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The substantia nigra is not the induction site in the brain of the neurodegenerative process that underlies Parkinson’s disease. Instead, the results of this semiquantitative study of 30 autopsy cases with incidental Lewy body pathology indicate that Parkinson’s disease in the brain commences with the formation of the very first immunoreactive Lewy neurites and Lewy bodies in noncatecholaminergic visceromotor neurons of the dorsal glossopharyngeusvagus complex, in projection neurons of the intermediate reticular zone, and in specific nerve cell types of the gain setting system (coeruleussubcoeruleus complex, caudal raphe nuclei, gigantocellular reticular nucleus), olfactory bulb, olfactory tract, and/or anterior olfactory nucleus in the absence of nigral involvement. The topographical parcellation of the nuclear grays described here is based upon known architectonic analyses of the human brain stem and takes into consideration the pigmentation properties of a few highly susceptible nerve cell types involved in Parkinson’s disease. In this sample and in all 58 ageand gendermatched controls, Lewy bodies and Lewy neurites do not occur in any of the known telencephalic Parkinson’s disease predilection sites (hippocampal formation, temporal mesocortex, proneocortical cingulate areas, amygdala, basal nucleus of Meynert, interstitial nucleus of the diagonal band of Broca, hypothalamic tuberomamillary nucleus).
Background: Severe allergic reactions during rush-specific immunotherapy (Rush-SIT) may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during Rush-SIT in a cohort of patients with allergy towards hymenoptera venom in the mediterranean population of Albania.
Methods: A retrospective study was performed using the clinical reports of 37 patients with venom of bee (apinae), wasp (vespidae, subfamily vespinae) or paperwasp (vespidae, subfamily polistinae) allergy treated with Rush-SIT between 1987 and 1996. After hymenoptera sting allergy diagnosis according to anamnesis and intracutaneous tests the patient were treated with Rush-SIT. The protocol lasted 3 - 4 d with an increase in the concentration from 0.01 microg/ml to 100 microg/ml. Anaphylactic reactions were classified according to the Mueller-classification.
Results: The frequency of reactions during Rush-SIT for bee-venom was 4.7% and for wasp-venom was 1.5% (p < 0.01). The mean frequency of reactions of Mueller grade II for the bee-venom Rush-SIT patients during the first 4 d (= 26 injections) was 0.73 and for the wasp-venom Rush-SIT patients 0.15. No patient experienced a third-degree reaction. 94.6% of the patient supported an end dose of 100 microg.
Conclusions: Rush-SIT is a reliable method for the treatment of anaphylactic reactions to hymenoptera venom even in less developed countries. Bee-venom Rush-SIT was found to cause higher numbers allergic reactions than wasp or paperwasp Rush-SIT.
Objectives: The possible effects of exposure to neurotoxic substances such as gasoline, diesel fuel, paint, varnish, and solvents on the pathogenesis of obstructive sleep apnea were examined.
Methods: Four hundred and forty-three persons with incident obstructive sleep apnea were recruited within the framework of a case-referent study. A reference population (N=397) was included as the first reference group. In addition 106 patients whose sleep laboratory findings confirmed that they were not suffering from obstructive sleep apnea were then included as a second reference group. Data were gathered with a questionnaire which had to be filled out by the persons with obstructive sleep apnea (cases) and the referents themselves. In the assessment of occupational exposure the questionnaires were filled out by the subjects themselves, and a job-exposure matrix was also used. Data were analyzed using logistic regression to control for age, region, body mass index, cigarette smoking, and alcohol consumption.
Results: None of the exposures were statistically significantly associated with obstructive sleep apnea. There was no correlation with occupation. Only current activities in service occupations revealed an increased odds ratio, 1.6 (95% confidence interval 1.1-2.4).
Conclusions: No suggestion was found of an association between exposure to solvents and obstructive sleep apnea.
In polarized cells, the multidrug resistance protein MRP2 is localized in the apical plasma membrane, whereas MRP1, another multidrug resistance protein (MRP) family member, is localized in the basolateral membrane. MRP1 and MRP2 are thought to contain an N-terminal region of five transmembrane segments (TMD0) coupled to 2 times six transmembrane segments via an intracellular loop (L0). We previously demonstrated for MRP1 that a mutant lacking TMD0 but still containing L0, called L0ΔMRP1, was functional and routed to the lateral plasma membrane. To investigate the role of the TMD0L0 region of MRP2 in routing to the apical membrane, we generated mutants similar to those made for MRP1. In contrast to L0ΔMRP1, L0ΔMRP2 was associated with an intracellular compartment, most likely endosomes. Co-expression with TMD0, however, resulted in apical localization of L0ΔMRP2 and transport activity. Uptake experiments with vesicles containing L0ΔMRP2 demonstrated that the molecule is able to transport LTC4. An MRP2 mutant without TMD0L0, ΔMRP2, was only core-glycosylated and localized intracellularly. Co-expression of ΔMRP2 with TMD0L0 resulted in an increased protein level of ΔMRP2, full glycosylation of the protein, routing to the apical membrane, and transport activity. Our results suggest that the TMD0 region is required for routing to or stable association with the apical membrane.
We investigated the molecular mechanism of cyclic GMP-induced down-regulation of soluble guanylyl cyclase expression in rat aorta. 3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1), an allosteric activator of this enzyme, decreased the expression of soluble guanylyl cyclase α1 subunit mRNA and protein. This effect was blocked by the enzyme inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b-1,4)oxazin-1-one (NS2028) and by actinomycin D. Guanylyl cyclase α1mRNA-degrading activity was increased in protein extracts from YC-1-exposed aorta and was attenuated by pretreatment with actinomycin D and NS2028. Gelshift and supershift analyses using an adenylate-uridylate-rich ribonucleotide from the 3′-untranslated region of the α1 mRNA and a monoclonal antibody directed against the mRNA-stabilizing protein HuR revealed HuR mRNA binding activity in aortic extracts, which was absent in extracts from YC-1-stimulated aortas. YC-1 decreased the expression of HuR, and this decrease was prevented by NS2028. Similarly, down-regulation of HuR by RNA interference in cultured rat aortic smooth muscle cells decreased α1 mRNA and protein expression. We conclude that HuR protects the guanylyl cyclase α1 mRNA by binding to the 3′-untranslated region. Activation of guanylyl cyclase decreases HuR expression, inducing a rapid degradation of guanylyl cyclase α1 mRNA and lowering α1 subunit expression as a negative feedback response.
Ceramide levels are strongly increased by stimulation of renal mesangial cells with nitric oxide (NO). This effect was shown previously to be due to a dual action of NO, comprising an activation of sphingomyelinases and an inhibition of ceramidase activity. In this study we show that the NO-triggered inhibition of neutral ceramidase activity is paralleled by a down-regulation at the protein level. A complete loss of neutral ceramidase protein is obtained after 24 h of stimulation. Whereas the selective proteasome inhibitor lactacystin blocked NO-evoked ceramidase degradation, several caspase inhibitors were ineffective. Moreover, the NO-induced degradation is reversed by the protein kinase C (PKC) activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), and also by the physiological PKC activators platelet-derived growth factor-BB (PDGF), angiotensin II and ATP, resulting in a normalization of neutral ceramidase protein as well as activity. In vivophosphorylation studies using 32Pi-labeled mesangial cells revealed that TPA, PDGF, angiotensin II, and ATP trigger an increased phosphorylation of the neutral ceramidase, which is blocked by the broad spectrum PKC inhibitor Ro-31 8220 but not by CGP 41251, which has a preferential action on Ca2+-dependent isoforms, thus suggesting the involvement of a Ca2+-independent PKC isoform. In vitro phosphorylation assays using recombinant PKC isoenzymes and neutral ceramidase immunoprecipitated from unstimulated mesangial cells show that particularly the PKC-δ isoform and to a lesser extent the PKC-α isoform are efficient in directly phosphorylating neutral ceramidase. In summary, our data show that NO is able to induce degradation of neutral ceramidase, thereby promoting accumulation of ceramide in the cell. This effect is reversed by PKC activation, most probably by the PKC-δ isoenzyme, which can directly phosphorylate and thereby prevent neutral ceramidase degradation. These novel regulatory interactions will provide therapeutically valuable information to target neutral ceramidase stability and subsequent ceramide accumulation.
Glycogen synthase kinase-3 couples AKT-dependent signaling to the regulation of p21Cip1 degradation
(2002)
Signaling via the phosphoinositide 3-kinase (PI3K)/AKT pathway is crucial for the regulation of endothelial cell (EC) proliferation and survival, which involves the AKT-dependent phosphorylation of the DNA repair protein p21(Cip1) at Thr-145. Because p21(Cip1) is a short-lived protein with a high proteasomal degradation rate, we investigated the regulation of p21(Cip1) protein levels by PI3K/AKT-dependent signaling. The PI3K inhibitors Ly294002 and wortmannin reduced p21(Cip1) protein abundance in human umbilical vein EC. However, mutation of the AKT site Thr-145 into aspartate (T145D) did not increase its protein half-life. We therefore investigated whether a kinase downstream of AKT regulates p21(Cip1) protein levels. In various cell types, AKT phosphorylates and inhibits glycogen synthase kinase-3 (GSK-3). Upon serum stimulation of EC, GSK-3beta was phosphorylated at Ser-9. Site-directed mutagenesis revealed that GSK-3 in vitro phosphorylated p21(Cip1) specifically at Thr-57 within the Cdk binding domain. Overexpression of GSK-3beta decreased p21(Cip1) protein levels in EC, whereas the specific inhibition of GSK-3 with lithium chloride interfered with p21(Cip1) degradation and increased p21(Cip1) protein about 10-fold in EC and cardiac myocytes (30 mm, p < 0.001). These data indicate that GSK-3 triggers p21(Cip1) degradation. In contrast, stimulation of AKT increases p21(Cip1) via inhibitory phosphorylation of GSK-3.
The yeast F1F0-ATP synthase forms dimeric complexes in the mitochondrial inner membrane and in a manner that is supported by the F0-sector subunits, Su e and Su g. Furthermore, it has recently been demonstrated that the binding of the F1F0-ATPase natural inhibitor protein to purified bovine F1-sectors can promote their dimerization in solution (Çabezon, E., Arechaga, I., Jonathan P., Butler, G., and Walker J. E. (2000) J. Biol. Chem. 275, 28353–28355). It was unclear until now whether the binding of the inhibitor protein to the F1 domains contributes to the process of F1F0-ATP synthase dimerization in intact mitochondria. Here we have directly addressed the involvement of the yeast inhibitor protein, Inh1, and its known accessory proteins, Stf1 and Stf2, in the formation of the yeast F1F0-ATP synthase dimer. Using mitochondria isolated from null mutants deficient in Inh1, Stf1, and Stf2, we demonstrate that formation of the F1F0-ATP synthase dimers is not adversely affected by the absence of these proteins. Furthermore, we demonstrate that the F1F0-ATPase monomers present in su e null mutant mitochondria can be as effectively inhibited by Inh1, as its dimeric counterpart in wild-type mitochondria. We conclude that dimerization of the F1F0-ATP synthase complexes involves a physical interaction of the membrane-embedded F0 sectors from two monomeric complexes and in a manner that is independent of inhibitory activity of the Inh1 and accessory proteins.