18 research outputs found
Ether phospholipids as inhibitors of the arachidonoyl-CoA:1-acyl-sn-glycero-3-phosphocholine acyltransferase in macrophages
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Potent platelet stimulating activity of enantiomers of acetyl glyceryl ether phosphorylcholine and its methoxy analogues
No full textThe effect of membrane active agents on human leukaemia cells
No full textThis Thesis investigates the effect of membrane-active agents, such as synthetic ether lipids (SEL), local anaesthetics and polyunsaturated fatty acids (PUFAs) on human leukaemia cells. The two cell lines used were human acute myeloblastic leukaemia (HL60) cells and human myelogenous leukaemia (K562) cells. SEL, local anaesthetics and PUFAs were found to be cytotoxic to both cell lines at certain concentrations. The SEL ET-18-OCH(_3) was found to be cytotoxic to both cell lines but the HL60 cells were found to be the more sensitive cell line. HL60 cells were found to be so sensitive to the action of the local anaesthetic dibucaine that a subtoxic concentration that killed ≤10% was not determined. However, in K562 cells the combination of a subtoxic dibucaine concentration together with a range of ET-I8-OCH(_3) concentrations increased the cytotoxicity over that of ether lipid alone. PUFAs were shown to incorporate into plasma membrane phospholipids at concentrations as low as 1 μM after an incubation of 48 hours. PUFAs were shown to be cytotoxic, but the addition of vitamin E reduced the cytotoxicity of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid in HL60 cells, and of docosahexaenoic acid in K562 cells. This implied that lipid peroxidation was involved in PUFA cytotoxicity. This was, however, not confirmed. PUFA in combination with ET-I8-OCH3 resulted in a slight decrease in cytotoxicity. PUFA combined with dibucaine did not alter cytotoxicity. Cells were also treated with a combination of PUFA and 1-β-D- arabinofliranosylcytosine (ara-C), which is an agent known to induce cell differentiation. Onset of differentiation was determined by following haemoglobin accumulation in K562 cells. PUFA on their own were found to promote accumulation of haemoglobin. The greatest accumulation of haemoglobin was observed with K562 cells treated with PUFA and ara-C
The role of leishmania proteophosphoglycans in sand fly transmission and infection of the Mammalian host.
No full textLeishmania are transmitted by the bite of their sand fly vector and this has a significant influence on the virulence of the resulting infection. From our studies into the interaction between parasite, vector, and host we have uncovered an important missing ingredient during Leishmania transmission. Leishmania actively adapt their sand fly hosts into efficient vectors by secreting Promastigote Secretory Gel (PSG), a proteophosphoglycan (PPG)-rich, mucin-like gel which accumulates in sand fly gut and mouthparts. This has the effect of blocking the fly, such that during bloodfeeding both parasites and gel are co-transmitted in an act of regurgitation. We are discovering that this has further implications for the mammalian infection, again, in favor of the parasite. Experimentally, PSG exacerbates cutaneous and visceral leishmaniasis and can promote the chronicity of Leishmania infection, even in mouse strains normally capable of controlling leishmaniasis. The underlying mechanism of PSG's action is a major focus of our ongoing work. This review aims to synthesize what is known about the role and action of PSG and its constituent proteophosphoglycans, for parasite colonization of the sand fly, transmission, and mammalian infection. Lastly, we discuss potential exploitation of this important vector-transmitted product and future avenues of research
Innate immune response to intramammary infection with Serratia marcescens and Streptococcus uberis
No full textStreptococcus uberis and Serratia marcescens are Gram-positive and Gram-negative bacteria, respectively, that induce clinical mastitis. Once initial host barrier systems have been breached by these pathogens, the innate immune system provides the next level of defense against these infectious agents. The innate immune response is characterized by the induction of pro-inflammatory cytokines, as well as increases in other accessory proteins that facilitate host recognition and elimination of the pathogens. The objective of the current study was to characterize the innate immune response during clinical mastitis elicited by these two important, yet less well-studied, Gram-positive and Gram-negative organisms. The pro-inflammatory cytokine response and changes in the levels of the innate immune accessory recognition proteins, soluble CD14 (sCD14) and lipopolysaccharide (LPS)-binding protein (LBP), were studied. Decreased milk output, induction of a febrile response, and increased acute phase synthesis of LBP were all characteristic of the systemic response to intramammary infection with either organism. Infection with either bacteria similarly resulted in increased milk levels of IL-1 beta, IL-8, IL-10, IL-12, IFN-gamma, TNF-alpha, sCD14, LBP, and the complement component, C5a. However, the duration of and/or maximal changes in the increased levels of these inflammatory markers were significantly different for several of the inflammatory parameters assayed. In particular, S. uberis infection was characterized by the sustained elevation of higher milk levels of IL-1 beta, IL-10, IL-12, IFN-gamma, and C5a, relative to S. marcescens infection. Together, these data demonstrate the variability of the innate immune response to two distinct mastitis pathogens
O papel da maresina 1, um mediador lipídico derivado do ácido graxo poliinsaturado omega-3, na colite experimental em camundongos
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2013Os óleos de peixe, bem como alguns vegetais apresentam quantidades significantes de ácidos graxos poliinsaturados ômega-3, sendo que os principais encontrados em derivados marinhos são: o ácido graxo eicosapentaenóico (EPA) e o ácido graxo docosahexaenóico (DHA). Estudos prévios têm demonstrado que uma dieta rica em óleo de peixe pode exercer efeitos benéficos sobre inúmeras doenças com características inflamatórias, dentre as quais se destacam as doenças inflamatórias intestinais (IBD). Um novo mediador lipídico derivado do DHA, denominado maresina 1 (MaR1) têm apresentado potente atividade analgésica, antiinflamatória e pró-resolutiva em distintos modelos experimentais de inflamação, sendo assim, foi hipotetizado que o processo de resolução desencadeado pela MaR1 também poderia prevenir ou atenuar a inflamação intestinal em camundongos. Dessa forma, o presente estudo buscou avaliar o papel da MaR1, no modelo de colite aguda induzida pelo sulfato sódico de dextrana (DSS) (com um ou dois ciclos de DSS), e no modelo de colite aguda induzido pelo ácido trinitrobenzenosulfônico (TNBS) em camundongos. Os resultados observados demonstraram que o tratamento sistêmico com a MaR1 reduziu o escore clínico experimental e o dano tecidual colônico nos modelos de colite induzida pelo DSS (tanto no primeiro quanto no segundo ciclo), bem como na colite aguda induzida pelo TNBS. O efeito benéfico da MaR1 parece estar associado com sua habilidade em reduzir a liberaçaõ das citocinas: interleucina (IL)-1?, factor de necrose tumoral (TNF)-?, IL-6 e interferon (IFN)-? no modelo agudo com um único ciclo com DSS, e IL-1? e IL-6, mas não TNF-? e IFN-? no modelo agudo com dois ciclos com DSS, além da inibição da expressão da molécula de adesão ICAM-1, e de proteínas relacionadas ao inflamassoma, como o NALP3 e a pró-caspase-1, e pela ação sobre a ativação do fator nuclear ?B (NF-?B). Adicionalmente, através de experimentos in vitro, evidenciou-se que a MaR1 reduziu a liberação de IL-1?, TNF-?, IL-6 e IFN-? provenientes de macrófagos, e parece induzir a polarização de macrófagos para o fenótipo antiinflamatório M2. Em conclusão, o conjunto dos resultados contribui para estender os conhecimentos acerca dos mecanismos de ação antiinflamatório e pró-resolutivos da MaR1 e sugere uma nova abordagem terapêutica para o tratamento das IBD
Estudo da cinética do infiltrado celular inflamatório induzido por adjuvantes de vacinas em bolhas de ar formadas no subcutâneo de camundongos
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-graduação em Biotecnologia.A inflamação é uma resposta do organismo a um estímulo agressor, químico, físico ou biológico, que tem como finalidade restaurar a integridade tecidual. Este fenômeno biológico é realizado através do acúmulo e ativação de leucócitos no local da injúria, que contribuem para a eliminação de antígenos e recuperação da homeostase. A inflamação é, também, fundamental para o estabelecimento da imunidade específica e eficiência da imunização. Uma das medidas de imunização mais eficaz é a vacinação. Uma vacina deve ter alto poder imunogênico para ser eficaz na profilaxia de doenças infecto-contagiosas. Desta forma, elas são geralmente associadas a substâncias adjuvantes, que amplificam a resposta protetora da vacina. Entretanto, alguns destes adjuvantes induzem efeitos indesejáveis, tais como excesso de inflamação local e sinais flogísticos sistêmicos. O presente estudo pretendeu verificar a atividade inflamatória induzida por seis adjuvantes, associados a uma vacina contra vírus rábico para futuro uso em animais. Os adjuvantes testados neste trabalho foram o Algamulin, Avridine, Hidróxido de Alumínio, b-Glucana (2 e 4 mg), SEPPIC-I e SEPPIC-II. Para este objetivo as diferentes formulações adjuvantes (50µl) adicionadas à vacina (50µl), a vacina pura (50µl) e PBS (Controle) foram inoculados em uma bolha de ar (3ml) formada do dorso (subcutâneo) de camundongos albinos da linhagem Swiss. Após 24 e 72 horas do desafio, os animais foram sacrificados e o conteúdo celular obtido da cavidade foi associado à intensidade do processo inflamatório. A contagem total de células leucocitárias e suas subpopulações foi realizada por Citometria de Fluxo. Para a análise de subpopulações, os leucócitos foram preparados e marcados, conforme o protocolo da PharMingen®, com anticorpos conjugados com fluoresceína ou ficoeritrina-R, específicos para as populações de Linfócitos B (anti-CD 19), Linfócitos T (anti-CD 3) e sub-população de Linfócitos T (anti-CD 4 e anti-CD 8). Nossos resultados permitem concluir que: 1. Todos os adjuvantes induzem inflamação cutânea; 2. Existe diferença de intensidade e na qualidade do infiltrado inflamatório induzido entre os diferentes adjuvantes utilizados. Alguns adjuvantes induzem um infiltrado inflamatório predominantemente de células mononucleares, Outros de polimorfonucleares; 3. Estas diferenças parecem resultar em padrões de resposta imune diferentes, de acordo com a célula mais estimulada. Os padrões de resposta predominantemente mononuclear foram observados com SEPPIC-I e SEPPIC-II. O Padrão de resposta apresentando grande quantidade de células polimorfonucleares foi observado com Hidróxido de Alumínio, Algamulin e Beta Glucana; 4. Avridine apresentou um infiltrado misto no qual havia a presença tanto de células mononucleares quanto polimorfonucleares
Literatur und Destruktion:die literarische Darstellung destruktiven Verhaltens im 20. Jahrhundert
No full textDet 20. århundrede er det mest destruktive i vor tidsregning. Ganske vist udmærker det sig ved, at man har opnået store teknologiske fremskridt, men disse fremskridt er ikke fulgt op af tilsvarende fremskridt på det humane område. Den store cæsur er Første Verdenskrig, som blev uventet langvarig og altødelæggende, hvorefter intet blev som før. Hvordan beskriver og overvinder litteraturen denne modsætning? Adorno skrev med udgangspunkt i Auschwitz, at det efter Auschwitz ville være barbarisk at skrive lyrik. Der redegøres for Adornos æstetiske teori, på baggrund af hvilken citatet kan gives mening. Derpå følger en præsentation af Karl Heinz Bohrers idé om skrækkens æstetik eller pludseligheden som æstetisk kategori. På den baggrund opstilles med henvisning til Freuds forelæsninger om psykoanalysen tesen, at litteraturen tilnærmer sig emnet som ”en forsøgsvis handlen med små energimængder”. Der inddrages i afhandlingen tre primærtekster, Peter Weiss’ oratorium Forundersøgelsen, Günter Grass’ roman Bliktrommen og Patrick Süskinds roman Parfumen. Historien om en morder, men ved siden af disse værker inddrages i periferien adskillige andre tekster, som har relevans for emnet. I Peter Weiss’ oratorium Forundersøgelsen forsøger digteren at fremmane konturerne af Auschwitz igennem de vidneudsagn, der blev fremført under retssagen imod bødlerne fra Auschwitz i Frankfurt i tidsrummet 1963 -1965. Peter Weiss gør altså brug af den dokumentariske teaterform, som kan føres tilbage til Erwin Piscator. Men i afhandlingen forsøges ikke blot at læse oratoriet som en gengivelse af fakta, men som et æstetisk tegn, som eksisterer uafhængigt af den historiske begivenhed, det relaterer til. I den forbindelse præsenteres Robert Jay Liftons idé om ”Auschwitzselvet”, som betegner en fælles tilstand for både fanger og bødler. Begge parter er henført til en anden verden, hvor der hersker en anden logik og oplevelsen af tiden er en anden. George Steiner beskriver dette i sit essay Postscript ved hjælp af jødisk mystik, ifølge hvilken tiden kan opdeles i gode tider og dårlige tider, hvilket også går under betegnelsen Zimzum. I Forundersøgelsen fremstilles således en overlevelsesstrategi, igennem hvilken både fanger og bødler holder skrækken på afstand, men af samme grund kommer dramaet ikke rigtigt tæt på skrækken. Tilstanden i koncentrationslejren kan snarere karakteriseres ved, hvad Robert Jay Lifton kalder ”psychic numbing”. I Bliktrommen gør Günter Grass brug af skælmeromanen til at omfatte en meget tragisk epoke i tysk historie, nemlig tidsrummet 1933-1945. De historiske begivenheder holdes på afstand ved fortællerens fejlbedømmelse, fejlfortolkning eller direkte løgnagtige omgåelse af begivenhederne. De fremstår ofte i et aldeles komisk lys, men komikken har en normfremmende funktion i forhold til de tragiske begivenheder, der ikke lader sig direkte fremstille. Hovedpersonen Oskar er symptomatisk for den tid, han fremstiller. Han udgør romanens demiurgiske centrum og gennemlever på den måde epokens storhedsvanvid, ligeså vel som han med tiden også bliver offer for det. Der gøres brug af psykoanalytikeren Heinz Kohuts idé om det grandiose selv, hvorved der også henføres til den primære narcissisme hos Freud. Oskar oplever skrækken forskudt i forhold til de tragiske historiske begivenheder, der bliver skildret i romanen. Den kommer til sidst til udtryk ved motivet med den sorte kokkepige, der er et objektivt korrelat for det angsttraume, Oskar opbygger igennem hele romanen. Romanen munder ud i dette Angsttraume, som er grunden til, at Oskar overhovedet begynder at skriver. Oskar drager til sidst eller – rettere – i starten den konklusion, at mennesket kun kan overvinde angsten igennem fortællingen. I Patrick Süskinds roman Parfumen. Historien om en morder udkastes profilen af et magtmenneske, som det 20. århundrede har været så rigt af eksempler på. Romanen udgør afhandlingens eksperiment, for så vidt som det ikke anses for intenderet fra Süskinds side at skrive om destruktion i det 20. århundrede. Men ud fra den hermeneutiske antagelse, at et værk altid indeholder mere end det, en given ophavsmand til det lægger ind i det, tolkes romanen i overensstemmelse med afhandlingens overordnede erkendelsesinteresse som et magtmenneskes tilblivelseshistorie. Der gøres brug af den schweiziske psykolog Arno Gruens bog Der Wahnsinn der Normalität. Realismus als Krankheit: eine Theorie der menschlichen Destruktivität, hvori indre tomhed forklares som årsagen til, at nogle mennesker angler efter magten. Hovedpersonen Grenouille er i bogstaveligste forstand opstået af ingenting, og han støder kun på afvisning fra omgivelsernes side. Hvis det ikke havde været for hans særlige talent, havde hans liv været fuldstændig tomt. Grenouilles særlige sans for lugte og dufte gør hans liv rigt og mangfoldigt, dog kun lige til den dag, hvor han opdager, at han ikke selv har nogen lugt. Det får ham til at ville fremstille en ny vidunderparfume og ny overnormalitet, som alle mennesker skal undergive sig. Romanen er en illustration af Horkheimer og Adornos tese om, at oplysningen slår tilbage i mytologi. Grenouille legemliggør fremskridtet inden for duftenes område, men vel at mærke et fremskridt, som ikke gennemføres uden ofre. The 20th century is the most destructive century in our modern era. It is true that it is distinguished by the fact that it has achieved a great technological progress, but this progress has not been followed up by a comparable progress in a humane sense. The great turning point is the First World War which was unexpectedly long and devastating, after which nothing was as before. How does literature describe and overcome this paradox? Adorno wrote on the basis of Auschwitz that after Auschwitz it would barbaric to write a poem. Adorno’s aesthetic theory is dealt with in the light of which the quotation can be given sense. After that comes a presentation of Karl Heinz Bohrer’s idea of the aesthetics of terror or suddenness as an aesthetic category. On this basis and with reference to Freud’s introductory lectures on psycho-analysis, the thesis is put forward that literature approaches the subject as “an experimental action carried out with small amounts of energy”. In the dissertation three primary texts, Peter Weiss’ oratorio The Investigation, Günter Grass’ novel The Tin Drum, and Patrick Süskind’s novel Perfume. The Story of a Murderer, are analyzed, but in addition several other texts are considered which are relevant to the theme. In the oratorio The Investigation Peter Weiss tries to conjure up the contours of Auschwitz through evidence, which was given during the war crime trial in Frankfurt during the period 1963-1965. Peter Weiss makes use of documentary theatre, which can be traced back to Erwin Piscator. But in the dissertation the oratorio is not only read as a representation of fact, but as an aesthetic sign which exists beyond the historical event it refers to. In this connection Robert Jay Lifton’s idea of “the Auschwitz self” is introduced, which stands for the common condition of both convicts and tormentors. Both sides are abandoned to another world in which another view of life rules and the experience of time is different. In his essay Postscript George Steiner describes this condition by means of Jewish mysticism according to which time can be divided into good times and bad times which can also is characterized as Zimzum. Thus The Investigation describes a strategy of survival through which both convicts and tormentors keep their distance to the terror, but the drama does not get really close to the terror for the same reason. The condition in the concentration camp can rather be characterized by what Robert Jay Lifton describes as “psychic numbing”. In The Tin Drum Günter Grass makes use of the picaresque novel in order to embrace a tragic era in German history. The historical events are kept at a distance by the narrator’s misjudgement, misinterpretation or simply untruthful rewriting of the events. They are presented in a completely comic light, but comic has a norm promoting purpose considering the tragic events which cannot be described directly. Oskar, the main character, is symptomatic of the time he describes. He forms the demiurgic centre of the novel and thus lives through the megalomania of his era just as he also eventually becomes the victim of it. The psychoanalyst Heinz Kohut’s idea of the grandiose self is referred to by means of which Freud’s primary narcissism is also dealt with. Oskar experiences the terror transposed compared to the tragic events which are described in the novel. It manifests itself through the motive of the black witch which is an objective correlative of the phobia of anxiety which Oskar builds up throughout the novel. The novel ends in this phobia of anxiety which is the reason why Oskar begins to write at all. Oskar arrives at last or – rather – at the start at the conclusion that man can only conquer the terror through the narrative. In Patrick Süskind’s novel Perfume. The Story of a Murderer the profile of the kind of person who seeks power is drawn. The novel makes up the experimental part of the dissertation in so far as it cannot be regarded as intended by Süskind to write about destruction in the 20th century. But according to the hermeneutic assumption that a work always implies more than a specified author reads into it, the novel is interpreted here as the genesis of a power-seeker in accordance with the main theme of the dissertation. In this connection Arno Gruen’s book Der Wahnsinn der Normalität. Realismus als Krankheit: eine Theorie der menschlichen Destruktivität is dealt with according to which inner blankness is the reason why some people angle for power. The main character Grenouille comes literally from nothing, and he meets only contempt from his surroundings. Had it not been for his special talent, his life would have been completely empty. Grenouille’s special sense of smells and scents makes his life rich and meaningful, until the day when he discovers that he has no smell himself. That makes him want to create a new wonder perfume and a new super normality which all people shall be subject to. In this respect the novel is a reflection of Horkheimer’s and Adorno’s thesis that enlightenment reverts to mythology. Grenouille embodies progress within the sphere of scents, but a progress that can only be made on the understanding that it claims victims. <br/
