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Efeito dos inibidores de serinoproteases rBmTI-A e rBmTI-6 em modelo de enfisema pulmonar em camundongos e em linhagem de células epiteliais pulmonares A549Duran, Adriana Feliciano Alves January 2018 (has links)
Orientador: Prof. Dr. Sergio Daishi Sasaki / Tese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, São Bernardo do Campo, 2018. / A doença pulmonar obstrutiva crônica é uma doença caracterizada por
progressiva limitação do fluxo aéreo e suas principais manifestações são a
bronquite crônica e o enfisema pulmonar. O quadro é geralmente irreversível e
engloba uma série de processos que incluem a resposta inflamatória anormal
dos pulmões com participação ativa de macrófagos, neutrófilos e linfócitos, a
falha na reparação de células anormais, a apoptose precoce e a destruição da
matriz extracelular ocasionada pelo desequilíbrio entre proteases e
antiproteases, sendo esse desequilíbrio apontado como um dos principais
mecanismos que levam à instalação da doença. O tabagismo é a principal causa
atribuída ao seu aparecimento, seguida por fatores genéticos e ambientais.
Algumas enzimas estão relacionadas ao processo de patogênese da DPOC
como a elastase de neutrófilos humana e as metaloproteinases 9 e 12. Em
trabalhos anteriores o uso do inibidor de serinoproteases rBmTI-A, inibidor do
tipo Kunitz-BPTI, resultou na prevenção do enfisema pulmonar por meio do
controle da resposta inflamatória comumente observada, além de redução da
atividade proteolítica presente no lavado broncoalveolar. Nesse trabalho, o
objetivo inicial foi dar prosseguimento à pesquisa com rBmTI-A, com a
caracterização da expressão gênica diferencial no modelo de enfisema animal
utilizando camundongos, indução realizada com a administração de elastase
pancreática porcina (PPE); para isso foi utilizado o ensaio de micro arranjo de
DNA (Microarray). Os ensaios de Microarray resultaram na identificação de
genes que respondem ao tratamento nos animais induzidos ao enfisema e que
receberam o tratamento com rBmTI-A, dentre estes genes estão: genes do
sistema imune e inflamação, genes da contração muscular, genes da tradução
em mitocôndria e genes de outras funções celulares. Na segunda parte do
trabalho, o inibidor de serinoproteases rBmTI-6-D1, inibidor Kunitz-BPTI, foi
aplicado no modelo de enfisema pulmonar em camundongos, resultados obtidos
previamente já haviam mostrado que rBmTI-6 também apresenta a capacidade
de prevenir o desenvolvimento do enfisema induzido por PPE, neste trabalho
mostramos que o tratamento utilizando rBmTI-6-D1 evita a perda do
recolhimento elástico dos pulmões dos animais induzidos ao enfisema, bem
como também evita a degradação alveolar, e o aumento do número de
macrófagos e linfócitos nos lavados broncoalveolares dos animais que
receberam tratamento em comparação com os que não receberam. Também foi
demonstrado que rBmTI-6 evita o aumento de atividade proteolítica (calicreínas
e elastase de neutrófilos) no lavado broncoalveolar de animais tratados com o
inibidor e induzidos ao enfisema em comparação aos controles. Na terceira parte
do trabalho, foram realizados ensaios em cultura de células A549 para investigar
o potencial anti-inflamatório dos inibidores rBmTI-A, rBmTI-6-D1 e rBmTI-6-D2/3,
a aplicação dos inibidores nestas células mostrou um aparente papel antiinflamatório
por meio da diminuição da secreção das citocinas IL-6 e IL-8, no
tratamento utilizando rBmTI-6-D1 e rBmTI-6-D2/3. Concluímos que os inibidores
rBmTI-A e rBmTI-6 apresentam atividade que previne o desenvolvimento do
enfisema induzido por PPE, devido às atividades antiproteases destes inibidores
e por interferirem na resposta inflamatória. / Chronic obstructive pulmonary disease is characterized by progressive
airflow limitation and its main manifestations are chronic bronchitis and
pulmonary emphysema. It is generally irreversible and encompasses a series of
processes that include the abnormal inflammatory response of the lungs with
active involvement of macrophages, neutrophils and lymphocytes, failure to
repair abnormal cells, early apoptosis, and destruction of the extracellular matrix
caused by the imbalance between proteases and antiproteases, and this
imbalance is one of the main mechanisms that lead to the establishment of the
disease. Smoking is the main cause attributed to its onset, followed by genetic
and environmental factors. Some enzymes are related to the pathogenesis of
COPD such as human neutrophil elastase and metalloproteinases 9 and 12. In
previous studies, the use of the serine proteinase inhibitor, rBmTI-A, a Kunitz-
BPTI inhibitor type, resulted in the prevention of pulmonary emphysema by
controlling of the inflammatory response commonly observed, as well as reducing
the proteolytic activity present in bronchoalveolar lavage. In this work, the initial
objective was to continue the research with rBmTI-A, with the characterization of
differential gene expression in the emphysema model using mice, induced to
emphysema by porcine pancreatic elastase (PPE) instillation; to reach this aim a
microarray assay was performed. The microarray results in the identification of
some genes which are affected by the treatment using rBmTI-A in animals that
received PPE instillation previously. Among these genes were identified immune
and inflammatory related genes, muscular contraction related genes, translation
in mitochondria related genes and genes of other cellular functions. In the second
part of this work, the serine proteinase inhibitor rBmTI-6-D1, other Kunitz-BPTI
inhibitor type, was applied in the emphysema model using mice; previous results
had shown that rBmTI-6 also presented the ability to avoid the emphysema
development in the PPE instillation model. The present work we showed that the
rBmTI-6-D1 treatment was sufficient to avoid the loss of elastic recoil, an effective
decrease in alveolar enlargement and in the number of macrophages and
lymphocytes in bronchoalveolar lavage fluid. Proteolytic analysis showed a
significant increase in elastase activity in induced emphysema group that is
controlled by rBmTI-6-D1. Kallikrein activity was decreased in the induced
emphysema and inhibitor treated group when compared to induced emphysema
group without treatment. In the third part of this work, assays using A549 cells
were performed to investigate the anti-inflammatory potential of rBmTI-A, rBmTI-
6-D1 and rBmTI-6-D2/3 inhibitors. These inhibitors presented an apparent antiinflammatory
role, due the reduced levels of IL-6 and IL-8 that were secreted by
A549 cell when treated with rBmTI-6-D1 and rBmTI-6-D2/3. We concluded that
rBmTI-A and rBmTI-6 inhibitors prevent the emphysema development induced
by PPE, due the anti-proteinases activities of these inhibitors and by its
interference in inflammatory response.
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Examination of healthcare workers’ response to rotating shift work during the COVID-19 pandemic in Greater Victoria care sitesHarrington, Marisa 16 August 2021 (has links)
Nurses are already exposed to plenty of stressors while at work, one of which
being the unavoidable nature of rotating shift work scheduling which can have profound
physiological effects carrying heightened long-term health risks. Working on the
frontlines of the COVID-19 pandemic has introduced new stressors while further
exacerbating the effects of pre-existing ones in this already understudied group of
essential workers. The purpose of this research was to examine physiological markers of
stress and health in nurses during the COVID-19 pandemic. Nine subjects (mean age
32.11 ± 7.25 years) from two hospitals in the Greater Victoria region collected data over
an eight-day shift roster consisting of two 12-hour day shifts, two 12-hour night shifts,
and four days off in two separate collection periods; remote data collection was used to
adhere to COVID-19 safety guidelines. Salimetrics ELISA kits were used to conduct
analyses for salivary cortisol, melatonin, and interleukin-6 (IL-6) content. Frequency
domain heart rate variability (HRV) was collected with a Polar H10 Chest Strap and
Polar Ignite Activity Tracker. A salivary sample and 5-minute HRV recording were
obtained upon waking or shortly thereafter on each day; a second saliva sample was
obtained after work for the four working days. The Expanded Nursing Stress Scale
(ENSS) was completed at the end of the last night shift in each period. There were no
significant differences between IL-6 concentrations across the eight days within each period; the same was observed for cortisol. Additionally, no difference was apparent
between the morning and evening salivary cortisol concentrations, thus demonstrating a
blunting of the diurnal release pattern. Evening salivary cortisol concentrations remained
elevated near the level of morning samples and were consistently above reference values
for the population age group. Morning salivary melatonin concentrations significantly
differed by day (F(5, 25) = 6.626, p < 0.001) but not period; melatonin concentrations
were lowest following night shifts, showing a suppression in release due to participants
being exposed to light at night with shift work. No statistically significant differences
were apparent between any frequency domain HRV parameters in either Period 1 or
Period 2. Perceived occupational stress was heightened in comparison to previously
published pre-pandemic research using the ENSS. The results of this research reveal
alterations to the circadian nature of cortisol and melatonin alongside elevated perceived
occupational stress; these physiological and psychological effects can compound the risk
for adverse health outcomes. While it is difficult to discern the root cause of these
responses, it nevertheless reveals insight into the effects of nurses working during the
COVID-19 pandemic and raises concern for potentially related disease risk. / Graduate
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Caractérisation des fonctions immunomodulatrices de la Cardiotrophin-Like CytokineSarah, Pasquin 03 1900 (has links)
No description available.
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DIVERSE ROLES FOR EGF RECEPTOR SIGNALING IN THE BREAST CANCER TUMOR MICROENVIRONMENTBalanis, Nikolas G. January 2013 (has links)
No description available.
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From <i>In Vitro</i> to <i>In Vivo:</i> Control of C-Reactive Protein Gene Expression by CytokinesYoung, Duprane Pedaci 04 February 2008 (has links)
No description available.
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Glutaredoxin Regulation of Pro-Inflammatory Responses in a Model of Diabetic RetinopathyShelton, Melissa D. January 2009 (has links)
No description available.
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Increased Bacterial Adherence and Decreased Bacterial Clearance in Urinary Tract Infections with Diabetes MellitusOzer, Ahmet 23 August 2013 (has links)
No description available.
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The antimicrobial effectiveness and cytokine response of <i>Pseudomonas aeruginosa</i> bacteriophages in a human lung tissue culture modelShiley, Joseph Robert January 2016 (has links)
No description available.
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Inflammatory Responses to Combinations of: Mental Load, Repetitive Lifting and Subject Personality.Splittstoesser, Riley Emiel January 2016 (has links)
No description available.
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Rolle von Cardiotrophin-1 für die Pathogenese von KardiomyopathienHaßfeld, Sabine 28 April 2004 (has links)
Cardiotrophin-1 ist ein Zytokin der Familie Interleukin-6-Familie, zu der auch IL-11, CNTF, OSM und LIF gehören. Diese Substanzen wirken über die gemeinsame Rezeptoruntereinheit gp130. CT-1 induziert die Hypertrophie von Kardiomyozyten und inhibiert die Apoptose kardialer und Zellen. In verschiedenen Tiermodellen der Herzinsuffizienz konnte eine gesteigerte myokardiale CT-1 Expression beobachtet werden. Kardiomyopathien sind wiederum kardiale Erkrankungen, die mit einer Hypertrophie und Apoptose einhergehen und zu einer Herzinsuffizienz führen können. Man geht davon aus, dass 25-50 Prozent der familiär sind. Hierbei handelt es sich um eine monogenetische Erkrankung, die überwiegend autosomal-dominant vererbt werden. Daneben konnten aber auch modifizierende Polymorphismen in neurohumoralen Faktoren identifiziert werden. Basierend auf diesen Ergebnissen war das Ziel dieser Arbeit die Analyse der möglichen Beteiligung genetischer Varianten der kodierenden sowie der regulatorischen Region an der Pathogenese der Hypertrophen bzw. Dilatativen Kardiomyopathie. Zusätzlich sollte die mRNA-Expression von CT-1 in Myokardbiopsien von Patienten mit Herzinsuffizienz quantifiziert werden. Hierfür musste zunächst die Sequenzen der 5´-flankierenden Region identifiziert und bezüglich ihrer regulatorischen Eigenschaften analysiert werden. Es konnten 1,1 kb der 5´-flankierenden Region sequenziert werden. Die anschließende Luciferase-Reportergen-Analyse wies regulatorische Aktivitäten für den gesamten Bereich nach. Diese Region enthält zahlreiche cis-aktive DANN-Sequenzen aber keine TATA-Box. Für die Mutationssuche wurden 64 Patienten mit DCM, 53 Patienten mit HCM sowie 100 Kontrollpersonen mittels PCR-SSCP-Analyse untersucht. Es konnte eine kodierende Variante A92T bei jeweils einem DCM- bzw. HCM-Patienten identifiziert werden. Diese Substitution liegt in einem Bereich, der zwischen verschiedenen Spezies (Ratte, Maus, Mensch) konserviert ist. Diese Mutation könnte eine Veränderung der Sekundärstruktur bewirken und liegt in einem möglichen funktionellen Bereich. Die Promotorregion wies eine Basenpaarsubstitution bei -130 (G/T) sowie eine Deletion der Basen CTTT zwischen -992 und -995 auf. Der Polymorphismus an Position -130 fand sich tendenziell häufiger bei Patienten mit Dilatativer Kardiomyopathie. Die CTTT-Deletion konnte nur bei einer Patientin mit HCM nachgewiesen werden. Für die Quantifizierung der CT-1 mRNA wurden rechtsventrikuläre Endomyokardbiopsien von 6 Patienten mit eingeschränkter LVEF (CHI), 5 Patienten nach Herztransplantation (TX) sowie 3 Kontrollpatienten (KO) eingesetzt. Es konnte ein relativer Anstieg der CT-1 Expression um 82% bei den Patienten mit eingeschränkter LVEF festgestellt werden. Interessanterweise besteht eine enge Korrelation zur Schwere der eingeschränkten Herzfunktion sowie zur Zunahme der Hypertrophie. / Cardiotrophin-1 is a cytokine, which belongs to the interleukin-6 family, which includes IL-11, CNTF, OSM and LIF. These factors act via the receptor subunit gp130. CT-1 induces the hypertrophy of cardiomyocytes and inhibits the apoptosis of cardiac cells. Studies in animal models of congestive heart failure showed an enhanced expression of CT-1 in the myocardium. Cardiomyopathies are cardiac diesorders, which are charakterized by hypertrophy and apoptosis and which can terminate with congestive heart failure. About 25-50 percent of all cases are familial. It is a monogenetic mendelian disorder with an autosomal-dominant inheritance in most cases. Beside this, modifying polymorphisms in neurohunoral factors could be identified. Based on these facts, the aim of this study was to identify genetic variants within the coding and regulatory region of the CT-1 gene, which could influence the pathogenesis of hypertrophic or dilated cardiomyopathy. Additionally, the mRNA-expression of CT-1 in myocardial biopsies of heart failure patients should be quantified. First, it was necessary to sequence the 5´-untranslated region and to analyse its regulatory function. We could sequence 1.1 kb of the 5´-UTR. The luciferase reportergene assay showed a significant promoter activity for the whole region. The region contains various cis-active DNA sequences but no TATA-box.The TRANSFAC-analysis identified different binding sites for transcription factors but no TATA-box. The genetic material of 64 DCM and 53 HCM patients and 100 controls was screened for mutaions by using a PCR-based SSCP-analysis. A coding variant A92T could be identified for a patient with DCM and for an HCM patient. This mutation lies within a region which is conserved between different species (rat, mouse, human). This variant could disturb the secondary structure and lies in a probable functional region. Within the promoter we could identify a basepair substitution at position -130 (G/T) and a 4-basepair deletion between -992 and -995 (CTTTdel). The polymorphism at -130 showed a tendency for a higher occurrence in DCM patients. One HCM patient was heterozygous for the CTTT-deletion. To quantify the CT-1 mRNA we used endomyocardial biopsies of 6 patients with reduced LVEF (CHI), 5 patients after heart transplantation (TX) and 3 controls (KO). We performed a semiquantitative analysis by using HPLC and an external standard (PDH mRNA). We found an increased expression of CT-1 by 82% for patients with heart failure. Interestingly, we saw a tight correlation with to the reduction in LV function and to the degree of hypertrophy.
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