Novi derivati 9-aminoakridina kao inhibitori botulinum neurotoksina i P. falciparum parazita malarije

Steroidal and adamantane aminoacridine derivatives were prepared and tested as both botulinum neurotoxin (BoNT) inhibitors and antimalarials.. Steroid-bound acridines provided good potency against both the BoNT/A and BoNT/B light chains (LCs). The observed inhibition of the BoNT/B LC by ca. 50 % is the highest attained inhibitory activity against this serotype by acridine-based compounds to date. With respect to the antimalarial activity, the adamantane acridines were the most potent derivatives (IC50 = 6-9 nM, SI gt 326), indicating that an adamantyl group is a better carrier than a steroidal motif for this indication.Sintetisani su derivati steroidnih i adamantil-akridina i ispitana je njihova inhibitorna aktivnost prema botulinum neurotoksinima (BoNT) i parazitu malarije. Steroidni akridini pokazuju dobru inhibiciju prema kratkom nizu (LCs) BoNT/A i BoNT/B. Ostvarena inhibicija BoNT/B LC od oko 50% je najviša postignuta vrednost akridinskih derivata prema ovom serotipu. Adamantil-akridinski derivati su pokazali najveću antimalarijsku aktivnost (IC50 u opsegu 6-9 nM, SI gt 326), pokazujući da je adamantil-grupa bolji nosač farmakofore u poređenju sa steroidnim, prema ovoj indikaciji.

Supplementary data for article: Opsenica, I.; Tot, M.; Gomba, L.; Nuss, J. E.; Sciotti, R. J.; Bavari, S.; Burnett, J. C.; Šolaja, B. A. 4-Amino-7-Chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity. Journal of Medicinal Chemistry 2013, 56 (14), 5860–5871. https://doi.org/10.1021/jm4006077

Supporting information for: [https://doi.org/10.1021/jm4006077]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1381

Distribution épidémiologique de l’infection à VIH chez les femmes enceintes dans les dix régions du Cameroun et implications stratégiques pour les programmes de prévention

Introduction: le Cameroun se situe dans un contexte d'épidémie  généralisée du VIH. La sous-population des femmes enceintes, facilementaccessible au sein de la population générale, représente une cible  robante pour mener la surveillance du VIH et estimer l'évolution épidémiologique. L'objectif de notre étude était d'évaluer la distribution épidémiologique du VIH chez les femmes enceintes.Méthodes: étude transversale menée en 2012 chez 6521 femmes  enceintes (49,3% âgées de 15-24 ans) en première consultation prénatale (CPN1) dans 60 sites des 10 régions Camerounaises. L'algorithme en série a été utilisé pour le sérodiagnostic du VIH.Résultats: la prévalence du VIH était de 7,8% (508/6521), avec une  différence non significative (p=0,297) entre milieu rural (7,4%) et milieu urbain (8,1%). En zone rurale, cette prévalence variait de 0,7% à  l'Extrême-Nord à 11,8% au Sud. Cependant, en zone urbaine elle variait de 4% à l'Ouest à 11,1% au Sud-Ouest. Suivant l'âge, la prévalence était plus élevée (11,3%) chez les femmes de 35-39 ans. Suivant le niveau de scolarisation, la prévalence du VIH était plus faible (4,4%) chez celles non-scolarisées, et plus élevée (9,3%) chez celles ayant un niveau  primaire. Selon la profession, l'infection était plus élevée chez les  coiffeuses (15,5%), secrétaires (14,8%), commerçantes (12,9%) et  institutrices/enseignantes (10,8%). Conclusion: la prévalence du VIH reste élevée chez les femmes enceintes au Cameroun, sans distinction entre milieux rural et urbain. Les stratégies de prévention devraient s'orienter préférentiellement chez les femmes enceintes âgées, celles du niveau d'instruction primaire, et celles du  secteur des petites et moyennes entreprises

Supplementary data for article: Opsenica, I.; Tot, M.; Gomba, L.; Nuss, J. E.; Sciotti, R. J.; Bavari, S.; Burnett, J. C.; Šolaja, B. A. 4-Amino-7-Chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity. Journal of Medicinal Chemistry 2013, 56 (14), 5860–5871. https://doi.org/10.1021/jm4006077

Supporting information for: [https://doi.org/10.1021/jm4006077]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1381

Alteration of sarcoplasmic reticulum Ca²⁺ ATPase expression in lower limb ischemia caused by atherosclerosis obliterans

Atherosclerosis is a disease caused by a build-up of fatty plaques and cholesterol in the arteries. The lumen of the vessels is obliterated resulting in restricted blood supply to tissues. In ischemic conditions, the cytosolic Ca2+ level of skeletal muscle may increase, indicating the alteration of Ca2+ removal mechanisms. Ca2+ is transported from cytosol into the sarcoplasmic reticulum by Ca2+ ATPase (SERCA), with its 1a isoform expressed in adult, while its 1b isoform in neonatal and regenerating fast-twitch skeletal muscle. To investigate the role of these isoforms in ischemic skeletal muscle, biopsies from musculus biceps femoris of patients who underwent amputation due to atherosclerosis were examined. Samples were removed from the visibly healthy and hypoxia-affected tissue. Significantly increased SERCA1a expression was detected under the ischemic conditions (246 ± 69%; p  0.05), whereas SERCA2a did not change. In addition, in primary cultures derived from hypoxia-affected tissue, the diameter and fusion index of myotubes were significantly increased (30 ± 1.6 µm vs. 41 ± 2.4 µm and 31 ± 4% vs. 45 ± 3%; p < 0.05). We propose that the increased SERCA1a expression indicates the existence and location of compensating mechanisms in ischemic muscle

Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2

Larval development and ecology of

The life cycle of Baetis liebenauae has been investigated in a lowland spring of Northern Italy that shows a relative stability of water temperature. Nine postlarvula morphological stages of the larva were identified and a «jump development» of the wingpads between stage pairs has been noted. B. liebenauae is here a typical polyvoltine species and three generations can be defined, with the late-summer/autumn generation being the main one. During this generation the species is often the dominant taxon of the benthic community and shows a high larval density. Marquet differences have been in comparison noted with the development of this species in Poland. This is probably due to the different thermal features of the two regions. A temporal shift of the main generations seems to allow the coexistence of B. liebenauae and other high density Baetidae species. In Southern Europe the species is typical of small lowland streams with slow flowing waters. Its larvae live on aquatic macrophytes and their presence on mineral substrata can be considered as occasional

DRIVEN DROPLETS BY THERMOCAPILLARY EFFECT

We study the migration of droplets on a solid surface which is under a uniform temperature gradient. The present article focus on partial wetting fluids which surface tension depends on the squared temperature. These type of liquids, called self-rewetting, show a complex dynamics and here we will compare with those liquids of linear dependence in the temperature. Unlike to the latter ones, the droplet width increases with the time.Peer reviewe