice with noninsulin dependent diabetes mellitus." CSUSB ScholarWorks, 1995. https://scholarworks.lib.csusb.edu/etd-project/1025.
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Nicholl, Tessa Anne. "Effect of free fatty acids and dichloroacetic acid on the diabetic isolated working rat heart." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/29641.
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It is well established that a cardiomyopathy independent of atherosclerosis develops in both humans and animals with diabetes mellitus. The etiology of diabetic cardiomyopathy is very complex involving many different processes, one of which may be the increased fatty acid utilization, and/or the concomitant decrease in glucose utilization, by the diabetic heart. We compared control and 6-week streptozotocin(STZ)-induced diabetic isolated working rat hearts and were able to demonstrate cardiac dysfunction in the diabetic as assessed by depressed heart rate (HR), heart rate peak systolic pressure product (HR X PSP), left ventricular developed pressure (LVDP), rate of pressure rise (+dP/dt) and rate of pressure decline (-dP/dt). Paralleling depressed cardiac function in the diabetic were hyperglycemia, hyperlipidemia and decreased body weight gain as compared to age-matched controls. The addition of free fatty acids, in the form of 1.2 mM palmitate, to the isolated working heart perfusate had no effect on either control or diabetic heart function, with the exception of a depressive effect on +dP/dt of diabetic hearts and -dP/dt of control hearts. But, diabetic hearts perfused with palmitate-containing perfusate plus the glucose oxidation stimulator dichloroacetate (DCA) showed a marked improvement in function. Heart rate, HR X PSP, LVDP and +/-dP/dt were all restored to control heart values in diabetic hearts perfused in the presence of DCA. Creatine phosphate and adenosine 5'-triphosphate (ATP) levels were similar under all perfusion conditions, therefore eliminating energy stores as the limiting factor in heart function. Results indicate that DCA-induced stimulation of glucose oxidation acutely reversed diabetic cardiac function depression. Therefore, depression of glucose oxidation in the diabetic heart may be contributing to diabetic cardiomyopathy.<br>Pharmaceutical Sciences, Faculty of<br>Graduate
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Alvino, De la Sota Nora, and Calderón Javier Pacheco. "Diseño de Agentes Antidiabéticos de Vanadio: Desarrollo y Avances Recientes." Revista de Química, 2007. http://repositorio.pucp.edu.pe/index/handle/123456789/100688.
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El descubrimient o del mayor efecto hipoglicémic o del bis(maltolato)oxovanadio (IV) (BMOV) con respecto a las salesde vanadio, propició el diseño, síntesis y evaluación in vitro e in vivo de una amplia variedad de complejos de oxovanadio(IV) con diversos ligandos orgánicos para su potencial uso como fármacos antidiabéticos que reemplacen , parcial ototalmente , las incómodas inyecciones de insulina en el tratamiento de la diabetes mellitus tipo 1 o los fármacos oraleshipoglicemiante s empleados generalment e en terapias combinadas para la tipo 2.Recientemente , un complejo etil sustituido , análogo al BMOV, ha completado favorablemente la fase clínica I deensayos en humanos. El diseño de nuevos tipos de complejos y el desarrollo de nuevos modos de administración constituyenactualmente un activo campo de investigación<br>Design of Vanadium Antidiabetic Agents: Development and Recent AdvancesThe discovery of the enhanced hypoglycemic activity of bis(maltolate)oxovanadiu m (IV) (BMOV) compared to simplevanadium salts stimulated the design, synthesis and both in vitro and in vivo evaluation of a large variety of oxovanadium (IV)complexes with different organic ligands for their potential use as antidiabetic drugs that may be able to substitute, either partially or totally, the daily insulin injections used in the treatment of type 1 diabetes mellitus or the orally available hypoglycemic drugs usually used in combined therapy for type 2 diabetes.Recently, a close BMOV analogue, an ethyl substitute, has already successfully completed the phase 1 clinical trial in humans. The design of new types of complexes and the development of alternative delivery methods represent an active research field today.
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Rahim, Mir Munir Ahmed 1975. "Pathogenesis of HIV-1 nef in adult mice." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115698.
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Development of a suitable animal model of AIDS is much needed in AIDS research to study infection and pathogenesis as well as to evaluate methods of prevention and treatment of HIV infection. Small animals such as rodents are attractive candidates for AIDS research due to the availability of various inbred and genetically engineered strains, extensive knowledge or their immune system, especially in mice, and the relative ease of breeding and maintaining animal colonies. Transgenic small animal models carrying entire HIV genome or selected genes have been instrumental to understand functions of HIV genes in vivo and their role in HIV pathogenesis. The type of cells in which HIV genes are expressed seems to be an import prerequisite for the study of HIV gene functions in transgenic mice. Mice constitutively expressing the entire HIV-1 genome or HIV-1 nef gene in CD4 + T cells and in the cells of macrophage/dendritic lineage develop an AIDS-like disease very similar to AIDS disease in humans. Similarly, expression of Nef in adult mice, using inducible system, results in the AIDS-like disease. This disease is characterized by thymic atrophy, impaired thymocyte maturation, loss of CD4+ T cells, increased activation and turnover of T cells, which can occur in the absence of lymphypenia, and non-lymphoid organ disease involving the lungs and kidneys. Susceptibility of adult mice to the pathological effects of Nef suggests that the AIDS-like disease in the constitutively expressing Nef Tg mice is not due to developmental defects caused by early expression of Nef. This model highlights the important role of Nef in HIV-1 pathogenesis. The high similarity in the disease in these Tg mice with human AIDS strongly suggest that these mice are a relevant model to study AIDS. This study further evidence that mouse cells can support functions of Nef and these Tg mice represent a unique model to study Nef functions in vivo in the context of the primary immune system. Moreover, the inducible Nef Tg model has given us the ability to control the level and time of expression of Nef which was impossible to do in the previously reported constitutive Nef Tg mouse models. These mice will be useful to study immune reconstitution since Nef expression can be turned off after withdrawal from dox.
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Guarino, Maria Pedro Sucena. "Caracterização da função do monóxido de azoto e glutationo hepáticos na sensabilidade periférica à insulina." Doctoral thesis, Faculdade de Ciências Médicas. Universidade Nova de Lisboa, 2007. http://hdl.handle.net/10362/5203.
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RESUMO
A acção da insulina no músculo esquelético depende de um reflexo parassimpático
hepático que conduz à libertação de uma substância hepática sensibilizadora da
insulina, designada por HISS, responsável por cerca de 55% do efeito hipoglicemiante da
insulina. A acção da HISS é finamente regulada pelo monóxido de azoto (NO) hepático e pelo estado prandial, aumentando no período pós-prandial imediato e diminuindo
progressivamente com as horas de jejum. A secreção da HISS pode ser inibida cirúrgica
ou farmacologicamente, quer por desnervação selectiva do plexo anterior hepático,
quer por administração de atropina, quer por inibição do sintase do NO (NOS) hepático.
O objectivo geral do trabalho apresentado nesta dissertação foi a caracterização da via
de transdução de sinal que conduz à libertação da HISS. O modelo utilizado neste estudo foi o rato Wistar. A sensibilidade à insulina foi avaliada através do teste rápido de sensibilidade à insulina (RIST).
A primeira hipótese de trabalho testada foi que a sequência de eventos que conduzem à secreção da HISS inicia-se com a activação do sistema parassimpático hepático seguida de activação do NOS hepático com subsequente produção de NO e activação do guanilato ciclase (GC). Observou-se que a administração de um dador de NO reverteu a resistência à insulina induzida, quer por inibição do NOS hepático, quer por
antagonismo dos receptores muscarínicos com atropina. Em contraste, a resistência à
insulina produzida por inibição do NOS hepático não foi revertida por administração
intraportal de acetilcolina (ACh). Constatou-se que a inibição do GC hepático diminuiu a sensibilidade à insulina. Estes resultados sugerem que: a ACh libertada no fígado induz a síntese de NO hepático que conduz à libertação da HISS, que por sua vez é modulada pelo GC hepático.
A libertação da HISS em resposta à insulina é regulada pelo estado prandial. Uma vez
que os níveis hepáticos de glutationo (GSH) se encontram, tal como a HISS, diminuídos no
estado de jejum e aumentados após a ingestão de uma refeição, testou-se a hipótese de
que o GSH hepático está envolvido na secreção da HISS. Observou-se que a depleção
do GSH hepático induziu resistência à insulina, comparável à obtida após inibição do NOS hepático. Estes resultados suportam a hipótese de que o GSH hepático desempenha
um papel crítico na acção periférica da insulina.
Considerando que, no estado de jejum, tanto os níveis de GSH hepático como os
níveis de NO hepático são baixos, testou-se a hipótese de que a co-administração
intraportal de um dador de GSH e de um dador de NO promove um aumento da sensibilidade à insulina no estado de jejum, devido ao restabelecimento do mecanismo da HISS. Observou-se que a administração sequencial de dadores de GSH e de NO no fígado provocou um aumento na sensibilidade à insulina, dependente da dose de dador de GSH administrada. Concluiu-se portanto que ambos, GSH e NO, são essenciais para
que o mecanismo da HISS esteja completamente funcional.
O GSH e o NO reagem para formar um S-nitrosotiol, o S-nitrosoglutationo (GSNO). Os resultados supra-mencionados conduziram à formulação da hipótese de que a
secreção/acção da HISS depende da formação de GSNO. Observou-se que a administração intravenosa de S-nitrosotióis (RSNOs) aumentou a sensibilidade à insulina,
em animais submetidos a um período de jejum, ao contrário da administração intraportal
destes fármacos, o que RSNOs têm uma acção periférica, mas não hepática, na sensibilidade à insulina.
Os resultados obtidos conduziram à reformulação da hipótese da HISS, sugerindo que a ingestão de uma refeição activa os nervos parassimpáticos hepáticos levando à
libertação de ACh no fígado que, por sua vez activa o NOS. Simultaneamente, ocorre um
aumento dos níveis de GSH hepático que reage com o NO hepático para formar um composto nitrosado, o GSNO. Este composto mimetiza a acção hipoglicemiante da HISS no músculo esquelético. SUMMARY
Insulin action at the skeletal muscle depends on a hepatic parasympathetic reflex that
promotes the release of a hepatic insulin sensitizing substance (HISS) from the liver, which contributes 55% to total insulin action. HISS action is modulated by hepatic nitric oxide (NO) and also by the prandial status so as to, in the immediate ostprandial state, HISS action is maximal, decreasing with the duration of fasting. HISS secretion may be inhibited by interruption of the hepatic parasympathetic reflex, achieved either by surgical
denervation of the liver or by cholinergic blockade with atropine, or by prevention of
hepatic NO release, using NO synthase (NOS) antagonists.
The main objective of this work was to characterize the signal transduction pathways
that lead to HISS secretion by the liver. Wistar rats were used and insulin sensitivity was evaluated using the rapid insulin sensitivity test (RIST).
The first hypothesis tested was that the sequence of events that lead to HISS secretion starts with an increase in the hepatic parasympathetic tone, followed by the activation of hepatic NOS and subsequent triggering of guanylate cyclase (GC). We observed that insulin resistance produced either by muscarinic receptor antagonism with atropine or by hepatic NOS inhibition was reversed by the intraportal administration of an NO donor. In contrast, intraportal acetylcholine (ACh) did not restore insulin sensitivity after NOS
inhibition. We also observed that GC inhibition lead to a decrease in insulin sensitivity.These results suggest that the release of ACh in the liver activates hepatic NO synthesis in order to allow HISS secretion, through a signaling pathway modulated by GC. HISS release in response to insulin is controlled by the prandial status. The second hypothesis tested was that glutathione (GSH) is involved in HISS secretion since the hepatic levels of GSH are, like HISS action, decreased in the fasted state and increased after ingestion of a meal. We observed that hepatic GSH depletion led to insulin resistance of the same magnitude of that observed after inhibition of hepatic NOS. These results support the hypothesis that hepatic GSH is crucial in peripheral insulin action.
Since, in the fasted state, both hepatic GSH and NO levels are low, we tested the
hypothesis that intraportal o-administration of a GSH donor and an NO donor enhances
insulin sensitivity in fasted Wistar rats, by restoring HISS secretion. We observed that GSH and NO increased insulin sensitivity in a GSH dose-dependent manner. We concluded that HISS secretion requires elevated levels of both GSH and NO in the liver. GSH and NO react to form a S-nitrosothiol, S-nitrosoglutathione (GSNO). The last hypothesis tested in this work was that HISS secretion/ action depends on the formation of GSNO. We observed that intravenous administration of -nitrosothiols (RSNOs) increased insulin sensitivity in animals fasted for 24 h, in contrast with the intraportal administration of the drug. This result suggests that RSNOs enhanced insulin sensitivity through a peripheral,
and not hepatic, mechanism. The results obtained led to a restructuring of the HISS hypothesis, suggesting that the ingestion of a meal triggers the hepatic parasympathetic nerves, leading to the release of Ach in the liver, which in turn activates NOS. Simultaneously, hepatic GSH levels increase
and react with NO to form a nitrosated compound, GSNO. S-nitrosoglutathione mimics
HISS hypoglycaemic action at the skeletal muscle.
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Xiang, Li. "Metabolomics study of regulatory effects of exercise training on db/db type 2 diabetic mice." HKBU Institutional Repository, 2018. https://repository.hkbu.edu.hk/etd_oa/489.
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Type 2 diabetes mellitus (T2DM) is mainly caused by genetic modifications and inappropriate life styles. The complexity of T2DM has brought us challenges for a comprehensive understanding of altered metabolic pathways that contributing to the development of T2DM. Therefore, a comprehensive metabolic analysis is needed. To date, taking regular exercise is a common and effective therapeutic way known to antagonize the metabolic disorders of T2DM. However, the regulatory effects of exercise on T2DM or T2DM induced complications have not been clearly characterized. Here, we present the effect of physical activity on biochemical changes in diabetic db/db mice in plasma, urine, skeletal muscle and kidney samples. Based on liquid chromatography coupled with high resolution Orbitrap mass spectrometry (LC-MS) and gas chromatography coupled with mass spectrometry (GC-MS), two major approaches, untargeted and targeted metabolomics studies, have been developed to delineate metabolic signatures in various kinds of biofluid and tissue samples. Targeted quantification methods on acylcarnitines and acyl-CoA have been developed. Untargeted metabolomics analysis by GC-MS and LC-MS have also been developed to draw a more comprehensive view of the metabolic changes in response to T2DM and exercise on db/db diabetic mice. The transcript expressions of mRNA in pathways of interest have also been measured to confirm the hypothesis. Firstly, a targeted quantification method of acylcarnitines by using high resolution parallel reaction monitoring (PRM) on LC-MS platform has been developed. A total of 117 acylcarnitines were detected from plasma and urine samples. The application of targeted profiling of acylcarnitines in db/m+ control and db/db diabetic mice indicated incomplete amino acid and fatty acid oxidation in diabetic mice. Interestingly, the reduction of medium odd-numbered chain acylcarnitines in urine samples was firstly observed between db/m+ and db/db mice. The high resolution PRM method makes it possible to monitor the widespread metabolic changes of the acylcarnitines in response to stimuli. Besides, the accurate MS and MS/MS spectra data of the 117 acylcarnitines could be used as mass spectrometric resources for the identification of acylcarnitines. In addition to targeted metabolomics analysis, untargeted metabolomics profiling analysis in plasma samples indicated that db/db diabetic mice may be more susceptible to exercise for energy expenditure. Interestingly, all the results from plasma, skeletal muscle and kidney samples may demonstrate that physical activity could mitigate insulin resistance in T2DM mice through improving fatty acid β-oxidation (FAO) and eliminating overloaded intermediate which contribute to insulin resistance. Specifically, the results from kidney samples demonstrated that exercise exhibit beneficial effect in reducing hyperlipidemia, expression levels of inflammatory markers (TNFα, IL-6 and COX2) and fibrosis markers (Collagen 1), and alleviating diabetic nephropathy (DN) induced mesangial expansion in kidneys of diabetic mice. The results of metabolic changes in kidney of db/db mice revealed that the accumulation of acyl-CoA, phospholipids and hydroxylated acylcarnitines were substantially ameliorated by exercise, and the reduction of important enzymes CTP1α and Acadl in FAO were partially reversed. In addition, branched-chain amino acids (BCAA) metabolism which positively related to inflammation (TNFα) was down-regulated in DN mice by exercise. What’s more, the accumulation of uric acid, which contributes to inflammation and tubulointestitial fibrosis in kidney disease, together with its six precursors have also been substantially reduced. The results in kidney samples demonstrated that in addition to beneficial effect in alleviating lipotoxicity through improving FAO efficiency, exercise also ameliorated diabetic induced inflammation and fibrosis via promoting BCAA catabolism and accelerating the elimination of uric acid. Together, the mass spectrometry-based metabolomics study is a powerful tool to investigate the regulatory effect of exercise on complex metabolic diseases. The results may provide informative insights into the underlying the mechanism of exercise on T2DM and T2DM induced complications.
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Klöting, Nora. "Phenotypic and genetic analysis in animal models and humans with type 1 diabetes or metabolic syndrome: unraveling complex mammalian diseases." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974087254.
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Song, Dongzhe. "Cardiovascular function in animal models of metabolic syndrome and type 2 diabetes : the role of inducible nitric oxide synthase (iNOS)." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/822.
Full textAbstract:
Activation of inducible nitric oxide synthase (iNOS) and oxidative stress have been shown to be associated with compromised cardiovascular function in streptozotocin (STZ)-induced type 1 diabetes. The aim of the project is to investigate cardiovascular abnormalities in a rat model of type 2 diabetes (Zucker diabetes fatty or ZDF rats) and two models of metabolic syndrome (fructose-fed rats and Zucker obese rats), and to provide direct evidence linking iNOS and oxidative stress to abnormal cardiovascular function in these disorders. Blood pressure, cardiac contractility, cardiac index, regional flow, vascular resistance and venous tone were measured in diseased as well as normal rats. Biochemical analyses such as activities of iNOS, immunostaining of iNOS and western-blot analysis of iNOS in the heart tissue were carried out. The results showed that cardiac contractile response to dobutamine was compromised in the ZDF rats, and this was associated with increased myocardial protein expression as well as activity of iNOS. The formation of peroxynitrite was increased in the heart tissue of the ZDF rats. Selective inhibition of iNOS by 1400W (N-3-aminomethyl-benzyl-acetamidine) did not alter responses to dobutamine in the control rats, but augmented the contractile effects of dobutamine in the diabetic rats. The regional blood flow was altered in the ZDF rats, and iNOS played a negligible role in regulating regional flow in the ZDF rats. Although venous response to noradrenaline was also altered in the Zucker obese rats, NOS may not be involved in venous tone regulation. Anti-oxidative treatment with N-acetylcysteine inhibited the development of insulin resistance, blood pressure elevation and the increase of 8-isoprostane formation in the fructose-fed rats. We conclude that heart function is compromised and regional blood flow is altered in the ZDF rats. Activation of iNOS plays an important role in suppressing heart dysfunction but does not affect regional blood flow. In Zucker obese rats with metabolic syndrome, iNOS may not be involved in changes of venous function. Oxidative stress is associated with both abnormality of heart dysfunction in type 2 diabetes (by formation of peroxynitrite due to iNOS activation) and development of hypertension and insulin resistance in metabolic syndrome.
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Wang, Yiqun, and 王逸群. "Berberine as a potential therapeutic agent for treating vascular dysfunction in diabetes: targeting AMP-activated protein kinase." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B43703616.
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Witczak, Carol A. "Regulation of coronary smooth muscle intracellular Ca²⁺ levels in porcine models of hyperlipidemia, diabetic dyslipidemia, and exercise training." free to MU Campus, others may purchase, 2003. http://www.lib.umi.com/cr/mo/fullcit?p3091979.
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Lau, Tik-yan Ivy, and 劉荻茵. "Macrophage-adipocyte cross-talk in the initiation of obesity-related insulin resistance and type 2 diabetes: roleof adiponectin." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B4129046X.
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Andersen, Ditte K. "The role of microRNAs in skeletal muscle insulin resistance." Thesis, Royal Veterinary College (University of London), 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701676.
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Afonso, Ricardo Alexandre da Silva Santos. "Sensibilidade à insulina pós-prandial: mecanismos fisiológicos e de activação e fisiopatologia na obesidade." Doctoral thesis, Faculdade de Ciências Médicas. Universidade Nova de Lisboa, 2008. http://hdl.handle.net/10362/5102.
Full textAbstract:
RESUMO
A acção hipoglicemiante da insulina é máxima no estado pós-prandial e depende
da substância hepática sensibilizadora da insulina (HISS). Esta dissertação visa o estudo
do mecanismo de acção da insulina no estado pós-prandial e em particular da via
dependente da HISS, em modelos animais fisiológicos e patológicos (obesidade e
diabetes mellitus tipo 2).
Avaliaram-se diferentes tipos de refeição quanto ao seu efeito potenciador da
acção da insulina, em ratos Sprague-Dawley (modelo fisiológico). A administração
intragástrica de glícidos não afecta a acção da insulina, mas a refeição mista (lípidos,
glícidos e proteínas), promove a sensibilização para a acção da insulina, através de um
processo que parece ser iniciado no intestino e envolve a activação da via da HISS.
Nos estudos de obesidade, o primeiro modelo utilizado foi o rato alimentado com
dieta hiperlipídica (HFD), no qual se observou uma insulinorresistência pós-prandial
devida quase exclusivamente à perda de acção da HISS, que se correlaciona com a
adiposidade (corporal e abdominal) e parece ser devida à diminuição da sua síntese.
O segundo modelo de obesidade usado foi o rato Zucker obeso (OZR), modelo
genético que apresenta uma diminuição idêntica de ambas as componentes de acção da
insulina (dependente e independente da HISS). A alteração na via da HISS parece
localizar-se a jusante da sua síntese, sugerindo que um ou vários pontos comuns entre
as vias de sinalização intracelular da HISS e da insulina per se estão alterados,
resultando num diminuto aporte de glucose. No OZR, a acção da HISS não se altera com
a idade, apresentando-se baixa também às 52 semanas de idade. Em ratos não obesos
(LZR), a acção da HISS diminui entre as 9 e 52 semanas, sendo acompanhada por um
decréscimo menos acentuado, embora significativo, da acção da insulina per se. A
diminuição da acção da HISS com a idade parece ser a principal causa de
insulinorresistência pós-prandial em LZR velhos, não se agravando no OZR.
No modelo de diabetes tipo 2 estudado, o rato Zucker diabético (ZDF), também
ambas as componentes de acção da insulina estavam diminuídas. No entanto, a
alimentação com ração Purina, ligeiramente mais energética e lipídica do que a ração
standard, agrava a disfunção da via da HISS nestes animais, sugerindo que a
sensibilidade à insulina em ratos ZDF é muito susceptível a factores nutricionais.
A via da HISS é essencial para potenciar a acção da insulina do estado de jejum
para o pós-prandial e a sua disfunção é em grande medida responsável pela
insulinorresistência observada nos modelos animais de obesidade e diabetes estudados.
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SUMMARY
Hypoglycemic insulin action is maximal in the postprandial state and depends on
the hepatic insulin sensitizing substance (HISS). The present thesis focus on the
postprandial insulin action and, in particular, on the HISS-dependent pathway, both in physiological and pathological (obesity and type 2 diabetes mellitus) animal models.
Different meals were tested in Sprague-Dawley rats (physiological model) for
their capacity to potentiate insulin action. It was observed that intragastric
administration of either glucose or sucrose does not affect insulin sensitivity, unlike the
mixed meal, composed of lipids carbohydrates and proteins, which significantly
potentiated insulin action through a process that seems to be initiated at the intestine
and involves activation of the HISS pathway.
For the obesity studies, the first of the two obesity models used was the high
fat-fed rat (HFD), in which the postprandial insulin resistance was almost exclusively
caused by the decrease of HISS action, probably due to the impairment of HISS
synthesis. This impairment correlates with both corporal and abdominal adiposity.
The second obesity model used was the obese Zucker rat (OZR), a genetic model,
which presented a similar impairment of both components of insulin action (HISSdependent
and –independent). The modification in HISS pathway in OZR seems to be located downstream from HISS synthesis, that is, at its site of action – the skeletal
muscle -, suggesting that one or several points common to both HISS and insulin per se
signaling cascades are defective, resulting in a decreased glucose uptake.
In OZR, HISS action does not decrease with age and is also low at 52 weeks of
age. In non-obese rats (LZR), HISS action decreases from 9 to 52 weeks and it is
accompanied by a lower, although significant, impairment of insulin action per se. HISS action impairment with aging seems to be the major cause of insulin resistance in old LZR, whereas insulin resistance is not aggravated in aging OZR.
In the type 2 diabetes model, the diabetic Zucker rat (ZDF), both components of
insulin action were also equally impaired. However, feeding the animals with Purina rat
chow, which is slightly more caloric and more lipidic, induces additional HISS
deterioration when compared with the standard lab diet, suggesting that insulin
sensitivity in ZDF is very susceptible to nutritional factors.
In conclusion, HISS pathway is essential to potentiate insulin action from the
fasted to the fed state and its dysfunction is highly responsible for the insulin resistance observed in the obesity and diabetes animal models studied.
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Jiao, Hong. "Genetic dissection of multifactorial disease models in the rat /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-287-6.
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Ye, Dewei, and 叶得伟. "Toll-like receptor-4 mediates obesity-induced nonalcoholic steatohepatitis through activation of X-box binding protein-1 in mice." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47752919.
Full textAbstract:
Background and objectives:
Nonalcoholic steatohepatitis (NASH), which is characterized by concurrent
existence of hepatic steatosis and predominantly lobular necroinflammation, represents
the more advanced stage in the spectrum of nonalcoholic fatty liver disease (NAFLD).
NASH exhibits dramatically increased risk of progression to end-stage liver diseases
than simple steatosis. Therefore, the progression of hepatic steatosis to steatohepatitis is
the crucial step in the development of obesity-related NASH. Toll like receptor 4
(TLR4), a master regulator of innate immunity, is the principal receptor for endotoxin,
which is a central mediator of liver inflammation associated with both alcoholic and
nonalcoholic liver disease. However, due to a lack of suitable animal models which
fully recapitulate the natural history of obesity-induced NASH, the precise
pathophysiological function of TLR4 signaling in the development of this disease
remains poorly understood.
The objective of this study is to investigate the role of TLR4 in mediating
inflammatory responses in obesity-induced NASH using both in vivo and ex vivo
approaches, and to unveil cellular and molecular mechanisms responsible for TLR4
actions.
Key findings:
1. To address the role of TLR4 in the pathogenesis of NASH, we crossed ApoEdeficient
mice (ApoE-/-) with TLR4 mutant mice (TLR4-/-) to generate ApoE-/-
/TLR4 wild type mice (ApoE-/-/TLR4-WT) and ApoE-/-/TLR4-/- mice. Noticeably,
when fed with high fat high cholesterol (HFHC) diet, ApoE-/-/TLR4-WT mice
developed the typical pathology of NASH (hepatic steatosis, lobular inflammation,
and hepatocyte ballooning) in the context of obesity and metabolic syndrome,
suggesting HFHC-fed ApoE-/- mice as a suitable animal model for NASH.
2. TLR4 inactivation protected ApoE-/- mice against HFHC diet-induced liver injury,
as indicated by a significant improvement in liver histology, a a marked reduction
in serum ALT activity, a dramatic repression of inflammatory infiltrates, as well as
an obvious decrease in hepatic production of pro-inflammatory cytokines.
3. In ApoE-/-/TLR4-WT mice, TLR4 expression was selectively elevated in Kupffer
cells in response to HFHC diet feeding.
4. The activation of XBP1, a transcription factor involved in endoplasmic reticulum
stress, was markedly elevated in liver of ApoE-/-/TLR4-WT mice fed with HFHC
diet, whereas this change was abrogated in HFHC diet-fed ApoE-/-/TLR4-/- mice.
5. In rat primary Kupffer cells, treatment with anti-oxidants blocked endotoxininduced
activation of XBP1 and NF-κB, leading to decreased cytokine production.
In addition, siRNA-mediated knockdown of XBP1 inhibited NF-κB activation and
cytokine production resulted from the treatment with the TLR4 agonist LPS.
6. In ApoE-/-/TLR4-WT mice, adenovirus-mediated expression of dominant negative
XBP1 had no obvious effect on HFHC diet-induced hepatic steatosis and ROS
production, but markedly decreased lobular inflammation, NF-κB activation,
cytokine production in the liver and significantly reduced serum levels of ALT.
Conclusions:
These findings support the role of TLR4 in Kupffer cells as a key player in
mediating the progression of simple steatosis to NASH, by inducing ROS-dependent
activation of XBP1. In light of the obligatory role of XBP1 in TLR4-induced liver
inflammation and injury, therapeutic interventions that inhibit TLR4/XBP1 activation
may represent a promising strategy for treatment of NASH.<br>published_or_final_version<br>Medicine<br>Doctoral<br>Doctor of Philosophy
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Shi, Yi, and 史懿. "Endothelial dysfunction and changes in vascular smooth muscle responsiveness in femoral arteries of rats with type I diabetes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38286075.
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Marshall, Aiden Christopher James 1976. "The role of Fas and TNFα in experimental autoimmune gastritis". Monash University, Dept. of Pathology and Immunology, 2003. http://arrow.monash.edu.au/hdl/1959.1/9413.
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Yong, Jing. "A neuroprotective vaccine for a mouse model of Parkinson's disease and multimodality imaging of Beta-cells in animal models of type I and II diabetes." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1723178171&sid=12&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Neel, Sarah Elizabeth. "Transplantation of iPS cells reduces apoptosis and fibrosis and improves cardiac function in streptozotocin-induced diabetic rats." Master's thesis, University of Central Florida, 2010. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4686.
Full textAbstract:
Background: Streptozotocin (STZ) induced diabetes leads to various complications including cardiomyopathy. Recent data suggests transplanted bone marrow stem cells improve cardiac function in diabetic cardiomyopathy. However, whether modified ES, iPS cells, or factors released from these cells can inhibit apoptosis and fibrosis remains completely unknown. The present study was designed to determine the effects of transplanted ES cells overexpressing pancreatic transcription factor 1 a (Ptf1a), a pro-pancreatic endodermal transcription factor, iPS cells, or their respective conditioned media (CM) on diabetic cardiomyopathy. Methods: Experimental diabetes was induced in male Sprague Dawley rats (8-10 weeks old) by intraperitoneal STZ injections (65 mg/kg body weight for 2 consecutive days). Animals were divided into six experimental groups including control, treated with sodium citrate buffer IP, STZ, STZ + ES-Ptf1a cells, STZ + iPS cells, STZ + ES-Ptf1a CM and STZ + iPS CM. Following STZ injections, appropriate cells (1 X 106/mL/injection/day) or CM (2 mL injection/day) were given intravenously for 3 consecutive days. Animals were sacrificed and hearts were harvested at day 28. Histology, TUNEL staining, and Caspase-3 activity were used to assess apoptosis and fibrosis. ERK1/2 phosphorylation was quantified using ELISAs. M-mode echocardiography fractional shortening was used to assess cardiac function. Results: Animals transplanted with ES cells, iPS cells, or both CMs showed a significant (pless than]0.05) reduction in interstitial fibrosis, and apoptosis compared with STZ group. ERK expression was not significantly different compared with STZ. Echocardiography showed a significant (pless than]0.05) improvement in fractional shortening in cell and media transplanted groups compared with STZ. Conclusions: Our data suggest that ES cells, iPS cells, and/or CMs inhibit apoptosis, reduce fibrosis, and improve cardiac function in STZ-treated diabetic rats.<br>ID: 029049879; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Thesis (M.S.)--University of Central Florida, 2010.; Includes bibliographical references (p. 33-40).<br>M.S.<br>Masters<br>Burnett School of Biomedical Sciences<br>Medicine
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Ayeleso, Ademola Olabode. "Influence of two plant products (red palm oil and rooibos) on streptozotocin-induced hyperglycaemia and its implications on antioxidant status and other biochemical parameters in an animal model." Thesis, Cape Peninsula University of Technology, 2012. http://hdl.handle.net/20.500.11838/1517.
Full textAbstract:
Thesis submitted in fulfilment of the requirements for the
Doctor of Technology: Biomedical Technology
In the Faculty of Health and Wellness
At the
CAPE PENINSULA UNIVERSITY OF TECHNOLOGY, 2012<br>Diabetes mellitus is a major health problem not only in urban, but also in the rural areas and is diagnosed by the presence of high glucose levels in the blood. Oxidative stress is known to be actively involved in the onset and progression of diabetes and its complications. Antioxidants have important roles in biological systems by scavenging free radicals which may result in oxidative damage of biological molecules such as lipids, proteins and DNA. Red palm oil, originally from the tropical area of Africa, generally consumed as cooking oil, is known to have some beneficial health effects due to the presence of lipid soluble antioxidants such as carotenoids, tocopherols and tocotrienols. It also contains almost an equal proportion of both saturated and unsaturated fatty acids which makes it distinctive from other vegetable oils. Rooibos, on the other hand, is grown in the Cederberg area of the Western Cape in South Africa and it is commonly consumed as a beverage. It contains a complex profile of water soluble antioxidants (flavonoids) and its health promoting potentials have been reported extensively. Some of the flavonoids present in rooibos include aspalathin, nothofagin, quercetin, rutin and orientin.
The objective of this research project was to examine the potential beneficial effects of the dietary intake of red palm oil and rooibos on streptozotocin-induced hyperglycaemia and its influence on the antioxidant status and some biochemical parameters in male Wistar rats. The preliminary phase of this study was designed to investigate the biochemical effects of these two plant products at different dosages following consumption for a period of 7 weeks. The preliminary study did not reveal any adverse effects of the different dosages of red palm oil (1 ml, 2 ml and 4 ml) and rooibos (2%, 4% and 6%) on the experimental rats following dietary intake for 7 weeks. However, these natural products showed an improvement in the antioxidant status of the rats at the different doses. Using a single dose each of both plant products from the preliminary study, the main study was performed to investigate the influence of these two plant products singly and in combination on the blood and liver of streptozotocin-induced hyperglycaemic male Wistar rats.
In the main study, streptozotocin (50 mg/kg) dissolved in 0.1 M citrate buffer (pH 4.5) through intramuscular injection was used for the induction of diabetes which was confirmed by the presence of high blood glucose after 72 hours. Red palm oil or rooibos extract alone did not have any effect on the control of blood glucose in the diabetic rats. The dietary intake of the combined treatment with red palm and rooibos had more health promoting effects on the diabetic rats which included a decrease in blood glucose, glycosylated haemoglobin,
fructosamine and increased insulin levels. There was a marked increase in liver glycogen levels in all the diabetic groups. Treatment with rooibos alone showed a decrease in glycogen levels in the diabetic rats. The presence of liver enzymes in the serum, commonly used as indicators of liver damage was increased in all the diabetic rats. However, the combined treatment of diabetic rats with red palm oil and rooibos protected the liver from injury. Red palm oil improved high density lipoprotein cholesterol levels (HDL-cholesterol) in the diabetic rats. There was no effect on the activity of glucokinase, the first enzyme in the the glycolytic pathway in both the untreated and treated diabetic rats. However, the activity of pyruvate kinase, the last enzyme in the glycolytic pathway was reduced in all the diabetic groups. The combined treatment with both red palm and rooibos increased the activity of pyruvate kinase.
Oxidative stress was confirmed in the diabetic rats with an increase in the plasma thiobarbituric acid reactive substances (TBARS), an indicator of lipid peroxidation. Treatment of diabetic rats with rooibos and the combination of red palm oil and rooibos brought plasma TBARS to a level that was not significantly different from the normal control group. There was a non-significant reduction of total glutathione in the non-treated and treated diabetic groups. A non-significant increase in the activity of liver catalase was observed in all the treated diabetic groups. The activity of superoxide dismutase was significantly decreased in the liver of diabetic rats. Diabetic rats treated with red palm oil, rooibos and the combined treatment showed an increased activity of superoxide dismutase in the liver. Red palm oil and the combined treatment increased the activity of glutathione peroxidase in both the red blood cells and liver of diabetic rats. Red palm oil, rooibos and their combined treatments also improved the plasma antioxidant capacity such as ferric reducing antioxidant power (FRAP) and oxygen reducing absorbance capacity (ORAC) in the diabetic rats.
In conclusion, oxidative stress is actively involved in the progression of diabetes mellitus. Red palm oil and rooibos, most especially their combined treatment showed significant beneficial health promoting effects in the diabetic rats. The remarkable effects of the combined treatment of red palm oil and rooibos in the diabetic rats could be due to their antioxidant profiles. Based on the findings from this study, it can be adduced that these plant products could help in the management of diabetes and its complications and therefore, suggested the need for further research studies on antioxidant therapy in the management of diabetes mellitus.
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Mazucanti, Caio Henrique Yokoyama. "Sinalização intracelular desencadeada por concentrações subtóxicas de estreptozotocina em células neuro-2A: modelo in vitro de neurodegeneração associada à doença de Alzheimer." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-26092013-102423/.
Full textAbstract:
A estreptozotocina (STZ) é utilizada como modelo de indução do Diabetes, e mais recentemente, sua injeção intracerebroventricular (icv) tem sido utilizada como modelo animal de DA. Nosso objetivo neste trabalho é o de avaliar os efeitos causados por doses subtóxicas de STZ em uma linhagem de neuroblastoma sobre a cascata intracelular associada à sinalização de insulina. Os resultados confirmam a doação espontânea de NO pela STZ e sugerem que a droga é capaz de modular a cascata intracelular associada ao receptor de insulina devido à doação do radical livre. O perfil de produção de EROs induzido por STZ pode ser a causa da sua neurotoxicidade. Por fim, foi visto que o tratamento com STZ, bem como a indução de resistência à insulina, é capaz de impedir a formação de neuritos pelo tratamento com NGF. Dessa forma, este trabalho contribui para a elucidação dos mecanismos pelos quais a injeção icv de STZ pode causar algumas características de toxicidade neuronal semelhantes à DA.<br>Streptozotocin (STZ) has been used as an animal model for Diabetes and, more recently, its intracerebroventricular (icv) injection as an AD animal model. Our objective involves the assessment of the effects caused by subtoxic doses of STZ in a neuroblastoma cell line upon insulin signaling associated intracellular cascade. Results confirm STZ spontaneous NO donation and suggest that the drug is capable of modulating the intracellular cascade associated to insulin receptor due to the spontaneous donation of the free radical. Therefore, EROs production may play an important role in the mechanism linked to STZ induced neurotoxicity. Ultimately, it has been shown that STZ treatment, as well as insulin resistance alone, is capable of impair neurite outgrowth by NGF treatment. This work contributes for the elucidation of the mechanisms by which STZ icv injection may cause features similar to DA.