43 research outputs found
Fluconazole and amphotericin-B resistance are associated with increased catalase and superoxide dismutase activity in Candida albicans and Candida dubliniensis
Sterol 14α-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana
Amphotericin B has emerged as the therapy of choice for use against the leishmaniases. Administration of the drug in its liposomal formulation as a single injection is being promoted in a campaign to bring the leishmaniases under control. Understanding the risks and mechanisms of resistance is therefore of great importance. Here we select amphotericin B-resistant Leishmania mexicana parasites with relative ease. Metabolomic analysis demonstrated that ergosterol, the sterol known to bind the drug, is prevalent in wild-type cells, but diminished in the resistant line, where alternative sterols become prevalent. This indicates that the resistance phenotype is related to loss of drug binding. Comparing sequences of the parasitesâ genomes revealed a plethora of single nucleotide polymorphisms that distinguish wild-type and resistant cells, but only one of these was found to be homozygous and associated with a gene encoding an enzyme in the sterol biosynthetic pathway, sterol 14α-demethylase (CYP51). The mutation, N176I, is found outside of the enzymeâs active site, consistent with the fact that the resistant line continues to produce the enzymeâs product. Expression of wild-type sterol 14α-demethylase in the resistant cells caused reversion to drug sensitivity and a restoration of ergosterol synthesis, showing that the mutation is indeed responsible for resistance. The amphotericin B resistant parasites become hypersensitive to pentamidine and also agents that induce oxidative stress. This work reveals the power of combining polyomics approaches, to discover the mechanism underlying drug resistance as well as offering novel insights into the selection of resistance to amphotericin B itself
Caenorhabditis elegans susceptibility to gut Enterococcus faecalis infection is associated with fat metabolism and epithelial junction integrity
Expression and function of G-protein-coupled receptorsin the male reproductive tract
This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisĂŁo enfatiza a expressĂŁo e a função dos receptores muscarĂnicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressĂŁo dos receptores muscarĂnicos e adrenoceptores α1 em compartimentos especĂficos de dĂșctulos eferentes, epidĂdimo, ductos deferentes, vesĂcula seminal e prĂłstata de vĂĄrias espĂ©cies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do mĂșsculo liso, incluindo efeitos na fertilidade masculina. AlĂ©m disso, a ativação dos receptores muscarĂnicos leva Ă transativação do receptor para o fator crescimento epidermal e proliferação das cĂ©lulas de Sertoli. Os receptores para relaxina estĂŁo presentes no testĂculo, RXFP1 nas espermĂĄtides alongadas e cĂ©lulas de Sertoli de rato e RXFP2 nas cĂ©lulas de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogĂȘnico. A localização de ambos os receptores na porção apical das cĂ©lulas epiteliais e no mĂșsculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo Ă Pesquisa do Estado de SĂŁo Paulo (FAPESP)Conselho Nacional de Desenvolvimento CientĂfico e TecnolĂłgico (CNPq)Universidade Federal de SĂŁo Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL