South America -- Guyana -- Georgetown
Caribbean

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
Among 103 patients with multidrug-resistant HIV who initiated raltegravir, etravirine, and darunavir/ritonavir-containing regimen in the ANRS 139 TRIO trial, 100 participated in extended follow-up and continued study treatment until week 96. Among them, 87 (87%) received an optimized background therapy including either nucleoside reverse transcriptase inhibitors or enfuvirtide, they were 78 (78%) at week 96. At week 96, 88% achieved durable virologic response (<50 copies/mL). CD4 response was maintained (median change of +150 cells/mm(3)). No major toxicity was reported. This triple drug combination showed sustained efficacy and thus should be strongly considered for patients with multiclass-resistant virus.
ISSN: 1525-4135

hal-00875207
https://hal.archives-ouvertes.fr/hal-00875207
DOI : 10.1097/QAI.0b013e31824bb720
PUBMED : 22293546

Éditeur(s) : HAL CCSD American Academy of Neurology
Résumé : International audience
OBJECTIVE: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs was associated with survival after a diagnosis of HIV-related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis. METHODS: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIV-infected patients diagnosed with a first neurologic AIDS-defining event in the pre-combination antiretroviral therapy (cART) (1992-1995), early cART (1996-1998), or late cART (1999-2004) periods. Follow-up was subdivided (CPE < 1.5 and CPE ≥ 1.5), and relative rates (RR) of death were estimated using multivariable Poisson regression models. RESULTS: In the pre-cART and early cART periods, regimens with CPE ≥ 1.5 were associated with lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47-0.86 and RR 0.45; 95% CI 0.35-0.58) and after PML (RR 0.79; 95% CI 0.55-1.12 and RR 0.45; 95% CI 0.31-0.65), compared to regimens with CPE < 1.5, while in the late cART period there was no association between the CPE score and the mortality. A higher CPE score was also associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI 0.56-0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34-0.74). Whatever the neurologic event, these associations were not maintained after adjustment on updated plasma HIV-RNA (missing, <500, ≥500 copies/mL) with RR ranging from 0.82 (95% CI 0.36-1.91) to 1.02 (0.69-1.52). CONCLUSION: At the beginning of the cART era, the CPE score was of importance for survival after severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control.
ISSN: 0028-3878

hal-00875434
https://hal.archives-ouvertes.fr/hal-00875434
DOI : 10.1212/WNL.0b013e31820c3089
PUBMED : 21248274

Éditeur(s) : HAL CCSD Cancer Research UK
Résumé : International audience
BACKGROUND: Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent. METHODS: Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells. RESULTS: Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells. CONCLUSION: These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.
ISSN: 0007-0920

hal-00684528
https://hal.archives-ouvertes.fr/hal-00684528
DOI : 10.1038/bjc.2012.6
PUBMED : 22294184

Éditeur(s) : HAL CCSD Vsevolod Gurevich
Résumé : International audience
Chemotherapy is frequently used to treat primary or metastatic cancers, but intrinsic or acquired drug resistance limits its efficiency. Sphingolipids are important regulators of various cellular processes including proliferation, apoptosis, differentiation, angiogenesis, stress, and inflammatory responses which are linked to various aspects of cancer, like tumor growth, neoangiogenesis, and response to chemotherapy. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions, whereas sphingosine-1-phosphate and other derivatives have opposing effects. Among the variety of enzymes that control ceramide generation, acid or neutral sphingomyelinases and ceramide synthases are important targets to allow killing of cancer cells by chemotherapeutic drugs. On the contrary, glucosylceramide synthase, ceramidase, and sphingosine kinase are other targets driving cancer cell resistance to chemotherapy. This chapter focuses on ceramide-based mechanisms leading to cancer therapy sensitization or resistance which could have some impacts on the development of novel cancer therapeutic strategies.
Handb Exp Pharmacol

inserm-00871347
http://www.hal.inserm.fr/inserm-00871347
PUBMED : 23563652
DOI : 10.1007/978-3-7091-1511-4_4

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases.
ISSN: 0260-437X

hal-01526425
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526425
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526425/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526425/file/Zebrafish%20larva%20as%20a%20reliable%20model-Podechard%20JAT%202016%20revised.pdf
DOI : 10.1002/jat.3421

Éditeur(s) : HAL CCSD
Résumé : The aim of this work was to search for new bioactive compounds, displaying either antiplasmodial or antifungal activity. Two strategies were developed here: the evaluation of traditional remedies identified as antimalarial through ethnopharmacological study, and the search for antifungal essential oils, the criterium being here a bioinspired approach. Our work led to the discovery that the antimalarial activity of Quassia amara L. (Simaroubaceae) fresh young leaves was due to the presence of a known quassinoid, simalikalactone D. In the case of Psidium acutangulum DC. (Myrtaceae), a flavonol glycosides mixture explained the activity observed for the decoction. The search for antifungal essential oils from the Amazonian flora lead to the identification of several interesting species, thus validating our bioinspired strategy. The essential oil of Otacanthus azureus (Linden) Ronse was among the most active ones, either alone or in combination with azole drugs. Eventually, a metabolomic study of the GC/MS composition of these oils allowed us to develop a statistical tool which could help to select interesting antifungal products. This work thus demonstrate the major interest of the two strategies - ethnopharmacology and bioinspiration - for the search of new bioactive compounds.
L'objectif du travail effectué était la recherche de nouvelles substances actives d'origine végétale, présentant soit une activité antiplasmodiale soit une activité antifongique. Cette étude a été menée suivant deux stratégies différentes: l'étude de remèdes traditionnels antipaludiques identifiés suite à des enquêtes ethnopharmacologiques, et la mise en évidence des propriétés antifongiques d'huiles essentielles grâce à une stratégie bioinspirée. La première partie du travail a permis de mettre en évidence le rôle d'un quassinoïde connu, la simalikalactone D, dans l'activité antipaludique d'une tisane de jeunes feuilles fraîches de Quassia amara L. (Simaroubaceae). Dans le cas de la décoction de rameaux de Psidium acutangulum DC. (Myrtaceae), c'est cette fois un mélange de flavonoïdes glycosylés qui est responsable de l'activité du remède. Dans le cadre de la recherche de nouvelles substances antifongiques, le criblage effectué a permis d'identifier de nombreuses huiles essentielles présentant des activités intéressantes, validant ainsi la démarche bioinspirée retenue dans ce cas. L'huile essentielle d'Otacanthus azureus (Linden) Ronse a en particulier démontré une activité remarquable, à la fois seule et en combinaison avec des antifongiques azolés. Enfin, l'étude métabolomique de la composition des huiles essentielles a permis de mettre au point un outil pouvant orienter la sélection des huiles en fonction des données obtenues en GC/MS dans l'optique de la recherche de nouvelles substances antifongiques. Ce travail démontre donc la validité des stratégies retenues - ethnopharmacologie et bioinspiration - dans la recherche de nouvelles substances bioactives.
https://tel.archives-ouvertes.fr/tel-00718910

tel-00718910
https://tel.archives-ouvertes.fr/tel-00718910
https://tel.archives-ouvertes.fr/tel-00718910/document
https://tel.archives-ouvertes.fr/tel-00718910/file/TheseEH2011_SUBST_BIOACTIVES.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
ETHNOPHARMACOLOGICAL RELEVANCE: Cutaneous leishmaniasis is a neglected disease with a high incidence in French Guiana, mainly in the middle and upper Oyapock basin, where Amerindian and some Brazilian people live. The main goals of this work were (i) to assess the knowledge about leishmaniasis in the different populations of the middle and upper Oyapock basin, (ii) to study the therapeutic strategies adopted by people affected by leishmaniasis and (iii) to document the use of phytotherapeutic remedies for leishmaniasis. Knowledge, attitudes and practices (K.A.P.) related to this disease and its treatments have been studied according to cultural group and geographical settlement. Within the Wayãpi group, the evolution of the knowledge of phytoremedies over the last 20 years has been characterised by literature-based comparisons. MATERIALS AND METHODS: A total of 144 questionnaires were administered in all the villages of the upper Oyapock and Camopi basins. Correspondence analyses were used for multivariate analysis. Plant species were identified at the Cayenne Herbarium (CAY). RESULTS: The biomedical concept of leishmaniasis correlates well with the Teko and Wayãpi concepts of kalasapa and kalasapau. Although the vector of this disease was not correctly identified, the most commonly cited aetiology (74.5%) was vector-borne, and related epidemiological schemes correlate well with the one encountered in French Guiana. Theoretically and practically, health centres were the most commonly used resource for diagnostic in instances of leishmaniasis infection (65.9%), independently of the patient's cultural group, along with the use of pharmaceutical drugs (85.3%). Pharmaceuticals were commonly utilised despite the frequent (51.5%) use of phytotherapeutic remedies, alone or in combination with drugs. The most cited medicinal plant species for the treatment of leishmaniasis included Eleutherine bulbosa (Mill.) Urb. (Iridaceae, cited 14 times), Euterpe oleracea Mart. (Arecaceae, 9), Cecropia obtusa Trecul (Cecropiaceae, 8), Jatropha curcas L. (Euphorbiaceae, 7), Ceiba pentandra (L.) Gaertn. (Bombacaceae, 6) and Carica papaya L. (Caricaceae, 6). Multiple correspondence analyses demonstrated that the species used in leishmaniasis remedies are more prone to vary by the user's place of residence than by their cultural origin, which indicates that exchange of knowledge about leishmaniasis remedies has occurred across different cultural groups. Literature-based comparisons between the remedies for leishmaniasis used by the Wayãpi during the 1980s showed a striking evolution, both in terms of diversity of species and number of plants used. The large number of species shared with other Guianese groups argues for intercultural exchange and may explain the majority (57.1%) of the newly used species highlighted in our study. CONCLUSIONS: Leishmaniasis is a well-known disease in the studied area. Phytotherapeutic treatments are still in use, although they are not the main source of remedies, and should undergo pharmacological studies to evaluate their potential therapeutic value.
ISSN: 0378-8741

pasteur-00634597
https://hal-riip.archives-ouvertes.fr/pasteur-00634597
DOI : 10.1016/j.jep.2011.07.044
PUBMED : 21816216

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Recently it has become clear that exposure to xenobiotics may result in various forms of cell death; not only passive cell deaths like necrosis, or programmed cell deaths such as apoptosis, but also regulated necrosis, autophagy, senescence, or mitotic catastrophe. Complex cell signaling networks influence the processing of cell death. Furthermore, recent research has revealed early complex molecular interactions between organelles prior to the final triggering of cell death. The plasma membrane may play an important role in the early cell death signaling events. Regarding this latter aspect, drugs and environmental pollutants have been reported to affect plasma membrane characteristics which may further affect cell fate. Changes in membrane fluidity or in composition and function of specialized membrane microdomains (plasma membrane remodeling) have been proven to be involved in the regulation of many important physiological signaling pathways, including cell death. Furthermore, it has been suggested that a crosstalk between chemical-induced cellular membrane effects and other organelles may be of vital importance to explain the final outcome of chemical exposure. Here, we review the effects of plasma membrane remodeling on cell survival and cell death; we describe how the cell signaling pathways activated by changes in plasma membrane characteristics may influence cell fate. Since plasma membrane function plays an important role in the regulation of a number of cellular responses, it has been implicated in the development or progress of several diseases. A better knowledge of the effects of various chemicals on plasma membrane remodeling may be important for understanding the pathogenesis of major diseases, and may assist in developing new therapeutic strategies.
ISSN: 0300-483X

inserm-00818916
http://www.hal.inserm.fr/inserm-00818916
DOI : 10.1016/j.tox.2012.12.014
PUBMED : 23287390

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Sphingolipids, in particular ceramide, have been described as important components of cellular signalling pathways. Ceramide can be produced via multiple mechanisms including through the hydrolysis of sphingomyelin by acid and neutral sphingomyelinase or by a de novo synthesis pathway. Recent studies have identified sphingomyelinases and ceramide synthases as important targets for γ-irradiation and chemotherapeutic drugs. Likewise, common cancer treatment modalities, such as γ-irradiation and many chemotherapeutic agents, induce cell death via the generation of ceramide. This suggests that the manipulation of ceramide production and metabolism could offer promising a means for the enhancement of anti-tumor therapies. The focus of this mini-review will be to discuss contemporary evidence suggesting that ceramide forming pathways and ceramide itself are important targets for the treatment of tumors and the development of novel tumor treatment strategies.
ISSN: 0304-3835

hal-00682458
https://hal.archives-ouvertes.fr/hal-00682458
DOI : 10.1016/j.canlet.2011.07.010
PUBMED : 21862212

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Up to now, several studies have investigated estrogen receptor (ER)–estrogen response element (ERE) interaction using biosensors such as surface plasmon resonance. These strategies have aimed to understand the molecular mechanism of such interaction as well as the effect of the ligand on this interaction. These approaches start to be used to determine the mechanisms of protein/DNA interaction, in particular in the context of drug discovery or environmental applications. However, some physical and biochemical parameters (incubation time, temperature, protease inhibitor cocktail, and bovine serum albumin (BSA)) are not completely described in the literature and could deeply modify the obtained results. This paper aims to focus not only on the preliminary steps of sample preparation such as protein thawing and incubation conditions (time and temperature) but also on the evaluation of protease inhibitor cocktail and BSA effect on the measurement of ER–ERE interactions.
ISSN: 1618-2642

hal-01418341
https://hal.archives-ouvertes.fr/hal-01418341
https://hal.archives-ouvertes.fr/hal-01418341/document
https://hal.archives-ouvertes.fr/hal-01418341/file/Estrogen%20Receptor%20preparation%20effects_accepted.pdf
DOI : 10.1007/s00216-016-9967-0

Résumé : L’objectif du travail effectué était la recherche de nouvelles substances actives d’origine végétale, présentant soit une activité antiplasmodiale soit une activité antifongique. Cette étude a été menée suivant deux stratégies différentes: l’étude de remèdes traditionnels antipaludiques identifiés suite à des enquêtes ethnopharmacologiques, et la mise en évidence des propriétés antifongiques d’huiles essentielles grâce à une stratégie bioinspirée. La première partie du travail a permis de mettre en évidence le rôle d’un quassinoïde connu, la simalikalactone D, dans l’activité antipaludique d’une tisane de jeunes feuilles fraîches de Quassia amara L. (Simaroubaceae). Dans le cas de la décoction de rameaux de Psidium acutangulum DC. (Myrtaceae), c’est cette fois un mélange de flavonoïdes glycosylés qui est responsable de l’activité du remède. Dans le cadre de la recherche de nouvelles substances antifongiques, le criblage effectué a permis d’identifier de nombreuses huiles essentielles présentant des activités intéressantes, validant ainsi la démarche bioinspirée retenue dans ce cas. L’huile essentielle d’Otacanthus azureus (Linden) Ronse a en particulier démontré une activité remarquable, à la fois seule et en combinaison avec des antifongiques azolés. Enfin, l’étude métabolomique de la composition des huiles essentielles a permis de mettre au point un outil pouvant orienter la sélection des huiles en fonction des données obtenues en GC/MS dans l’optique de la recherche de nouvelles substances antifongiques. Ce travail démontre donc la validité des stratégies retenues – ethnopharmacologie et bioinspiration – dans la recherche de nouvelles substances bioactives.
The aim of this work was to search for new bioactive compounds, displaying either antiplasmodial or antifungal activity. Two strategies were developed here: the evaluation of traditional remedies identified as antimalarial through ethnopharmacological studies, and the search for antifungal essential oils, the criterium being here a bioinspired approach. Our work led to the discovery that the antimalarial activity of Quassia amara L. (Simaroubaceae) fresh young leaves was due to the presence of a known quassinoid, simalikalactone D. In the case of Psidium acutangulum DC. (Myrtaceae), a flavonol glycosides mixture explained the activity observed for the decoction. The search for antifungal essential oils from the Amazonian flora led to the identification of several interesting species, thus validating our bioinspired strategy. The essential oil of Otacanthus azureus (Linden) Ronse was among the most active ones, either alone or in combination with azole drugs. Eventually, a metabolomic study of the GC/MS composition of these oils allowed us to develop a statistical tool which could help to select interesting antifungal products. This work thus demonstrates the major interest of the two strategies – ethnopharmacology and bioinspiration – for the search of new bioactive compounds.

http://www.theses.fr/2011AGUY0415/document

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
Invasive aspergillosis is a major cause of mortality in allogeneic bone marrow transplant recipients and patients treated for blood malignancies. The diagnostic tools, treatments and preventive strategies, essentially developed for neutropaenic patients, have not been assessed in populations whose immune systems are considered to be competent. Beside the standard picture of chronic Aspergillus infection, the incidence of invasive aspergillosis is increasing in non neutropaenic patients, such as those with chronic lung diseases or systemic disease treated with long-term immunosuppressive drugs and solid organ transplant recipients. This study reviews the specific features of invasive aspergillosis in non neutropaenic subjects (NNS) and discusses the value of the diagnostic tools and treatment in this population. A better understanding of the pathophysiology and the epidemiological characteristics of invasive aspergillosis would provide a means of adapting the staging and classification of the disease for NNS. Invasive aspergillosis is under diagnosed in NNS who may already be colonised when they receive immunosuppressive treatment; this can lead to an adverse outcome in patients who are considered to be a moderate risk population.
ISSN: 0761-8425

hal-01118185
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118185
DOI : 10.1016/j.rmr.2010.01.004
PUBMED : 20965392