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Seven new eunicellin-based diterpenoids, krempfielins K¡ÐQ (1¡Ð7), along with six known compounds, litophynin I (8), krempfielin A (9), krempfielin D (10), sclerophytin F (11), litophynol B (12), and litophynol I monoacetate (13), have been isolated from the soft coral Cladiella krempfi which was collected from Penghu Island of Taiwan. Their structures were determined through extensive spectroscopic data (IR, MS, 1H NMR, 13C NMR, HSQC, HMBC, COSY, and NOESY) and by comparison of the spectral data with those of the related known compounds. The structure of compound 1 is rare due to the presence of a tetrahydropyran ring constituted from C2¡ÐC6 and oxygen atom. Compound 7 is the first discovery of eunicellin-based dimer. The anti-inflammation activity of twelve compounds (1¡V6 and 8¡V13) at 10 £gM was studied. The results showed that compound 4 inhibited more than 70% express of elastase released in FMLP/CB-induced human neutrophils .

Liposomal ciprofloxacin (Lipo-CPFX) is being developed for inhalation, with a goal of sustaining the therapeutic activity, compared to unformulated ciprofloxacin (CPFX). However, the kinetics and mechanism of its sustained local lung retention and pharmacological activity are yet to be fully characterized. This project hypothesized that Lipo-CPFX enables slower and sustained lung epithelial transport and uptake, compared to CPFX, thereby producing prolonged local pharmacological actions. The human bronchial epithelial Calu-3 cells were used as monolayers to characterize the kinetics and mechanism of transport and/or uptake, and to assess the effects of such slow kinetics for Lipo-CPFX on its inhibition against lipopolysaccharide (LPS)-induced proinflammatory IL-8 release. The transport fluxes for Lipo-CPFX across the highly restricted Calu-3 cell monolayers was transepithelial electrical resistance-independent, which suggested predominant transcellular transport. Compared to CPFX, Lipo-CPFX showed 6-18 times slower transport, while the flux was increased with increasing concentration proportionally without saturation. Its unaltered transport by cellular energy depletion, transport inhibition by a reduced temperature (4 oC) and endocytosis/lipid fusion inhibitors, filipin and LysoPC, and increased transport by excess empty liposomes collectively suggested cell energy-independent, lipid bilayer fusion mechanisms for the Lipo-CPFX transport across the Calu-3 cells. Likewise, Lipo-CPFX showed 2-4 fold lower cellular uptake than CPFX, proportional to concentration. Lipo-CPFX exhibited significant inhibitory activities at ≥ 0.01 mg/mL on LPS-induced IL-8 release from the Calu-3 cells, which was equipotent to CPFX. Upon 24 h pre-incubation, Lipo-CPFX caused 36.9 and 47.5 % inhibition at 0.01 and 0.05 mg/mL, respectively, while CPFX failed to do so. However, the effect was negated upon repeated wash of the mucosal cell surface, speculating the importance of cell membrane-associated drug/formulation on the inhibitory activities for Lipo-CPFX. Upon 24 h transport, Lipo-CPFX retained 79.0 % of the 4 µg dose on the mucosal cell surface, which was 1.9-times greater than 40.7 % for CPFX. As a result, when LPS was added at 24 h of the transport, Lipo-CPFX was still capable of causing 60.1 % inhibition, as its sustained local anti-inflammatory activity; CPFX however also exhibited equipotent inhibition, by virtue of comparable cellular drug uptake/transport.

The beneficial effects of angiotensin II type 1 (AT1) receptor blockers (ARB) in cerebrovascular disease have been shown in clinical trials. However, the effects of ARBs vary based on their unique pharmacologic properties. In this study, we focused on telmisartan, a fat-soluble ARB with selective peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity, and investigated its effects on ischemic injury in cerebral vasculature using murine models of both transient and permanent focal ischemia. Analysis by triphenyltetrazolium-staining revealed that pre-treatment of mice with telmisartan reduced stroke volume 72 h after the transient ischemic insult in a dose-dependent manner, though such treatment did not reduce stroke volume due to permanent ischemia. Transient ischemia induced pro-inflammatory adhesion molecules, such as ICAM-1 and P-selectin in the ischemic region, and treatment with telmisartan diminished the expression of these adhesion molecules with diminished infiltration of inflammatory cells. The beneficial effect of telmisartan was attenuated, in part, by administration of a PPARγ antagonist. Treatment with valsartan (an ARB without PPARγ agonist activity) also decreased ischemic injury after transient ischemia, though to a lesser extent than telmisartan. Our findings indicate that telmisartan has a beneficial effect in a murine model of ischemia/reperfusion injury through blockade of AT1 receptors, and, in addition, due to a positive effect via its specific anti-inflammatory PPARγ agonist activity.

Intra-articular glucocorticoid injections are commonly used to treat synovitis and osteoarthritis in horses. These agents are highly effective at relieving pain, swelling, and other symptoms of joint inflammation. The drugs also have therapeutic benefits by down regulating the expression of cytokines and protease enzymes that participate in the degradation of articular cartilage. However, detrimental effects on chondrocyte function and cell viability that is independent of osteoarthritis pathogenesis have been described and linked to glucocorticoid use. These side effects are both drug- and dose-dependent. This study tested the hypothesis that manufacture recommended dosage levels of methylprednisolone, betamethasone, and triamcinolone that are widely used in equine clinical practice are cytotoxic to articular chondrocytes. Drug-induced chondrocyte cytotoxicity was evaluated in monolayer cultures, cartilage explants, and equine fetlock joints. Total RNA was isolated from control and IL-1β stimulated primary chondrocytes and synoviocytes in culture. Changes in steady state mRNA for targeted gene transcripts related to inflammation and normal cell function were measured using reverse transcription and quantitative PCR. Inducible nitric oxide synthase activity was evaluated using nitrite production. Drug-induced chondrocyte cytotoxicity occurred at drug dosage levels frequently used in equine clinical practice. Both drug- and dose-dependent effects on chondrocyte and synoviocyte gene expression were observed. Maximum anti-inflammatory activities for the glucocorticoids were observed at in vitro concentrations below manufacturer-recommended levels. Results from this study suggest that lower glucocorticoid dose ranges for intra-articular therapy in horses should be validated to maximize the ratio of their therapeutically beneficial anti-inflammatory efficacy against detrimental effects on cell function and viability.

Dans le cadre d’une hospitalisation, l’escarre est un souci majeur aussi bien pour le confort des patients que d’un point de vue économique. Le vieillissement de la population confronte de plus en plus le personnel soignant à la prévention et au traitement des escarres. La prophylaxie n’en est donc que plus essentielle dans les milieux hospitaliers. Force est de constater qu’il existe en la matière peu de produits spécialisés dont l’efficacité a été éprouvée. En partenariat avec le laboratoire RIVADIS, nous avons donc voulu élaborer un système galénique contenant une association d’actifs naturels innovants afin de prévenir l’escarre. Un état de l’art complet a été effectué sur la thématique des escarres afin d’en comprendre tous les facteurs de risques. Par la suite, une recherche approfondie a permis de sélectionner les plantes et molécules pouvant être utilisées comme actifs dans la prévention et/ou le traitement de cette pathologie. Notre attention s’est particulièrement attardée sur le pouvoir anti-inflammatoire, cicatrisant, antioxydant et anti-adhésion bactérienne de ces actifs. Les deux meilleurs actifs obtenus sont la pectine de pomme et l’extrait sec de Centella asiatica L., dont les résultats se sont avérés significatifs sur au moins trois propriétés recherchées. L’étude des effets combinés de ses deux actifs a même montré une synergie sur le pouvoir anti-adhésion bactérienne. Ils ont alors été incorporés sous forme galénique, de façon à rendre possible la réalisation d’un effleurage aussi facile que celui permis par les huiles déjà présentes sur le marché tout en autorisant l’incorporation d’actifs hydrophiles. / In the case of a hospitalization, bedsores are a major issue regarding the comfort of the patient as well as economical reasons. Due to the aging population, the nurses are more and more confronted to prevention and treatment of bedsores. Thus, prevention is now considered as essential in hospitals. It must be noted that in matter of bedsores, there exist only a few specialized products which efficiency has been proved. Therefore, in association with RIVADIS Laboratory, we planed to work on a galenic formulation which contains a combination of innovative natural active. A complete compilation of specialized publications on this topic has been realized in order to fully understand all the risk factors. Then, thanks to an extensive research, we identified the plants and molecules that could be used as actives for the prevention and/or treatment of this pathology. We focused on their anti-inflammatory, healing, antioxidant and bacterial anti-adhesive properties. The two best actives thus obtained are apple pectin and dry Centella asiatica L. extract, they present significant results on at least three of the four wanted properties. Studying the combined effects of these two actives even showed a synergy on bacterial anti-adhesive property. They have then been incorporated in a galenic formulation that makes the massage as easy as the one allowed by already commercialised oils and enables the incorporation of hydrophilic actives.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Himatanthus drasticus (Apocynaceae) à uma espÃcie tradicionalmente utilizada na medicina popular da regiÃo nordeste deste paÃs. Sua distribuiÃÃo ocorre das Guianas ao sudeste do Brasil. O lÃtex desta planta à obtido apÃs uma injÃria no caule e amplamente comercializado em mercados pÃblicos. As pessoas ingerem o lÃtex, conhecido como Leite de Janaguba (LJ), para o tratamento e/ou prevenÃÃo de diferentes doenÃas inflamatÃrias, gastrite, Ãlcera, cÃncer, entre outras. Apesar das diversas informaÃÃes oriundas da medicina popular, nÃo existem relatos cientÃficos suficientes confirmando tais propriedades farmacolÃgicas. Neste trabalho, LJ foi investigado com o propÃsito de validar sua tÃo popularmente relatada atividade anti-inflamatÃria. A fraÃÃo proteica deste lÃtex (HdLP) tambÃm foi investigada quanto à presenÃa de atividades anti-inflamatÃria, antinociceptiva, alÃm de seus efeitos toxicolÃgicos. LJ inibiu a resposta inflamatÃria induzida por carragenina em ratos (98%, p < 0.05), assim como o fez a fraÃÃo HdLP, independente da rota de administraÃÃo. HdLP reduziu a infiltraÃÃo de neutrÃfilos na cavidade peritoneal (96%, p < 0.05). Paralelamente a isto, ocorreu o aumento da sÃntese de Ãxido nÃtrico no plasma e a reduÃÃo de citocinas prÃ-inflamatÃrias (IL-1 e TNF-&#945;) no fluido peritonal. Esta fraÃÃo tambÃm preveniu a vacuolizaÃÃo e hiperplasia das cÃlulas de Kupfer, causadas pelo efeito da carragenina no fÃgado. Atividade anti-inflamatÃria està provavelmente associada com a fraÃÃo proteica de LJ. HdLP exibiu um efeito anti-inflamatÃrio mesmo apÃs aquecimento (100 &#61616;C, 30 minutos) ou proteÃlise. AlÃm desta atividade, um efeito prÃ-inflamatÃrio foi observado apÃs o tratamento com HdLP. Esta tambÃm suprimiu contraÃÃes abdominais induzidas por Ãcido acÃtico e reduziu a lambedura de pata induzida por formalina, ambos de maneira dose-dependente. A avaliaÃÃo da toxicidade aguda demonstrou a ausÃncia de efeitos tÃxicos apÃs tratamento com LJ e HdLP (v.o.) mesmo utilizando doses 5000 vezes maiores que as recomendadas. Uma dosagem qualitativa de fitoquÃmicos em HdLP mostrou a ausÃncia de lupeol e presenÃa de saponinas, taninos e esterÃides livres. Entretanto, as propriedades farmacolÃgicas provavelmente nÃo estÃo relacionadas com estas molÃculas. Desta forma, concluÃmos que o lÃtex de H. drasticus exibe duas das atividades farmacolÃgicas relatadas por seus usuÃrios e a fraÃÃo proteica deste lÃtex à um importante contribuinte para tais propriedades medicinais. A resistÃncia ao aquecimento e à proteÃlise pode explicar a efetividade de HdLP quando administrada oralmente. A ausÃncia de efeitos tÃxicos por via oral torna esta planta uma potencial candidata a fitoterÃpico. / Himatanthus drasticus (Apocynaceae) is traditionally used in folk medicine in Northeastern Brazil. The plant is wildly distribuited from Guianas until Southeast Brazil. Latex obtained by cutting its stem bark is mixed with water and extensively sold in public markets. People use Janaguba milk (âLeite de Janagubaâ- LJ) to treat or prevent different inflammatory disorders such as gastritis, ulcers as well as cancer, among other uses. Despite, there is not enough scientific data confirming these pharmacological properties. In this work, Janaguba milk was preliminarily investigated in an attempt to validate its anti- inflammatory activity. Its major protein fraction (HdLP) was assessed for the presence of anti- inflammatory, anti-nociceptive and toxicological effects. LJ inhibited the inflammatory response induced by carrageenan in rats (98%, p < 0.05), whereas HdLP did it independent of the route of administration. HdLP significantly reduced the infiltration of neutrophils into the peritoneal cavity (96%, p < 0.05) concomitant with increased nitric oxide synthesis in plasma and decrease of pro-inflammatory cytokines IL- 1 and TNF-&#945; in peritoneal fluid. This fraction also prevented vacuolization and Kupfer cell hyperplasia caused by carrageenan in liver. Further, the anti-inflammatory properties were shown to be associated with the protein fraction of LJ. HdLP exhibited anti-inflammation, even after heat-treatment (100 &#61616;C, 30 min) or proteolysis. Moreover, a pro-inflammatory effect was observed after HdLP treatment. It also suppressed abdominal constrictions in acetic acid-treated mice and reduced paw licking induced by formalin, both in a dose-dependent manner. An acute toxicological evaluation demonstrated no toxic effects after 14 days from LJ and HdLP administration by oral route even when high doses were tested. A qualitative phytochemical analysis showed the absence of lupeol and presence of saponinas, tannins and free steroids in HdLP. However, pharmacological properties are probably not related to them. It is therefore concluded that the latex of Himatanthus drasticus exhibits both the anti-inflammatory and anti-nociceptive activities claimed by its users. The protein fraction of the latex is an important contributor to the pharmacological properties of LJ. Resistance to heat and proteolytic treatment can explain the effectiveness of HdLP even when administered orally. The absence of toxic effects by oral route confirms the potential use of this plant as a phytotherapic agent.

La recrudescence des maladies dégénératives ces dernières décennies dans le monde a amené plusieurs chercheurs et médecins à médiatiser les antioxydants à cause des vertus qu’on leur prête: de la protection contre les maladies cardiovasculaires à la prévention de certains cancers. Le présent travail a été mené avec pour objectif principal d’évaluer le pouvoir antioxydant des épices entrant dans la préparation de la sauce en vue du développement d’un complément alimentaire nutraceutique. Pour ce faire, vingt épices largement consommées ont été choisies sur la base d’une enquête exploratoire menée au Cameroun. Les différentes épices réduites en poudres ont été analysées pour leurs teneurs en composition nutritionnelle. Le pouvoir antiradicalaire in vitro des extraits méthanoliques des différentes épices a été déterminé ainsi que le pouvoir anti-inflammatoire et antistress sur des rats adultes à stress induit. Les résultats obtenus ont montré des variations très significatives de la composition des épices. L’activité antioxydante utilisant la méthode au N’ N-diphényl-N’-picrylhydrazyl (DPPH), au « trolox equivalent antioxidant capacity » (TEAC) et le pouvoir réducteur total (PRT) ont révélé que Z. leprieurii et D. glomerata présentent les activités particulièrement élevées. Les extraits de ces deux épices ont servi de base à la préparation de mélange dont l’effet a été testé sur des rats mâles à inflammation induite. Les résultats obtenus ont montré que les épices individuelles et leur mélange à des doses de 100 mg/kg et 150 mg/kg présentent une activité anti-inflammatoire importante comparable à ceux commerciaux: inodméthacine, déxaméthasone et célécoxib. La variation de la teneur en malonaldéhyde (marqueur de l’oxydantion lipidique) a révélée l’action antioxydante in vivo des extraits, démontrant ainsi leur potentiel dans le développement de compléments alimentaires à effet antistress / Increasing evidences from current research point to the fact that certain disease conditions can be prevented through the consumption of antioxidant rich foods. The present work was carried out to evaluate the antioxidant potentials of twenty Cameroonian spices commonly used in some Cameroonian cuisine. The nutritional properties of spices, the in vitro antioxidant potential of their methanolic extracts as well as the in vivo antioxidant potential of the methanolic extracts of some selected samples were determined. The antioxidant activity brought about by N’ N-diphenyl-N’-picrylhydrazyl (DPPH), «trolox antioxidant equivalent capacity» (TEAC) and the total reduction power (PRT) methods have revealed that Z. leprieurii and D. glomerata presented the highest activities. The extracts of the two spices were used to prepare a mixture whose effect was tested on male rats with induced inflammation. The results obtained indicate that the individual spices and their mixture at 100 mg/kg and 150 mg/kg present an important anti-inflammatory activity comparable to that of commercial anti-inflammatory like indomethacin, dexamethasone and celecoxib. The variation of malondialdehyde content (a lipidic oxidant marquer) revealed the in vivo antioxidant action of extracts, thus demonstrating their potential for the development of functional foods with anti-stress effect

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-05-25T17:26:15Z No. of bitstreams: 1 AhirlanCastro.pdf: 821881 bytes, checksum: 3392f8d9400d159c99f7053ff6c00bd6 (MD5) / Made available in DSpace on 2017-05-25T17:26:15Z (GMT). No. of bitstreams: 1 AhirlanCastro.pdf: 821881 bytes, checksum: 3392f8d9400d159c99f7053ff6c00bd6 (MD5) Previous issue date: 2016-05-27 / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) / Inflammation comprises a biological mechanism of the body's defense in response to injury by exogenous or endogenous agents and aims to restore homeostasis. Morus nigra L., commonly known as black mulberry tree is traditionally used to treat inflammatory diseases. Thus, the aim of this study was to evaluate the pharmacological potential of the hydroalcoholic extract and ethyl acetate fraction of Morus nigra leaves and the likely mechanisms of action in models of inflammation in vivo and in vitro involving neutrophils and mediators of the inflammatory process. Therefore, the dried leaves were sprayed and soaked in 70% ethanol to obtain the hydroalcoholic extract (EHA). EHA was subjected to partitioning with hexane (FH), chloroform (FC) and ethyl acetate (FAE). Quantification of phenolic and total flavonoid compounds showed higher levels of these secondary metabolites in the EHA and FAE. Analysis by HPLC-UV showed the presence of chlorogenic acid, rutin, quercetin and kaempferol in EHA and FAE of Morus nigra. In the acute toxicology studies, treatment of male and female rats with EHA (2000 mg / kg, o.v.) in a single dose produced no death, nor change in consciousness, motor and autonomic and central nervous system; body weight and organs; consumption of water and food; haematological and biochemical parameters; when compared to the control group. EHA and FAE of Morus nigra presented antiedematogenic and anti-inflammatory activity by reducing the paw edema induced by carrageenan. EHA and FAE decreased migration of leukocytes and neutrophils for subcutaneous air pouch inflammatory stimulation by carrageenan, inhibiting TNF-α production and MPO. EHA and FAE also promoted decreased migration of leukocytes and neutrophils into the peritoneal cavity of rats stimulated with LPS, decreasing the production of NO, TNF- α, IL-1β and IL-8. Further, the EHA and FAE of Morus nigra decreased neutrophils chemotaxis in Boyden chamber assay modified front of chemotactic agents fMLP and IL-8. Together the data presented demonstrate that the EHA and FAE of Morus nigra had significant anti-inflammatory activity and can thus be used to treat inflammatory processes. / A inflamação compreende um mecanismo biológico de defesa do organismo em resposta a lesão por agentes exógenos ou endógenos e tem por finalidade restaurar a homeostase do organismo. Morus nigra L., popularmente conhecida por amoreira negra, é tradicionalmente utilizada no tratamento de doenças inflamatórias. Sendo assim, o objetivo deste trabalho foi avaliar o potencial farmacológico do extrato hidroalcoólico e fração acetato de etila das folhas de Morus nigra e os prováveis mecanismos de ação em modelos de inflamação in vivo e in vitro envolvendo neutrófilos e mediadores do processo inflamatório. Para tanto, as folhas secas foram pulverizadas e maceradas em etanol a 70%, para obtenção do extrato hidroalcoólico (EHA). O EHA foi submetido ao particionamento com hexano (FH), clorofórmio (FC) e acetato de etila (FAE). A quantificação de compostos fenólicos e flavonoides totais demonstraram níveis maiores destes metabólitos secundários no EHA e FAE. A análise por HPLC-UV demonstrou a presença de ácido clorogênico, rutina, quercetina e canferol no EHA e FAE de Morus nigra. No estudo toxicológico agudo, o tratamento de ratos machos e fêmeas com o EHA (2000 mg/kg, v.o.) em dose única, não produziu morte nem alterações no estado de consciência, motoras e do sistema nervoso central e autônomo; de peso corporal e de órgãos; consumo de água e ração; de parâmetros hematológicos e bioquímicos; quando comparados ao grupo controle. O EHA e FAE de Morus nigra apresentaram atividade antiedematogênica e anti-inflamatória através da redução do edema de pata de rato induzido por carragenina. O EHA e FAE diminuíram a migração de leucócitos e neutrófilos para bolsa de ar subcutânea com estimulação inflamatória por carragenina, inibindo a produção de TNF-α e mieloperoxidase. O EHA e FAE também promoveram a diminuição da migração de leucócitos e neutrófilos para a cavidade peritoneal de ratos estimulados com LPS, diminuindo a produção de óxido nítrico, TNF-α, IL-1β e IL-8. Ainda, o EHA e FAE de Morus nigra diminuíram a quimiotaxia de neutrófilos em ensaio de câmara de Boyden modificado frente aos agentes quimiotáticos fMLP e IL-8. Em conjunto, os dados apresentados demonstram que o EHA e FAE de Morus nigra apresentaram atividade antiinflamatória importante, podendo desta forma serem utilizados no tratamento de processos inflamatórios.

No description available.