|
| ||
|
|
||
Candidate Mechanism (candidate + mechanism)
Selected AbstractsPreferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunctionJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Imane Nafia Abstract Nigral depletion of the main brain antioxidant GSH is the earliest biochemical event involved in Parkinson's disease pathogenesis. Its causes are completely unknown but increasing number of evidence suggests that glutamate transporters [excitatory amino acid transporters (EAATs)] are the main route by which GSH precursors may enter the cell. In this study, we report that dopamine (DA) neurons, which express the excitatory amino acid carrier 1, are preferentially affected by EAAT dysfunction when compared with non-DA neurons. In rat embryonic mesencephalic cultures, l -trans-pyrrolidine-2,4-dicarboxylate, a substrate inhibitor of EAATs, is directly and preferentially toxic for DA neurons by decreasing the availability of GSH precursors and lowering their resistance threshold to glutamate excitotoxicity through NMDA-receptors. In adult rat, acute intranigral injection of l -trans-pyrrolidine-2,4-dicarboxylate induces a large regionally selective and dose-dependent loss of DA neurons and ,-synuclein aggregate formation. These data highlight for the first time the importance of excitatory amino acid carrier 1 function for the maintenance of antioxidant defense in DA neurons and suggest its dysfunction as a candidate mechanism for the selective death of DA neurons such as occurring in Parkinson's disease. [source] Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitisALLERGY, Issue 11 2009D.-Y. Oh Background:, Atopic dermatitis (AD) is a chronic inflammatory skin disease with a multifactorial pathogenesis and increasing incidence in the Western world. A genetically determined defective function of pattern recognition receptors such as toll-like receptors (TLRs) has been proposed as a candidate mechanism in the pathogenesis of AD. Aim:, To study the impact of genetic predisposition of five genes encoding for pattern recognition-related molecules for the phenotype of AD. Methods:, We examined nine different single-nucleotide polymorphism (SNP) frequencies in the genes encoding TLR1, -2, -4, -9 and the adapter molecule TIRAP by PCR with subsequent melting curve analysis in a case/control cohort of 136 adult AD patients and 129 age and gender matched non-atopic, healthy individuals. TLR2-expression and -function in cells from genotyped individuals were analysed. Results:, For the SNPs examined, similar genotype frequencies were found in both groups. In a subgroup of patients suffering from severe AD (SCORAD >50), a significantly increased representation of the A-allele in position ,16934 of the tlr2 gene was present (P = 0.004). Constitutive tlr2 mRNA expression in peripheral monocytes was independent of this tlr2 promoter SNP. Stimulation assays indicated that IL-6, but not TNF-, secretion following TLR2 stimulation is reduced in homozygous tlr2 -16934-A allele carriers. Conclusion:, These data indicate that TLR2 is relevant for the phenotype of severe AD in adults. [source] Spondylarthritis in HLA,B27/human ,2 -microglobulin,transgenic rats is not prevented by lack of CD8ARTHRITIS & RHEUMATISM, Issue 7 2009Joel D. Taurog Objective HLA,B27 predisposes to spondylarthritis by an unknown mechanism. A logical candidate mechanism is through recognition of B27 by CD8+ T cells. The purpose of this study was to examine the effects of a lack of CD8 on the spondylarthritis that develops in B27/human ,2 -microglobulin (Hu,2m),transgenic rats. Methods A missense mutation in the CD8a gene that causes a loss of CD8, expression was identified in offspring of a male Sprague-Dawley rat that had been treated with the mutagen N -ethyl- N -nitrosourea. The mutation was crossed into B27/Hu,2m-transgenic lines on the Lewis background. CD8a,/, and CD8a+/, progeny were compared on a mixed SD-LEW background as well as after at least 10 backcrosses to LEW rats. CD8 function was assessed by generating cytolytic T lymphocytes (CTLs) against allogeneic DA strain antigens. Results Homozygous mutant rats showed normal CD8a and CD8b messenger RNA levels but no detectable expression of either protein and an almost complete abrogation of the allogeneic CTL response. Two disease phenotypes previously observed in different B27/Hu,2m-transgenic lines also occurred in the respective CD8a,/, -transgenic rat lines. There was no significant difference in disease prevalence or severity between CD8a,/, rats and CD8a+/, rats. Conclusion All of the previously described disease manifestations in HLA,B27/Hu,2m-transgenic rats arise in the absence of any functional CD8+ T cells. It thus seems unlikely that classic T cell recognition of HLA,B27 is of primary importance in this animal model. The possibility of a secondary role of a CD8-dependent mechanism cannot be entirely excluded. [source] DILP-producing median neurosecretory cells in the Drosophila brain mediate the response of lifespan to nutritionAGING CELL, Issue 3 2010Susan J. Broughton Summary Dietary restriction extends lifespan in diverse organisms, but the gene regulatory mechanisms and tissues mediating the increased survival are still unclear. Studies in worms and flies have revealed a number of candidate mechanisms, including the target of rapamycin and insulin/IGF-like signalling (IIS) pathways and suggested a specific role for the nervous system in mediating the response. A pair of sensory neurons in Caenorhabditis elegans has been found to specifically mediate DR lifespan extension, but a neuronal focus in the Drosophila nervous system has not yet been identified. We have previously shown that reducing IIS via the partial ablation of median neurosecretory cells in the Drosophila adult brain, which produce three of the seven fly insulin-like peptides, extends lifespan. Here, we show that these cells are required to mediate the response of lifespan to full feeding in a yeast dilution DR regime and that they appear to do so by mechanisms that involve both altered IIS and other endocrine effects. We also present evidence of an interaction between these mNSCs, nutrition and sleep, further emphasising the functional homology between the DILP-producing neurosecretory cells in the Drosophila brain and the hypothalamus of mammals in their roles as integration sites of many inputs for the control of lifespan and behaviour. [source] The role of cytoplasmic streaming in symplastic transportPLANT CELL & ENVIRONMENT, Issue 1 2003W. F. PICKARD ABSTRACT The distributing of materials throughout a symplastic domain must involve at least two classes of transport steps: plasmodesmatal and cytoplasmic. To underpin the latter, the most obvious candidate mechanisms are cytoplasmic streaming and diffusion. The thesis will be here advanced that, although both candidates clearly do transport cytoplasmic entities, the cytoplasmic streaming per se is not of primary importance in symplastic transport but that its underlying molecular motor activity (of which the streaming is a readily visible consequence) is. Following brief tutorials on low Reynolds number flow, diffusion, and targeted intracytoplasmic transport, the hypothesis is broached that macromolecular and vesicular transport along actin trackways is both the cause of visible streaming and the essential metabolically driven cytoplasmic step in symplastic transport. The concluding discussion highlights four underdeveloped aspects of the active cytoplasmic step: (i) visualization of the real-time transport of messages and metabolites; (ii) enumeration of the entities trafficked; (iii) elucidation of the routing of the messages and metabolites within the cytoplasm; and (iv) transference of the trafficked entities from cytoplasm into plasmodesmata. [source] CARDIOVASCULAR AND METABOLIC EFFECTS OF OBESITYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2008Margaret J Morris SUMMARY 1Obesity is an important risk factor for hypertension and its incidence is increasing around the world. 2The mechanisms underlying obesity-related hypertension include sympathetic activation, altered vascular responses, hormonal changes, enhanced inflammatory markers and structural changes. 3This review summarizes recent evidence of the underlying impact of obesity on blood pressure. A number of candidate mechanisms include increased sympathetic activity, activation of the renin-angiotensin system, altered vasoconstrictor or dilator responses and the attendant systemic inflammatory state. 4While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant hypertension, evidence suggests that the programming of obesity may occur following over-nutrition during development. A growing body of evidence links maternal obesity, offspring obesity and hypertension. 5Finally, epigenetic modification of genes relevant to hypertension may contribute to the development of hypertension following a suboptimal intrauterine environment. To date the cardiovascular effects of early nutritional changes have been largely investigated following maternal under-nutrition or protein restriction; further work is necessary to determine the impact of maternal obesity. [source] | |||||||||||||