Dissertations / Theses: 'INOS'

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Duarte, Andressa. "Participação da via PI3K/AKT na produção de óxido nítrico por macrófagos peritoneais." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-21102013-112320/.

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A imunidade inata é responsável pela resposta inicial aos microrganismos, uma vez que impede, controla ou elimina a infecção. Esse sistema consiste em barreiras epiteliais, proteínas plasmáticas e células circulantes e teciduais. Dentre esses componentes, os macrófagos possuem grande importância, sendo capazes de controlar e eliminar agentes patogênicos através da fagocitose e produção de espécies reativas de oxigênio e nitrogênio. A ativação de PRRs por constituintes oriundos dos patógenos em macrófagos desencadeia eventos da resposta imune inata, ativados por diversas vias de sinalização intracelular. A via das PI3Ks é conhecida por regular várias funções nas células, como a regulação do ciclo celular, migração e produção de espécies reativas de oxigênio e nitrogênio. O NO é um mediador central na imunidade inata que, após estímulos inflamatórios, é produzido em altas quantidades através da iNOS. Macrófagos deficientes em PI3K produzem menos NO e apresentam prejudicado controle da infecção quando infectados por T. cruzi. O objetivo do presente trabalho foi investigar o papel da via PI3K na produção de NO por macrófagos peritoneais estimulados com LPS. Os macrófagos empregados no estudo, WT e PI3K-/-, possuem o mesmo fenótipo. Observamos que macrófagos PI3K-/- possuem uma menor produção de NO e expressam menos iNOS. A reduzida expressão de iNOS, após estímulo com LPS, é também observada quando macrófagos WT são tratados com inibidores seletivos da PI3K e AKT. Além disso, demonstramos que, concomitantemente à menor expressão da iNOS, ocorre deficiência na fosforilação da AKT e diminuição da ativação do fator de transcrição NF-kB, sugerindo que a PI3K participa da ativação do NF-kB. Foi observado ainda que o tratamento com PTX também diminui a expressão da iNOS. No entanto, macrófagos PAFR-/- expostos ao LPS presentam maior expressão da iNOS, enquanto os macrófagos CCR2-/- apresentam menor expressão dessa enzima nessas condições. Para investigar a implicação da via PI3K in vivo foi administrado LPS i.v., como modelo de choque endotoxemico, no qual observamos maior sobrevida em animais PI3K-/- comparado aos animais WT e menores níveis de nitrito no soro. Nossos dados sugerem que a enzima PI3K é crítica para expressão de iNOS e produção de NO pelos macrófagos, possivelmente através da ativação do receptor CCR2, estando envolvida na fisiopatologia do choque induzido por LPS.
Innate immunity is the initial response to microorganisms, since it prevents, controls and eliminates infection. This system consists in epithelial barriers, plasma proteins and circulating and tissue cells. Among these components, macrophages have great importance, being capable of control and eliminate pathogen agents through phagocytosis and production of reactive oxygen and nitrogen species. Activation of PRRs by pathogens constituents in macrophages triggers events of the innate immune response, activated by various intracellular signaling pathways. PI3Ks pathway is known to regulate several functions in the cell, such as regulation of the cell cycle, migration and production of reactive oxygen and nitrogen species. NO is a central mediator in innate immunity, which after inflammatory stimuli, is produced in high levels by iNOS. PI3K-deficient macrophages produce less NO and exhibit impaired control of infection when infected by T. cruzi. The aim of the present study is to investigate the role of PI3K pathway in NO production by LPS-estimulated peritoneal macrophages. The macrophages used in this study, WT and PI3K- / -, have the same phenotype. We observed that PI3K- / - macrophages have a lower NO production and express less iNOS. The low expression of iNOS after stimulation with LPS was also observed in WT macrophages treated with selective inhibitors of PI3K and AKT. Furthermore, we demonstrate that, along to lower iNOS expression, there is deficiency in AKT phosphorylation and decreased activation of the transcription factor NF-kB, suggesting that PI3K participates of the NF-kB activation. It was also observed that PTX treatment has decreased iNOS expression. However, LPS-exposed PFAR-/- macrophages present greater expression of iNOS, while CCR2-/- macrophage exhibit lower expression of this enzyme under these conditions. To investigate involvement of the PI3K pathway has \"in vivo\",LPS was administered i.v., as an endotoxic model, in which we observed a higher survival in PI3K- / - animals compared to WT animals and lower nitrite levels in serum. Our data suggest that PI3K enzyme is critical to iNOS expression and NO production by macrophages, possibly through activation of the CCR2 receptor, being involved in the LPS-induced shock pathophysiology

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2

Gather, Fabian Matthias [Verfasser]. "Analyse der Expression der humanen induzierbaren NO-Synthase (iNOS)Einfluss der 5’-UTR auf die Expression der humanen iNOS und Expression der humanen iNOS in Modellen der neuronalen Differenzierung / Fabian Matthias Gather." Mainz : Universitätsbibliothek Mainz, 2020. http://d-nb.info/1205813624/34.

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3

Zholobenko, Aleksey. "Biomimetic vectors for breast cancer iNOS gene therapy." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580137.

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While the field of gene delivery has matured dramatically in the last decade, there is still no gene delivery agent that can combine safety, efficacy and specificity into a single vehicle. In this work two protein based vectors, the Designer Biomimetic Vector (DBV) and RALA were investigated for the delivery of the gene coding for iNOS to breast cancer cells. Protein based vectors have the advantage of biocompatibility, bioderadabiliy and the high degree of control over the composition of the vector. They are not, however, widely studied at the present day. The DBV is a multi-domain recombinant chimeric protein, while RALA is a synthetic peptide with a single bi-functional domain. The DBV was found to form nanoparticles in the range of around 100mn and achieve a transfection efficacy of up to 10% in ZR-75-1 cells when complexed with pEG FP-NI. When complexed with a plasmid which allowed expression of iNOS under a constitutive CMV promoter (pENi), high concentrations of NO were produced (10μM) and near total cell kill was observed. Consequently, when the DBV/pEGP-N1 was tested in vivo, transfection was found in all organs and tissues tested, including tumour. Treatment with DBV/pENi nanoparticles resulted in a tumour growth delay of 17 days for both single dose and bi-weekly dose groups. Bi-weekly dosing was found to be toxic in an iNOS dependant manner. RALA was tested as an alternative vector and found ton form nanoparticles between 30-1 OOmn in diameter and give a transfection efficacy of up to 35% in ZR-75-1 cells when complexed with pEGFP-Nl. In in vivo models, RALAlpEGFP-N1 was found to transfect all organs and tissues tested, including tumour. In addition, in immunocompetant C57B mouse models, RALA was found to be no more immunogenic than mock injections while reducing the immunogenicity of plasmid DNA. RALA/pEGFP-N1 nanoparticles were found to protect the cargo DNA from both serum and freeze-drying. The relative efficacy and tolerability of both the DBV and RALA set aside a role for the two vehicles as prototypes for future targeted gene delivery systems

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Zheng, Xilong. "Tyrosine kinase pathways, smooth muscle function and iNOS induction." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq24569.pdf.

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Campbell, Holly R. 1976. "Chlorine-induced lung injury and the role of iNOS." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111574.

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Reactive airways dysfunction syndrome (RADS), a form of irritant-induced asthma (IIA) has been observed in humans following acute chlorine (Cl 2) gas exposure in occupational and domestic settings. Following Cl 2 injury, subepithelial fibrosis, mucous hyperplasia, and non-specific airway hyperresponsiveness have been reported. Based on the disease profile, we hypothesized that pulmonary damage may be oxidative in nature.
The aim of this work was to develop a murine model of irritant-induced asthma in order to investigate the pathogenic processes and potential oxidative mechanisms involved in response to Cl2 exposure, with a secondary aim of examining the role of iNOS in response to Cl2 inhalation.
A/J, C57BI/6J (wild type) and iNOS-1- mice exposed to various concentrations of Cl2 were mechanically ventilated for measurement of lung mechanics and responses to i.v. methacholine (MCh). Bronchoalveolar lavage was performed to examine total protein, cell populations and nitrate/nitrates. Tissues were harvested for histology and immunocytochemistry for iNOS, 3NT and carbonyl residues. To examine the role of iNOS, a subset of animals were treated with a selective iNOS inhibitor (1400W) and non-selective NOS inhibitor LNAME.
Chlorine exposure caused airway hyperresponsiveness, which appeared to be mitigated by iNOS blockade with 1400W, however this was not the case in iNOS-1- mice. Cl2 exposure also caused increases in total BAL protein, total cells, NOx, neutrophils, iNOS, 3NT and carbonyl residues.
In conclusion, chlorine exposure causes lung injury, similar to reactive airways dysfunction syndrome, characterized by airway hyperresponsiveness, epithelial sloughing, inflammatory cell influx, oxidative injury and increases in both the activity and expression of iNOS. Chlorine-induced airway hyperresponsiveness is mitigated, in part, by selective blockade of iNOS with the use of pharmacological intervention.

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Godoi, Fernanda Nascimento de. "?leo de soja em dietas para eq?inos atletas." Universidade Federal Rural do Rio de Janeiro, 2008. https://tede.ufrrj.br/jspui/handle/tede/580.

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This work aimed to evaluate intake in athletic horses fed diets with soybean oil inclusion and the effects of apparent digestibility of nutrients, digestive kinetics, faeces characters and physiologic, hematological and biochemical parameters and. In first essay, fifteen horses were used in a completely randomized design with three diets and five repetitions. Diets used were: diet without soybean oil inclusion (control); diet with inclusion of 8.5% soybean oil; diet with inclusion of 19.5% soybean oil. Trial had 34 days of duration, 30 days to adaptation of diets and four days to samples collection. Kinetics of liquid phase of digesta was estimated by LIPE? (Isolated Lignin Purified Enriched) in liquid form. The LIPE? was given only one time by oral infusion in 30th day of essay and faeces samples were collected at 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, 72 and 78 hours after. Faeces characteristics were evaluate on 33th and 34th day of essay. Blood samples were taken before and at 34th day. Data were submitted to variance analysis and means compared by Student Newman-Keuls test, at 5% of significance. In secund essay, twelve horses were used in a completely randomized design with two diets and six repetitions. Diets used were: diet without soybean oil inclusion (control); diet with inclusion of 10% soybean oil. The trial had 82 days of duration, with three physical effort tests before, at 60th and at 82th day of trial. Heart frequency and body temperature were evaluation and blood samples for analyze of hematological and biochemical parameters were taken in five moments in function of physical effort tests. The first data collection, before the test, with horses at rest, and immediately after the test, and 10, 20 and 120 minutes after the physical effort tests. Data were submitted to non parametric analysis, at 5% of significance. There was a significant reduction of dry matter intake in horses fed high fat diet. Apparent digestibility of fat increased in high fat diets (P<0.05) and apparent digestibility of cellulose decrease (P>0.05) in diet with 19.5% soybean oil inclusion. Apparent digestibility of others nutrients, except crude protein, digestive kinetics and faeces characteristics were not affecting (P>0.05) in horses fed diets with soybean oil inclusion. Horses fed high fat diet increased (P<0.05) in blood level of erythrocytes, hemoglobin and triglycerides and reduction of mean corpuscular volume. Soybean oil in diets did not affect physiological, hematological and biochemical parameters along the time intake time and in function physical effort tests. High fat diets were palatable and safety without any colic or diarrheas cases. The soybean oil can used in diet for horses, reducing dry matter intake and increasing energy density of diets that is interesting to athletic horses
Objetivou-se avaliar o consumo de dietas com diferentes n?veis de inclus?o de ?leo de soja por eq?inos atletas e os efeitos na digestibilidade aparente dos nutrientes, cin?tica digestiva, caracter?sticas fecais, nos par?metros fisiol?gicos, hematol?gicos e bioqu?micos. No primeiro ensaio foram utilizados quinze eq?inos em delineamento experimental inteiramente casualizado com tr?s dietas e cinco repeti??es. As dietas utilizadas foram: dieta sem inclus?o de ?leo de soja (controle); dieta com inclus?o de 8,5% de ?leo de soja; dieta com inclus?o de 19,5% de ?leo de soja. O ensaio teve dura??o de 34 dias, sendo 30 dias de adapta??o dos eq?inos ?s dietas e quatro dias de coleta de amostras. A cin?tica da fase l?quida da digesta foi estimada pelo LIPE? (Lignina Isolada, Purificada e Enriquecida) na forma l?quida, fornecido no 30? dia de ensaio, em dose ?nica, e as amostras fecais foram coletadas nos tempos 0, 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, 72 e 78 horas ap?s o fornecimento. As caracter?sticas fecais foram avaliadas no 33? e 34? dia e, as coletas das amostras sang??neas no in?cio e 34? dia do ensaio. Os resultados foram submetidos ? an?lise de vari?ncia e as m?dias comparadas pelo teste Student Newman-Keuls, com n?vel de signific?ncia de 5%. No segundo ensaio foram utilizados doze eq?inos em delineamento experimental inteiramente casualizado com duas dietas e seis repeti??es. As dietas utilizadas foram: dieta sem inclus?o de ?leo de soja (controle); dieta com inclus?o de 10% de ?leo de soja. O ensaio teve a dura??o de 82 dias, com a realiza??o de tr?s testes de esfor?o f?sico ao in?cio, 60? e 82? dia. Nesses testes foram avaliadas freq??ncia card?aca e temperatura corporal e coletadas amostras de sangue para an?lises hematol?gicas e bioqu?micas. A primeira coleta de dados ocorreu antes do teste, com os eq?inos em repouso e, imediatamente, 10, 20 e 120 minutos ap?s o t?rmino dos testes de esfor?o f?sico. Os valores m?dios dos par?metros fisiol?gicos, hematol?gicos e bioqu?micos foram submetidos ? an?lise n?o param?trica, a 5% de signific?ncia. Houve redu??o significativa no consumo de mat?ria seca das dietas com a inclus?o de ?leo de soja. O coeficiente de digestibilidade aparente do extrato et?reo aumentou (P<0,05) nas dietas hiperlipid?micas e o coeficiente de digestibilidade da celulose reduziu com a inclus?o de 19,5% de ?leo de soja. A digestibilidade dos demais nutrientes, exceto da prote?na bruta, a cin?tica da digesta no trato gastrointestinal e as caracter?sticas fecais n?o foram alteradas (P>0,05) pela inclus?o de ?leo nas dietas. Os eq?inos consumindo as dietas hiperlipid?micas apresentaram aumento (P<0,05) nos n?veis sang??neos de eritr?citos, hemoglobina e triglicer?dios e redu??o no volume corpuscular m?dio. N?o houve altera??o nos par?metros fisiol?gicos, hematol?gicos e bioqu?micos dos eq?inos alimentados com a dieta hiperlipid?mica ao longo do tempo de consumo das dietas e em fun??o dos testes de esfor?o f?sico. As dietas mostraram-se palat?veis e seguras, sem ocorr?ncia de casos de c?licas ou diarr?ias. O ?leo de soja pode ser utilizado nas dietas de eq?inos atletas visando suprir a demanda energ?tica e reduzir o consumo de mat?ria seca, desej?vel em eq?inos da modalidade esportiva Concurso Completo de Equita??o.

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Yang, Bo. "Mechanism of age-related cardiac dysfunction: Role of iNOS." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/289915.

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It is well documented that in the human free of pathological change, there is cardiac diastolic dysfunction with decreased reserved systolic function. Inducible nitric oxide synthase (iNOS) expressed in cardiac myocytes is related to heart failure of various etiologies. We hypothesized that the high levels of nitric oxide (NO) produced by iNOS over-expressed in the myocardium caused age-related cardiac dysfunction by affecting calcium cycling proteins. To test our hypothesis, first, we validated the volumetric measurement of the conductance catheter system (CCS) in mice. The heart function characterized by CCS decreased in aged mice (16-month-old, n = 9) compared to Young mice (6-month-old, n = 9). The left ventricular (LV) dysfunction in aged WT mice was reversed by iNOS specific inhibitors, aminoguanidine (AMG, 10 mg/Kg, i.v. or infusion, n = 15) and S-methyl-isothiourea (MITU, 3 mg/Kg, i.v. n = 7) separately and worsened by substrate L-arginine (10 mg/Kg, i.v. n = 7). All three drugs had no effects on young WT mice or old (16-month-old) iNOS knockout (KO) mice. Cardiac iNOS mRNA and protein expression were identified with northern blot, western blot and immunohistochemistry singularly in old WT mice and not in young WT mice. The NOx and cGMP levels were significantly higher only in the old WT mice (n = 6) compared to young WT mice and cGMP levels decreased to normal with AMG administration in the old WT mice. Northern blot showed the expression of ryanodine receptor, sarco/endoplasmic reticulum (SERCA 2a) did not change in the aging process. However western blots showed that total phospholamban (PLB), phosphorylated PLB (p < 0.05) and more importantly the ratio of phosphorylated PLB to total PLB significantly decreased in aged mice (p < 0.01). AMG (10 mg/kg bolus iv) significantly improved diastolic function only in the old WT mice with decreased tau and increased dP/dtmin, but had no effects on both young or old PLB knockout mice. Taken together, we concluded that iNOS overexpression was one of the mechanisms leading to age-related cardiac dysfunction by affecting phosphorylation of PLB via iNOS/NO/cGMP pathways and inhibition of iNOS could reverse the age-related cardiac dysfunction.

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Vakkala, née Mustonen M. (Merja). "Apoptosis in breast lesions." Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514256506.

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Abstract In this work the extent of apoptosis was studied in a set of 504 benign and malignant breast lesions to elucidate its role in breast tumor development and progression. Also the correlation of apoptosis with estrogen and progesterone receptor positivity, cell proliferation and patients' prognosis was studied. The breast lesions were also analyzed immunohistochemically with antibodies to apoptosis regulating proteins bcl-2 and bax, and caspases 3, 6 and 8. In addition, the immunohistochemical expression of NO• synthesizing enzyme iNOS in relation to apoptosis and angiogenesis was studied. Furthermore, the expression of the antioxidative enzyme MnSOD was studied in relation to apoptosis and cell proliferation. According to the results, the apoptotic index was lowest in benign breast lesions. It was higher in in situ carcinomas, where a gradual increase in the extent of apoptosis from grade I to III in situ carcinoma was seen. The apoptotic index in invasive carcinomas was higher than in in situ carcinomas, and also in invasive carcinomas there was a gradual increase in apoptosis from grade I to III carcinomas. The apoptotic index was highest in recurrent carcinomas. Strong bcl-2 expression was usually found in benign breast lesions but the immunoreactivity decreased in in situ and invasive carcinomas. There was a significant inverse association between bcl-2 immunoreactivity and the extent of apoptosis. Low bcl-2 immunoreactivity also associated with estrogen- or progesterone receptor negativity. In contrast, bax expression did not show any significant association with apoptosis, hormone receptors or the histologic types of tumors. Strong cytoplasmic caspase 3, 6 and 8 immunoreactivity was found in most carcinomas. It was weaker in in situ carcinomas and only weak immunoreactivity could be seen in benign breast lesions. There was a significant association between the extent of apoptosis and caspase immunoreactivity. iNOS expression was found in both tumor and stromal cells. iNOS expression in tumor cells was more frequently found in invasive than in in situ carcinomas. Its expression correlated significantly with a high apoptotic index and high vascularization of the lesion. There was significantly less MnSOD immunoreactivity in invasive breast carcinomas compared to in situ carcinomas or benign hyperplasias. MnSOD immunoreactivity did not associate with the extent of apoptosis, but there was a marginal inverse association between cell proliferation and MnSOD expression. Increased apoptosis was significantly associated with a high cell proliferation, and inversely associated with a positive estrogen status. A high apoptotic index (< 0.50%) was associated with a decreased survival of the patients. The results of this study show that apoptosis plays a decisive role in the development and progression of breast carcinoma. It is influenced not only by apoptosis regulating proteins, such as bcl-2 and caspases, but also by the estrogen receptor status. Apoptosis was also associated with iNOS positivity, the effect of which is mediated through increased NO• production. In line with the suggested role of MnSOD as a tumor suppressor gene, its expression was downregulated in invasive breast carcinoma. In conclusion, the association of apoptosis with patient survival in breast carcinoma may be secondary to its association with tumor cell proliferation and high tumor grade, not necessarily suggesting any causal association between apoptosis and survival.

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Arevalo, Iracema. "Cutaneous leishmaniasis : iNOS gene expression and a novel immunomodulatory therapy." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=31183.

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Nitric oxide (NO) has been shown to be lethal for a variety of intracellular pathogens including Leishmania. In murine models, the inducible nitric oxide synthase gene (iNOS) is expressed in activated macrophages and is involved in the synthesis of NO. Because the role of NO and iNOS in human leishmaniasis was less clear, we examined the expression of the iNOS gene in human macrophages infected with Leishmania in vitro and in biopsy tissue from subjects with cutaneous leishmaniasis.
Pentavalent antimony (Sb5+) in the form of Pentostam(TM) or Glucantime(TM) is still the treatment of choice despite its toxicity. Aldara(TM) (5% imiquimod) is an immune-response modifying agent that has been approved by the Food and Drug Administration in the USA for treating genital warts caused by papillomaviruses. We conducted an open-label, prospective study of combined Glucantime(TM) + Aldara(TM) therapy in subjects with CL who had previously failed a complete course of Glucantime(TM) treatment at regular doses. (Abstract shortened by UMI.)

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Vittur, Sebastian Bernhard Frederik [Verfasser]. "Kontraktion und Kompensation iNOS-überexprimierender Mauskardiomyozyten / Sebastian Bernhard Frederik Vittur." Gießen : Universitätsbibliothek, 2013. http://d-nb.info/1065394861/34.

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Sartoretto, Simone Marcieli. "Avaliação dos mecanismos envolvidos na redução da contração vascular em aortas de ratas diabéticas: papel da iNOS e insulina." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-26062014-165520/.

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No presente estudo, observamos aumentada expressão de iNOS e de proteínas s-nitrosiladas (S-NT) em aorta (AO) e concentração de NO no plasma de ratas diabéticas (DB), que foram corrigidas pelo tratamento com insulina (INS), que foi incapaz de normalizar a glicemia. O tratamento com o inibidor da iNOS L-NIL reduziu a expressão de S-NT e a concentração de NO. A contração induzida por agonistas adrenérgicos (ADRs), mas não por cloreto de potássio, que estava reduzida em anéis de AO sem endotélio de ratas DB, foi corrigida pelos tratamentos com INS e L-NIL. A expressão dos receptores de estrógeno ESR2 e GPER estava aumentada em AO de ratas DB e foi corrigida pelo tratamento com INS. Nossos resultados mostram que o aumento da expressão da iNOS/geração de NO é responsável pela redução da contração mediada por receptor ADR, mas não daquela induzida por despolarização direta da membrana. A INS modula negativamente a expressão da iNOS e dos receptores ESR2 e GPER em aorta de ratas DB, efeito que pode contribuir com a restauração da contração induzida por agonistas ADRs.
In the present study, we observed that in aortas (AO) of diabetic (DB) female rats have an increase in iNOS and S-nitrosilated (S-NT) proteins expression along with higher levels of plasmatic NO. Although insulin (INS) treatment did not normalize blood glucose levels, it corrected protein expression and NO concentrations. The iNOS inhibitor treatment reduced the altered expression of S-NT proteins and NO levels. The reduced adrenergic agonists (ADR)-induced contractions in DB without endothelium were corrected by INS and L-NIL treatments, such treatments did not affect the reduced vasoconstriction response to KCl in DB AO. The increase expression of estrogen receptors GPER and ESR2 found in DB AO was recovered by INS treatment. Our results showed that the increased expression of iNOS/NO generation is responsible for reducing ADR-induced contraction, but not for membrane depolarization-induced contraction. INS negatively modulates protein expression of iNOS, ESR2, and GPER receptors in DB AO; such effect may contribute to restore ADR-induced vascular contraction.

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Lima, Carina Buzzo de. "Avaliação dos mecanismos moleculares envolvidos na expressão de iNOS mediada pelo eixo NAIP5/NLRC4-Caspase-1." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-11072014-093448/.

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O reconhecimento da flagelina é compartilhado pelo receptor transmembrânico TLR5 e citosólico NAIP5/NLRC4. Entretanto, pouco se sabe sobre os mecanismos efetores individuais induzidos a partir do reconhecimento extra e intracelular da flagelina. Aqui, nós demonstramos que macrófagos estimulados com a flagelina citosólica (FLA-BSDot) induziu a expressão de iNOS, enzima responsável pela produção do óxido nítrico (NO). A expressão de iNOS foi dependente do eixo NAIP5/NLRC4/caspase-1 e independente de IL-1β, IL-18 e MyD88, descartando a via de ativação dos TLRs. Ainda, esta via não requer a ativação do fator de transcrição IRF-1, mas envolve a ativação do NF-kB, assim como a clivagem da enzima PARP-1 (poly(ADP-ribose)polymerase-1). Por fim, avaliamos a relevância biológica desta via no controle das infecções por L. pneumophila e S. Typhimurium, dados que definem um mecanismo efetor adicional no controle de patógenos.
Recognition of flagellin is shared by transmembranic TLR5 and cytosolic NAIP5/NLRC4. However, little is known about the individual effector mechanisms induced by extra and intracellular flagellin. Here, we have demonstrated that cytosolic flagellin-stimulated macrophages (FLA-BSDot) induced iNOS expression, an enzyme responsible for the production of nitric oxide (NO). iNOS expression was dependent of the NAIP5/NLRC4/caspase-1 axis and independent of IL-1β, IL-18 and MyD88, discarding TLRs signaling pathway. Still, this pathway do not require the activation of IRF-1 transcriptional factor, but involves NF-kB activation as well as the cleavage of the enzyme, PARP-1 (poly(ADP-ribose)polymerase-1). Finally, we have evaluated the biological relevance of this pathway in the control of the infections by L. pneumophila e S. Typhimurium, which define an additional effector mechanism to the control of pathogens.

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Gélinas, Stéphanie. "Caractérisation des complexes oxygénés générés par l'oxyde nitrique synthase inductible (INOS)." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24681/24681.pdf.

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Morgado, Eliane da Silva. "Digest?o dos carboidratos de alimentos e dietas em eq?inos." Universidade Federal Rural do Rio de Janeiro, 2007. https://tede.ufrrj.br/jspui/handle/tede/570.

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This work was carried out to evaluate the fractions of nonfiber carbohydrate, hydrolyzable carbohydrate and rapidly fermentable carbohydrate of forages and diets and evaluate the apparent digestibility of these nutrients in horses. The study was constituted by four digestion essays with horses fed different diets. Digestion essays were characterized by: Essay I - evaluation of apparent digestibility of nutrients of forages alfalfa, peanuts forage, Stylosanthes, Desmodium and Macroptyloma and coastcross hay with mobile bags; Essay II - evaluation of apparent digestibility of coastcross with four different forms: long hay, chopped hay, ground hay (5mm) and ground hay (3mm); Essay III - evaluation of apparent digestibility of diets with forages and with concentrate inclusion. Essay IV - evaluation of apparent digestibility in horses fed diets with different levels of soybean oil inclusion, containing 5, 13 and 21% ether extract in diet. Samples of feeds, feces and colon digesta of horses fistulated at ventral right colon the essays I and II, were analyzed determination of dry matter (DM), crude protein (CP), crude fat (CF), ash, neutral detergent fiber (NDF), acid detergent fiber (ADF), and hydrolyzable carbohydrate (CHO-H). Nonfiber carbohydrate (NFC) were calculated by NFC = 100-CP-ash-CF-NDF. Hydrolyzable carbohydrates were analyzed directly and rapidly fermentable carbohydrates (CHO-RF) were calculated by difference between nonfiber carbohydrate and hydrolyzable carbohydrates. Total carbohydrates were calculated by: CHO-T = CHO-H + CHO-RF + NDF. Results demonstrated that horse has efficient digestion of nonfiber carbohydrate the feeds. Among analyzed forages and peanut forage, presented higher coefficients of digestibility analyzed nutrients demonstrating potential in the use in diets for horses. Processing coastcross hay in different grinding degrees doesn't interfere in digestibility of fibrous carbohydrate and nonfiber carbohydrate fractions. Inclusion of concentrate in the diet increased the digestibility of nonfiber carbohydrate, hydrolyzable carbohydrate, rapidly fermentable carbohydrate and total carbohydrate, without affecting the digestibilidade of the fiber, while in diets with levels of 13% of ether extract, the digestibility the fractions of nonfiber of fibrous carbohydrate were not affected, however, in diets with 21% of ether extract, there was reduction in the digestibility of cellulose, nonfiber carbohydrate, hydrolyzable carbohydrate and rapidly fermentable carbohydrate.
O trabalho foi realizado com objetivo de determinar as fra??es dos carboidratos n?o fibrosos, hidrolis?veis e rapidamente ferment?veis em alimentos volumosos e dietas e, estimar a digestibilidade aparente destes nutrientes em ensaios de digest?o com eq?inos. O estudo foi constitu?do por quatro ensaios de digest?o em eq?inos alimentados com diferentes dietas. Os ensaios de digest?o foram caracterizados em: Ensaio I avalia??o da digestibilidade in situ dos nutrientes dos alimentos volumosos, alfafa, amendoim forrageiro, Desmodium ovalifolium, Stylosanthes guianensis, feij?o guandu, Macroptyloma axillare e capimcoastcross, pela t?cnica de sacos m?veis. Ensaio II avalia??o da digestibilidade aparente de dietas exclusivas com feno de capim-coastcross com quatro diferentes formas f?sicas, feno inteiro, picado, mo?do a 5 mm e finamente mo?do a 3 mm. Ensaio III avalia??o da digestibilidade aparente de dietas com alimentos volumosos e com inclus?o de concentrado. Ensaio IV avalia??o da digestibilidade aparente em eq?inos alimentados com dietas contendo diferentes n?veis de inclus?o de ?leo de soja, contendo 5, 13 e 21% de extrato et?reo na dieta. Nas amostras dos alimentos, das fezes e da digesta do c?lon dos eq?inos fistulados no c?lon ventral direito, utilizados nos ensaios I e II, foram efetuadas an?lises para a determina??o dos teores de mat?ria seca (MS), prote?na bruta (PB), extrato et?reo (EE), cinzas (MM), fibra em detergente neutro (FDN), fibra em detergente ?cido (FDA) e carboidratos hidrolis?veis (CHO-H). Os carboidratos n?o fibrosos (CNF) foram estimados pela f?rmula CNF = 100-PB-MM-EE-FDN. Os carboidratos hidrolis?veis foram determinados por an?lise direta e os carboidratos rapidamente ferment?veis (CHO-RF) foram estimados pela diferen?a entre os carboidratos n?o fibrosos e os carboidratos hidrolis?veis. Os carboidratos totais foram estimados pela f?rmula: CHO-T = CHO-H + CHO-RF + FDN. Os resultados demonstraram que os eq?inos digerem com alta efici?ncia os carboidratos n?o fibrosos dos alimentos. Nos alimentos volumosos avaliados o amendoim forrageiro apresentou maior digestibilidade dos nutrientes analisados demonstrando potencial na utiliza??o em dietas para os eq?inos. O processamento do feno de capim-coastcross em diferentes graus de moagem n?o interfere na digestibilidade das fra??es dos carboidratos fibrosos e n?o fibrosos. A adi??o de concentrado ?s dietas aumentou a digestibilidade dos carboidratos n?o fibrosos e suas fra??es, sem afetar a digestibilidade da fibra, enquanto em dietas com n?veis de at? 13% de extrato et?reo, a digestibilidade das fra??es dos carboidratos fibrosos e n?o fibrosos n?o foram afetadas, no entanto, em dietas com 21% de extrato et?reo, houve redu??o na digestibilidade da celulose e dos carboidratos n?o fibrosos e suas fra??es hidrolis?veis e rapidamente ferment?veis.

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15

Silva, Vin?cius Pimentel. "Digest?o Total e Cecal de Alimentos Volumosos em Eq?inos." Universidade Federal Rural do Rio de Janeiro, 2007. https://tede.ufrrj.br/jspui/handle/tede/576.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior
This work aimed to evaluate digestibility and degradability of nutrients, and kinetics of passage in horses fed with forages using mobile bag and in situ cecal digestion. Two digestion trials were carried out and seven forages were used, lucerne (Medicago sativa), peanut (Arachis pintoi), Desmodium ovalifolium, Stylosanthes guianensis, Cajanus cajan, Macroptyloma axilares and coastcross (Cynodon dactylon cv. coastcross). Basal diet were composed by 80% hay and 20% concentrate. In first assay with mobile bags, five crossbreed horses were used with age varying from 17 to 27 years and average weight of 350 kg. A nylon cloth were used with 45? pore size, and bags with dimensions of 7,5 x 2 cm, containing 510mg DM of sample/bag. These assay had 12 days of duration, and three for adaptation, five days for naso-gastric insertion of bags and four days for bags collection in feces. Randomized block design were used with seven treatments and five repetitions. Naso-gastric insertion of bags were made twice a day, at morning and afternoon, inserting 29 bags, and four bags of each feed and one blank. Transit time and excretion of bags were evaluated until 96h from insertion. Nutrients digestibility of forages were calculated through residues inside the bags. In situ assay was conducted with caecum fistulated horse, weight 210Kg. Bags with 20x 6,5cm were used with 5,2g of sample incubated inside caecum along times 0, 2, 4, 6, 8, 12, 24, and 48 hours. A randomized design was used with seven treatments and three repetitions during 30 days. Orskov & McDonald degradation model was used to fit the nutrients degradation curves. Nutrients digestibility of peanut, Desmodium and Macroptiloma were high than others roughages (P<0.05). Any difference were observed (P>0.05) among transit time, mediun retention time and passage rate, average values were 23.34, 48.63 and 2.07, respectively. Degradation rate were high to peanut, Desmodium and Macroptyloma. Peanut fiber and protein degradability is superior to others tropical legumes, and peanut presented high protein contents. Tropically forages peanut, Stylosanthes guianensis and Macroptyloma axilares presented potential to be use in horse diets.
Este trabalho foi realizado com o objetivo de estimar a digestibilidade e a degrada??o dos nutrientes e a cin?tica de passagem de alimentos volumosos em eq?inos utilizando as t?cnicas de sacos de n?ilon m?veis e da digest?o in situ. Foram realizados dois ensaios de digest?o e os alimentos volumosos utilizados nos dois estudos foram, alfafa (Medicago sativa), amendoim forrageiro (Arachis pintoi), Desmodium ovalifolium, Stylosanthes guianensis, guandu (Cajanus cajan), Macroptyloma axilares e capim coastcross (Cynodon dactylon cv. coastcross). A alimenta??o foi uma dieta basal composta por 80% de feno e 20% de concentrado. No primeiro ensaio, com sacos m?veis, foram utilizados cinco eq?inos mesti?os com idades variando de 17 a 27 anos, com peso vivo m?dio de 350kg. Para a confec??o dos sacos, utilizou-se tecido de n?ilon com porosidade de 45? com dimens?es de 7,5x 2cm, inserindo 510mg de MS de amostra/saco. O ensaio teve dura??o de 12 dias, sendo tr?s para a adapta??o, cinco para inser??o g?strica dos sacos e quatro de coleta dos sacos. O delineamento foi em blocos inteiramente casualizados com sete tratamentos e cinco repeti??es. A sonda nasog?strica foi inserida duas vezes ao dia, de manh? e ? tarde com 29 sacos, sendo quatro para cada alimento e um em branco, anotou-se o tempo de tr?nsito e a excre??o dos sacos foi considerada at? 96 horas ap?s a inser??o. A estimativa da digestibilidade dos nutrientes dos alimentos volumosos foi calculada atrav?s do res?duo obtido no saco. No ensaio in situ utilizou-se um animal fistulado no ceco, com peso vivo de 210 Kg e sacos de 20 x 6,5 cm, com 5,2 g de amostra, incubadas no ceco nos tempos de 0, 2, 4, 6, 8, 12, 24 e 48 horas. Utilizou-se o delineamento inteiramente casualizado com sete tratamentos e tr?s repeti??es, com dura??o de 30 dias e o modelo de degrada??o citado por Orskov & McDonald para descrever as curvas de degrada??o dos nutrientes. A digestibilidade dos nutrientes dos alimentos volumosos Amendoim, Desmodium e Macroptyloma foram maiores (P<0,05). N?o houve diferen?a (P>0,05) entre os alimentos em rela??o ao tempo de tr?nsito, tempo m?dio de reten??o e taxa de passagem dos sacos, observando-se os valores m?dios de 23,3 h, 48,6 h e 2,0 h, respectivamente. Os valores da taxa de degrada??o foram superiores no Amendoim, Desmodium e Macroptiloma. A degrada??o da fibra do amendoim forrageiro ? superior ?s demais leguminosas tropicais, assim como seu conte?do prot?ico. Os alimentos volumosos tropicais amendoim, Stylosanthes guianensis e Macroptyloma axilares apresentaram potencial para o uso em dietas para eq?inos.

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Costa, Vivian Vasconcelos. "Papel do IFN- e da iNOS na patogênese do dengue experimental." Universidade Federal de Minas Gerais, 2009. http://hdl.handle.net/1843/BUOS-8S8JVB.

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Dengue is currently the most important mosquito-borne disease that affects humans and constitutes a serious world health problem. The lack of specific treatment and vaccine, and the incipient knowledge about pathogenesis contribute to the growing numbers of cases. A major limitation in the field of DENV research is the lack of animal models that mimic the human disease. Here, first, we aimed to create a newmodel of infection with DENV-3. The adaptation process allowed DENV-3 to multiply and cause disease in adult mice when given by intraperitoneal rout. The major findings after the inoculation of DENV-3 included increased vascular permeability, thrombocytopenia, increased systemic levels of cytokines (IL-6, TNF-, IFN- and CXCL-1), elevated levels of hepatic transaminases, greater tissue damage and inoculum-dependent lethality. In this work, we highlighted the cytokine IFN-, which has important functions in immunity to infectious agents. We evaluated the role played by IFN- and by one of its effectors molecules, nitric oxide, during the response to DENV-3 infection. For this, we used mice deficient in IFN- production (IFN--/-) and iNOS (iNOS-/-). After infection with DENV-3, wild type mice were able produce IFN- . Furthermore, IFN--/- presented higher lethality rates after DENV-3 infection if compared with their control counterparts. These animals presented increased tissuedamage and higher viral load in target organs. The roles of IL-12 and IL-18 cytokines were evaluated after infection with DENV-3 because this cytokines act in synergism to induce IFN- production. Indeed, IL-12p40 and IL-18-defficient mice presented higher lethality after DENV-3 infect, due to reduced hability to produce IFN-g and consequent increased viral loads. Finally, despite the high levels of IFN- produced duringinfection, iNOS-/- mice seemed to be unable to control DENV-3 replication, had higher tissue damage and died. Then, we conclude that IFN--induced NO production is an important pathway during response to dengue virus infection. In addition, IL-12 and IL- 18 appear to control IFN- production during DENV-3 infection. In the absence of these molecules, there is reduced ability of the host to control viral replication, resulting inincreased tissue damage and death of the infected animals. . Strategies capable to enhance production of these molecules may result in benefits during the control of primary infection by DENV-3.
A dengue a mais importante arbovirose que acomete o homem na atualidade e constitui um sério problema de saúde pública no mundo, especialmente nos países tropicais e subtropicais, onde as condições do meio ambiente favorecem o desenvolvimento e a proliferação do Aedes aegypti, o principal mosquito vetor. A ausência de tratamento específico ou mesmo de uma vacina disponível, somado ao escasso conhecimento acerca dos mecanismos envolvidos na patogênese da doença, contribuem a cada dia para o aumento do número de casos. Uma variedade de modelos experimentais tem sido proposta na literatura, contudo, grande parte não é ideal para investigar os mecanismos envolvidos na patogênese da doença. Neste trabalho,inicialmente, objetivamos desenvolver um modelo de infecção para o sorotipo-3 do vírus da dengue (DENV-3). Para isso, realizamos a adaptação de um isolado clínico ao hospedeiro murino. Os animais adultos selvagens (WT), infectados sistemicamente com o DENV-3 adaptado, desenvolveram os sinais clássicos característicos da doençahumana: trombocitopenia, hemoconcentração, aumento da permeabilidade vascular, hipernocicepção articular inflamatória, aumento dos níveis das transaminases hepáticas no soro, produção sistêmiica de mediadores inflamatórios, dano tecidual acentuadoassociado com elevada carga viral nos órgãos-alvo e morte. É importante ressaltar que o aparecimento desses sinais ocorreram de maneira inóculo e linhagem dependente. Embora o conhecimento sobre a patogênese da doença seja incipiente, atribui-se um papel importante às citocinas na resposta do hospedeiro infecção. Dentre estaspodemos destacar o IFN-, uma citocina com importante função na imunidade contra agentes infecciosos. No presente trabalho, avaliamos o papel desempenhado pelo IFN- e pela enzima iNOS, na resposta do hospedeiro infecção pelo DENV-3. Al disso, também avaliamos o papel das citocinas IL-12 e IL-18 durante infecção, visto que conjuntamente essas citocinas atuam estimulando a produção do IFN-. Vimos que os camundongos selvagens (WT) liberam uma grande quantidade de IFN- após a infecção com o DENV-3. Além disso, os animais deficientes na expressão dessa citocina (IFN-- /-) presentaram taxas elevadas de letalidade ap a infeco com o DENV-3. Estamaior susceptibilidade infecção e consequentemente, baixa sobrevida, foi associada maior lesão tecidual nos órgão-alvo para a infecção e com o prejuízo no controle da replicação viral por parte do hospedeiro. Interessantemente, a produção de IFN- parece ser modulada pelas citocinas IL-12 e IL-18. Para avaliar o mecanismo de proteção deIFN-, avaliamos também o papel da enzima iNOS no nosso modelo. Os animais WT infectados com o DENV-3 apresentaram aumento da express da isoforma induzida da enzima ácido nítrico sintase (iNOS). Além disso, após a infecção pelo DENV-3 e concomitante estimulação com IFN- in vitro, células dendríticas (DCs) produziram elevados níveis de NO no sobrenadante. Somado a esses achados, animais deficientesna expressão da iNOS (iNOS-/-) também apresentaram susceptibilidade aumentada infecção pelo DENV-3. Estes animais de maneira semelhante aos animais IFN--/-, apresentaram letalidade acentuada frente infecção, bem como aumentado dano tecidual em fígado e pulmões. Por fim, mesmo sendo capazes de produzir IFN- , osanimais iNOS-/- se mostraram inaptos em controlar a replicação do vírus da dengue, como verificado pelo alto título viral nos ógãos-alvo da infecção. Desta forma, concluímoos que a produção de ácido nítrico (NO) via iNOS induzida pelo IFN- uma via importante na resposta do hospedeiro à infecção pelo DENV-3. Na ausência dessas moléculas, hmarcante incapacidade de controle da replicação viral por parte dohospedeiro, levando a uma manifestação mais grave da infecção e conseqnte morte dos animais. Além disso, as citocinas IL-12 e IL-18 parecem ser importantes na indução da produção do IFN- neste modelo. Estratégias que elevem a produção dessas moléculas podem resultar em benefícios por parte do hospedeiro no controle da infecçãoprimária pelo DENV-3.

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17

Song, Wook. "Exercise training reverses age-induced inducible nitric oxide synthase upregulation." Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/1609.

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The risk of injury, inflammation, and oxidative stress increases in skeletal muscle with aging. It has been postulated that pro-oxidant signaling, including upregulation of inducible nitric oxide synthase (iNOS) contributes to inflammation, pathology, and aging in the brain, liver and heart. Exercise training reduces the risk of injury and inflammation. The purpose of this study was: 1) to identify the mechanisms that upregulate iNOS, pro-oxidant and pro-inflammatory signaling in skeletal muscle, and 2) to identify the mechanisms by which exercise training reduces pro-oxidant signaling. Protein levels and activity of iNOS were measured in 4 groups of male Fischer-344 rats (5 mo and 24 mo, n=10/group), old-control (OC), old-trained (OT), young-control (YC), and young-trained (YT). Exercise training protocol was 60 min at 15 m/min at 15° incline for 5 d/wk for 12 wk. Both iNOS protein expression and activity were significantly higher in OC compared to YC, but exercise training reversed the elevation of iNOS levels lower than OC in tibialis anterior. Surprisingly, NF-κB DNA binding activity was significantly lower in OC than YC, while increased with exercise training in white and red gastrocnemius in both OT and YT. In contrast, protein expression of p65, a regulatory subunit of NF-κB was significantly greater in OC than YC, while exercise training significantly reduced p65 in OT compared to OC from the white gastrocnemius. These data indicate that regulation of NF-κB activity with aging is post-translational and alterations in iNOS expression may result from alternative NF-κB pathways. As decreased NF-κB activity with aging could result in downstream increase in pro-apoptotic signaling, we tested follow-up hypotheses that aging would increase pro-apoptotic regulator Bax and decrease the anti-apoptotic regulator Bcl-2. Bax increased while Bcl-2 decreased in OC in white gastrocnemius when compared to YC. In contrast, exercise training resulted in a dramatic upregulation of Bcl-2 and downregulation of Bax protein expression in OT when compared to OC. These novel results indicate that alterations in pro-inflammatory and pro-apoptotic signaling occur in skeletal muscle during the aging process. Importantly, our findings strongly support the hypothesis that exercise training reverses age-induced changes in pro-inflammatory and pro-apoptotic signaling.

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18

Craig, Graham Peter. "INOS mediates increased RhoA expression and altered cell signaling in diabetic cardiomyopathy." Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/32344.

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The RhoA/ROCK pathway is a well established signaling pathway which regulates cellular contractility. Previous studies, from this lab have shown that acute inhibition of ROCK improves heart function in 12 week STZ-diabetic rats. Here we wished to determine, 1) whether the RhoA/ROCK pathway was upregulated in the diabetic rat heart, 2) what factors may. be contributing to altered activity of this pathway during diabetes, and 3) determine the consequences of the altered RhoA/ROCK signaling might be. RhoA expression was significantly elevated in hearts and cardiomyocytes from rats with STZ-induced diabetes. Our preliminary studies also showed elevated iNOS expression in hearts from rats with STZ-induced diabetes. We hypothesized that NO from iNOS mediates elevated RhoA expression. This hypothesis is supported by a number of our observations. Elevated iNOS expression and activity was observed to be concomitant with increased RhoA expression in diabetic rat hearts. In cultured cardiomyocytes exposure to the NO donor, SNP, and the iNOS inducer, LPS , caused elevated RhoA expression. The iNOS inhibitor, L-NIL, blocked increased RhoA expression in LPS treated cardiomyocytes and in hearts from diabetic animals. Increases in RhoA expression correlated strongly with increased levels of active RhoA in diabetic cardiomyocytes. We also observed increased phosphorylated LIMK, a marker for activation of the RhoA/ROCK pathway. LIMK phosphorylation was reduced to levels similar to control after chronic treatment of diabetic rats with L-NIL, suggesting that iNOS also contributes to increased activity of this pathway in the STZ-diabetic rat heart. The actin cytoskeleton is a well established downstream target of the RhoA/ROCK pathway. The level of polymerized actin in diabetic rat cardiomyocytes was found to be significantly elevated, but was normalized after acute ROCK inhibition. Given this observation, we suggest that normalization of actin polymerization may contribute to ROCK inhibitor-mediated improvement of contractile function of hearts from diabetic rats. The findings presented in this thesis indicate a central role for iNOS in the upregulation of the RhoA/ROCK pathway, which is believed to contribute to impaired contractility in the diabetic heart. Our findings also support the suggestion that ROCK is an excellent therapeutic target in the treatment of diabetic cardiomyopathy.
Pharmaceutical Sciences, Faculty of
Graduate

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19

Aristóteles, Luciana Ritha de Cassia Rolim Barbosa. "Modulação da mecânica do tecido pulmonar periférico e da resposta do estresse oxidativo pela inibição da arginase e da iNOS em modelo experimental de inflamação crônica pulmonar." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5165/tde-31072012-113923/.

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Introdução: A importância do parênquima pulmonar na fisiopatologia da asma tem sido recentemente enfatizada, particularmente nos pacientes com asma grave e de difícil controle. O óxido nítrico (NO) é um importante modulador da resposta contrátil, inflamatória e de remodelamento pulmonar que ocorrem na asma. Embora seu papel na modulação em vias aéreas proximais e distais já tenha sido estabelecido, seus efeitos no parênquima pulmonar foram pouco investigados. Objetivos: Avaliar se a inibição da arginase 2, por intermédio do tratamento com N-hydroxy-nor-L-arginine (nor-NOHA), e da iNOS, por intermédio da administração de 1400W, pode modular a resposta constritora de parênquima distal, o estresse oxidativo, a expressão de iNOS, assim como a atividade da arginase, em modelo de inflamação alérgica crônica pulmonar em cobaias. Métodos: Os animais foram expostos a sete inalações com soro fisiológico ou com ovoalbumina em doses crescentes (1~5mg/ml- 4 semanas) e tratados com 1400W (2mg/Kg ip. diariamente) iniciando após a 7ª inalação e nor- NOHA (10M - infusão no banho durante a avaliação da mecânica oscilatória), ou associação de 1400W + nor-NOHA (administrado conforme descrito anteriormente). Setenta e duas horas após a sétima inalação os animais foram anestesiados, exsanguinados e a foi realizada a avaliação da mecânica oscilatória do parênquima pulmonar, sendo obtidos os valores de resistência e elastância tecidual na condição basal e após desafio (0,1% de ovoalbumina). Em seguida, os fragmentos de tecido pulmonar periférico foram fixados em solução de formolaldeído a 4%, por 48 horas. Depois de terminada a fixação, o material foi submetido às técnicas histológicas habituais com parafina, para obtenção de cortes de 4m de espessura. Os cortes foram corados para Hematoxilina e Eosina e utilizando técnica de imunohistoquímica foram avaliados o número de células iNOS positivas, a expressão de PGF2, do fator de transcrição NF-kB e de arginase 2 no septo alveolar, por intermédio de avaliação morfométrica. A expressão de arginase 2, NF-kB e PGF2 nos fragmentos de tecido pulmonar periférico foram avaliados em aumento 400X utilizando o programa Image-Pro Plus 4.5v Image Analysis System e os resultados foram expressos em porcentagem. Em relação ao número de células iNOS positivas nos fragmentos pulmonares, foi utilizada a técnica de contagem de pontos, determinada pelo número de pontos que coincidiam em células positivas em cada campo dividido pelo número de pontos que incidiam no tecido pulmonar, no aumento de 1000x. Foram analisados 10 campos por corte, selecionados de forma randômica. Os resultados foram expressos como células por unidade de área (104m2). Para a avaliação da atividade da arginase 2, foi utilizado o método descrito no kit da BioAssay Systems que utiliza um cromogênio, que forma um complexo corado com uréia, produzido na reação de arginase. A determinação da atividade da arginase 2 envolveu a medida da velocidade de reação, expressa em termos de atividade por miligrama de proteína (U/mg). Resultados: Não houve alteração no percentual de estruturas (vasos, vias aéreas e tecido alveolar) no tecido pulmonar nos quatro grupos experimentais, sendo que mais de 90% de tecido do fragmento pulmonar foi constituído de alvéolos. Os animais que foram expostos à ovoalbumina apresentaram um aumento da resistência e da elastância tecidual (após desafio antigênico), no número de células iNOS positivas, na percentagem de expressão de PGF2, arginase 2 e NF-kB no septo alveolar, assim como da atividade de arginase 2 comparativamente aos grupos controles (p<0,001). O tratamento com nor-NOHA ou 1400W isoladamente em animais expostos à ovoalbumina atenuou a resposta de elastância e resistência teciduais após desafio antigênico (p<0,001), o número de células iNOS positivas (p<0,001), na expressão de PGF2, de arginase 2 e NF-kB no septo alveolar (p<0,001). Porém a atividade da arginase 2 só foi reduzida nos grupos que foram tratados com nor-NOHA e na associação de 1400W e nor-NOHA (p<0,05). A associação de 1400W e nor-NOHA em animais expostos à ovoalbumina potencializou a atenuação da expressão PGF2 no septo alveolar (p<0,001). Conclusões: O presente estudo sugere que, neste modelo experimental de inflamação crônica pulmonar, a inibição da arginase tem papel importante na modulação das repostas constritoras e de estresse oxidativo no parênquima pulmonar distal. A associação da inibição da iNOS à da arginase 2 potencializa o controle da resposta de estresse oxidativo. Estas respostas são, pelo menos em parte, moduladas pela ativação de NF-kB. A inibição destas vias enzimáticas pode representar uma estratégia futura para o tratamento de pacientes com asma grave e de difícil controle
Introduction: The importance of the lung parenchyma in the pathophysiology of asthma has recently been emphasized, particularly in patients with severe asthma and difficult to control. Nitric oxide (NO) is an important modulator of contractile response, lung inflammation and remodeling occurring in asthma. Although its role in the modulation proximal and distal airways tone control has already been established, its effects on the lung parenchyma were rarely investigated. Aims: To evaluate the inhibition of arginase 2, through treatment with N-hydroxy-nor-L-arginine (nor-NOHA) and / or iNOS, through the administration of 1400W, can modulate the constrictor response of distal parenchyma, oxidative stress, the expression of iNOS and the activity of arginase, in a model of chronic allergic lung inflammation in guinea pigs. Methods: The seven animals were exposed to inhaled saline or ovalbumin with increasing doses (1~5mg/ml-4 weeks) and treated with 1400W (2mg/kg ip daily) beginning after the 7th inhalation and nor-NOHA (10M - infusion in the bath during the evaluation of mechanical oscillation), or combination of 1400W + nor- NOHA (administered as formerly). Seventy-two hours after the seventh inhalation the animals were anesthetized, and exsanguinated and it was performed evaluation was made of oscillatory mechanics of lung parenchyma, and obtained the values of tissue resistance and elastance at baseline and after challenge (0.1% ovalbumin). Then the peripheral lung tissue fragments were fixed in formolaldeíde 4% for 48 hours. After completion of fixation, the material was subjected to routine histological techniques with paraffin to obtain sections of 4m thickness. The sections were stained with Hematoxylin and Eosin and by using immunohistochemical technique, we assessed the number of iNOS positive cells and expression of PGF2, of the transcription factor NF-kB and arginase 2 in the alveolar septum, through morphometric analysis. The expression of arginase 2, NF-kB and PGF2 in peripheral lung tissue fragments were evaluated at 400X increase by Image - Pro Plus Image Analysis System 4.5v and the results were obtained as a ratio between the amount of expression of arginase 2, NF-kB and PGF2 and are expressed as percentage. Regarding the content of iNOS in lung fragments, we used the technique of counting points, determined by the number of points coinciding in the positive cells in each field divided by the number of points that focused on lung tissue, using the increase of 1000x. Were increase of 10 fields analyzed per section, selected randomly. The results were expressed as cells per unit area (104m2). To assess the activity of arginase 2 we used the method bioassay described in the kit Systems using a chromogen which forms a colored complex with urea produced in the reaction of arginase. The determination of the activity of arginase 2 involved the measurement of reaction rate, expressed in terms of activity per milligram of protein (U/mg). Results: There were no changes in the percentages of structures (vessels, airways and alveolar tissue) lung tissue in four experimental groups, with more than 90% of the tissue fragment consisted of pulmonary alveoli. The animals that were exposed to ovalbumin, showed an increase in tissue resistance and elastance after antigen challenge, the number of iNOS positive cells, the of expression of PGF2, of NF-kB and arginase 2 in the alveolar septum well as in the activity of arginase 2, compared to control groups (p <0.001). The treatment with nor-NOHA or 1400W alone in animals exposed to ovalbumin attenuated the tissue elastance and resistance after antigenic challenge (p <0.001), the number of iNOS positive cells (p <0.001), the expression of PGF2, arginase 2 and NFkB in the alveolar septum (p<0.001). However the activity of arginase 2 was reduced in only in the groups that were treated with nor-NOHA and the association of 1400W and nor-NOHA (p <0.05). The combination of 1400W and nor-NOHA, in animals exposed to ovalbumin enhanced the attenuation of the expression of PGF2 in the alveolar septum (p <0.001). Conclusions: The present study suggests that in this experimental model of chronic pulmonary inflammation, inhibition of arginase 2 plays an important role in the modulation of constrictor responses and oxidative stress in the distal lung parenchyma. The association of iNOS inhibition to the arginase 2 enhances the control of oxidative stress response. These responses are, at least in part, modulated by the activation of NF-kB. The inhibition of these enzyme pathways may represent a future strategy for the treatment of patients with severe asthma and difficult to control

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Cunha, João Paulo da. "Expressão do microRNA-27b, eNOS e iNOS nos corpos cavernosos de ratos submetidos ao alcoolismo e diabetes mellitus." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17137/tde-10012017-110614/.

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A Disfunção Erétil (DE) é um problema de elevada prevalência e mostra-se relacionada com o envelhecimento, diabetes, etilismo, obesidade, dislipidemia, tabagismo e outras doenças que se demonstram relacionadas com disfunção endotelial. O Óxido Nítrico (NO), produto da ação da Óxido Nítrico Sintetase (NOS), foi comprovado ser o mais importante vasodilatador de musculatura lisa associado à ereção. Os microRNAs (miRNA) são moléculas recentemente descobertas, que supõe-se atuar como reguladoras de aproximadamente um terço dos genes humanos. O miRNA-27b está relacionado à função endotelial e angiogênese. O presente trabalho tem por objetivo estudar a expressão da NOS endotelial (eNOS) e indutível iNOS), além do miRNA-27b nos corpos cavernosos e sangue periférico de ratos saudáveis, diabéticos, alcoolizados e com as duas patologias. Foram criados 4 grupos de 12 ratos Winstar: grupo controle(saudáveis) (C), grupo com alcoolismo (A), grupo diabético (D) e grupo com as duas patologias (A+D). Em cada grupo, 6 animais foram estudados pors imunohistoquimica para eNOS e iNOS e 6 animais tiveram a expressão gênica da eNOS, iNOS e miRNA-27b avaliados por qT-PCR nos corpos cavernosos e sangue periférico. Os resultados demonstraram diminuição da expressão do miRNA-27b nos grupos A, D e A+D tanto na amostra tecidual quanto do sangue periférico. A imunohistoquimica mostrou maior expressão de eNOS no grupo D+A e de iNOS nos grupos A e A+D.
Erectile Dysfunction (ED) is a high prevalence problem and appears to be related to aging, diabetes, alcoholism, obesity, dyslipidemia, smoking and other diseases that show related to endothelial dysfunction. Nitric oxide (NO), a product of Nitric Oxide Synthase (NOS), was shown to be the most important vasodilator of smooth muscles associated with the erection. Micro-RNAs (miRNA) are recently discovered molecules which are supposed to act as regulators of approximately one third of human genes. The miRNA-27b is related to endothelial function and angiogenesis. This work aims to study the expression of endothelial and inducible NOS in addition to the miRNA-27b in the corpus cavernosum and peripheral blood of healthy rats, diabetic, alcoholic and with both pathologies. Were created four groups of 12 rats Winstar: control group (healthy) (C), a group with alcoholism (A), diabetic group (D) and group with both disorders (A + D). In each group 6 animals were studied for eNOS and iNOS immunohistochemistry and 6 animals the gene expression of eNOS, iNOS and miRNA-27b evaluated by qT-PCR in the corpus cavernosum and peripheral blood. The results showed increase expression of miRNA-27b in Group A, D and A+D in both the tissue sample and peripheral blood. Immunohistochemistry showed a increase of eNOS expression in group A+D and iNOS high expression in groups A and A+D.

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Aheng, Marie-Caroline. "Etude de la protéine mitochondriale UCP2 au cours de l'encéphalite auto-immune expérimentale." Paris 6, 2010. http://www.theses.fr/2010PA066106.

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La protéine découplante UCP2 fait partie de la famille des transporteurs mitochondriaux. Son expression prédomine dans les cellules immunitaires. Chez la souris, le gène est situé dans une région chromosomique fortement associée à l’Encéphalite Auto-immune Expérimentale (EAE), un modèle murin de sclérose en plaques (SEP). En absence d’UCP2, la réponse auto-immune est amplifiée. Sur le plan clinique, cela se traduit par des troubles moteurs beaucoup plus sévères. Le but de ce travail était, dans un premier temps, de comprendre les relations entre UCP2 et la NO synthase inductible (iNOS), une enzyme surexprimée chez les souris Ucp2-/- pendant l’EAE. Chez les souris inactivées pour ces deux gènes, la maladie apparaît plus tardivement, l’inflammation et le stress oxydant sont diminués. Le gène Ucp2 s’exprime également dans diverses régions du système nerveux central. Ces observations nous ont conduit à étudier la réactivité des souris Ucp2-/- en réponse à un stress environnemental, reproduit expérimentalement par la disruption sociale. Les résultats montrent un état d’anxiété plus grand chez la souris Ucp2-/-. Enfin, l’étude d’UCP2 au cours de l’anesthésie montre que son expression est augmentée par différents produits anesthésiques. Par ailleurs, la délétion du gène entraîne un phénotype d’hyperactivité locomotrice.

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Pelosi, Valeria. "Ruoli distinti delle due isoforme di recettori degli estrogeni nella disfunzione vascolare in modelli animali di diabete." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425115.

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Recent large-scale clinical trials found a significantly lower incidence of diabetes in postmenopausal women on hormone replacement therapy despite no improvement in vascular outcomes. The mechanisms accounting for this outcome, however, are largely unknown although estrogen is increasingly recognized as an important regulator of glucose homeostasis. Because the endogenous hormone binds to its receptors with identical affinity, the metabolic effects of individual estrogen receptor (ER) isoforms, ERa and ERb, are hard to entangle and appear to be tissue- and species-specific. Accordingly, there is little information as to how ERa and ERb affect the course and timeline of diabetic vascular dysfunction, which ultimately results in macrovascular complications of clinical relevance. We previously demonstrated that estrogen’s anti-inflammatory activity is attenuated in vascular smooth muscle cells (SMCs) from streptozotocin (STZ)- diabetic rats, which display ERb overexpression with respect to normoglycemic controls. The biological significance of ERb overexpression in vascular cells from diabetic rats is as yet unclear. Data from our group indicate that moderately selective ERb agonists induce the expression of inflammatory enzymes in rat vascular SMCs. There is also evidence that ERa mediates protective antiinflammatory effects in vascular and nonvascular tissues including pancreatic b- cells. ERa-selective, but not ERb-selective agonists improve vascular function by mediating vessel relaxation at concentrations where receptor selectivity is maintained. Based on this knowledge, we set out to assess the relative contribution of ER isoforms to the progression of experimental insulin-deficient diabetes and the accompanying vascular dysfunction in rodents through a comprehensive physiological and pharmacological approach using ER-deficient mice, cultured vascular SMCs and ER-selective agonists. Primary cultures of vascular smooth muscle cells prepared from control and streptozotocin-injected rats were stimulated with a cytokine mixture comprising TNF-a, interleukin-1b and interferon-g for 24 h in the presence or absence of test compounds, the ER-selective agonists PPT and DPN. The increased expression of inducible NO sythase (iNOS), a classical indicator of vascular inflammation, was significantly reduced in a concentration-dependent manner by the ERa selective agonist PPT, while the ERb selective ligand DPN further enhanced iNOS expression. To explore potential mechanisms of the distinct iNOS regulation mediated by ERa and ERb and the observed loss of regulation through ERa in SMCs from diabetic rats, we transfected both ER isoforms at increasing plasmide:reporter ratios into SMCs and measured ERE-TATA-luc activity after E2 treatment. ERa and ERb transcriptional activity in response to 1 nmol/L E2 treatment for 24 h consistently increased in both SMC groups. This suggests that the transcriptional machinery of ER isoforms is maintained in SMCs from diabetic rats. The opposite regulation of iNOS function by ER-selective agonist in control SMCs could be secondary to differential modulation of nuclear p65 translocation, an important component of E2 anti-inflammatory action. Whereas LPS enhanced the nuclear staining of p65, PPT and DPN blocked this pathway, suggesting that ER-mediated iNOS control in vascular SMCs was independent from the NF-kB system. Fasting serum glucose levels were higher in ERa -/- compared with ERb -/- or wild-type (wt) mice. Diabetes was induced in 8-week-old mice by a single i.p. injection of STZ (150 mg/Kg). Despite similar worsening of glycaemic control, exposure to STZ caused significantly greater mortality in ER? -/- (41%) than in ER? -/- (12%) or wt (14%) mice. Vascular biology studies were performed in cultured aortic rings isolated from wt and ER-knockout mice. Aortic rings were stimulated with inflammatory agents in the presence and absence of test compounds. Treatment of isolated mouse aortic rings with 1 nM 17b-estradiol for 24 h attenuated cytokine-driven formation of inducible NO synthase (iNOS) as detected by Western blotting. This effect was shared by the ERa-selective agonist PPT but not by the ERb-selective agonist DPN. Accordingly, 17b-estradiol reduced iNOS formation in aortic rings from ERb -/- but not ERa -/- mice. To sum up, combined use of ER-knockout mice and ER-selective agents provided evidence for an anti-inflammatory role for ER? as well as a potential pro-inflammatory role for ER? in the arterial wall. Cellular and animal experiments indicated that ER? and ER? play a relevant role in the control of glucose metabolism, vascular inflammatory responses and diabetes progression in rodents. Based on the present findings, ER?-selective activation may represent a promising pharmacologic approach to the therapeutic modulation of diabetic vascular dysfunction.

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Souza, Flavia Castro Ribas de. "Efeitos dos tratamentos com glicocorticóides, com antagonista do receptor do cisteinil-leucotrieno D4 e com o inibidor específico da iNOS na resposta inflamatória e de remodelamento no tecido pulmonar periférico em mode." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-25052012-173836/.

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Introdução: Estima-se que 10% dos doentes com asma tm sintomas e limitaes importantes, como exacerbaes freqentes ou reduo persistente da funo respiratria As alteraes do parnquima pulmonar distal tem sido recentemente abordadas na fisiopatologia da asma. Apesar do uso de corticosterides, pacientes com asma refratria tm mais estresse oxidativo, assim como apresentam ativaao da iNOS. Alm disso, muitos dos dispositivos utilizados para administrao de esterides inalatrios geram partculas que no chegam efetivamente s vias areas distais e ao parnquima pulmonar. Objetivos: Avaliamos os efeitos do tratamento com montelucaste ou dexametasona tratamentos associados ou no a um inibidor especfio da iNOS (1400W) na resposta eosinoflica, remodelamento da matriz extracelular, estresse oxidativo, contedo de actina, clulas positivas para IL4, IL5, MMP9, TIMP1, IFN, TGF do parnquima em cobaias com inflamao crnica pulmonar. Métodos: As cobaias foram inaladas com ovalbumina (grupo OVA) 2X/semana por 4semanas. Aps a 4 inalao, as cobaias foram tratadas diariamente com montelucaste (grupo OVAM 10mg/Kg/PO/dia) ou dexametasona (grupo OVAD 5mg/Kg/IP/dia). O inibidor da iNOS, 1400W (grupo OVAW 1mg/kg/dia) foi administrado intraperitonealmente nos ltimos 4 dias (OVAW, OVADW e grupos OVAMW). Aps 72 horas da 7 inalao, as cobaias foram anestesiadas, e os fragmentos de tecido pulmonar distal foram submetidos avaliao histopatolgica. Resultados: Houve um aumento no infiltrado eosinoflco, nas clulas positivas para IL4, IL5, TIMP1, MMP9, iNOS, IFN TGF, contedo de actina, isoprostano PGF2 alfa, fibras colgenas e elsticas nos animais OVA em comparao com animais SAL (p<0,05). Houve uma diminuio no nmero de eosinfilos, clulas positivas para IL4, IL5, MMP9, TIMP1, IFN, TGF, contedo de actina, colgeno e isoprostano PGF2 alfa em todos os grupos tratados em comparao com animais OVA (p<0,05). O contedo de fibras elsticas foram reduzidas somente nos grupos OVAMW, OVADW e OVAW em comparao com animais OVA (p<0,05). A associao de 1400W e o tratamento com montelucaste (grupo OVAMW) potencializou a reduo do contedo de actina, fibras elsticas, isoprostano PGF2 alfa de clulas positivas para IL4, IL5, TIMP1, IFN TGF e iNOS em relao ao grupo montelucaste (OVAM) (p<0,05). Os tratamentos com 1400W e dexametasona (grupo OVADW) contriburam para uma maior reduo do contedo das fibras elsticas, actina e isoprostanoPGF2 alfa e o nmero de clulas positivas para IL4, IL5, IFN e TIMP1 em relao ao grupo dexametasona (OVAD) (p<0,05). Conclusões: O tratamento com corticosterides associados inibio da iNOS contribuiu para uma maior reduo da remodelao da matriz extracelular, diminuiu o estresse oxidativo, e tambm foi eficiente para atenuar a resposta inflamatria Th2 no parnquima pulmonar distal. Por outro lado, o tratamento com montelucaste associado à inibição da iNOS mostrou uma maior eficácia para reduzir o teor de fibras elásticas, a ativação do estresse oxidativo, conteúdo de actina e expressão das células positivas para IL4, IL5 no parênquima pulmonar distal. Estas associações podem representar futuras ferramentas farmacológicas para o controle das alterações histopatológicas pulmonares distais induzidas pela inflamação crônica
Introduction: It is estimated that 10% of asthma patients have symptoms and important limitations such as frequent exacerbations or persistent reduction of resiratory function, despite the use of corticosteroids. The alterations of distal lung parenchyma have been recently evaluated on asthma pathophysiology, particulary in patients with refractory asthma and difficcult to control. These patients have increased oxidative stress responses, mainly with significant activation of iNOS. Aims: We evaluated the effects of montelukast or dexamethasone treatments associated or not to an iNOS inhibitor (1400W) on eosinophilic response, extracellular matrix remodeling, oxidative stress, actin content, IL4, IL5, MMP9, TIMP1, IFN gama, TGF beta positive cells of distal lung parenchyma in guinea pigs with chronic alergic inflammation. Methods: Guinea Pigs were inhaled with ovalbumin (OVA group) twice a week for four weeks. After 4th inhalation, GP were treated with montelukast (OVAM group-10mg/Kg/PO/day) or dexamethasone (OVAD group-5mg/Kg/IP/day). The treatment with iNOS inhibitor 1400W (OVAW group-1mg/kg/day) was given daily in the last 4 days (OVAW, OVADW and OVAMW groups). After 72 hours of 7th inhalation, GP were anesthetized, lung strips were retired and submitted to histopathological evaluation. Results: There was an increase in eosinophilic infiltrate, in the number of positive cells for IL4, IL5, TIMP1, MMP9, iNOS, IFN gama TGF beta, actin, isoprostane PGF2 alpha, elastic and collagen fiber contents in OVA animals comparing to SAL group (p<0,05). There was a decrease in the number of eosinophils, IL4, IL5, MMP9, TIMP1, IFN gama, TGF beta positive cells, collagen, actin and isoprostane PGF2 alpha content in all treated groups compared to OVA animals (p<0.05), but the treatment with montelukast did not reduce the positive cells for IFN gama, compared to OVA (p>0.05). Elastic fiber content were reduced only in OVAMW, OVADW and OVAW groups compared to OVA animals (p<0.05). The association of 1400W and montelukast treatments potentiated the reduction of actin, elastic fibres and isoprostane PGF2 alpha contents and the number of IL4, IL5, TIMP1, IFN gama, TGF beta and iNOS positive cells compared to montelukast group (p<0.05). The treatments with 1400W and dexamethasone contributed to a greater reduction of elastic fibers, actin and isoprostane PGF2 alpha contents and the number of IL4, IL5, IFNgama and TIMP1 positive cells compared to dexamethasone group (p<0.05). Conclusions: Corticosteroid treatment associated to iNOS inhibition contributes to a greater reduction of extracellular matrix remodeling, decreases the oxidative stress, and also is efficient to attenuate the Th2 inflammatory response in distal lung parenchyma. On the other hand, montelukast treatment associated to iNOS inhibition showed a higher efficacy to reduce elastic fibres content, oxidative stress activation, actin content and IL4 and IL5 expression in distal lung parenchyma. These associations may represent future pharmacological tools for controlling distal pulmonary histopathological alterations induced by chronic inflammation

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Seyffarth, Gunter. "The expression of iNOS and its control in human intrauterine tissues at term." Thesis, University of Wolverhampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343143.

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Reddick, Jennifer I. "Evolution and gene expression analysis of inducible nitric oxide synthase (iNOS) in fish." Thesis, University of Aberdeen, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420115.

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In this thesis, the full-length iNOS cDNA was sequenced from a cartilaginous fish, small spotted catshark (Scyliorhinus canicula), which had 77% amino acid (aa) similarity to chicken iNOS, and 73% aa similarity to trout iNOS. Expression studies in vivo also indicated that in S. canicula iNOS expression was strongest in the spleen. In addition, two full-length iNOS coding regions were sequenced from a bony fish species, goldfish (Carassius auratus). The two transcripts were designed iNOSa and iNOSb, with 93.5% aa similarity to each other and 93.4 and 92.0 % aa similarity to carp respectively. An in silico study to find iNOS and other NOS sequences from vertebrates and invertebrates in genomic and cDNA databases discovered full-length iNOS coding regions from several vertebrate species, including the western clawed frog (Xenopus tropicalis) and two distinct anciently duplicated genes from the zebrafish (Danio rerio). Partial or full-length NOS genes were also found in two species of urochordate (sea squirts, Ciona sp.), honey bee (Apis mellifera) and constitutive NOS genes from several vertebrates. Expression studies using the promoter region of rainbow trout (Oncorhynchus mykiss) iNOS in a luciferase reporter gene vector indicated that bacterial lipopolysaccharide (LPS) was a good inducer of iNOS expression in vitro, and required as little as 208bp of 5’ flanking region and intron 1. The promoter region of goldfish iNOS was sequenced, and had similar transcription factor binding sites to those of iNOS genes from other species.

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Roberts, Philip John. "The physiological expression of inducible oxide synthase (INOS) in the normal human colon." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395044.

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Maia, Robinson Magalhães. "Síntese total do ácido corcórico B: inibidor da óxido nítrico sintase induzível (INOS)." Universidade de São Paulo, 2003. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-16032009-211330/.

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O presente trabalho descreve a síntese do ácido corcórico B, isolado de folhas de Corchorus olitorius, L. (Tiliaceae). Este ácido graxo exerce atividade inibitória na produção de NO (óxido nítrico) induzida por lipopolissacarídeo bacteriano em cultura de macrófagos de peritôneo de rato. Uma vez que a produção excessiva de NO (óxido nítrico) é responsável por processos inflamatórios, reações imunológicas (vg., choque séptico causado por endotoxinas), a utilização do ácido corcórico B em terapêutica pode ser efetivo contra inflamação e choque séptico. A síntese total do ácido corcórico B, foi realizada através das reações de Wittig e de Stille, utilizadas na construção do sistema trienona (responsável por seu efeito biológico).
This present work describes the synthesis of the corchorifatty acid B, isolated from leaves of Corchorus olitorius, L. (Tiliaceae). This fatty acid exerts inhibitory activity on the lipopolysaccharide (LPS)-induced NO (nitric oxide) production in cultured mouse peritoneal macrophages. Since over-production of NO (nitric oxide) is the cause of inflammation, immunological responses (vg., endotoxin shocks), the therapeutic use of this fatty acid may be effective against inflammations cases and endotoxin shocks. The total synthesis of corchorifatty acid B, was achieved using the Stille and Wittig reactions to construct the trienone system (responsible for its biological effect.).

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Broadbelt, Nalini V. "Regulation of iNOS expression : in response to pressure in proximal tubule epithelial cells /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1619205731&sid=2&Fmt=2&clientId=8424&RQT=309&VName=PQD.

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Kankuri, Esko. "On the role of the inducible enzymes iNOS and COX-2 in colitis." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/kankuri/.

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Ramos, Renata Pinto. "Infecção esquistossomótica aguda: produção de citocinas em camundongos desnutridos e deficientes em iNOS." reponame:Repositório Institucional da FIOCRUZ, 2007. https://www.arca.fiocruz.br/handle/icict/3927.

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A esquistossomose está presente em 76 países, dentre eles o Brasil, atingindo 19 estados, estando Pernambuco entre os estados com maior número de casos. Em zonas endêmicas para o Schistosoma mansoni, observa-se, freqüentemente, uma sobreposição de subnutrição e infecção parasitária. Em estudos imunológicos em animais infectados pelo S. mansoni, ocorre um predomínio inicial da resposta Th1 que contribui para a formação do granuloma agudo, com a oviposição e sua deposição nos tecidos do hospedeiro. Essa resposta Th1 sofre uma substituição progressiva por uma resposta Th2. Diante disso, este trabalho teve como objetivo estudar a resposta imune celular em camundongos deficientes em iNOS, desnutridos e com infecção esquistossomótica aguda. Foram utilizados 200 animais subdivididos em C57BL/6 KO iNOS e C57BL/6 controles submetidos às dietas hipoprotéica ou controle e infectados com 30 cercárias de S. mansoni ou não infectados. A metodologia consistiu de análise da carga parasitária, da histopatologia e morfometria do fígado, cultura de células esplênicas para se obter os sobrenadantes e dosar as citocinas (IFN- , IL-4 e IL-10). Os resultados não revelaram diferenças quanto à recuperação dos vermes nos diferentes grupos. A análise histopatológica sugere que relacionado à variável deficiência em iNOS, esta atua inibindo a resposta inflamatória dos granulomas no início da infecção. Ainda em relação a variável deficiência de iNOS, no grupo KO EI, o único parâmetro morfométrico hepático mais elevado foi o volume dos granulomas em relação ao seu controle C57 EI, salientando que a ausência de óxido nítrico sugere um aumento da reação celular em torno dos ovos. O fator dieta não interfere na resposta inflamatória entre os animais deficientes em iNOS, em todos os tempos analisados. Em relação às citocinas de um modo geral, o fator deficiência em iNOS não aumentou a resposta Th2 (IL-4 e IL-10), e por isso a resposta Th1 (IFN-g) permaneceu maior nos grupos com deficiência em iNOS. No entanto, quando a dieta hipoprotéica é associada a essa deficiência ocorre uma diminuição da resposta Th2, no início da infecção. Portanto, o fator dieta e a deficiência em iNOS não parecem atuar sinergicamente e em algumas etapas sugere efeitos conflitantes

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Torihashi, Shigeko, Hiroshi Ozaki, Masatoshi Hori, Muneto Kita, Sachiyo Ohota, Hideaki Karaki, and 茂子鳥橋. "Resident macrophages activated by lipopolysaccharide (LPS) suppress muscle tension and initiate inflammatory response in the gastrointestinal muscle layer." Springer, 2000. http://hdl.handle.net/2237/7448.

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32

Horn, Michael [Verfasser], and G. U. [Akademischer Betreuer] Nienhaus. "Spektroskopische Untersuchungen an der induzierbaren Stickstoffmonoxid-Synthase (iNOS) / Michael Horn ; Betreuer: G. U. Nienhaus." Karlsruhe : KIT-Bibliothek, 2018. http://d-nb.info/1162540893/34.

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Malorgio, Francesca. "Espressione di iNOS e metabolismo dell'adenosina in cellule muscolari lisce vascolari di ratti diabetici." Doctoral thesis, Università degli studi di Padova, 2011. http://hdl.handle.net/11577/3427413.

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Diabetes mellitus is a major risk factor for cardiovascular diseases. Stimulation of inducible nitric oxide synthase (iNOS) production by inflammatory cytokines causes a significant production of peroxynitrite that is involved in many vascular disorders. In the cardiovascular system, extracellular adenosine has several vasoprotective properties: e.g. it induces vasodilatation, inhibits platelet aggregation, prevents platelet adhesion, inhibits growth of vascular smooth muscle cells (VSMCs) (Ikeda et al., 1997). Several studies demonstrate that in VSMCs adenosine modulates cytokine-induced iNOS expression and thus the release of NO from these cells via A2 receptors (Dubey et al., 1998; St. Hilaire et al., 2008). Since stimulation of iNOS production by inflammatory cytokines is involved in diabetic vascular dysfunction, we investigated the potential role of adenosine in this process by determining its influence on iNOS expression by VSMCs isolated from diabetic as compared to normoglycaemic rats. Diabetes was induced in Sprague-Dawley rats by intravenous injection of streptozotocin (STZ) and VSMCs were isolated from the aorta of control and STZ-diabetic rats 4 weeks after diabetes induction; only animals with blood glucose levels above 300 mg/dl on day 28 were considered diabetic. VSMCs from normal and diabetic rat aortas were incubated for 24 hours in the presence of LPS combined with a cytokine mixture (cytomix) to mimic the in vivo environment of some vascular inflammatory events and were exposed to exogenous adenosine. Incubation of VSMCs with LPS plus cytokine mixture for 24 h induced iNOS expression, which was undetectable in unstimulated VSMCs. Exogenous adenosine (1 mM) did not change iNOS levels in control VSMCs, but potentiated the response to cytokines in diabetic VSMCs. This response was unaffected by the equilibrative nucleoside transporter inhibitor, NBTI, but was further increased (+ 45%) by EHNA, an inhibitor of adenosine deaminase, the enzyme which deaminates adenosine to inosine. Exogenous inosine was ineffective in control and diabetic cells, but the adenosine precursor, AMP, mimicked the effect of adenosine on iNOS production in diabetic cells. Inhibition by AOPCP of ecto-5’-nucleotidase/CD73 (which dephosphorylates AMP in adenosine) did not significantly change iNOS protein levels. In the absence of exogenous adenosine, iNOS expression was reduced after treatment with EHNA in control but not in diabetic VSMCs, demonstrating that adenosine deaminase is responsible for adenosine elimination under non - pathological conditions. An HPLC method was used to quantify AMP, adenosine and their metabolites in the culture medium of VSMCs. At the end of 24 h-incubation, exogenous adenosine was undetectable in the culture medium of control as well as diabetic VSMCs, being converted into inosine and hypoxantine. In control VSMCs NBTI allowed the recovery of half of added adenosine whereas the recovery was lower in diabetic cells, indicating a different contribution of equilibrative transporters to the removal of the nucleoside in diabetes. In contrast, the addition of EHNA did not cause variations in the amount of adenosine recovered in control as compared with diabetic cells. After incubation with AMP, the nucleotide was not detectable and was converted mainly into inosine and hypoxanthine. Treatment with AOPCP allowed 47% recovery of AMP in control, but only 5% recovery in the medium of diabetic VSMCs indicating that diabetes markedly reduced CD73 sensitivity to pharmacological inhibition by AOPCP. These results show that alterations in adenosine-related inflammatory pathways may be present in diabetic vascular dysfunction; in addition, at high concentrations, adenosine seems to lose its protective effect as it stimulates the formation of iNOS, an effect that might be harmful to cells. Thus, diabetes would make VSMCs more sensitive to the potential proinflammatory effect of high concentrations of adenosine in terms of iNOS protein expression.
Il diabete è una malattia metabolica associata ad aumentato rischio cardiovascolare. Nel diabete inoltre, in seguito all’attivazione della proteina iNOS, si ha una notevole produzione di perossinitrito che è implicato in molti disordini vascolari. A livello cardiovascolare l’adenosina manifesta diverse proprietà vasoprotettive: induce infatti vasodilatazione, inibisce l’aggregazione piastrinica e ne previene l’adesione, inibisce la crescita delle cellule muscolari lisce vascolari (VSMC) (Ikeda et al., 1997). Diverse evidenze suggeriscono che l’adenosina prodotta dalle VSMC può indurre i suoi effetti in parte attraverso la produzione di NO a livello della parete dei vasi: il nucleoside, per interazione con i recettori A2, modula l’espressione della proteina iNOS indotta da citochine e di conseguenza il rilascio di NO dalle VSMC (Dubey et al., 1998; St. Hilaire et al., 2008). Dal momento che un’aumentata produzione di iNOS è coinvolta nella disfunzione vascolare diabetica, si è studiato il potenziale ruolo anti-infiammatorio dell’adenosina in tale processo, determinando l’effetto del nucleoside e dei composti ad esso correlati sull’espressione di iNOS in cellule muscolari lisce vascolari di ratti resi diabetici in confronto con ratti normoglicemici. A tale scopo ad una parte degli animali è stato indotto il diabete mediante iniezione nella vena caudale di streptozotocina. Il prelievo dell’aorta dei ratti per l’ottenimento delle colture cellulari è stato effettuato dopo quattro settimane dal trattamento, considerando diabetici solo gli animali con valore di glicemia superiore a 300 mg/dl. Per indurre l’espressione della proteina iNOS le cellule muscolari lisce vascolari di ratti sani e diabetici sono state stimolate per 24 h con una miscela costituita da LPS più citochine (citomix) e queste cellule sono state trattate con adenosina esogena. Dall’analisi di Western blot emerge che la purina impiegata in concentrazione 1 mM causa un aumento significativo dei livelli di iNOS nelle cellule di ratti diabetici. Questo aumento non è influenzato dal trattamento con NBTI, inibitore dei trasportatori equilibrativi per l’adenosina, ma è potenziato in seguito all’aggiunta di EHNA, inibitore dell’adenosina deaminasi, enzima che converte l’adenosina in inosina. L’inosina esogena non influenza l’espressione di iNOS nelle VSMC controllo e diabetiche, mentre il precursore dell’adenosina, AMP, mima l’effetto dell’adenosina sulla produzione di iNOS nelle cellule diabetiche. L’AOPCP, inibitore dell’enzima CD73, che promuove la defosforilazione di AMP in adenosina, non provoca variazione dell’espressione di iNOS, rispetto al trattamento con solo AMP. Stimolando le VSMC con citomix e NBTI, EHNA o AOPCP in assenza di purine esogene, si è dimostrato che solo il trattamento con EHNA causa, nelle cellule di ratti normoglicemici, una diminuzione significativa della produzione di iNOS, indicando che l’adenosina deaminasi rappresenta la principale via di eliminazione del nucleoside in condizioni non patologiche. Le quantità di adenosina rimasta nel medium di incubazione dopo 24 h e quella dei suoi metaboliti sono state monitorate con metodo HPLC. Al termine dell’incubazione l’adenosina scompare dal medium, mentre si accumulano inosina e ipoxantina. Nelle cellule controllo NBTI permette il recupero della metà dell’adenosina inizialmente aggiunta, mentre nelle cellule diabetiche il recupero è inferiore, indicando probabilmente un diverso contributo dei trasportatori equilibrativi alla rimozione del nucleoside nel diabete. Al contrario l’aggiunta di EHNA non causa variazioni nella quantità di adenosina recuperata nelle cellule controllo rispetto a quelle diabetiche. Anche l’AMP scompare dal medium dopo 24 h con produzione di inosina e ipoxantina; l’aggiunta di AOPCP permette il recupero del 47% del nucleotide nel medium di incubazione delle cellule di ratti sani e solo il 5% nel medium delle cellule di ratti diabetici, suggerendo un’alterazione dell’attività o dell’espressione dell’enzima CD73 associata al diabete. Questi risultati dimostrano che alterazioni a livello delle vie di eliminazione e formazione dell’adenosina sono presenti nella disfunzione vascolare diabetica. Inoltre, a concentrazioni elevate l’adenosina sembra perdere il suo effetto protettivo, in quanto stimola la formazione di iNOS, con conseguenze che possono essere dannose per la cellula. Il diabete rende, pertanto, le VSMC più sensibili al potenziale effetto proinfiammatorio di elevate concentrazioni di adenosina in termini di espressione della proteina iNOS.

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Neumann, Laura. "Charakterisierung von B-Zellen und Plasmazellen im Kontext einer chronischen Helicobacter pylori-Infektion." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19289.

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Helicobacter pylori ist ein humanpathogenes Bakterium, das den Magen kolonisiert und dadurch eine Immunantwort des Wirts induziert. Statt eine vollständige Eradikation von H. pylori durch die Immunreaktion zu erreichen, kommt es normalerweise zu einer lebenslangen Persistenz des Bakteriums und einer chronischen Infektion. Interessanterweise kommt es infolge einer Infektion zu einer Hochregulation der induzierbaren Stickstoffmonoxid-Synthase (iNOS), aber die zellulären Quellen und zugrundeliegenden Mechanismen von iNOS sind noch nicht vollständig verstanden. Der iNOS-abhängigen Produktion von Stickstoffmonoxid (NO) können sowohl antimikrobielle als auch pathologische Eigenschaften zugeschrieben werden. Daher wurden in der vorliegenden Arbeit iNOS-exprimierende Plasmazellen (PZ) aus der Magenmukosa H. pylori-infizierter Patienten isoliert und phänotypisch, vor allem mittels Durchflusszytometrie und molekularbiologisch hinsichtlich ihres Immunglobulin-Repertoires untersucht. Es wurde erstmals gezeigt, dass mukosale IgA-sezernierende PZ eine der wesentlichen iNOS+ Zelltypen während einer H. pylori-Infektion im Menschen darstellen und zusätzlich wurde ihre intrazelluläre NO-Produktion nachgewiesen. Da iNOS+ PZ in weiteren gastrointestinalen Infektionskrankheiten fehlten, scheint dies kein genereller Phänotyp von PZ der mukosalen Immunabwehr zu sein. Die Analyse der intrazellulären Zytokin-Expression der mukosalen B-Zellpopulationen in H. pylori-Patienten ergab eine Ko-Expression von IFN-γ und TNF-α in iNOS+ memory B-Zellen und eine TNF-α-Expression in iNOS+ PZ, aber nicht in den iNOS− Zellen. Die molekularbiologische Charakterisierung des Immunglobulin-Repertoires von iNOS+ und iNOS− PZ hinsichtlich der VHDJH-Regionen ergab keinen signifikanten Unterschied hinsichtlich der Isotyp-Verteilungen, der Nutzung der VH- und JH-Segmente, CDRH3-Längen sowie somatischen Mutationen und alle Antikörper zeigten typische Charakteristika einer T-zellabhängigen Affinitätsreifung.
Helicobacter pylori is a human-pathogenic bacterium that colonizes the stomach and thereby initiates host immune response. Instead of a complete eradication of H. pylori by the induced immune response, a lifelong bacterial persistence leads to chronic infections. Interestingly, up-regulation of inducible nitric oxide synthase (iNOS) has been observed in gastric mucosal tissue during the course of H. pylori infection in humans, however the cellular sources and underlying mechanisms of iNOS induction are not fully understood. iNOS-dependent production of nitric oxide (NO) is one of the factors commonly linked to both, anti-microbial immunity and pathology. Therefore, in this thesis iNOS-expressing plasma cells (PCs) in the stomach mucosa of H. pylori-infected patients were isolated and phenotypically analyzed by flow cytometry, as well as screened using molecular techniques regarding their immunoglobuline (Ig) repertoires. For the first time, we identified mucosal IgA-producing PCs as a major iNOS+ cell population during H. pylori infection in humans, and additionally confirmed their intracellular nitric oxide production. Since iNOS+ PCs were not detectable in other gastrointestinal infectious diseases, this reaction does not seem to be a general feature of mucosal PCs under conditions of infection. Additionally, intracellular cytokine expression analyses of mucosal B-lineage cells isolated from H. pylori patients revealed a co-expression of IFN-γ and TNF-α in iNOS+ memory B cells and the expression of TNF-α in iNOS+ PCs, but not in iNOS− cells. Molecular analysis of the Ig repertoire of iNOS+ and iNOS− PCs of the VHDJH regions revealed no significant differences regarding the Ig isotype composition, VH and JH gene family usage, CDRH3 length, and frequency of somatic mutations and all antibodies were characterized by typical properties of T cell-dependent affinity maturation.

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Silva, Aleksandra Alves. "Efeito de inibidores farmacologicos da iNOS na sensibilidade e sinalização de insulina em animais obesos." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311208.

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Orientador: Mario Jose Abdalla Saad
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: As óxido nítrico sintases (NOS) são divididas em dois grandes grupos de enzimas, NOS induzível (iNOS) e NOS constitutivas (cNOS). Embora o óxido nítrico (NO) seja um importante mediador de defesa do organismo, a produção excessiva de NO está envolvida na patogênese de muitas doenças inflamatórias e metabólicas. Alguns estudos demonstram que o óxido nítrico exógeno e o NO produzido pela iNOS pode induzir resistência à insulina em músculo e desempenha um papel importante na hiperglicemia de jejum. Este estudo teve como objetivo sintetizar e investigar o efeito de um potente e seletivo inibidor de atividade da iNOS, o Iodato de S-Metilisotiouréia (I-SMT) 5 mg/kg por dia, na hiperglicemia de jejum e na resistência à insulina em um modelo de obesidade induzida por dieta hiperlipídica. Foram observados os parâmetros metabólicos e de sinalização celular da Proteína quinase B/Akt (Akt) e os resultados fornecem evidências de que o grupo tratado com I-SMT foi protegido contra o desenvolvimento de resistência à insulina, e intolerância à glicose induzida por dieta hiperlipídica. Portanto, propomos que potentes inibidores farmacológicos, com seletividade significativa pela iNOS podem representar uma nova abordagem terapêutica para o tratamento da resistência à insulina e suas complicações como o diabetes tipo 2.
Abstract: Nitric oxide synthase (NOS) has been divided into two major sub-enzymes, inducible NOS (iNOS) and constitutive NOS (cNOS). Although nitric oxide (NO) is an important defense mediator, the excessive production of NO has been involved in the pathology of many inflammatory and metabolic diseases. Some studies demonstrate that exogenous nitric oxide (NO) and the NO produced by iNOS can induce insulin resistance in muscle and plays an important role in fasting hyperglycemia. This study investigates the effect of a potent and selective iNOS activity inhibitor, the S-Methylisothiourea Iodide (SMT-I) 5 mg/kg per day, in fasting hyperglycemia and insulin resistance in diet-induced obesity model. We observed the metabolic parameters and Akt signalization and these findings provide evidence that the SMT-I treated group are protected against the development of insulin resistance, glucose intolerance and diet-induced obesity. Therefore, we propose that highly selective inhibitors of iNOS activity may represent a novel therapeutic approach for the therapy of insulin resistance and its complications as type 2 diabetes.
Mestrado
Biologia Estrutural, Celular, Molecular e do Desenvolvimento
Mestre em Fisiopatologia Médica

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Franque, Marcos Pinheiro. "Aspectos biol?gicos de Boophilus microplus (Acari: Ixodidae) mediante infesta??es experimentais em eq?inos." Universidade Federal Rural do Rio de Janeiro, 2007. https://tede.ufrrj.br/jspui/handle/tede/745.

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This work aimed the evaluation of biological parameters of parasitic and non-parasitic phases of Rhipicephalus (Boophilus) microplus (= Boophilus microplus) in equine. Four equines were individually infested with approximately 40,000 larvae obteined of R. (B.) microplus females engorged in bovines, being in two of them established three infestations. In the place of larvae fixation, it was noticed development of an intense itchy reaction and the larvae involved in a serum exudates. A larval mortality of approximately 90% was observed, with a small number of larvae changing to nymph stage. The mortality of nymphs was around 60%, with reduction of the itchy reaction, and in the adult stage was observed approximately 30% of mortality. As for the susceptibility, it was observed that two equine were resistant, one moderately resistant and one sensitive to the establishment of infestation by R. (B.) microplus. In the equine considered sensitive, were made observations of parasitic and non-parasitic phase of this ixodid. According to the parameters of the parasitic phase of R. (B.) microplus, of the three experimental infestations, the day at the beginning of detachment of females occurred among infestations were 28 and 31 days, during 12 days at first infestation and 20 days at second and thirst infestation, presentin modal day at 32?; 36? and 37? day, respectively. Were recovered 179 females of R. (B.) microlus at first infestation, 187 and 358 at the second and thirst infestation, corresponding to a mean recovery rate between 0.90 and 1.79%. The means periods of parasitic phase increase among infestations, during between 33. 27 and 38.51 days, being obteined females with mean weight of 90.0mg at the first infestation, 81.5 mg at second and 109.4mg at thirst infestation, considering all females recovered. For the estudy of the non-parasitic phase were selected form each infestation 20, 49, 71 females, presenting means weights of 151.8; 121.1 and 147.8 mg, respectively. The means periods of pre-posture were between 2.8 and 3.5 days. The means periods of posture were of 13.6; 11.7 and 13.4 days, respectively, with pick of posture occurring at the 3rd day after the beginning at three infestations. The means weights of posture were verified between 57.3 and 80.6mg corresponding to 1,146.9 and 1,611.4 eggs produced. The means periods of incubation of eggs produced by R. (B.) microplus studied females occurred between 23.7 and 29 days, presenting hatch means rates decreasing of 67% in the first infestation to 54.7% at the thirst infestation. The means of reprodutive efficiency index also decreased among infestations of 35.5% to 26.9% at the last infestation. It was verified that the means periods between the infestation date and the beginning of the larval appearance were between 60.0 and 64.9 days. These results demonstrate that, starting from experimental infestation in equine, R. (B.) microplus is able to complete the biological cycle for at least one generation, resulting in a number of larvae enough to infest pastures.
Este trabalho teve como objetivo avaliar par?metros biol?gicos de Rhipicephalus (Boophilus) microplus (= Boophilus microplus) mediante infesta??es expermentais em eq?inos. Foram utilizados quatro eq?inos infestados individualmente com aproximadamente 40.000 larvas, obtidas de f?meas de R. (B.) microplus alimentadas em bovino, sendo realizadas tr?s infesta??es em dois destes equinos. No local de fixa??o das larvas notou-se desenvolvimento de uma intensa rea??o pruriginosa e as larvas envolvidas em um exsudato seroso. Foi observada uma mortalidade larval de aproximadamente 90%, com um pequeno n?mero larvas mudando para o est?gio de ninfa. A mortalidade de ninfas ocorreu em torno de 60%, com redu??o da rea??o pruriginosa, e no est?gio adulto notou-se mortalidade de aproximadamente 30%. Quanto ? susceptibilidade, observou-se que dois eq?inos foram resistentes, um moderadamente resistente e um sens?vel ao estabelecimento da infesta??o por R. (B.) microplus. No eq?ino considerado sens?vel, foram realizadas as observa??es de fase parasit?ria e n?o parasit?ria deste ixod?deo. Em rela??o aos par?metros da fase parasit?ria de R. (B.) microplus, nas tr?s infeta??es, o dia de in?cio do desprendimento das f?mas ocorreu entre 28 e 31 dias, durando 12 dias na primeira infesta??o e 20 dias na segunda e terceira infesta??es, apresentando dia modal no 32?, 36? e 37? dia respectivamente, ap?s as infesta??es com as larvas. Foram recuperadas 179 f?meas de R. (B.) microplus na primeira infesta??o, 187 na segunda e 358 na terceira infesta??o, correspondendo a uma taxa de recupera??o entre 0,90 e 1,79%. O per?odo m?dio da fase parasit?ria aumentou entre a primeira e terceira infesta??es, ocorrendo entre 33,27 e 38,51 dias, verificando-se f?meas com peso m?dio de 90,0mg na primeira infesta??o, 81,5mg na segunda e 109,4mg na terceira infesta??o, considerando-se todas as f?meas recuperadas. Para o estudo da fase n?o parasit?ria foram selecionadas respectivamente 20, 49 e 71 f?meas de cada infesta??o que apresentaram peso m?dio, respectivamente, de 151,8mg; 121,1 mg e 147,8mg. Observou-se um per?odo m?dio de pr?-postura entre 2,8 e 3,5 dias. O per?odo m?dio de postura foi de 13,6; 11,7 e 13,4 dias, respectivamente, entre as infesta??es, com pico de postura ocorrendo no 3? dia ap?s seu in?cio. Verificou-se um peso m?dio de postura entre 57,3 a 80,6mg, nas infesta??es, o que corresponde ? produ??o m?dia de ovos entre 1.146,9 e 1.611,0. O per?odo m?dio de incuba??o dos ovos das f?meas estudadas de R. (B.) microplus, durou entre 23,7 e 29 dias, apresentando uma taxa de eclos?o m?dia decrescendo de 67% na primeira infesta??o, para 54,7% na terceira infesta??o. O ?ndice m?dio de efici?ncia reprodutiva tamb?m decresceu ente as infesta??es de 35,5%, para 26,9% na ?ltima infesta??o. Verificou-se que o per?odo m?dio entre a data de infesta??o e o in?cio da eclos?o larval ocorreu entre 60 e 64,9 dias. Estes resultados demonstram que, a partir de infesta??es experimentais em eq?inos, R. (B.) microplus ? capaz de completar seu ciclo biol?gico por pelo menos uma gera??o, resultando em um n?mero de larvas suficiente para infestar parstagens.

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Santos, Tiago Marques dos. "Efeitos Gastrointestinais e Sist?micos em Eq?inos Submetidos a Sobrecarga Diet?tica com Amido." Universidade Federal Rural do Rio de Janeiro, 2007. https://tede.ufrrj.br/jspui/handle/tede/747.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior
This work aimed to evaluate gastrointestinal and systemic disturbances, and mucosa and gut contents of gastrointestinal tract of horses subjected to overload carbohydrate. Eight crossbreed mature horses were used with body weight (BW) average of 364kg, geldings, adapted to diet composed by grass hay and concentrate, in a 60:40 proportion. A complete randomized design was used with horses allocated in three treatments. Treatment I: (Control) (n=2) horses were slaughtered without overload carbohydrate; Treatment II (n=3) and III (n=3), horses subjected to overload carbohydrate, with gastric infusion of 17.6 g starch/kg BW, and slaughtered after 24 and 36 hours, respectively. Horses were subjected to clinical, hematological and fecal evaluations before the overload and 2, 4, 8, 12, 16, 20, 24, 28, 32 and 36 hours after overload. Four hours after overload horses became depressed and keeping until the end of evaluation, and one horse presented lameness 36 hours after overload. Any difference (P>0.05) were observed in heart rate, respiratory rate, body temperature and hoof temperature. Increase in packed cell volume and plasma protein concentration were observed 24 hours after overload, varying from 26.7 to 32.0% and 7.1 to 8.1 g/dL, respectively (P<0.05). Differences were observed (P<0.05) in plasmatic lactate concentration in zero, 20 and 28 hours after overload, with values of 0.7, 1.04 and 1.22 mmol/L, respectively. Plasma endotoxin concentration didn't cross 0.1000 EU/mL and may be not present. There were any difference (P>0.05) in fecal and digesta water content, however, fecal pH reduced along 36 hours post-overload (P <0.01), varying from 6.09 to 4.46. Content of large intestine in horses subjected to overload presented whitish-green color, milk aspect, with gas bubbles and acid odor. There weren t difference (P>0.05) in water content of feces and digesta, however, fecal pH reduced along 36 hours post-overload (P <0.01), varying from 6.09 to 4.46. Buffering capacity of ceco-colon digesta and feces were reduced in horses subjected to overload. Right dorsal colon, transverse colon and descendent colon were segments, except stomach, that presented lower pH values, varying from 4.49 to 4.56. Eosinophils infiltration were presented in mucosa and submucosa of all horses, however, only horses submitted to overload presented neutrophils and eosinophils leucocitoestase with neutrophils predominance restricted to large intestine. Tract gastrointestinal circulatory alterations observed were congestion, edema and lymphatic vessels dilatation, more evident in submucosa, with larger inflammatory cells infiltration in horses subjected to overload. Intestinal mucosa 36 hours after overload presented larger degree of imunorreactivity anti-myeloperoxidase, followed by horses evaluated at 24 hours after overload and control horses, varying from 2.7 to 4.0, 1.0 to 3.7 and 1.0 to 2.5, respectively. Overload carbohydrate in horses promoted intensive fermentation in ceco-colon, predisposing clinical disturbances, digesta alterations and mucosa and submucosa lesions at gastrointestinal tract of horses with light to moderate degree,36 hours after overload.
Este trabalho teve como objetivo avaliar as altera??es sist?micas, da mucosa e conte?do do trato gastrointestinal de eq?inos submetidos ? sobrecarga diet?tica com amido. Foram utilizados oito eq?inos adultos castrados, com peso vivo m?dio de 364 kg, adaptados a dieta composta por feno de Coastcross e concentrado, na propor??o de 60:40. Foi utilizado um delineamento experimental com tr?s tratamentos: Tratamento I (Controle) (n=2), eutan?sia dos animais sem sobrecarga com amido; Tratamentos II (n=3) e III (n=3), animais submetidos ? sobrecarga com amido, com infus?o g?strica de 17,6 g amido/kg de peso corporal e eutan?sia ap?s 24 e 36 horas, respectivamente. Os eq?inos foram submetidos a avalia??es cl?nicas, hematol?gicas e f?sico-qu?micas das fezes antes da sobrecarga e 2, 4, 8, 12, 16, 20, 24, 28, 32 e 36 horas p?s-sobrecarga. Os animais apresentaram-se ap?ticos quatro horas ap?s a sobrecarga permanecendo assim at? o final da avalia??o e apenas um animal apresentou claudica??o, 36 horas p?s-sobrecarga. N?o houve diferen?a (P>0,05) na freq??ncia card?aca, freq??ncia respirat?ria, temperatura corporal e temperatura dos cascos. Houve aumento (P<0,05) no volume globular e prote?na plasm?tica total, 24 horas p?s-sobrecarga, variando de 26,7 a 32,0% e de 7,1 e 8,1 g/dL, respectivamente. Houve diferen?a (P<0,05) na concentra??o plasm?tica de lactato no tempo zero, 20 e 28 horas p?s-sobrecarga, com valores de 0,7, 1,04 e 1,22 mmol/L, respectivamente. A concentra??o plasm?tica de endotoxinas n?o ultrapassou 0,1000 EU/mL, podendo estar at? mesmo ausente. O conte?do do intestino grosso nos eq?inos submetidos ? sobrecarga apresentou cor verde esbranqui?ada, aspecto leitoso, com bolhas de g?s e odor ?cido. N?o houve diferen?a (P>0,05) no teor de ?gua das fezes e do conte?do da digesta, no entanto, o pH fecal reduziu ao longo de 36 horas p?s-sobrecarga (P<0,01), variando de 6,09 a 4,46. Houve redu??o na capacidade de tamponamento das fezes nos eq?inos submetidos ? sobrecarga e, de forma similar, ocorreu no conte?do do ceco-c?lon. O c?lon dorsal direito, c?lon transverso e c?lon descendente foram os segmentos, com exce??o do est?mago, que apresentaram a digesta com menores valores de pH, variando de 4,49 a 4,56. ? histopatologia, a infiltra??o de eosin?filos esteve presente na mucosa e submucosa de todos os eq?inos, no entanto, somente em dois eq?inos submetidos ? sobrecarga, observou-se leucocitoestase de neutr?filos e eosin?filos, com predomin?ncia de neutr?filos no intestino grosso. As altera??es circulat?rias observadas no trato gastrointestinal foram congest?o, edema e dilata??o de vasos linf?ticos, sendo mais evidentes na submucosa, local de maior infiltra??o de c?lulas inflamat?rias nos eq?inos submetidos ? sobrecarga. A mucosa dos segmentos do trato gastrointestinal dos eq?inos eutanasiados 36 horas p?ssobrecarga apresentou maior grau de imunorreatividade anti-mieloperoxidase, seguido dos eq?inos avaliados 24 horas p?s-sobrecarga e dos eq?inos do tratamento controle, variando de 2,7 a 4,0, 1,0 a 3,7 e 1,0 a 2,5, respectivamente. A sobrecarga diet?tica com amido em eq?inos promove fermenta??o intensa no ceco-c?lon, predispondo ao aparecimento de dist?rbios cl?nicos, altera??es do conte?do da digesta e les?es de leve a moderada na mucosa e submucosa do trato gastrointestinal dos eq?inos, ap?s 36 horas da sobrecarga.

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38

Herzfeld, Sophia. "Einfluss eines zusätzlichen iNOS knockouts auf den kardialen Phänotyp von human Endothelin-1 transgenen Mäusen /." Berlin : Mbv, 2008. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=016556016&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.

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39

Cabrié, Aimeric. "Coopération entre les isoformes TAp73 et la signalisation TGF-β dans la régulation de l'expression de la NO Synthase inductible." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS397/document.

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Le monoxyde d’azote (NO) est une molécule gazeuse synthétisée par les NO Synthases à partir de L-arginine. NO est une puissante molécule de signalisation dans de nombreux processus physiologiques comme la vasodilatation et la neurotransmission. Il module l’activité de multiples protéines (ex : guanylate cyclase soluble et ribonucléotide réductase) grâce à la nitrosylation de groupements thiol ou de métaux de transition. En tant que radical libre, NO peut réagir avec de nombreuses espèces comme l’oxygène moléculaire, et ainsi former des dérivés réactifs. Grâce à ces propriétés, NO est un acteur majeur de l’immunité innée et de l’inflammation. Les phagocytes produisent de grandes quantités de NO en réponse à des stimuli proinflammatoires, via l’activité NO Synthase inductible (iNOS). En raison des effets délétères des dérivés de NO, l’activité iNOS doit être finement régulée. Le suppresseur de tumeur p53 est capable de réprimer l’expression du gène Nos2 après avoir été lui-même activé en réponse à une accumulation de NO. La protéine p73 est un homologue de p53 encodé par un gène qui génère à la fois des isoformes actives (TAp73) et des isoformes qui sont dépourvues du domaine de transactivation N-terminal et exercent un effet dominant négatif (ΔNp73). Cette étude se focalise sur le rôle des isoformes TAp73 dans la régulation de l’expression de la iNOS. Nous démontrons que les isoformes TAp73 régulent négativement l’expression de la iNOS aux niveaux transcriptionnel et post-traductionnel en potentialisant l’effet répresseur du TGF-β, ce qui résulte en une forte surexpression de la iNOS dans les cellules TAp73-/-. Ces résultats confortent le rôle de la famille p53 comme un réseau essentiel de protéines régulatrices des fonctions du TGF-β
Nitric oxide (NO) is a gaseous molecule synthesized from L-arginine by Nitric Oxide Synthases. NO acts as a potent signaling molecule in various physiological processes like vasorelaxation and neurotransmission. It modulates the activity of many proteins (e.g. soluble guanylate cyclase and ribonucleotide reductase) through nitrosylation of thiol moieties or transition metal ions. As a free radical, NO can also react with a number of cellular species, notably molecular oxygen, to form reactive oxygen species and reactive nitrogen species. Thanks to these properties, NO appears as a major component of innate immune response and inflammation. Phagocytes produce large amounts of NO in response to proinflammatory through inducible Nitric Oxide Synthase (iNOS) activity. Because of the harmful effects of NO derivatives on cellular components, iNOS activity needs to be tightly regulated. The p53 tumor suppressor has been shown to repress Nos2 after being activated by NO itself. The p73 protein is an homologous encoded by the TP73 gene that generate transcriptionally active TAp73 isoforms and ΔNp73 isoforms that lack the transactivation domain and exert a dominant negative effect. This study focuses on the role of TAp73 isoforms in regulation of iNOS expression. We demonstrate that TAp73 isoforms potentiate the repressive effect of TGF-β on iNOS expression at transcriptional and post-traductional levels, resulting in a substantial iNOS overexpression in TAp73-/- cells. These results emphasize the emerging role of p53 family as a master regulator of TGF-β functions

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40

Sahin, Ebru Karpuzoglu. "Estrogen Regulates Interferon-gamma (IFN-g) and IFN-g-Inducible iNOS Gene Expression: Implications to Immunity and Autoimmunity." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/27129.

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It is now clear that estrogen not only modulates the differentiation and function of reproductive systems, but it also profoundly regulates the immune system of normal and autoimmune individuals. An important mechanism by which estrogen regulates the immune system is by altering the secretion and/or response to cytokines. We hypothesized that estrogen may alter the levels and/or response to IFN-g, a prototype Th1 cytokine, that plays a pivotal role in immunity against intracellular infections and in many autoimmune and inflammatory disorders. We found that estrogen treatment tended to upregulate the secretion of IFN-g protein and mRNA expression from Concanavalin-A (Con-A)-activated splenic lymphocytes. Impressively, we found that splenocytes from estrogen-treated mice when activated with Con-A also resulted in increased release of nitric oxide compared to placebo-treated mice. Furthermore, Con-A-activated splenocytes from estrogen-treated mice also had upregulated iNOS mRNA, iNOS protein, and nitric oxide-regulated COX-2 protein when compared to control mice. Blocking co-stimulatory signals mediated through interactions of CD28 and B7 molecules by using CTLA-4Ig markedly decreased not only IFN-g, but also nitric oxide, thereby implying an important role for CD28/B7 interactions in IFN-g/nitric oxide. Estrogen-induced upregulation of iNOS/nitric oxide is mediated through IFN-g since: (i) Estrogen alone did not upregulate iNOS/nitric oxide in IFN-g knockout mice; (ii) addition of rIFN-g to activated splenocytes from estrogen-treated mice further upregulated nitric oxide levels. We next investigated whether estrogen also upregulated IFN-g-inducing cytokines and select IFN-g-inducing transcription factors. Estrogen treatment resulted in increased mRNA and/or protein expression of IFN-g inducing cytokines and their receptors, including: IL-18, IL-15, IL-27, IL-12Rb2, and IL-18Rb. We also found that T-bet, a critical Th1 transcription factor, and STAT-4 phosphorylation, a key molecule in IL-12 signaling were both increased, while IRF-4, an important player in Th2 differentiation, was diminished in Con-A-activated splenocytes from mice treated with estrogen. Altogether, these studies are the first to demonstrate that estrogen regulates IFN-g-dependent iNOS and describes the potential mechanisms of how estrogen alters IFN-g-inducible genes, IFN-g inducing cytokines, and transcription factors in normal C57BL/6 mice. These studies may have profound implications to many autoimmune and inflammatory disorders, where estrogen is known to regulate the course of these diseases. Since estrogen may promote inflammatory disorders by upregulating pro-inflammatory biomolecules including IFN-g, nitric oxide, and COX-2, these studies may help in the design of therapeutic agents that regulate or block secretion and/or response to these inflammatory molecules.
Ph. D.

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41

Gottschalk, Oliver. "Der Einfluss der iNOS auf die Thrombozyten-Endothelzellinteraktion bei Antigen-induzierter Arthritis der Maus in vivo." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-78990.

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42

Arasapam, Ganesan. "Roles of COX-2 and iNOS in the bony repair of the injured growth plate cartilage /." Title page and abstract only, 2005. http://web4.library.adelaide.edu.au/theses/09SB/09sba6629.pdf.

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43

St-Amand, Emmanuelle. "La régulation du transport du glucose dans le muscle squelettique : l'implication des protéines AMPK et iNOS." Doctoral thesis, Université Laval, 2015. http://hdl.handle.net/20.500.11794/25783.

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Le tissu musculaire squelettique contribue considérablement au maintien de l’homéostasie du glucose chez l’humain. Que ce soit en situation postprandiale ou lors d’un travail musculaire, le muscle squelettique capte de grandes quantités de glucose sanguin à des fins d’entreposage ou de production d’énergie. Les voies de signalisation cellulaire impliquées dans la régulation du transport du glucose à l’intérieur de la cellule musculaire sont nombreuses et complexes. En présence de désordres physiologiques et/ou métaboliques, de nombreux médiateurs chimiques et enzymatiques peuvent interagir avec les différentes protéines de ces voies de signalisation et entraîner des perturbations importantes au niveau de l’homéostasie du glucose. Notre première étude nous a permis de confirmer l’implication de la protéine AMPK dans le transport du glucose induit par la contraction musculaire. L’AMPK est un senseur énergétique important activé dans le muscle squelettique au cours d’un effort physique. Toutefois, son rôle dans le transport du glucose induit par la contraction musculaire demeure controversé. Grâce à un modèle murin d’invalidation génétique de l’AMPK spécifique au tissu musculaire et à l’élaboration d’un protocole de contraction ex vivo approprié, nous avons établi l’importance de l’AMPK dans la régulation du transport du glucose. Notre seconde étude nous a permis de démontrer que l’incubation ex vivo prolongée du muscle épitrochléen modifie l’expression du transporteur de glucose GLUT1. Nous avons également observé l’induction de la protéine iNOS et la production du NO. Parallèlement, nous avons mesuré une augmentation de l’expression de GLUT1 à la suite d’une exposition au NO dans un modèle de cellules musculaires ainsi qu’une augmentation du transport basal du glucose. L’ensemble de nos résultats nous permet de consolider le lien causal entre la production du NO et la modulation de l’expression de GLUT1 et potentiellement, le développement de perturbations au niveau du métabolisme du glucose musculaire.

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44

Koçak, Ahmet Gökçimen Alpaslan. "Değişik dozlardaki asetaminofenin karaciğer nitrikoksit sentaz (iNOS) enzimi üzerindeki etkisinin immünohistokimyasal ve biyokimyasal yöntemler kullanılarak değerlendirilmesi /." Isparta : SDÜ Sağlık Bilimleri Enstitüsü, 2008. http://tez.sdu.edu.tr/Tezler/TT00385.pdf.

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45

Bingi, Praveen Kumar. "Effects of oxidative stress on the expression and function of inducible nitric oxide synthase (iNOS) in cultured vascular smooth muscle cells." Thesis, University of Hertfordshire, 2015. http://hdl.handle.net/2299/17660.

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The role of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) in atherosclerosis remains elusive. Several researchers argued whether iNOS and/or NO are pathogenic or cardio protective. The pathogenesis of atherosclerosis is complex and includes mechanisms associated with inducible nitric oxide synthase (iNOS). We have demonstrated that the expression and function of iNOS may be selectively down regulated by pro-oxidants such as antimycin A and diethyl maleate (DEM). To further explore the underlying mechanisms associated with these effects we have investigated whether antimycin A and/or DEM modulated the activation of key cellular signalling molecules associated with the induction of iNOS. Expression of p38 mitogen activated kinase (MAPK) and Akt were induced by exposure to lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). Oxidative stress (OS) was induced using antimycin A, DEM and hydrogen peroxide (H2O2). All three OS inducers caused a significant generation of free radicals whereas only antimycin A and DEM generated superoxide radical (O2-). Also nitrite production and iNOS expression may be down regulated, in part; by pro-oxidants generating O2- but not hydroxyl radicals (OH-). Antimycin A and DEM concentration dependently inhibited the phosphorylation of p38 MAPK and Akt and this was restored when the cells were pre-treated with Atorvastatin whereas H2O2 was without any significant effect. Taken together, the data suggest novel actions for both pro-oxidants and atorvastatin which may have important implications in coronary artery disease where suppression of iNOS may be deleterious and maintaining its expression may be cardio-protective.

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MOORE, ZACHARY W. Q. "APOLIPOPROTEIN E MODULATION OF VASCULAR SMOOTH MUSCLE CELL RESPONSE TO INJURY." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1127219075.

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47

Ahmad, Nashrah. "Preventive and Osteoarthritis Suppressive Effects of Peretinoin." Kent State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=kent1602519541029131.

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48

Zuniga, Tiffany M. "LPS-Induced iNOS mRNA and the Pro-Apoptotic Signaling Pathway in Leukocytes of Fit and Unfit Males." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5424.

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Overexpression of the enzyme iNOS induces apoptotic cellular death by increasing indices of pro-inflammation and oxidative stress. Aerobic physical activity has been known to have anti- inflammatory benefits and reduce oxidative stress. Purpose: Therefore, this study aimed to examine the impact of aerobic fitness on LPS-induced iNOS mRNA expression and the relationship of this expression with indices of oxidative stress, pro-inflammation and apoptosis in isolated leukocytes. Methods: Whole blood samples from aerobically fit and unfit males were stimulated with and without LPS. Thereafter, iNOS mRNA expression and MDA, TNF-α and p53 concentrations were analyzed. Results: iNOS mRNA expression levels following LPS stimulation were not increased in both groups, and correlational analyses were not consistent with mechanistic predictions. Discussion: Numerous factors including timing of sample quantification, the high level of health of the subject population, and alternative intracellular mechanisms impacting biomarkers analyzed, may have influenced leukocyte iNOS mRNA expression levels.

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49

Huang, Hong. "Inflammatory and oxidative mechanisms in endothelial cell activation and dysfunction." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1092663493.

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Thesis (Ph. D.)--Ohio State University, 2004.
Title from first page of PDF file. Document formatted into pages; contains xx, 475 p.; also includes graphics. Includes bibliographical references (p. 409-442).

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50

Ghaeni, Leyli [Verfasser]. "Die Rolle der induzierbaren Stickstoffmonoxid-Synthetase (iNOS) in einwandernden Leukozyten in einem Schlaganfallmodell der Maus / Leyli Ghaeni." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023231816/34.

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Dissertations / Theses on the topic 'INOS'

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