Home About us Contact
|
Home About us Contact | ||
|
|
||
Selective Accumulation (selective + accumulation)
Selected AbstractsBioavailability of decabromodiphenyl ether to the marine polychaete Nereis virensENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 4 2010Susan L. Klosterhaus Abstract The flame retardant decabromodiphenyl ether (BDE 209) accumulates in humans and terrestrial food webs, but few studies have reported the accumulation of BDE 209 in aquatic biota. To investigate the mechanisms controlling the bioavailability of BDE 209, a 28-d bioaccumulation experiment was conducted in which the marine polychaete worm Nereis virens was exposed to a decabromodiphenyl ether (deca-BDE) commercial mixture (>85% BDE 209) in spiked sediments, in spiked food, or in field sediments. Bioaccumulation from spiked substrate with maximum bioavailability demonstrated that BDE 209 accumulates in this species. Bioavailability depends on the exposure conditions, however, because BDE 209 in field sediments did not accumulate (<0.3 ng/g wet weight; 28-d biota-sediment accumulation factors [BSAFs] <0.001). When exposed to deca-BDE in spiked sediments also containing lower brominated congeners (a penta-BDE mixture), bioaccumulation of BDE 209 was 30 times lower than when exposed to deca-BDE alone. Selective accumulation of the lower brominated congeners supports their prevalence in higher trophic level species. The mechanisms responsible for limited accumulation of BDE 209 may involve characteristics of the sediment matrix and low transfer efficiency in the digestive fluid. Environ. Toxicol. Chem. 2010;29:860,868. © 2009 SETAC [source] Recombinase-deficient T cell development by selective accumulation of CD3 into lipid raftsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2008Denise Ferrera Abstract The pre-T cell receptor (pre-TCR) promotes the development of thymocytes with productive rearrangement at the TCR ,,chain locus by signaling in a ligand-independent fashion. The TCR ,,chain associates with the invariant pre-T, (pT,) chain, which bears specific charged residues in the extracellular portion mediating pre-TCR self-oligomerization. In recombinase-deficient thymocytes, calnexin (CNX) associated with CD3 chains is inefficiently retained in the endoplasmic reticulum (ER) and weakly expressed in the plasma membrane. Deliberate cross-linking of CNX/CD3 complexes mimics pre-TCR signaling. Here, we show that, analogously to the pT, chain, surface CNX is palmitoylated and that CD3 prominently accumulated in lipid rafts upon cross-linking. Mutant CNX isoforms devoid of ER retention determined pre-TCR-like signaling and simulated ,,selection only when stably translocating CD3 to lipid rafts. Inclusion of the palmitoylated cytoplasmic tail from the pT, chain in recombinant CNX strikingly improved the pre-TCR-like signaling efficiency of CNX/CD3 in rafts. This study indicates that lipid rafts in the plasma membrane represent proficient microdomains for the initiation of pre-TCR signaling, and supports the view that ,,selection by oligomerized pre-TCR is implemented by the pT, cytoplasmic tail. [source] Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivoJOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2010Anke J Roelofs Abstract Bisphosphonates are effective antiresorptive agents owing to their bone-targeting property and ability to inhibit osteoclasts. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogues, carboxyfluorescein-labeled risedronate (FAM-RIS) and Alexa Fluor 647,labeled risedronate (AF647-RIS), were used to address this question. Twenty-four hours after injection into 3-month-old mice, fluorescent risedronate analogues were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogues were present in osteocytic lacunae in close proximity to vascular channels and localized to the lacunae of newly embedded osteocytes close to the bone surface. Following injection into newborn rabbits, intracellular uptake of fluorescently labeled risedronate was detected in osteoclasts, and the active analogue FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14high bone marrow monocytes showed relatively high levels of uptake of fluorescently labeled risedronate, which correlated with selective accumulation of unprenylated Rap1A in CD14+ cells, as well as osteoclasts, following treatment with risedronate in vivo. Similar results were obtained when either rabbit or human bone marrow cells were treated with fluorescent risedronate analogues in vitro. These findings suggest that the capacity of different cell types to endocytose bisphosphonate is a major determinant for the degree of cellular drug uptake in vitro as well as in vivo. In conclusion, this study shows that in addition to bone-resorbing osteoclasts, bisphosphonates may exert direct effects on bone marrow monocytes in vivo. © 2010 American Society for Bone and Mineral Research [source] Fc, receptor,dependent expansion of a hyperactive monocyte subset in lupus-prone miceARTHRITIS & RHEUMATISM, Issue 8 2009Marie-Laure Santiago-Raber Objective Lupus-prone BXSB mice develop monocytosis characterized by selective accumulation of the Gr-1, monocyte subset. The aim of this study was to explore the possible role of activating IgG Fc receptors (Fc,R) in the development of monocytosis and to characterize the functional phenotype of the Gr-1, subset that accumulates in lupus-prone mice bearing the NZB-type defective Fcgr2b allele for the inhibitory Fc,RIIB. Methods The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factor,transgenic C57BL/6 mice deficient in activating Fc,R. Moreover, we assessed the expression levels of activating Fc,R and inhibitory Fc,RIIB on Gr-1+ and Gr-1, monocyte subsets in C57BL/6 mice bearing the C57BL/6-type or the NZB-type Fcgr2b allele. Results We observed monocytosis with expansion of the Gr-1, subset in anti-IgG2a,transgenic C57BL/6 mice expressing IgG2a, but not in those lacking IgG2a. Moreover, monocytosis barely developed in BXSB and anti-IgG2a,transgenic C57BL/6 mice deficient in activating Fc,R. The Gr-1, subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory Fc,RIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating Fc,RIV. This was in contrast to high levels of Fc,RIIB expression and no Fc,RIV expression on the Gr-1+ subset. Conclusion Our results demonstrated a critical role of activating Fc,R in the development of monocytosis and in the expansion of a Gr-1,Fc,RIIBlowFc,RIV+ hyperactive monocyte subset in lupus-prone mice. Our findings further highlight the importance of the NZB-type Fcgr2b susceptibility allele in murine lupus, the presence of which induces increased production of hyperactive monocytes as well as dysregulated activation of autoreactive B cells. [source] Vitamin D and Its Analog EB1089 Induce p27 Accumulation and Diminish Association of p27 with Skp2 Independent of PTEN in Pituitary Corticotroph CellsBRAIN PATHOLOGY, Issue 4 2002Wei Liu Disruption of the gene for the cyclin dependent kinase inhibitor (CDKI) p27/kip1 results in pituitary corticotroph hyperplasia while diminished expression of this protein has been described in aggressive human pituitary tumors. We have previously shown that 1,25-vitamin D3 (VD) hypophosphorylates p27 and interferes with the degradation of this CDKI in thyroid carcinoma cells. In this study we investigated whether VD/EB1089 can induce p27 accumulation and cause growth arrest of pituitary corticotroph cells. VD and EB1089 exhibited a significant reduction in AtT20 corticotroph but not PRL235 Iactotroph cell growth. These changes were accompanied by selective accumulation of p27 in AtT20 but not in PRL235 cells. As p27 levels are highly dependent on protein degradation, we examined the effect of VD/EB1089 on p27 association with factors that target this CDKI to the proteasome. VD/EB1089 significantly restricted the association of p27 with Skp2 as well as with cyclin dependent kinase 2 (CDK2). As the tumor suppressor and phosphatase PTEN has been implicated in p27 regulation, we tested whether the effects of VD/EB1089 on p27 accumulation in corticotrophs could be mediated through this pathway. VD/EB1089 did not appreciably alter PTEN expression. Moreover, transfection of PTEN did not influence the effect of VD on p27 accumulation in corticotrophs. We conclude that VD/EB1089 can selectively arrest pituitary corticotroph growth and induce p27 accumulation. This effect is mediated at least partially through diminished p27 association with Skp2 and with CDK2. In contrast to other cell systems, PTEN does not participate in the regulation of corticotroph p27 and is not involved in mediating the effect of VD on p27 in these cells. Our findings highlight p27 and VD analogs as targets for manipulation and drug development respectively in the treatment of inoperable corticotroph adenomas. [source] Targeting of photosensitizers to head and neck tumours by the use of monoclonal antibodiesCLINICAL OTOLARYNGOLOGY, Issue 4 2001G.A.M.S. Van Dongen Introduction. The objective was to improve the selectivity of photodynamic therapy (PDT) by targeting photosensitizers to tumours by the use of monoclonal antibodies (mAbs). Two sensitizers were selected for this approach. Meta-tetrahydroxyphenylchlorin (mTHPC) was selected because it is one of the most effective photosensitizers in free form. Aluminium (III) phthalocyanine tetrasulphonate [AlPc(SO3H)4] was selected because of its ideal photochemical properties. However, owing to its hydrophilicity, this latter sensitizer is not able to enter the tumour cell and, therefore, in free form is ineffective in PDT. We hypothesized that AlPc(SO3H)4 might become suitable for PDT when coupled to tumour-selective mAbs. Methods. These were developed to couple the sensitizers to mAbs, including mAb 425 directed against the epidermal growth factor receptor. These conjugates were evaluated for efficacy in PDT in vitro and for tumour-targeting capacity in vivo. Results.,In vitro PDT showed that the AlPc(SO3H)4,mAb 425 conjugate was ,7500 times more toxic to A431 cells than the free sensitizer (IC50 values 0.12 nm versus 900 nm), and was also more toxic than the mTHPC,mAb 425 conjugate and free mTHPC (IC50 values 7.3 nm versus 2.0 nm). Biodistribution analysis of the conjugates in tumour-bearing nude mice showed selective accumulation in the tumour. Conclusion. These data show that AlPc(SO3H)4, in particular, has high potential for use in PDT when coupled to tumour-selective mAbs. [source] | ||||||||||