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Coste, Emmanuel. "Development of small molecules as anti-inflammatory and anti-resorptive drugs." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/9941.
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Rheumatoid arthritis is an auto-immune inflammatory disease that leads to stiff and swollen joints. Patients also have severe bone destruction of the affected joints and another common symptom of rheumatoid arthritis is a generalised bone loss that can lead to osteoporosis. Currently, there are many treatments for rheumatoid arthritis, which provide a recession of the inflammatory symptoms. However, none of these treatments are able to provide a complete protection against the rheumatoid arthritis-induced bone loss. Furthermore, the most effective available treatments such as glucocorticoids or the new biological drugs are not optimal since they either cause severe side effects or are very expensive and difficult to produce. Hence, there is a real need for new cost-effective treatments that can act on both inflammation and bone loss symptoms of rheumatoid arthritis. ABD compounds are small molecules, relatively easy to synthesize at reasonable cost. In this thesis, I discuss the effects of these small molecules on both rheumatoid arthritis-induced inflammation and bone loss. Daily treatments with the ketones ABD328 and ABD345, or with the sulphonamide ABD455 prevent inflammation in an animal model of rheumatoid arthritis. Furthermore, micro-CT and histology analysis showed that these treatments also provide a reliable protection against bone destruction of affected joints and generalised bone loss. In vitro data showed that this protective effect on bone was osteoclast specific. Indeed, Ishow here that treatment of other bone cells (such as osteoblasts or macrophages) with ABD compounds does not affect their biology. The mechanism of action of these compounds has also been studied and I show here that ABD compounds inhibit both inflammation and osteoclastogenesis by inhibiting the signalling pathways that are activated in response to pro-inflammatory cytokines such as TNF . This work led to the design and synthesis of further improved compounds, such as ABD599, that are currently considered as very interesting candidates for clinical trials. In conclusion, the ABD compounds, as small cost-effective molecules, represent a novel class of rheumatoid arthritis treatments by acting on both inflammation and bone loss symptoms of the disease.
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Battu, Ganga Rao. "Anti-inflammatory and phytochemical studies of a Kenyan traditional medicinal plant, Commiphora kua." Thesis, University of Strathclyde, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366837.
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Prins, Louis Hendrik Albertus. "Polycyclic cage compounds as carrier molecules for neuroprotective non-steroidal anti-inflammatory drugs / Louis H.A. Prins." Thesis, North-West University, 2007. http://hdl.handle.net/10394/1479.
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Eduardo, Da Silva Acarilia. "Nanotechnological delivery systems for the oral administration of active molecules : Polymeric microparticles and microemulsions applied to anti-inflammatory and anti-infectious drugs." Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-00856598.
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This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit® S-100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spray-dried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on medium-chain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophilic-lipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 µg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB.
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Silva, Acarilia Eduardo da. "Nanotechnological delivery systems for the oral administration of active molecules: Polymeric microparticles and microemulsions applied to anti-inflammatory and anti-infectious drugs." Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13309.
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This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit? S- 100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spraydried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on mediumchain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophiliclipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 μg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB
Esta tese teve como objetivo o desenvolvimento de novos sistemas de libera??o para duas mol?culas distintas. Na primeira parte, micropart?culas ? base de xilana e Eudragit? S-100 foram produzidas para encapsular ?cido 5-aminosalic?lico visando ? libera??o c?lonespec?fica. A xilana foi extra?da de sabugos de milho e caracterizada quanto ?s suas propriedades f?sico-qu?micas, reol?gicas e toxicol?gicas. Em seguida, dois m?todos de microencapsula??o foram utilizados: reticula??o interfacial polim?rica e secagem por aspers?o. Os sistemas produzidos foram caracterizados quanto ? morfologia, tamanho m?dio e distribui??o, estabilidade t?rmica, cristalinidade, taxa de encapsula??o e libera??o do f?rmaco in vitro. Foram obtidas micropart?culas com adequadas caracter?sticas f?sicas e rendimentos satisfat?rios atrav?s dos dois m?todos, embora os sistemas aspergidos tenham apresentado maior estabilidade t?rmica e sejam considerados mais interessantes devido a sua maior estabilidade t?rmica e aus?ncia de agentes t?xicos. No entanto, ajustes precisam ser feitos para melhorar a encapsula??o e libera??o do f?rmaco. Na segunda parte, microemuls?es do tipo ?leo em ?gua (MEs O/A) com base em triglicer?deos de cadeia m?dia (MCT) foram produzidas visando ao carreamento de anfotericina B (AmB) e aumento da sua solubilidade. Foram obtidas MEs O/A sem e com AmB com got?culas em torno de 80 e 120 nm, respectivamente, e ?ndices de polidispers?o de 0,25 e 0,31, respectivamente. A taxa de incorpora??o da AmB foi alta e dependente do volume da fase dispersa. A viabilidade celular n?o foi afetada at? 25 μg/mL da AmB. Portanto, MEs O/A a partir de MCT podem ser promissores sistemas de libera??o para AmB
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Huang, Tzu-Hsuan. "Fusion of anti-HER2/neu with inflammatory cytokines IFN-a and TNF-a results in molecules that elicit an anti-tumor response or potentiate wound healing." Diss., Restricted to subscribing institutions, 2006. http://proquest.umi.com/pqdweb?did=1276406491&sid=11&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Gnansounou, Senankpon Martial. "Etude des activités anti-inflammatoire, antioxydante et screening par chromatographie gazeuse couplée à la spectrométrie de masse d’extraits éthanoliques de trois fabacées du Bénin : isolement de molécules bioactives." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0603.
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Face à la résurgence de pathologies infectieuses, notre étude a porté sur le potentiel thérapeutique de Dialium guineense, Parkia biglobosa et Tamarindus indica afin de rechercher des molécules bioactives pouvant contrer l’antibiorésistance ou ses corolaires. L’état de l’art des molécules bioactives des trois plantes a montré que de nombreuses familles de composés sont identifiées dans différents organes aériens. Toutefois le lien avec les activités biologiques reste non élucidé. Ensuite, nous avons évalué quelques activités biologiques des extraits éthanoliques ou hydro-éthanoliques des feuilles, fruits et écorces. Avec de bons taux de viabilité cellulaires, les extraits de D. guineense (écore) ainsi que ceux de P. biglobosa (feuilles) et T. indica (écorce) ont des ratios d’activités antiinflammatoires de 458,2 ; 161 et 174,6 respectivement. Ces valeurs sont supérieures à celle de la dexaméthasone utilisée comme témoin. Le test KRL a montré une activité antiradicalaire dose dépendante dans la gamme de 0 à 20mg/L. In vitro, 1g de chacun des extraits susmentionnés présente une capacité antioxydante respectivement équivalente à 1585 ; 2092 ; 5071 et 2246 mg de Trolox. Les extraits ont par la suite été analysés par GC-MS révélant pour la première fois la présence de lupéol et de sitostérol dans l’écorce de D. guineense. Enfin, l’étude nutritionnelle des trois fruits révèle, à travers les fortes teneurs en nutriments (80% de sucre pour D. guineense), leur possible contribution à la lutte contre la malnutrition au Bénin et la nécessité d’œuvrer à leur conservation.Mots-clés : Pathologies infectieuses, antibiorésistance, anti-inflammatoire, antioxydant, molécules bioactivesIn a context of infectious diseases resurgence, our study focused on therapeutic potential of Dialium guineense, Parkia biglobosa and Tamarindus indica in order to search for bioactive molecules that can counter antibiotic resistance or its corollaries. The state of the art of on bioactive molecules from the three plants has shown that many families of compounds are identified in different aerial organs. However, the link with biological activities remains unclear. Next, we evaluated some biological activities of ethanolic or hydroethanolic extracts of leaves, fruits and bark. With good cell viability levels, extracts of D. guineense (bark) as well as those of P. biglobosa (leaves) and T. indica (bark) have anti-inflammatory activity ratios of 458.2; 161 and 174.6 respectively. These values are higher than that of dexamethasone used as positive control. The KRL test showed dose-dependent antiradical activity in the range of 0 to 20mg / L. In vitro, 1 g of each of the abovementioned extracts has an antioxidant capacity respectively equivalent to 1585 ; 2092 ; 5071 and 2246 mg of Trolox. The extracts were then analyzed by GC-MS revealing for the first time the presence of lupeol and sitosterol in the bark of D. guineense. Finally, the nutritional study of the three fruits reveals, through the high levels of nutrients (80% sugar for D. guineense), their possible contribution to fight malnutrition in Benin and the need of their conservation. Keywords : Infectious diseases, antimicrobial resistance, anti-inflammatory, antioxidant, bioactive molecules
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D'ORAZIO, GIUSEPPE. "Glycoderivatives: drug candidates and molecular tools." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/41154.
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The research project is focused on the development and the synthesis of glycoderivatives as potential drug candidates, for therapeutic use, and as molecular tools, for the study of biological processes. The project includes the study of SGLT1 (Sodium-Glucose co-transporter 1), its role in inflammatory processes and the development of potential carbohydrate-based anti-inflammatory agents. Furthermore, new glycoderivatives and glycoconjugates will be synthetized for other potential pharmacological applications such as the targeting of cytotoxic drugs, as novel potential anticancer agents, and for the development of molecular tools to study several biological phenomena.
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Pujo, Julien. "Caractérisation de molécules lipidiques produites par les bactéries probiotiques Escherichia coli Nissle 1917 : rôle dans l’homéostasie intestinale." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30199.
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De nombreuses études portant sur le microbiote intestinal ont mis en évidence son importance dans la physiologie et la physiopathologie de l’hôte. Les bactéries, acteurs majeurs du microbiote, participent au maintien de l’homéostasie intestinale en régulant plusieurs fonctions essentielles allant de la protection de la barrière intestinale au développement du système immunitaire. Des altérations de la composition et de la diversité de ce microbiote ont été observées dans des pathologies du tractus digestif comme le syndrome de l’intestin irritable et les maladies inflammatoires chroniques de l’intestin. Afin de restaurer l’homéostasie intestinale, des thérapies utilisant des bactéries probiotiques ont été utilisées. Parmi les bactéries probiotiques testées, Escherichia coli Nissle 1917 (E. coli Nissle 1917) a été décrite comme exerçant des fonctions anti-diarrhéiques, analgésiques et anti-inflammatoires. Néanmoins les mécanismes d’actions impliqués dans ces activités demeurent inconnus. Afin de les mettre en évidence, nous avons utilisé deux approches en spectrométrie de masse pour analyser les lipides bactériens. Une première approche sans apriori, nous a permis de mettre en évidence la production de lipopeptides dont le C12AsnGABAOH constitué d’un acide gras de 12 carbones, d’une asparagine et du GABA, le neurotransmetteur inhibiteur majoritaire du système nerveux. Ce lipopeptide était produit par des enzymes codées par des gènes faisant partis d’un cluster : l’îlot pks. A l’inverse du GABA seul, le C12AsnGABAOH traversait la barrière épithéliale intestinale (BEI) in vitro et in vivo. L’ajout de l’aminolipide par la bactérie confère donc au GABA la capacité d’atteindre les terminaisons nerveuses sensitives. Ce lipopeptide diminuait l’activation neuronale induite par l‘activation de nocicepteurs dans des cultures de neurones sensitifs via le récepteur GABAB. In vivo, il inhibait l’hypersensibilité viscérale induite par l’activation de nocicepteurs chez la souris. Dans une deuxième étude, nous avons réalisé une étude en spectrométrie de masse avec apriori en recherchant les acides gras à longue chaine (AGLC) hydroxylés dans différentes souches d’E. coli. Le C18-3OH un AGLC de 18 carbones possédant une hydroxylation en position 3 était produit en plus grande quantité par les bactéries E. coli Nissle 1917 indépendament de l’ilôt pks. Le C18-3OH n’était pas capable de traverser la BEI et s’accumulait dans les cellules in vitro, dans les tissus ex vivo, et dans le colon in vivo. Dans les tissus, le C18-3OH modulait l’expression de gènes qui était sous la dépendance du récepteur PPAR-γ. Enfin nous avons mis en évidence dans un modèle de colite induite par le DSS que le C18-3OH réduisait la perméabilité paracellulaire et les paramètres inflammatoires chez la souris. Ces travaux de thèse nous ont permis de démontrer pour la première fois que les bactéries E. coli Nissle 1917 pouvaient communiquer avec les cellules de l’hôte en sécrétant des lipopeptides et des AGLC. Deux d’entre eux le C12AsnGABAOH et le C18-3OH étaient des molécules bioactives. Le C12AsnGABAOH inhibait l’hypersensibilité viscérale et le C18-3OH réduisait le statut inflammatoire des cellules épithéliales intestinales. Ces composés lipidiques pourraient être impliqués dans les effets probiotiques exercés par E. coli Nissle 1917 et représenter des agents thérapeutiques dans le traitement de la douleur viscérale et de l’inflammation intestinaleNumerous studies have highlighted the importance of intestinal microbiota in the physiology and physiopathology of the host. Bacteria, the most represented microorganisms of the microbiota, contribute to the maintenance of intestinal homeostasis by regulating several essential functions ranging from the protection of the intestinal barrier to the development of the immune system. Impairment in the composition and diversity of this microbiota have been observed in pathologies of digestive tract such as irritable bowel syndrome and inflammatory bowel disease. In order to restore intestinal homeostasis, therapies using probiotic bacteria were used. Among probiotic bacteria tested, Escherichia coli Nissle 1917 (E. coli Nissle 1917) has been used for its anti-diarrheal, analgesic and anti-inflammatory properties. Nevertheless, the mechanisms of action involved in these therapeutic effects remain unknown. In order to study them, we used two approaches in mass spectrometry to analyse bacterial lipids. A first untargeted approach, allowed us to highlight the production of lipopeptides including C12AsnGABAOH composed by a fatty acid of 12 carbons, an asparagine and GABA (gamma amino butyric acid), the main inhibitory neurotransmitter of the nervous system. This lipopeptide was produced by enzymes encoded by genes of a cluster call the pks island. In contrast to GABA alone, C12AsnGABAOH crosses the intestinal epithelial barrier (IEB) in vitro and in vivo. The addition of the aminolipid by the bacteria confer to the GABA the ability to reach sensory nerve endings. This lipopeptide decreased neuronal activation induced by activation of nociceptors in sensory neuron primary cultures via the GABAB receptor. In vivo, it inhibited visceral hypersensitivity induced by activation of nociceptors in mice. In a second study, we carried out a mass spectrometry targeted approaches looking for hydroxylated long chain fatty acids (LCFA) in different strains of E. coli. C18-3OH a LCFA of 18 carbons with a hydroxylation on its third position was produced in higher amounts by E. coli Nissle 1917 independently of the pks island. The C18-3OH was not able to cross the IEB and accumulated in cells in vitro, in tissues ex vivo and in colon in vivo. In tissues, C18-3OH modulated the expression of genes regulated by PPAR-γ receptor. Finally, in a DSS-induced colitis in mice, C18-3OH decreased paracellular permeability and inflammatory parameters. These thesis works allowed us to demonstrate for the first time that E. coli Nissle 1917 could signal to host cells by secreting lipopeptides and LCFAs. Two of them C12AsnGABAOH and C18-3OH were bioactive molecules. C12AsnGABAOH inhibited visceral hypersensitivity and C18-3OH reduced the inflammatory status of intestinal epithelial cells. These lipid compounds could be involved in the probiotic effects exerted by E. coli Nissle 1917 and represent therapeutic agents in the treatment of visceral pain and intestinal inflammation
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Simi, Anastasia. "Molecular basis for the anti-inflammatory properties of chlomethiazole /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-621-9/.
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GURAU, FELICIA. "Anti-inflammatory effects of natural compounds: focus on miRNA modulation." Doctoral thesis, Università Politecnica delle Marche, 2020. http://hdl.handle.net/11566/274459.
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Una stimolante e promettente nuova branca della ricerca sull’invecchiamento è l’identificazione di nuove molecole naturali capaci di modulare il fenotipo secretorio associato alla senescenza (SASP). Questo è il fenotipo che caratterizza le cellule senescenti (SC) e può contribuire ad alimentare uno stato proinfiammatorio sistemico associato all’invecchiamento e allo sviluppo delle più comuni malattie derivanti da esso (ARDs).
L’obiettivo di questo studio è stato quello di valutare l’attività anti-SASP della curcuma (CUR), resveratrolo (RSV) e β-cariofillene (BCP), da soli o in combinazione (MIX), in due modelli cellulari umani coinvolti nella promozione della risposta infiammatoria, quali la linea cellulare monocitica, THP-1, e la linea cellulare endoteliale primaria, HUVEC.
Le HUVEC interessate da senescenza replicativa e indotta dalla doxorubicina (RS- e IS-HUVECs) sono state trattate con le sostanze singolarmente o in combinazione. In particolare, il MIX di sostanze è stato capace di ridurre più efficacemente e significativamente i livelli di espressione di IL-1β e IL-6, così come quelli di miR-21 e miR-146a, mentre ha aumentato l’espressione di miR-126 in entrambi i modelli di cellule senescenti. Inoltre, il MIX ha significativamente contribuito a ristabilire i livelli di SIRT1 e proteina p16ink4a sempre in entrambi i tipi di HUVEC senescenti.
Nelle THP-1 simulate con LPS il MIX è stato capace di diminuire l’espressione di IL-1β, IL-6, TNF-α e miR-146a in comparazione con i modelli non trattati.
Per concludere, i nostri risultati mostrano un effetto sinergico di CUR, RSV e BCP nell’attenuare il SASP sia nelle HUVEC che nelle THP-1.A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate senescence-associated secretory phenotype (SASP). SASP is the phenotype that characterize senescent cells (SCs) and can contribute to fuel the chronic pro-inflammatory systemic status associated with aging and with the development of the most common age-related diseases (ARDs). The aim of this study was the evaluation of the anti-SASP activity of Curcuma (CUR), resveratrol (RSV) and β-caryophyllene (BCP), alone and in combination (MIX), in two human cellular models involved in promoting inflammatory responses, such as the monocytic cell line, THP-1 and the endothelial primary cell line, HUVECs. Replicative and doxorubicin-induced senescent HUVECs (RS- and IS-HUVECs) were treated with the single natural compounds or with the mix of these substances. Notably, the mix was able to reduce more efficiently and significantly IL-1β and IL-6 expression levels, as well as to induce a significant down-regulation of miR-21 and miR-146a expression, and a significant up-regulation of miR-126 in both RS- and IS-HUVECs compared to single compounds. Moreover, the mix significantly contribute to restore the level of SIRT1 and p16ink4a protein in both RS- and IS-HUVECs. In LPS-stimulated THP-1 cells the mix was able to reduce the expression of IL-1β, IL-6, TNF-α and miR-146a compared to the non-treated cells. Our results showed a synergic effect of CUR, RSV and BCP in restrain SASP in HUVECs and the inflammatory response in THP1cells.
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Clarke, Christopher Jeremy Paul. "Molecular mechanisms of the anti-inflammatory cytokines interleukin-4 and interleukin-10." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285172.
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Manabe, Yuki. "Studies on anti-inflammatory effects and underlying molecular mechanisms of marine carotenoids." Kyoto University, 2020. http://hdl.handle.net/2433/252997.
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Kyoto University (京都大学)0048
新制・論文博士
博士(農学)
乙第13346号
論農博第2889号
新制||農||1080(附属図書館)
学位論文||R2||N5253(農学部図書室)
京都大学大学院農学研究科応用生物科学専攻
(主査)教授 菅原 達也, 教授 佐藤 健司, 教授 澤山 茂樹
学位規則第4条第2項該当
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England, Ross N. "Cellular Mechanisms of the Anti-Inflammatory Effects of Interleukin-19." Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/216875.
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PhysiologyPh.D.
BACKGROUND: Atherosclerotic vascular disease is a significant medical and socioeconomic problem and contributes to mortality in multiple diseases including myocardial infarction (MI), stroke, renal failure, and peripheral vascular disease. Atherosclerosis, as well as other vascular diseases including post-intervention restenosis and allograft vasculopathy, is known to be driven by chronic inflammation and, consequently, pro- and anti-inflammatory cell signaling molecules have been an important target of cardiovascular research. Interleukin (IL)-19 is a recently discovered member of the IL-10 family of anti-inflammatory cytokines. IL-19 is expressed in injured vascular cells, including vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), where it exerts an anti-inflammatory effect. In VSMCs, IL-19 signaling results in inhibition of proliferation, migration, spreading, production of reactive oxygen species (ROSs), and expression of pro-inflammatory genes. In ECs, IL-19 signaling is pro-angiogenic and results in increased EC proliferation, migration, and spreading. AIMS and HYPOTHESIS: The goal of the present study was to explore the hypothesis that IL-19 mediates anti-inflammatory effects on vascular cells by inhibiting the expression of pro-inflammatory genes, such intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, IL-1β, IL-8, and monocyte chemotactic protein (MCP)-1, through modulation of the mRNA stability factor HuR by post- transcriptional (e.g., microRNA) and post-translational (e.g., serine phosphorylation) mechanisms. METHODS and RESULTS: We found that IL-19 can significantly inhibit tumor necrosis factor (TNF)-α-driven ICAM-1 and VCAM-1 mRNA and protein abundance in cultured human coronary artery ECs (p < 0.01). IL-19 treatment of ECs, but not monocytes, significantly inhibited monocyte adhesion to cultured EC monolayers (p < 0.01). In wild-type mice, systemic administration of IL-19 significantly reduced TNF-α-induced leukocyte rolling and adhesion as quantitated by intravital microscopy (p < 0.05). IL-19 failed to inhibit TNF-α-induced nuclear factor (NF)-κB activation in ECs. IL-19 inhibited nuclear-to-cytoplasmic translocation of HuR and significantly reduced mRNA stability of ICAM-1 and VCAM-1 (p < 0.01 ). IL-19 significantly inhibited serine-phosphorylation of HuR, which is required for its translocation, and significantly increased expression of the putative HuR regulator microRNA (miR)-133 in VSMCs. CONCLUSIONS: These data are the first to report that IL-19 can reduce leukocyte-EC interactions, and to propose reduction in HuR-mediated mRNA stability of ICAM-1 and VCAM-1 as a mechanism. We conclude that expression of IL-19 by ECs and VSMCs may represent an auto-regulatory mechanism to promote resolution of the vascular response to inflammation. These results suggest that IL-19 is anti-inflammatory in vascular cells and, therefore, may be of therapeutic value in atherosclerotic vascular disease.
Temple University--Theses
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Bournazou, Irini. "Lactoferrin : an anti-inflammatory molecule released by apoptotic cells to inhibit granulocyte migration." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/9889.
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Apoptosis is a physiological form of cell death. It is a highly evolutionarily conserved process that is non-inflammatory or anti-inflammatory in nature. This anti-inflammatory nature of apoptosis is evident by the fact that neutrophils are histologically absent from sites where homeostatic apoptosis rates are high. The rapid phagocytosis of apoptotic cells as a means to prevent the release of noxious inflammatory compounds also accounts for the anti-inflammatory environment of such sites. However, the mechanisms that enable mononuclear phagocytes to migrate to sites where homeostatic apoptosis rates are high, and not granulocytes, the professional phagocytes that accumulate at sites of inflammation, have not been determined yet. Using Burkitt’s lymphoma (BL) as a model of apoptosis, the aim of this thesis was to identify the regulatory mechanisms or factors underlying the non-phlogistic features of sites where homeostatic apoptosis rates are high and in particular, those preventing the recruitment of neutrophils - a major granulocyte subclass to these sites. BL is a highly aggressive B cell lymphoma that is mainly characterised by a high rate of apoptosis. By carrying out a series of in vitro chemotaxis assays and biochemical approaches, it was found in this thesis that BL cells actively inhibit neutrophil migration by releasing factors that were identified to be lactoferrin, a 80 kDa iron-binding glycoprotein with anti-bacterial and anti-inflammatory properties. It was further demonstrated that lactoferrin selectively inhibited migration of granulocytes (both neutrophils and eosinophils) but not mononuclear phagocytes and this effect was irrespective of its iron saturation status and the chemoattractant used. Also, lactoferrin potently inhibited neutrophil migration, as assessed by thioglycollate-induced in vivo model of mouse peritonitis. This anti-inflammatory function of lactoferrin was attributed to its effect on granulocyte signalling pathways that regulate cell adhesion and motility. Finally, it was demonstrated that in cell types of diverse lineages, induction of apoptosis results in de novo synthesis and secretion of lactoferrin. In subsequent proliferation assays determining the in vitro growth of a number of BL cell types, it was demonstrated that lactoferrin is an essential component of BL cells and promotes their proliferation, as its antibody-mediated neutralisation or shRNA-mediated expression knockdown, reduced BL cell growth. Together, the results of this thesis identified lactoferrin as one of the few characterised antiinflammatory components of the apoptosis milieu that negatively regulate granulocyte migration. This effect may provide opportunities for broad therapeutic interventions concerning the use of lactoferrin in chronic inflammatory conditions characterised by aberrant neutrophil influx as well as atopic allergic disorders, such as asthma. Moreover, based on the tumour-supporting role of lactoferrin described in this study, targeting its expression in tumours could lead to tumour regression and thus, be a promising therapeutic molecule in tumour immunotherapy.
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Al-Adlaan, Asaad A. "A NOVEL ANTI-INFLAMMATORY ROLE OF OSTEOACTIVIN/GPNMB INPOST-TRAUMATIC OSTEOARTHRITIS." Kent State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=kent15114587826723.
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Herman, Allison. "RNA-binding proteins mediate anti-inflammatory regulation of vascular disease." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/554883.
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Biomedical SciencesPh.D.
This work identifies the Fragile X-related protein (FXR1) as a reciprocal regulator of HuR target transcripts in vascular smooth muscle cells (VSMC). FXR1 was identified as an HuR interacting protein by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The-HuR-FXR1 interaction is abrogated in RNase-treated extracts, indicating that their association is tethered by mRNAs. FXR1 expression is induced in diseased, but not normal arteries. SiRNA knock down of FXR1 increases abundance and stability of inflammatory mRNAs, while overexpression of FXR1 reduces their abundance and stability. RNA-EMSA and RIP demonstrate that FXR1 directly interacts with an ARE and a previously uncharacterized element in the 3’UTR of TNFa. FXR1 expression is increased in VSMC challenged with the anti-inflammatory cytokine IL-19, and FXR1 is required for IL-19 reduction of HuR. This suggests FXR1 is an anti-inflammation responsive, HuR counter-regulatory protein that reduces abundance of pro-inflammatory transcripts. Additionally, we observed significantly increased poly-A-Binding protein (PABP) expression localizing to discrete punctate structures in both vascular smooth muscle (VSMC) and endothelial cells (EC) of the aortic arch of Ldlr-/- mice, as compared to WT controls. EIF2α phosphorylation, requisite for SG formation, was also induced by clotrimazole and oxLDL in these cells. Interestingly, VSMCs pre-treated with anti-inflammatory cytokine IL-19 followed by clotrimazole significantly reduced the formation of SGs and eIF2a phosphorylation, suggesting a relationship between inflammation and SG formation in vascular cells. Reduction of SG component G3BP1 by siRNA knockdown significantly reduced stress granule formation and inflammatory gene abundance in hVSMC. Microtubule inhibitors reduced SG formation in hVSMC. These results support the hypothesis that SG formation in atherosclerosis is driven by inflammation, SG may mediate the cellular response to inflammation, and that anti-inflammatory treatment may lessen atherosclerosis progression and plaque formation by reduction of SGs.
Temple University--Theses
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Sciara, Aubrey N. "Characterization of Pro-inflammatory and Anti-inflammatory Microglia in the Anterior Cingulate Cortex in Autism Spectrum Disorder." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3109.
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Autism spectrum disorder (ASD) is associated with functional abnormalities of the anterior cingulate cortex (ACC), a brain area that mediates social behavior. Given evidence of a role of inflammation in ASD, markers of pro-inflammatory and anti-inflammatory microglia were studied using postmortem ACC tissues from ASD and age-matched typically developed control donors. Gene expression levels of pro-inflammatory (CD68, HLA-DRA, IL1B, NOS2, PTGS2) and anti-inflammatory (ARG1, IGF1, MRC1, PPARG) microglial genes were measured using quantitative real-time PCR. Additionally, brain sections were immunohistochemically stained for a microglial marker. Expression levels of IGF1 were modestly higher, while the expression of MRC1 was modestly lower in ASD donors when compared to control donors. No other differences in gene expression levels between the two groups of donors were observed. Statistical significance for changes in expression levels IGF1 and MRC1 did not survive correction for multiple comparisons. Further research on anti-inflammatory microglial involvement in ASD is warranted.
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Chakrabarti, Arindam. "PKR DEPENDENT UPREGULATION OF IMMEDIATE EARLY GENES AND ANTI-INFLAMMATORY CYTOKINE IL-10." Kent State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1176136341.
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Chennamaneni, Snigdha. "FROM NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSIAD) INDOMETHACIN TO ANTI-CANCER AGENTS: DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MECHANISM INVESTIGATION." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1421084668.
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Diaz-Cruz, Edgar S. "Interrelationships between aromatase and cyclooxygenase-2 and their role in the autocrine and paracrine mechanisms in breast cancer." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117117648.
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Gatbonton-Schwager, Tonibelle N. "Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628.
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Cristante, Enrico. "Impact of peripheral inflammation in the brain : new roles for the anti-inflammatory molecule Annexin A1." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/14415.
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Growing evidence has shown that peripheral inflammation can trigger a central nervous system response, sometimes worsening pre-existing neurological conditions, breaking down the concept of brain as an immune-privileged organ. Understanding which components contribute to periphery-to-brain communication may help identify molecules exploitable for therapeutic intervention. Usually, inflammation is followed by resolution: one of the main effectors in this process during peripheral inflammation is Annexin A1, while its implications in the CNS are still unclear. This thesis provides evidence for a new face for the molecule: we observed a well-defined expression at blood brain barrier (BBB) at endothelial level and we detected, in vivo, significantly higher BBB permeability in the AnxA1 null mice due to disrupted inter-endothelial cell tight junctions, essentially as a consequence to changes in the actin cytoskeleton. Such changes are reminiscent of early MS pathology, a relationship confirmed by detecting a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of MS patients. Under peripheral inflammatory conditions (i.p. lipopolysaccharide, LPS), in vivo data suggested an inherent sex difference in BBB response, while in vitro studies confirmed the protective action of sex hormone 17β-Estradiol on the endothelium through ANXA1 modulation. Within the CNS, we detected a constitutively higher microglial density and pro-inflammatory environment in the Anxa1 null mouse, which worsened upon peripheral inflammation. In a neurodegeneration model (6-hydroxydopamine), genotype-related differences in microglial invasion occurred, while subsequent peripheral inflammatory challenges synergised and caused worse dopaminergic neuronal loss only in the knock-out model. These original data unveil a novel functional paradigm for ANXA1 as a “translator” between peripheral immune system and CNS through novel pathways compared to its well-characterized peripheral role. In addition, this study opens up a novel path to find therapeutic applications against disorders characterized by central and peripheral inflammation.
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Singh, Raminder [Verfasser], Rainer [Akademischer Betreuer] Haas, and Ulrich [Akademischer Betreuer] Rüther. "Molecular mechanisms of the anti-leukemic properties of Non-steroidal Anti Inflammatory Drugs / Raminder Singh. Gutachter: Ulrich Rüther. Betreuer: Rainer Haas." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2011. http://d-nb.info/1017354839/34.
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Naidoo, Vinasan. "Diclofenac in Gyps vultures : a molecular mechanism of toxicity." Thesis, University of Pretoria, 2008. http://hdl.handle.net/2263/26027.
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Over the last decade, three species of Gyps vultures on the Asian subcontinent have declined dramatically in population numbers, some as much as 97 to 99%. Although the initial cause was believed to be infectious, it was later shown to be due to an inadvertent exposure to diclofenac via the food chain. In order to protect the remaining wild vultures, diclofenac needed to be removed from the food chain. Unfortunately the Indian government was reluctant to ban diclofenac until an alternate veterinary non-steroidal anti-inflammatory drug (NSAID) that was both safe in vultures and effective in cattle could be identified. Although meloxicam was tentatively identified as this drug, toxicity testing still needed to be undertaken. Using a previously validated model, two studies were undertaken to determine the acute toxic effect of diclofenac in vulture as well as to ascertain if the drug had the potential to accumulate. In the first study, meloxicam in formulation was shown to be safe as a single oral dose up to 2mg/kg in African White Backed-Vultures (Gyps africanus). To further demonstrate the safety of food borne meloxicam, vultures were exposed to meat rich in meloxicam residues, with once again no signs of toxicity being evident. In the second study the drugs ability to accumulate was evaluated pharmacokinetically in Cape Griffon Vultures (Gyps corprotheres). From this study meloxicam was shown to have a very short half-life of elimination, making it unlikely that the drug could be a cumulative toxin. This was subsequently confirmed clinically by the absence of toxicity in birds receiving repeated doses of meloxicam. Although meloxicam was shown to be adequately safe, the safety of other veterinary NSAIDs still required elucidation. While further testing in vultures would have been possible, the small population size of the various vulture species made this unethical. Therefore a surrogate species needed to be identified. With the domestic chicken (Gallus domesticus) being commonly available, attempts were made to validate the chicken as a model. Although the dosed chickens did show similar toxicity patterns from clinical pathology to histopathology, a major problem was their higher tolerance making it impossible to use them as a surrogate. It was, however, concluded that the domestic chicken may be used in mechanistic studies in an attempt to establish an in vitro model. From the mechanistic studies both diclofenac and meloxicam were directly toxic to chicken and vulture renal tubular epithelial cells following 48h of incubation. It was later shown that this toxicity was associated with an increased production of reactive oxygen species (ROS), which could be temporarily ameliorated by pre-incubation with uric acid due to its anti-oxidant activity. When cultures were incubated with either drug for only two hours, meloxicam showed no toxicity in contrast to the cellular toxicity present for diclofenac. In both cases no increase in ROS production was evident. In addition diclofenac influenced the excretion of uric acid by interfering with p-amino-hippuric acid channels. The effect on uric acid excretion persisted after the removal of the diclofenac. It was therefore concluded that vulture susceptibility to diclofenac results from a combination of an increase in cellular ROS, a depletion of intracellular uric acid concentration and most importantly the drug’s long half-life in the vulture. Unfortunately the importance of the drug’s half-life in the toxicodynamics makes it unlikely that in vitro testing will be possible.Thesis (PhD (Paraclinical Sciences))--University of Pretoria, 2007.
Paraclinical Sciences
unrestricted
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Acosta, Sandra Antonieta. "Multivariate Anti-inflammatory Approaches to Rescue Neurogenesis and Cognitive function in Aged Animals." Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/3712.
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Studies have shown that there is a strong correlation between aging and neurodegenerative diseases. Aging is considered the number one risk factor to develop neuropathologies such as memory loss, senile dementia, Alzheimer's disease (AD), and Parkinson's disease. Neurodegenerative diseases tend to start during adulthood, and aggravate over time, making them difficult to prevent and to treat. In the Unites States, demographic studies by U.S. Bureau of the Census have determined that our aging population of >65 years is expected to increase from the present 35 million to 78 million in 2030. This would result, not only to an increase of age-related chronic illness, and mental disability, but to a decrease of quality of life, and an elevation of medical cost. Thus, this dissertation has focused on investigating the molecular mechanisms during the process of aging and its correlation to chronic inflammation and cognitive impairments. The etiology of neurodegenerative diseases is not very well understood, but research has shown that the process of aging is a key factor, which involved oxidative stress, an over reactive microglia, and increased production of pro-inflammatory cytokines. All these factors are known to decrease cell proliferation, which limit neuroplasticity and they might lead the transition from normal aging to more severe cognitive dysfunction associated with neurodegenerative diseases. Previously, we have shown that natural compounds such as polyphenols from blueberry, and green tea, and amino acids like carnosine are high in antioxidant and anti-inflammatory activity that decreases the damaging effects of reactive oxygen species (ROS), in the blood, brain, and other tissues of the body. Therefore, we examined the hypothesis that the pro-inflammatory cytokine TNF-[U+F061] may be a critical factor that modulates classical conditioning behavior, the effects of NT-020 on adult neurogenesis, inflammatory markers of the CNS, and the effect of NT-020 on cognitive function as shown using spatial navigation task. The results show that in aged rats, endogenous production of pro-inflammatory cytokine TNF-α impairs the acquisition of learning and memory consolidation in the delay eyeblink classical conditioning task (EBC). It was shown that this effect can be replicated by infusing young rats with exogenous TNF-α prior to EBC. Using NT-020 as a dietary supplement for one month, it was found that NT-020 ameliorates the age-related impairments typically found in aged rats in the spatial navigation tasks Morris water maze and radial arm water maze. By looking at immunohistochemistry analysis, it was found a decreased number of OX6 MHC II positive cells, increased neurogenesis, and increased number of proliferating cells in the dentate gyrus (DG) of the hippocampus in the aged rats fed with NT-020 relative with their counterpart aged control. In the CNS, Inflammatory markers were analyzed, and it was found that aged rat fed with NT-020 supplemented diet has decrease levels of pro-inflammatory cytokines in compared with aged rats fed with NIH-31 control diet. In conclusion, TNF-α, a pro-inflammatory cytokine has shown to have a modulatory effect during classical conditioning. Moreover, NT-020 may promote a healthy CNS milieu, proliferation of neuronal progenitors, and maintenance of nature neurons in the aged rats and it might exert anti-inflammatory actions which promote a functional stem cell pool in the CNS of aged rats.
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Nicholas, Courtney. "The Anti-Inflammatory Mechanisms of the Flavonoid Apigenin In Vitro and In Vivo." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259783472.
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Labzin, Larisa [Verfasser]. "Investigating the molecular mechanism of the anti-inflammatory effects of High Density Lipoprotein in macrophages / Larisa Labzin." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1077289634/34.
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Borges, Alexandre [UNESP]. "Estudos de modelagem molecular de lignanas em complexos com ciclooxigenases-1 e 2." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/140137.
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Os inibidores seletivos da ciclooxigenase-2 (COX-2), como o rofecoxibe (2) e o celecoxibe (1), formam uma importante classe de medicamentos anti-inflamatórios desenvolvidos a partir da descoberta das duas isoformas das ciclooxigenases (COX-1 e COX-2) na década de 1979. A isoforma 1 esta relacionada com a citoproteção gástrica, agregação plaquetária e função renal e a isoforma 2 relacionada a processos inflamatórios. Estes inibidores seletivos apesar de não apresentarem os efeitos colaterais (ulceras e gastrites) dos anti-inflamatórios não esteroidais (AINEs) clássicos por inibirem apenas a COX-2, apresentam grave risco cardiovascular, o que motivou à retirada do rofecoxibe do mercado. Porém, por ser um eficiente inibidor seletivo da COX-2 a estrutura do rofecoxibe tornou-se referência no estudo de novas substâncias capazes de inibir seletivamente a COX-2. Dentre as ferramentas utilizadas na busca destas novas estruturas está a modelagem molecular através de programas como o GOLD 5.1, que foi utilizado neste trabalho. O uso do GOLD 5.1 possibilitou o estudo do comportamento das estruturas avaliadas em ligação com as ciclooxigenases. O objetivo foi obtenção de estruturas com comportamento semelhante ao rofecoxibe (em relação às COXs) como potenciais candidatos ao desenvolvimento de novos inibidores seletivos para a COX-2. O estudo foi realizado com 480 estruturas modeladas a partir de lignanas naturais como a hinoquinina, cubebina, deoxipodofilotoxina e podofilotoxina, que apresentam atividade anti-inflamatória in vivo ou in vitro, além de semelhanças estruturais com o rofecoxibe. A deoxipodofilotoxina por apresentar seletividade para a COX-2 em ensaio in vitro também foi utilizada como estrutura de referência além do rofecoxibe. Os resultados observados a partir da simulação molecular permitiram concluir que embora tanto o rofecoxibe como a deoxipodofilotoxina (3) inibam seletivamente a COX-2 in vitro, o fazem de modo diferente. Em relação a COX-2 as duas estruturas ocupam a mesma região do sítio ativo, mas o rofecoxibe apresenta interações mais fortes com o bolso hidrofílico desta isoforma (condição necessária para a inibição seletiva para os coxibes). Já para a COX-1 enquanto o rofecoxibe ocupa a porção superior do canal hidrofóbico (sítio ativo) como os demais AINEs, a deoxipodofilotoxina ocupa uma região vizinha. Pelos resultados obtidos é possível sugerir que tanto a maior flexibilidade das estruturas como a presença do anel lactônico, são importantes para um comportamento análogo ao rofecoxibe ou à deoxipodofilotoxina. Com relação à interação com o bolso hidrofílico da COX-2, os resultados sugerem que a presença de grupos aceptores de prótons menos volumosos nas posições C3 e C4, C3’ e C4’ ou C4 levam a resultados melhores que grupos aceptores de maior volume. A presença de grupos doadores de prótons apesar de permitirem forte interação com o bolso hidrofílico da COX-2 leva a resultados globais insatisfatórios, pois formam interações fortes com o resíduo Arg120 do sítio ativo da COX-1, interação considerada importante para a inibição não seletiva. Resultado semelhante à deoxipodofilotoxina foi observado apenas para a estrutura 17. As estruturas 37, 188, 266, 267, 348 e a hinoquinina (4) apresentam resultados semelhantes ao rofecoxibe, para as duas isoformas. Deste modo permite-se sugerir a partir dos resultados obtidos neste estudo que a hinoquinina (4) e as estruturas 17, 37, 188, 266, 267 e 348 apresentam-se como possíveis protótipos de fármacos que atuem como inibidores seletivos para a COX-2.
The selective inhibitors of the cyclooxygenase-2 (COX-2) as rofecoxib (2) and celecoxib (1), form an important class of anti-inflammatory drugs developed from the discovery of two isoforms of cyclooxygenases (COX-1 and COX-2) in the late 1979. Isoform 1 is related to the gastric cytoprotection, platelet and renal function and isoform 2 related to inflammatory processes. These selective inhibitors although they did not side effects (ulcers and gastritis) of the classic NSAIDs to inhibit only COX-2, have severe cardiovascular risk, which led to the withdrawal of rofecoxib from the market. However, to be an effective selective COX-2 to rofecoxib structure has a reference in the study of new substances capable of selectively inhibiting COX-2. Among the tools used in the search of these new structures is by molecular modeling program such as GOLD 5.1, which was used in this work. Using GOLD 5.1 made it possible to study the behavior of structures evaluated in binding with the cyclooxygenases. With the objective of obtaining structures with similar behavior to rofecoxib (regarding behavior with COX) as potential candidates for the development of new selective inhibitors for COX-2. The study was conducted with 480 structures modeled from natural lignans as hinokinin, cubebin, deoxypodophyllotoxin and podophyllotoxin, which have anti-inflammatory activity in vivo or in vitro as well as structural similarities with rofecoxib. The deoxypodophyllotoxin for presenting selectivity for COX-2 in the in vitro assay was also used as a reference structure beyond rofecoxib. The results observed from the molecular simulation showed that although both rofecoxib (2) as deoxypodophyllotoxin (3) selectively inhibit COX-2 in vitro, they do differently. In relation to COX-2 the two structures occupy the same region of the active site, but rofecoxib has stronger interactions with the hydrophilic pocket of this isoform (a necessary condition for the selective inhibition for coxibs). As for the COX-1 while rofecoxib occupies the upper portion of the hydrophobic channel (active site) like other NSAIDs, the deoxypodophyllotoxin occupies a neighboring region. From the results it is possible to suggest that the greater flexibility of the structures such as the presence of the lactone ring, are important for a similar behavior to rofecoxib or deoxipodofilotoxina. With respect to the interaction with the hydrophilic pocket COX-2, the results suggest that the presence of acceptors groups less bulky protons in posítions C3 and C4, C3 ' and C4' and C4 lead to better results than acceptors groups of larger volume. The presence of proton donors groups despite allowing strong interaction with the hydrophilic pocket COX-2 lead to poor overall results, since they form strong interactions with Arg120 residue of COX-1 active site, considered important interaction for inhibiting non-selective. Results similar to deoxipodofilotoxina was only observed for structure 17. Structures 37, 188, 266, 267, 348 and hinokinin (4) show results similar to rofecoxib for the two isoforSA. Thus it allows suggest from the results obtained in this study hinokinin (4) and structures 17, 37, 188, 266, 267 and 348 are shown as possible prototype drugs that act as selective inhibitors for COX-2.
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Borges, Alexandre. "Estudos de modelagem molecular de lignanas em complexos com ciclooxigenases-1 e 2 /." Ilha Solteira, 2016. http://hdl.handle.net/11449/140137.
Full textAbstract:
Orientador: Rosangela da Silva de LaurentizResumo: Os inibidores seletivos da ciclooxigenase-2 (COX-2), como o rofecoxibe (2) e o celecoxibe (1), formam uma importante classe de medicamentos anti-inflamatórios desenvolvidos a partir da descoberta das duas isoformas das ciclooxigenases (COX-1 e COX-2) na década de 1979. A isoforma 1 esta relacionada com a citoproteção gástrica, agregação plaquetária e função renal e a isoforma 2 relacionada a processos inflamatórios. Estes inibidores seletivos apesar de não apresentarem os efeitos colaterais (ulceras e gastrites) dos anti-inflamatórios não esteroidais (AINEs) clássicos por inibirem apenas a COX-2, apresentam grave risco cardiovascular, o que motivou à retirada do rofecoxibe do mercado. Porém, por ser um eficiente inibidor seletivo da COX-2 a estrutura do rofecoxibe tornou-se referência no estudo de novas substâncias capazes de inibir seletivamente a COX-2. Dentre as ferramentas utilizadas na busca destas novas estruturas está a modelagem molecular através de programas como o GOLD 5.1, que foi utilizado neste trabalho. O uso do GOLD 5.1 possibilitou o estudo do comportamento das estruturas avaliadas em ligação com as ciclooxigenases. O objetivo foi obtenção de estruturas com comportamento semelhante ao rofecoxibe (em relação às COXs) como potenciais candidatos ao desenvolvimento de novos inibidores seletivos para a COX-2. O estudo foi realizado com 480 estruturas modeladas a partir de lignanas naturais como a hinoquinina, cubebina, deoxipodofilotoxina e podofilotoxina, que apre... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The selective inhibitors of the cyclooxygenase-2 (COX-2) as rofecoxib (2) and celecoxib (1), form an important class of anti-inflammatory drugs developed from the discovery of two isoforms of cyclooxygenases (COX-1 and COX-2) in the late 1979. Isoform 1 is related to the gastric cytoprotection, platelet and renal function and isoform 2 related to inflammatory processes. These selective inhibitors although they did not side effects (ulcers and gastritis) of the classic NSAIDs to inhibit only COX-2, have severe cardiovascular risk, which led to the withdrawal of rofecoxib from the market. However, to be an effective selective COX-2 to rofecoxib structure has a reference in the study of new substances capable of selectively inhibiting COX-2. Among the tools used in the search of these new structures is by molecular modeling program such as GOLD 5.1, which was used in this work. Using GOLD 5.1 made it possible to study the behavior of structures evaluated in binding with the cyclooxygenases. With the objective of obtaining structures with similar behavior to rofecoxib (regarding behavior with COX) as potential candidates for the development of new selective inhibitors for COX-2. The study was conducted with 480 structures modeled from natural lignans as hinokinin, cubebin, deoxypodophyllotoxin and podophyllotoxin, which have anti-inflammatory activity in vivo or in vitro as well as structural similarities with rofecoxib. The deoxypodophyllotoxin for presenting selectivity for COX... (Complete abstract click electronic access below)
Doutor
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Lu, Pinyi. "Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/64370.
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Lanthionine synthetase C-like protein 2 (LANCL2) is a member of the LANCL protein family, which is broadly expressed throughout the body. LANCL2 is the molecular target of abscisic acid (ABA), a compound with insulin-sensitizing and immune modulatory actions. LANCL2 is required for membrane binding and signaling of ABA in immune cells. Direct binding of ABA to LANCL2 was predicted in silico using molecular modeling approaches and validated experimentally using ligand-binding assays and kinetic surface plasmon resonance studies. The therapeutic potential of the LANCL2 pathway ranges from increasing cellular sensitivity to anticancer drugs, insulin-sensitizing effects and modulating immune and inflammatory responses in the context of immune-mediated and infectious diseases. A case for LANCL2-based drug discovery and development is also illustrated by the anti-inflammatory activity of novel LANCL2 ligands such as NSC61610 against inflammatory bowel disease in mice. This dissertation discusses the value of LANCL2 as a novel therapeutic target for the discovery and development of new classes of orally active drugs against chronic metabolic, immune-mediated and infectious diseases and as a validated target that can be used in precision medicine.
Specifically, in Chapter 2 of the dissertation, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of LANCL1 as a template. Our molecular docking studies predicted that ABA and other PPAR - agonists share a binding site on the surface of LANCL2.
In Chapter 3 of the dissertation, structure-based virtual screening was performed. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis.
In Chapter 4 of the dissertation, we developed a novel integrated approach for creating a synthetic patient population and testing the efficacy of the novel pre-clinical stage LANCL2 therapeutic for Crohn's disease in large clinical cohorts in silico. Efficacy of treatments on Crohn's disease was evaluated by analyzing predicted changes of Crohn's disease activity index (CDAI) scores and correlations with immunological variables were evaluated. The results from our placebo-controlled, randomized, Phase III in silico clinical trial at 6 weeks following the treatment shows a positive correlation between the initial disease activity score and the drop in CDAI score. This observation highlights the need for precision medicine strategies for IBD.Ph. D.
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Abrantes, Vanessa Erika Ferreira. "A modelagem molecular da proteína pha-like de Acacia Farnesiana revela mecanismo anti-inflamatório." Universidade Federal da Paraíba, 2013. http://tede.biblioteca.ufpb.br:8080/handle/tede/3655.
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Previous issue date: 2013-02-21Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Lectins are proteins or glycoproteins of non-immune origin that have at least one non-catalytic site which binds reversibly to carbohydrates and glycoconjugates, which makes them ideal models for studies of cell-cell interactions and cell-virus, being good models for the design of new drugs. Some carbohydrate-binding proteins resembling the lectins but with some structural and functional differences, that exclude of this group. The Fabaceae Acacia farnesiana has in its seeds an agglutinin chitin-binding (AFAL), classified as PHA-like1. Its standard chromatographic revealed time-dependent oligomerization. This dynamic behavior complicates the protein crystallization and determining of the three dimensional structure. To better understand the structure-function relationship, this study aimed to examine AFAL anti-inflammatory activity through structural comparison with legume lectins. For both, it was the molecular modeling and docking with a glycan and carrageenan. AFAL model is folded as a β sandwich, which differs from the template used (Pisum sativum lectin) in loop regions, number of β-sheets and carbohydrate site. The docking showed that the protein binds to the carrageenan and glycan at different sites, which can be explained by absence of the sixth β-sheet (frontal β-sheets) and two β-sheets in posterior region. The A. farnesiana agglutinin can inhibit carrageenan induced inflammation due binding it, preventing its entrance into the cell and triggers the inflammatory process reactions.
Lectinas são proteínas e/ou glicoproteínas de origem não imune que possuem, no mínimo, um sítio não-catalítico que se liga de forma reversível a carboidratos e glicoconjugados, o que as tornam modelos ideais de estudos de interações célula-célula, célula-vírus, sendo bons modelos para o desenho de novos fármacos. Algumas proteínas possuem capacidade de se ligar a carboidratos, assemelhando-se às lectinas, porém com algumas diferenças estruturais e funcionais, que as excluem desse grupo. A Fabaceae Acacia farnesiana possui em suas sementes uma aglutinina ligante de quitina (AFAL), classificada como PHA-like1. Seu padrão cromatográfico revelou oligomerização tempo-dependente. Esse comportamento dinâmico dificulta a cristalização dessa proteína, bem como determinação da estrutura tridimensional. Visando compreender melhor a relação estrutura-função, este trabalho teve por objetivo analisar a atividade anti-inflamatória de AFAL através de comparação estrutural com lectinas de leguminosas. Para tanto, fez-se a modelagem e docking molecular com um glicano e a carragenina. A AFAL apresentou um modelo dobrado como um sanduiche de folhas β, que difere do molde utilizado (lectina de Pisum sativum) em regiões de loops, no número de folhas β e no sítio de ligação à carboidratos. O docking revelou que a proteína se liga à carragenina e ao glicano em sítios diferentes, o que pode ser explicado pela ausência de uma sexta folha β frontal e de duas folhas β na região posterior. A aglutinina de A. farnesiana pode inibir a inflamação causada por carragenina, por se ligar a ela, impedindo sua entrada na célula e o desencadeamento de reações típicas do processo inflamatório.
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Shamsudin, Khan Yasmin. "Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2 : Binding modes and mechanisms from computational methods and free energy calculations." Doctoral thesis, Uppsala universitet, Beräkningsbiologi och bioinformatik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328478.
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Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of drugs. They target the cyclooxygenases (COX) 1 and 2 to reduce the physiological responses of pain, fever, and inflammation. Due to their role in inducing angiogenesis, COX proteins have also been identified as targets in cancer therapies. In this thesis, I describe computational protocols of molecular docking, molecular dynamics simulations and free energy calculations. These methods were used in this thesis to determine structure-activity relationships of a diverse set of NSAIDs in binding to their target proteins COX-1 and 2. Binding affinities were calculated and used to predict the binding modes. Based on combinations of molecular dynamics simulations and free energy calculations, binding mechanisms of sub-classes of NSAIDs were also proposed. Two stable conformations of COX were probed to understand how they affect inhibitor affinities. Finally, a brief discussion on selectivity towards either COX isoform is discussed. These results will be useful in future de novo design and testing of third-generation NSAIDs.
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Du, Bin. "Effect of molecular weight and structure on anti-inflammatory properties of polysaccharide from submerged mycelial fermentation of schizophyllum commune /Du Bin." HKBU Institutional Repository, 2016. https://repository.hkbu.edu.hk/etd_oa/363.
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Medicinal mushrooms are therapeutic agents in traditional folk medicines. Previous studies have shown that a number of biologically active compounds in medicinal mushrooms contributed therapeutic functions against many diseases. These compounds include mainly large molecular weight (MW) compounds such as polysaccharides, dietary fibre and lipids. Mushroom polysaccharides have attracted great attention in food and pharmacology fields because of their biological activities. Polysaccharides vary in molecular weight, degree of branching and conformational structure. It has been reported that fine structure, molecular weight, and conformation of polysaccharide influence biological activities. The incidence and prevalence of inflammatory bowel disease (IBD) have been increasing worldwide, which is characterized by chronic inflammation of the gastrointestinal tract but without satisfactory treatment. Although there are many studies for the immuno-pharmacological activity of mushroom polysaccharides, their intestinal anti-inflammatory property has not been investigated sufficiently. Therefore, it is very important to elucidate whether there is the relationship among the MW, structure and anti-inflammatory activity of polysaccharide in IBD. Firstly, an exopolysaccharide from a mycelial culture of S. commune was obtained by isolation and purification using DEAE-52 cellulose and Sephadex G-150 column chromatography. The structure, conformation and chemical properties were investigated, including elemental compositions, MW, monosaccharide compositions, fourier transform infrared spectrum, thermogram analysis, nuclear magnetic resonance (NMR) spectrum, circular dichroism (CD) study, methylation analysis, and scanning electron microscope (SEM). The findings indicate that the exopolysaccharide is a homogeneous protein-bound heteropolysaccharide carrying molecular weight of 2900 kDa with a β-type glycosidic linkage. It belongs to a kind of β-(13)-D-glucans consisting of a backbone of β-(13)-linked glucose residues branched with (14) and (16)-β-D-glucopyranosyl residues on main-chain residues. The elemental analysis of this exopolysaccharide discover the element compositions as: C, 25.84%; H, 5.45%; and N, 0.65%. The total carbohydrate, protein and uronic acid contents of exopolysaccharide is 89.0%, 2.20% and 7.52%, respectively. In addition, lipopolysaccharide (LPS) was not detected in the exopolysaccharide. Glucose is the main monosaccharide structural unit in this exopolysaccharide, the content is 57.5%. The degradation temperature of exopolysaccharide is 278.9°C from the thermogram analysis curve. This exopolysaccharide looks like thin film with smooth and glittering surface in SEM photography. It is clear from these images that the exopolysaccharide is linear in structure and branched and coiled in aqueous solution. With these extraction, the preliminary anti-inflammatory activity of S. commune exopolysaccharide was conducted by inhibiting the production of nitric oxide (NO), activity of inducible nitric oxide synthase (iNOS) and activity of 5-lipoxygenase (5-LOX) from RAW 264.7 macrophages. The results showed that exopolysaccharide significantly inhibit LPS-induced iNOS expression levels in a dose-dependent manner(p < 0.05). It inhibits the production of 5-LOX in cells, but not in dose-dependence. Further, in dextran sulfate sodium (DSS)-induced colitis model, the results showed that exopolysaccharide attenuated body weight loss, diarrhea, fecal blood, and the shortening of colon and improved histological changes. Furthermore, exopolysaccharide treatment would reduce NO production and some cytokines' secretion such as IL-4 and IL-17A. These results indicate that exopolysaccharide might be exploited as an effective anti-inflammatory agent for application in IBD. Secondly, ultrasound technology was applied to modify the physicochemical properties (MW and viscosity) of this fungal exopolysaccharide, and fractions of different MWs were obtained through ultrasonic degradation method. Effect of the MW degradation, viscosity and anti-inflammatory property of exopolysaccharide under ultrasonic treatment were optimized with response surface methodology. The best ultrasonic treatment parameters were obtained with a three-variable-three-level Box-Behnken design. The optimized conditions for efficient anti-inflammatory activity include: Initial concentration - 0.4%; ultrasonic power - 600 W; and duration of ultrasonic treatment - 9 min. Under these conditions, the NO inhibition rate is 95 ± 0.03% which agreed closely with the predicted value (96%). Average MW of exopolysaccharide decreased after ultrasonic treatments, but no significant change in the preliminary structure by infrared spectroscopy analysis. The viscosity of degraded exopolysaccharide dropped compared with native exopolysaccharide. The results suggest that ultrasound technology is an effective approach to reduce the MW of exopolysaccharide. Our results also showed that exopolysaccharide from S. commune was degraded into three fractions (low, medium, and high MW) by ultrasonic treatment. The changes of MW, atomic force microscope morphology, X-ray diffraction, particle size distribution and viscosity analysis indicate the triple helical structure of exopolysaccharide was dissociated into single helical structure and random coiled structure by breaking of inter- and intramolecular hydrogen bonds. The medium and high MW exopolysaccharide had the mixture of triple helix and single helix conformation. Moreover, the low MW exopolysaccharide exhibit random coiled conformation. As for their anti-inflammatory effect in DSS-induced colitis mice model, the results showed that medium and high MW exopolysaccharide significantly recovered DSS-induced colitis in body weight loss, shortening of colon lengths, colon weight loss, diarrhea and rectal bleeding, histological score, myeloperoxidase (MPO) activity, NO and cytokines (IFN-γ, IL-10 and IL-17) production in inflamed tissues. Moreover, exopolysaccharide with medium and high MW reduced DSS-induced infiltration of macrophages. These results showed that medium and high MW exopolysaccharide had intestinal anti-inflammatory activity. The degraded exopolysaccharide with medium and high MW had a triple and single-helical structure. These results suggested that the intestinal anti-inflammatory activity of exopolysaccharide from S. commune is related to both helical structure and MW.
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Alanazi, Samyah T. "The effects of small molecule analogues of the anti-inflammatory parasitic worm product ES-62 on the metabolome of mouse bone marrow-derived macrophages." Thesis, University of Strathclyde, 2018. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=30466.
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Lipopolysaccharide (LPS) and Cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) cause macrophages to produce the proinflammatory cytokines IL-12, IL-6 and TNF-α. Pre-treatment of the macrophages with ES-62, an anti-inflammatory glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae suppresses the production of these cytokines. Although able to prevent disease development in mouse models of allergy and autoimmunity, ES-62 is not suitable for drug therapy due to its potential immunogenicity. A library of small molecule analogues (SMAs) therefore was designed and tested for the previously mentioned inhibitory effects. SMAs 11a and 12b among library members were found to mimic ES-62’s anti-inflammatory effects. These findings rationalised further testing in order to determine their mechanism of action based on their effects on the metabolome of primary macrophages. From analysis of cellular extracts using hydrophilic interaction chromatography in combination with high resolution mass spectrometry it could be seen that stimulation of macrophages with either LPS or CpG produced metabolic changes in various pathways. Stimulation of macrophages with LPS or CpG in the presence of SMAs 11a and 12b revealed that many of the metabolic shifts were the same as observed with LPS and CpG alone. However, there were clear effects of the SMAs in producing downregulation in creatine metabolism/uptake and upregulation in glutathione biosynthesis. By downregulating creatine metabolism/uptake, the SMAs may be controlling the availability of creatine for transporting high energy phosphate from the mitochondria to where it is required for biological functions including cell signalling, phagocytosis and motility. By causing an upregulation of the glutathione biosynthesis pathway the SMAs may be protecting the cells from oxidative stress and of note SMA12b has been previously linked to increased activity of the Nrf2/ARE/HO-1 anti-oxidant pathway. The SMAs may be downregulating the availability of the energy produced by oxidative phosphorylation in general without targeting the TCA cycle directly since they do not affect NADH levels in comparison with LPS or CpG stimulation alone. Finally, in the process of examining the response of the cells to LPS and CpG additional potential anti-inflammatory targets were revealed.
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Large, Martin [Verfasser], Franz [Akademischer Betreuer] Rödel, Markus [Akademischer Betreuer] Löbrich, and Bodo [Akademischer Betreuer] Laube. "Cellular and molecular aspects of the anti-inflammatory effects of low-dose radiation therapy / Martin Large. Betreuer: Franz Rödel ; Markus Löbrich ; Bodo Laube." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2015. http://d-nb.info/1112268855/34.
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Jacobo-Herrera, Nadia Judith. "Anti-inflammatory properties and bioactive natural products from Witheringia solanacea, Withania frutescens (Solanaceae) and Valeriana officinalis (Valerianaceae) using NF-kappa as a molecular target." Thesis, University College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420313.
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Santos, Bruna Celeida Silva. "Síntese e modelagem molecular de análogos do metil chavicol e seus potenciais farmacológicos." Universidade Federal de Juiz de Fora (UFJF), 2017. https://repositorio.ufjf.br/jspui/handle/ufjf/6070.
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Metil chavicol é um fenilpropanoide encontrado em óleos essenciais e suas atividades antimicrobiana, anti-inflamatória, anestésica local e inseticida têm sido destacadas. O objetivo deste estudo foi sintetizar e avaliar o perfil de interação molecular do metil chavicol e análogos, assim como investigar as atividades antioxidante, antilipidêmica e anti-inflamatória tópica usando métodos in vivo, in vitro e in silico. A síntese dos análogos foi realizada por reações clássicas da química orgânica. A atividade antioxidante foi determinada pelos métodos DPPH e peroxidação lipídica, enquanto o efeito antilipidêmico foi testado contra a enzima lipase pancreática. O efeito anti-inflamatório tópico foi avaliado pelo método de edema de orelha usando óleo de Cróton, fenol e histamine como agentes irritantes. Análises histopatológicas e ensaios de mieloperoxidase (MPO), N-acetil-β-D-glicosaminidase (NAG), óxido nitrico, fator necrose tumoral (TNF-α), interleucina 6 (IL-6) e ciclooxigenase in vitro foram realizados. Os ligantes foram gerados pelo Programa Marvin Sketch e refinado por método PM7 presente no Programa MOPAC2012. As enzimas foram obtidas do Protein Data Bank sob os códigos 1EQG e 5IKT (COX-1 e -2), 1R35 (iNOS) e 1LPA (lipase pancreática). O reconhecimento molecular foi definido usando o programa Discovery Studio v 4.5 2016. 2-[(4-metoxifenil)metil] oxirano (2), 3-(4-metoxifenil)propan-1,2-diol (8), 2-metoxi-3-(4 metoxifenil)propan-1-ol (10), 1-metoxi-3-(4 metoxifenil)propan-2-ol (17) e 3-(4-metoxifenil)propanal (18) foram os análogos sintetizados. Metil chavicol reduziu significativamente (p < 0,001) a espessura e a massa do edema de orelha induzido por óleo de Cróton, fenol e histamina. Houve uma redução significativa de mieloperoxidase, N-acetil-β-D-glicosaminidase, óxido nítrico, fator necrose tumoral (TNF-α) e interleucina 6 (IL-6). Metil chavicol foi incapaz de inibir COX-1 e -2 em estudo in vitro e o docking molecular mostrou ausência de interação, incluindo os análogos 2, 8, 17 e 18. Além disso, os estudos in vitro e de docking molecular revelaram que o metil chavicol e seus análogos inibiram a enzima lipase pancreática. Os resultados obtidos sugerem que o metil chavicol e seus análogos são promissores agentes terapêuticos que podem ser utilizados em doenças associadas a processos inflamatórios, oxidativos e metabólicos.
Methyl chavicol is a phenylpropanoid found in essential oils and its antimicrobial, anti-inflammatory, local anesthetic and insecticide activities have been highlighted. The objective of this study was to synthesize and evaluate the molecular interaction profile of the methyl chavicol and analogues, as well as to investigate the antioxidant, antilipidemic and topical anti-inflammatory activities using in vivo, in vitro and in silico methods. Synthesis of the analogues was performed by classical reactions of organic chemistry. Antioxidant activity was determined by DPPH and lipid peroxidation methods, while the antilipidemic effect was essayed against to pancreatic lipase. Anti-inflammatory activity was evaluated using Croton oil-, phenol-, and histamine-induced ear edema models in mice. Histopathological analyzes and the myeloperoxidase (MPO), N-acetyl-β-D-glucosaminidase (NAG), nitric oxide, tumor necrosis tumor (TNF-α), interleukin 6 (IL-6) and cyclooxygenase assays were determined. The bindings were generated by the Marvin Sketch Program and refined by PM7 method present in the MOPAC2012 Program. Enzymes were obtained from protein database under 1EQG and 5IKT (COX-1 and -2), 1R35 (iNOS) and 1LPA (pancreatic lipase) codes. Molecular recognition was determined using the program Discovery Studio v 4.5 2016. 2 - [(4-methoxyphenyl) methyl] oxirane (2), 3-(4-methoxyphenyl) propane-1,2-diol (8), 2- Methoxy-3-(4-methoxyphenyl) propan-1-ol), 1-methoxy-3-(4-methoxyphenyl) propan-2-ol (17) and 3-(4-methoxyphenyl) propanal (18) were the synthesized analogues. Methyl chavicol significantly decreased the thickness and mass of ear edema induced by irritants (p < 0.001). A significant reduction on myeloperoxidase, N-acetyl-β-D-glucosaminidase, nitric oxide, tumor necrosis tumor (TNF-α) and interleukin 6 (IL-6) was revealed (p < 0.05, p < 0.01 or p < 0.001). Methyl chavicol was unable to inhibit COX-1 and-2 in in vitro test and the molecular docking showed no interaction, including the analogues 2, 8, 17 and 18. In addition, molecular docking showed an inhibitory effect of the methyl chavicol and its analogues on the pancreatic lipase. The results indicate that methyl chavicol and its analogues are promising therapeutic agents that can be used in diseases associated with inflammatory, oxidative and metabolic processes.
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GOMES, Marcelo do Nascimento. "Planejamento, síntese e avaliação farmacológica de novos candidatos a protótipos de fármacos anti-inflamatórios." Universidade Federal de Goiás, 2009. http://repositorio.bc.ufg.br/tede/handle/tde/2136.
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Previous issue date: 2009-06-15In the field of a research line that seeks the planning, the synthesis and the pharmacologycal evaluation of new candidates to prototypes of anti-inflammatory drugs, we will describe in this project the planning of derived new pyrazolics (LQFM 002-003), originally drawn starting from the nerolidilcatecol (24) and arylsulfonilpiperazines, (25) that present profile inhibition of the enzyme sPLA2. The compounds (E)-N-(3,7-dimethylocta-2,6-dienyl)-1,3-dimethtyl-1-H-pyrazol-5-amine (LQFM 002) and (E)-N-(3,7-dimethylocta-2,6-dienyl)-1,3-dimethyl-4-((4-methylpiperazin-1-il) methyl)-1H-pyrazol-5-amine (LQFM 003), were submitted to pharmacologycal rehearsals in vitro, seeking to evaluate the enzymatic inhibition activity of the sPLA2. For the prototype (LQFM 002) the inhibition halos were 14,43 ± 6,28%, 16,68 ± 2,45%, 23,61 ± 2,62%, 37,06 ± 3,25%, in the doses of 250, 500, 1000 and 2000 μg/mL respectively. For the compound (LQFM 003), the halos were 1,85 ± 1,38%, 9,29 ± 3,33%, 7,82 ± 3,32%, 13,21 ± 3,22%, respectively. Subsequently the rehearsal in vivo was accomplished to evaluate the profile of cellular migration. Being also analyzed the concentration of plasmatic protein by the methodology of the Evans of blue once the inflammatory process was induced. The compound (LQFM 002) presented inhibition on cellular migration of 50,46 ± 14,34% in the peritonit test, 68,7 ± 2,65% in the pleurisy test and reduction of 40,1 ± 6,40% of the plasmatics proteins for the method of coloration of the Evans of blue. The compound (LQFM 003) presented 25,89 ± 5,39% inhibition, in the doses of 50 mg/Kg, characterizing, significant anti-inflammatory profile for the prototype (LQFM 002). Parallel to the pharmacologycal synthetic work and, we carried out theoretical studies through the application of molecular dynamics. The parameters of the enzyme sPLA2 was more effective through the applications of the water box's, once the smaller state energy observed was of -175000kcal/mol. At the end of this project, we can conclude that the structural planning applied in the project was validated through the applications of the pharmacologycal rehearsals, once both molecules were recognized by the enzyme sPLA2 and they presented anti-inflammatory activity in the rehearsal of cellular migration. In addition, the applied synthetic methodology for obtaining of the prototypes pyrazolics (LQFM 002-003) studied was satisfatory.
No âmbito de uma linha de pesquisa que visa o planejamento, a síntese e a avaliação farmacológica de novos candidatos a protótipos de fármacos anti-inflamatórios, descreveremos neste trabalho o planejamento de novos derivados pirazólicos (LQFM 002-003), originalmente desenhados a partir do nerolidilcatecol (24) e arilsulfonilpiperazínicos (25), que apresentam perfil inibitório da enzima sPLA2. Os compostos (E)-N-(3,7-dimetilocta-2,6-dienil)-1,3-dimetil-1-H-pirazol-5-amina (LQFM 002) e (E)-N-(3,7-dimetilocta-2,6-dienil)-1,3-dimetil-4-((4-metilpiperazina-1-il) metil)-1H-pirazol-5-amina (LQFM 003), foram submetidos a ensaios farmacológicos in vitro, visando avaliar a atividade de inibição enzimática da sPLA2. Para o protótipo LQFM 002 os halos de inibição foram 14,43 ± 6,28%, 16,68 ± 2,45 %, 23,61 ± 2,62 %, 37,06 ± 3,25 %, nas doses de 250, 500, 1000 e 2000 μg/mL respectivamente. Para o composto LQFM 003, os halos foram 1,85 ± 1,38 %, 9,29 ± 3,33 %, 7,82 ± 3,32 %, 13,21 ± 3,22 %, respectivamente. Posteriormente foram realizados os ensaios in vivo o qual avalia o perfil de migração celular para cavidade peritoneal e pleural. Sendo também analisada a concentração de proteína plasmática pela metodologia do azul de Evans quando induzido o processo inflamatório. O composto LQFM 002 apresentou inibição sobre a migração celular de 50,46 ± 14,34 % no teste de peritonite, 68,7 ± 2,65 % no teste de pleurisia e redução de 40,1 ± 6,40 % das proteínas plasmáticas pelo método de coloração do azul de Evans. O composto LQFM 003 apresentou inibição de 25,89 ± 5,39%, nas doses de 50 mg/Kg, caracterizando, desta forma, perfil anti-inflamatório significativo para o protótipo (LQFM 002). Paralelamente ao trabalho sintético e farmacológico, foi realizado estudos teóricos através do emprego de dinâmica molecular. A parametrização da enzima sPLA2 foi mais efetiva através do emprego de caixa de água, uma vez que o estado de menor energia observado foi de -175000kcal/mol. Ao término deste trabalho, podemos concluir que o planejamento estrutural empregado no mesmo foi validado através dos ensaios farmacológicos empregados, uma vez que ambas as moléculas foram reconhecidas pela enzima sPLA2 e apresentaram atividade anti-inflamatória no ensaio de migração celular. Ademais, a metodologia sintética empregada se mostrou satisfatória para a obtenção dos protótipos pirazólicos (LQFM 002 - 003) estudados.
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Silva, Daiany Priscilla Bueno da. "Atividade anti-inflamatória e antinociceptiva de 4-((1-fenil-1h-pirazol-4-il) metil) piperazina-1-carboxilato: um novo derivado piperazínico." Universidade Federal de Goiás, 2015. http://repositorio.bc.ufg.br/tede/handle/tede/5497.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
The piperazines derivatives are an important class of chemical compounds with a broad spectrum of biological activities such as anti-infectious activity, anti-carcinogenic, anti-nociceptive, anti-hypertensive, anxiolytic and vasorelaxant and are attractive candidates for development of new analgesics and anti-inflammatories drugs. The aim of this study was evaluate the effects of piperazine compound LQFM-008 (4-[(1-phenyl-1H-pyrazol-4-yl) methyl]1-piperazine carboxylic acid ethyl ester) in acute tests of nociception and inflammation and characterize that the mechanisms are involved in the antinociceptive effect. For this study were used male mice weighing between 25 and 35g. In the formalin test, the treatments with LQFM-008 at doses of 48 and 96 μmol/kg (p.o.) reduced the licking time at both neurogenic and inflammatory phases of this test. The anti-inflammatory activity was confirmed, since LQFM-008 at doses of 48 and 96 μmol/kg (p.o.) reduced the formation of paw edema induced by carrageenan at all hours of the test and LQFM-008 in pleurisy test at dose of 96 μmol/kg (p.o.) also reduced leukocyte migration and protein exudation. In the tail-flick and the hot plate tests, the treatment with LQFM-008 at doses of 48 and 96 μmol/kg (p.o.) increased the latency to thermal stimulus, suggesting the involvement of central mechanisms in the antinociceptive effect LQFM-008. The pre-treatment of animals with naloxone (7.5 μmol/kg s.c.) reversed the antinociceptive effect of LQFM-008 only in the first phase of the formalin test, however, the pre-treatment with NAN-190 (1.3 μmol/kg i.p.) and PCPA (500 μmol/kg i.p.) reversed the antinociceptive effect of LQFM-008 in both phases of the test. Thus, the piperazine derivative LQFM-008 exhibit antinociceptive and anti-inflammatory activities in acute test and the antinociceptive effect is resulting from a central action with involvement of opioid receptors and the serotonin pathway.
Os derivados piperazínicos constituem uma importante classe de compostos químicos com largo espectro de atividades biológicas, tais como atividade anti-infecciosa, anti-cancerígena, antinociceptiva, anti-hipertensiva, vasorrelaxante e ansiolítica, tornando-se candidatos atrativos para desenvolvimento de novos fármacos analgésicos e anti-inflamatórios. O objetivo do presente trabalho foi avaliar os efeitos do composto piperazínico LQFM-008 (4-((1-fenil-1H-pirazol-4-il) metil) piperazina-1-carboxilato) em testes agudos de nocicepção e inflamação, buscando caracterizar quais os mecanismos de ação estariam envolvidos no efeito antinociceptivo. Para este estudo foram utilizados camundongos machos, pesando entre 25 e 35g. No teste da formalina os tratamentos com LQFM-008 nas doses de 48 e 96 μmol/kg (v.o.) reduziram o tempo de reatividade à dor tanto na fase neurogênica quanto na fase inflamatória do teste. A atividade anti-inflamatória foi confirmada, uma vez que LQFM-008 nas doses de 48 e 96 μmol/kg (v.o.) reduziu a formação do edema de pata induzido por carragenina em todas as horas deste teste e no teste de pleurisia LQFM-008 na dose de 96 μmol/kg também reduziu a migração de leucócitos e a exsudação proteica. Nos testes de flexão de cauda e da placa quente, o tratamento com LQFM-008 48 e 96 μmol/kg (v.o.) aumentou a latência ao estímulo térmico, sugerindo o envolvimento de mecanismos centrais no efeito antinociceptivo de LQFM-008. O pré-tratamento dos animais com naloxona (7,5 μmol/kg s.c.) reverteu o efeito antinociceptivo de LQFM-008 apenas na primeira fase do teste da formalina, no entanto, os pré-tratamentos com NAN-190 (1,3 μmol/kg i.p.) e PCPA (500 μmol/kg i.p.) reverteram o efeito antinociceptivo de LQFM-008 em ambas as fases do teste. Assim o derivado piperazínico LQFM-008 apresenta atividade antinoceptiva e anti-inflamatória em testes agudos, sendo efeito antinociceptivo decorrente de uma ação central com envolvimento dos receptores opióides e da via serotoninérgica.
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Pereira, M?rcia de Oliveira. "Avalia??o de efeitos biol?gicos de antiinflamat?rios derivados do ?cido propi?nico atrav?s de modelos experimentais em n?vel molecular e celular." Universidade Federal do Rio Grande do Norte, 2010. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13319.
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Previous issue date: 2010-08-31Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
Derivatives of propionic acid NSAIDs are irreversible inhibitors of cyclooxygenase enzyme widely used. The aim of this study was to evaluate, through different experimental models, biological effects of derivatives of propionic acid (fenoprofen, naproxen, ibuprofen and ketoprofen) in cellular and molecular level. The labeling of blood constituents with technetium-99m (99mTc) and morphological analysis of erythrocytes of blood of rats, as well as growth, survival of cultures of Escherichia coli (E. coli) and the assessment of bacterial plasmid electrophoretic profiles were models used for experimental evaluation of possible biological effects of antiinflammatory drugs. The results show that, in general, anti-inflammatory drugs evaluated were not able to alter the labeling of blood constituents with 99mTc, the morphology of red blood cells from blood of rats, as well as the growth of cultures of E. coli and the electrophoretic profile of plasmid DNA. However, naproxen appears to cytotoxic effect on bacterial cultures, plasmids and genotoxic effects in reducing the action of stannous chloride in cultures of E. coli. The use of experimental fast performance and low cost was important for assessment of biological effects, contributing to a better understanding of the properties of propionic acid derivatives studied. anti-inflammatory, blood constituents, technetium-99m, stannous chloride, Escherichia coli; DNA
Os derivados do acido propi?nico s?o antiinflamat?rios n?o esteroidais inibidores irrevers?veis da enzima cicloxigenase amplamente utilizados. O objetivo deste trabalho foi avaliar, atrav?s de diferentes modelos experimentais, efeitos biol?gicos de derivados do ?cido propi?nico (fenoprofeno, naproxeno, ibuprofeno e cetoprofeno) em n?vel celular e molecular. A marca??o de constituintes sangu?neos com tecn?cio 99m (99mTc) e a an?lise morfol?gica de hem?cias de sangue de ratos Wistar, bem como, o crescimento, sobreviv?ncia de culturas de Escherichia coli (E. coli) e a avalia??o do perfil eletrofor?tico plasm?dios bacterianos, foram modelos experimentais utilizados para avalia??o de poss?veis efeitos biol?gicos dos antiinflamat?rios. Os resultados obtidos demonstram que, de modo geral, os antiinflamat?rios avaliados n?o foram capazes de alterar a marca??o de constituintes sangu?neos com 99mTc, a morfologia de hem?cias de sangue de ratos Wistar, assim como, o crescimento de culturas de E. coli e o perfil eletrofor?tico de plasm?dios. Entretanto, o naproxeno parece apresentar efeito citot?xico em culturas bacterianas, efeito genot?xico em plasm?dios e diminui??o da a??o do cloreto estanoso em culturas de E. coli. A utiliza??o de modelos experimentais de r?pida realiza??o e baixo custo se mostrou importante para avalia??o de efeitos biol?gicos, contribuindo para uma melhor compreens?o das propriedades dos derivados do ?cido propi?nico estudados. Esse trabalho teve car?ter multidisciplinar e na vig?ncia dos aux?lios concedidos pela CAPES, FAPERJ e CNPq
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Pokrzywa, Malgorzata. "A Drosophila Disease-Model for Transthyretin-associated Amyloidosis." Doctoral thesis, Umeå : Umeå University, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1677.
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Karaderi, Tugce. "Genetics of ankylosing spondylitis." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:8c0e848a-e712-4603-b923-a96a2f1644ac.
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Ankylosing spondylitis (AS) is a common inflammatory arthritis of the spine and other affected joints, which is highly heritable, being strongly influenced by the HLA-B27 status, as well as hundreds of mostly unknown genetic variants of smaller effect. The aim of my research was to confirm some of the previously observed genetic associations and to identify new associations, many of which are in biological pathways relevant to AS pathogenesis, most notably the IL-23/TH17 axis (IL23R) and antigen presentation (ERAP1 and ERAP2). Studies presented in this thesis include replication and refinement of several potential associations initially identified by earlier GWAS (WTCCC-TASC, 2007 and TASC, 2010). I conducted an extended study of IL23R association with AS and undertook a meta-analysis, confirming the association between AS and IL23R (non-synonymous SNP rs11209026, p=1.5 x 10-9, OR=0.61). An extensive re-sequencing and fine mapping project, including a meta-analysis, to replicate and refine the association of TNFRSF1A with AS was also undertaken; a novel variant in intron 6 was identified and a weak association with a low frequency variant, rs4149584 (p=0.01, OR=1.58), was detected. Somewhat stronger associations were seen with rs4149577 (p=0.002, OR=0.91) and rs4149578 (p=0.015, OR=1.14) in the meta-analysis. Associations at several additional loci had been identified by a more recent GWAS (WTCCC2-TASC, 2011). I used in silico techniques, including imputation using a denser panel of variants from the 1000 Genomes Project, conditional analysis and rare/low frequency variant analysis, to refine these associations. Imputation analysis (1782 cases/5167 controls) revealed novel associations with ERAP2 (rs4869313, p=7.3 x 10-8, OR=0.79) and several additional candidate loci including IL6R, UBE2L3 and 2p16.3. Ten SNPs were then directly typed in an independent sample (1804 cases/1848 controls) to replicate selected associations and to determine the imputation accuracy. I established that imputation using the 1000 Genomes Project pilot data was largely reliable, specifically for common variants (genotype concordence~97%). However, more accurate imputation of low frequency variants may require larger reference populations, like the most recent 1000 Genomes reference panels. The results of my research provide a better understanding of the complex genetics of AS, and help identify future targets for genetic and functional studies.
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Chen, Wen-Yi, and 陳文藝. "In silico selections for design of anti-inflammatory therapeutic molecules." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/54215293572649529406.
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碩士慈濟大學
微生物學免疫學暨生物化學碩士班
100
Background: Human CXCL8 plays important roles in inflammation by activation of neutrophils through hCXCR1 and hCXCR2 receptors. The role of hCXCR1 and hCXCR2 in the pathogenesis of inflammatory responses has encouraged the development of antagonists of these receptors. Due to the fact that hCXCR1 and hCXCR2 are membrane proteins, they are difficult to be purified for X-ray crystallography. Therefore, hCXCR1 and hCXCR2 structures have not yet existed in ProteinDataBank. In this study, we simulated the three-dimensional structure of CXCR1 using homology modeling. And this structure is used for molecular docking in order to design anti-inflammatory drugs. Methodology/Principal Findings: Using the Phyre2 which applies a profile-profile alignment algorithm for searching the ideal template, 1U19, a new high-resolution (2.2 A) structure, was found. We performed homology modeling to construct 100 structures of hCXCR1 using Discovery Studio v. 3.1 by superimposed and analyzed top 10 structures with minimized energy. The Root Mean Squarer Deviation (RMSD) of these 10 structures was less than 0.4 A. The CXCR1 model was obtained by averaging the top10 structures. Subsequently, the CXCL8 and CXCR1 were docked to simulate the specific binding sites. The results showed that there were three fragments which might be important for the ligand-receptor binding. All the forces between the receptor and the ligand were calculated with the ZRank. The selected peptides were then synthesized and tested for their functions on the THP-1cell using flow cytometry. Summary/Significance: Our simulation results demonstrated that there are a large number of attractions between the selected peptides and CXCR1, such us hydrogen bonds and van der Waals forces. As observed in flow cytometry study, selected peptides did indeed associate with the cells. However, it is still not certain if the selected peptides have the ability to compete with CXCL8 so far.
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Lopes, Paloma Levy. "Development of anti-inflammatory starch-based dressings using tomato byproducts-derived molecules." Master's thesis, 2021. http://hdl.handle.net/10773/32833.
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Most wound dressings currently used are not ideal for a total, fast, and
effective healing process due to their reduced biocompatibility derived from their
synthetic nature and lack of bioactive properties. Alternatively, new bio-based
dressings with antimicrobial and/or anti-inflammatory activity have been
developed. However, the natural polymers currently used come from food, acting
as competitors for human nutrition. Agrifood byproducts-derived biomolecules
can help overcome this competition.
In this work, the feasibility of using tomato byproducts-derived molecules for
the development of starch-based dressings with anti-inflammatory properties
was studied. For this purpose, the influence of tomato pomace-derived hot-water
soluble extract concentration (1%, 5%, and 10% w/w in relation to starch dry
weight), rich in polysaccharides (TE) and/or phenolic compounds (PE), on the
chromatic, mechanical, physicochemical, and active properties (antimicrobial
and anti-inflammatory) of starch-based films obtained by solvent casting was
studied. In a circular economy concept, starch was recovered from industrial
potato processing slurries.
TE and PE extracts showed, respectively, 14.7% and 18.5% of protein,
43.7% and 28.6% of polysaccharides, 2.8% and 15.1% of phenolic compounds,
and promising antioxidant activity (IC50 values of 2.5 mg/mL and 0.8 mg/mL,
respectively). When incorporated into starch-based formulations, TE and PE
allowed to develop transparent films with a yellowish coloration and less rigid and
traction resistant films than the control films. TE originated hydrophobic and
flexible films, while PE decreased the films’ hydrophobicity and stretchability.
Regarding the active properties, after 24h, both films with TE and PE revealed
anti-inflammatory activity in the presence of a pro-inflammatory agent, where, for
starch-based films with 10% TE and 10% PE, the inflammation decreased by ca.
48% and 100%, respectively. To develop starch-based dressings, in this work
the electrospinning of starch-based solutions was also optimized. After adjusting
the solvent, starch concentration, and dissolution time, starch-based fibers were
obtained, although in small amount for application in the development of
dressings.
The tomato pomace-derived molecules and starch recovered from potato
washing slurries have shown to be promising raw materials for the development
of biobased anti-inflammatory dressings, which will allow to promote more
biocompatible and functional wound healing devices than the materials derived
from inert synthetic polymers.Muitos dos curativos para feridas atualmente utilizados não são os ideais para um processo de cura total, rápido e eficaz devido à sua reduzida biocompatibilidade, oriunda da sua natureza sintética e da ausência de propriedades funcionais. Como alternativa têm sido desenvolvidos novos curativos de origem biológica com atividade antimicrobiana e/ou anti inflamatória. No entanto, os polímeros de origem natural até à data utilizados provêm de alimentos, atuando como competidores para a alimentação humana. As biomoléculas derivadas dos subprodutos da indústria agroalimentar podem ajudar a superar esta competição. Neste trabalho foi estudada a viabilidade da utilização de moléculas derivadas dos subprodutos de tomate para o desenvolvimento de pensos à base de amido com propriedades anti-inflamatórias. Para o efeito foi estudada a influência da concentração (1%, 5% e 10% m/m em relação à massa seca de amido) de extratos solúveis em água quente derivados to repiso de tomate, ricos em polissacarídeos (TE) e/ou compostos fenólicos (PE), nas propriedades cromáticas, mecânicas, físico-químicas e ativas (anti-inflamatórias e antimicrobianas) dos filmes à base de amido obtidos pelo método de evaporação do solvente. Num conceito de economia circular, o amido foi recuperado de lamas provenientes do processamento industrial de batata. Os extratos TE e PE apresentaram, respetivamente, 14,7% e 18,5% de proteína, 43,7% e 28,6% de polissacarídeos, 2,8% e 15,1% de compostos fenólicos e promissora atividade antioxidante (IC50 de 2,5 mg/mL e 0,8 mg/mL, respetivamente). Quando incorporados em formulações à base de amido, os extratos TE e PE permitiram desenvolver filmes transparentes com coloração amarelada e menor rigidez e resistência à tração do que os filmes controlo. TE originou filmes hidrofóbicos e flexíveis, enquanto PE diminuiu a hidrofobicidade e extensibilidade dos filmes. Quanto às propriedades ativas, ambos os filmes com TE e PE demostraram atividade anti-inflamatória quando na presença de um agente pró-inflamatório, observando-se, ao fim de 24 h, uma diminuição da inflamação de cerca de 48% e 100% para os filmes à base de amido com 10% de TE e PE, respetivamente. Com o intuito de desenvolver pensos à base de amido, neste trabalho também se otimizou a eletrofiação de soluções à base de amido. Após o ajuste do solvente, da concentração de amido e do tempo necessário para a sua dissolução foram obtidas fibras à base amido, porém em baixa quantidade para posterior aplicação no desenvolvimento de pensos. As biomoléculas existentes no repiso de tomate e o amido recuperado das lamas de lavagem de batata mostraram-se promissores para o desenvolvimento de curativos anti-inflamatórios de origem biológica, o que permitirá promover dispositivos médicos para cura de feridas mais biocompatíveis e funcionais dos que os materiais derivados de polímeros sintéticos inertes.
Mestrado em Biotecnologia
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HSUEH, CHIH-CHI, and 薛志麒. "The Anti-inflammatory study of small molecules new dosage forms from Antrodia cinnamomea." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/94477797268686351279.
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碩士元培醫事科技大學
生物科技暨製藥技術系碩士班
105
The Antrodia cinnamomea are recognized as a folk medicine in Taiwan, detoxification effect with liver, however its mechanisms of detoxification until not clear. Therefore, the present experiment that we test the small molecule isolation of the Antrodia cinnamomea extract with new formulations of film-coated capsule, analysis its liver anti-inflammatory effect of the acute injury SD rats subjected to carbon tetrachloride (CCl4). The experimental results demonstrate that administration of carbon tetrachloride after injection, SD rats serum concentrations of nitric oxide (NO) and reactive oxygen species (ROS) are significantly increased on the CCl4 group but the NO and ROS concentration significantly reduced on the Antrodia cinnamomea group (P <0.05). We also find the small molecule isolation compound of the Antrodia cinnamomea extract from the liver tissues of the Antrodia cinnamomea group SD rats by HPLC method. The small molecule isolation of the Antrodia cinnamomea with new formulations could decrease the liver damage of SD rat subjected to CCl4. Taken together, these results indicate that the mechanism of new formulations the Antrodia cinnamomea extract involves the antioxidant metabolism and detoxification capacity through scavenging of NO and ROS in CCl4-stressed SD rat.
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Shepherd, Catherine. "Exploring low molecular weight molecules produced by hookworms (Ancylostoma caninum) and their use as anti-inflammatory agents." Thesis, 2017. https://researchonline.jcu.edu.au/56036/1/JCU_56036-shepherd-2017-thesis.pdf.
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The dog hookworm, Ancylostoma caninum is an experimental model for human hookworm. Relying on the ancient association of hookworms and their host and guided by the observations of the "Old friend's Theory" these parasites may be a valuable source for therapeutic discovery. This thesis is designed to study the small molecules produced by the adult hookworm with particular emphasis on identifying molecules with anti-inflammatory potential using experimental techniques not applied to any helminth previously.
To achieve this primary, aim the small molecular component of hookworm excretory/secretory fluid was extracted and separated. These fractions were separated using the small molecule techniques commonly employed in the study of ethnobotanicals. These extracts were tested in a mouse chemical colitis model known to exhibit Th1/Th17 responses, Th2 type hypertrophy, and innate immune response. This model is employed here as a broad-based bioactivity screen for immunomodulatory potential. Using these combined techniques, it was possible to identify several small molecule fractions exhibit a protective effect in TNBS mouse model of intestinal inflammation. These fractions have the potential to reveal therapeutic candidates for inflammatory disease.
During this study it was also possible to characterise the small molecule secretome of A. caninum using gas chromatography/ mass spectroscopy. This characterisation has been able to describe over 300 features never described for A. caninum. The majority of the molecules have no currently described immunomodulatory activity. This includes low-molecular weight molecules hereto undescribed. In addition to this, a number of metabolites were identified, and these could be assigned to the described pathways of the human hookworm Necator americanus.
It was possible to demonstrate that the small molecule milieu produced by adult dog hookworm is complex. Dog hookworm excretory/secretory material contains small molecule components that when administered to mice can prevent chemical colitis. These molecules present a novel pool of small molecules that have the potential to be used to treat inflammatory disease.
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Mencel, Malwina. "Potential Roles for the Neurotrophic Molecules Agrin and Neuregulin in Regulating Aspects of the Inflammatory Response." Thesis, 2014. http://hdl.handle.net/10012/8490.
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Agrin and neuregulin are neurotrophic molecules well known for their roles at synapses in the peripheral and central nervous systems. The expression of these two molecules is not restricted to these sites however, as they are broadly expressed across multiple organ systems. What roles do agrin and neuregulin play within these alternate systems; what is the function of these molecules outside the nervous system? Here I investigate potential roles for agrin and neuregulin in inflammation. Inflammation is an immediate response by innate immune cells, primarily macrophages, to infection and is characterized by the synthesis of pro-inflammatory mediators. The innate immune system possesses multiple redundant mechanisms to locally control inflammation. The neuro-immune axis is one means of control. Often called the cholinergic anti-inflammatory pathway, it acts to regulate local inflammation via nerve-secreted acetylcholine signaling through the homopentameric α7 nicotinic acetylcholine receptors (α7nAChR) present on macrophages.
Both agrin and neuregulin have been independently described to share an intricate relationship with acetylcholine receptors (AChR) in the nervous system. Agrin is best known for its role in AChR aggregation at the neuromuscular junction while neuregulin has related roles in AChR transcription, cell survival, communication and differentiation. Based on the common characteristics of synapses in the nervous and immune systems we were curious to see if agrin and neuregulin played analogous roles on macrophages.
Here we show that agrin and its receptor dystroglycan are expressed on RAW264.7 macrophages. In addition, agrin treated macrophages demonstrate increased endogenous agrin and α7nAChR expression. By blocking α-dystroglycan (α-DG), a receptor for agrin, with an anti-α-DG antibody we further saw a reduction in agrin expression. We also show that agrin is able to aggregate surface α7nAChRs and transmembrane agrin co-localizes with α7nAChRs therein. Agrin appears to induce approximately a 15-fold increase in anti-inflammatory cytokine IL-10 in macrophages but does not increase pro-inflammatory cytokine TNF-α or IL-6 synthesis. Agrin-treated macrophages challenged with LPS, a potent activator of inflammation, exhibit a 57% decrease in IL-6. Macrophages treated with agrin also exhibit a 4-fold increase in STAT3, a regulator of anti-inflammatory action.
The potential anti-inflammatory effects of agrin in the periphery parallel previous work describing the effects of neuregulin in the brain. Previous work completed by our lab suggests a role for neuregulin in augmenting the expression of α7nAChRs on microglia, the macrophages of the brain, but not in peripheral macrophages. Here we show that treatment of LPS challenged microglia with neuregulin produces an 88% decrease in IL-6 and a 33% decrease in TNF-α. These results indicate both agrin and neuregulin are able to induce an increase in α7nAChRs and augment the synthesis of pro- and anti-inflammatory cytokines in their respective systems. These results also further the support the evidence of neuro-immune crosstalk in the immune system. Taken together these results present two novel players in inflammatory regulation by macrophages in the periphery and CNS.
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Joone, Gisela Käthe. "Die immuunmodulerende eienskappe van oksihumaat : 'n in vivo en in vitro ondersoek (Afrikaans)." Thesis, 2004. http://hdl.handle.net/2263/26739.
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Taofiq, Oludemi. "The contribution of phenolic acids to the anti-inflammatory activity of mushrooms: screening in phenolic extracts, individual parent molecules and synthesized glucuronated and methylated derivatives." Master's thesis, 2015. http://hdl.handle.net/10198/12103.
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Mestrado em cooperação com a Universidade de SalamancaIn the present study, the ethanolic extracts of fourteen wild edible mushrooms were investigated for their anti-inflammatory potential in LPS (Lipopolysaccharide) activated RAW 264.7 macrophages. Furthermore the extracts were chemically characterized in terms of phenolic acids and related compounds. The identified parent molecules (p-hydroxybenzoic, p-coumaric and cinnamic acids) and their synthesised glucuronated and methylated derivatives obtained by chemical synthesis were evaluated for the same bioactivity, in order to establish a structure-activity relationship, and to understand the contribution of the compounds to the activity of the extracts. The extract Pleurotus ostreatus, Macrolepiota procera, Boletus impolitus and Agaricus bisporus revealed the strongest anti-inflammatory potential, presenting also the highest concentration in cinnamic acid, which was also the individual compound with the highest anti-inflammatory activity. The derivatives of p-coumaric acid revealed the strongest properties, especially the compound CoA-M1, that exhibited a very similar activity to the one showed by dexamethasone used as anti-inflammatory standard; by contrast, the p-hydroxybenzoic derivatives revealed the lowest inhibition of NO production. All in all, whereas the conjugation reactions change the chemical structure of phenolic acids and may increase or decrease their activity, the glucuronated and methylated derivatives of the studied compounds are still displaying anti-inflammatory activity.