Inflammation is a potentially self-destructive process that needs tight control. We have identified a novel nuclear signaling mechanism through which the low-density lipoprotein receptor-related protein 1 (LRP1) limits transcription of lipopolysaccharide (LPS)-inducible inflammatory genes in vitro and in vivo. Stimulation with LPS increases proteolytic processing of the LRP1 ectodomain, resulting in the γ-secretase-dependent release of the LRP1 intracellular domain (ICD) from the plasma membrane and its translocation to the nucleus, where it binds to and represses the interferon-γ promoter. Basal transcription of LPS target genes and LPS-induced secretion of proinflammatory cytokines are increased in the absence of LRP1. Physical interaction of the LRP1 ICD with IRF-3 promotes its nuclear export and proteasomal degradation. Feedback inhibition of the inflammatory response through intramembranous processing of LRP1 thus defines a novel physiological role for γ-secretase.
R-type calcium channels (RTCCs) are well known for their role in synaptic plasticity, but little is known about their subcellular distribution across various neuronal compartments. Using subtype-specific antibodies, we characterized the regional and subcellular localization of Ca v 2.3 in mice and rats at both light and electron microscopic levels. Ca v 2.3 immunogold particles were found to be predominantly presynaptic in the interpeduncular nucleus, but postsynaptic in other brain regions. Serial section analysis of electron microscopic images from the hippocampal CA1 revealed a higher density of immunogold particles in the dendritic shaft plasma membrane compared with the pyramidal cell somata. However, the labeling densities were not significantly different among the apical, oblique, or basal dendrites. Immunogold particles were also observed over the plasma membrane of dendritic spines, including both synaptic and extrasynaptic sites. Individual spine heads contained Ͻ20 immunogold particles, with an average density of ϳ260 immunoparticles per m 3 spine head volume, in accordance with the density of RTCCs estimated using calcium imaging (Sabatini and Svoboda, 2000). The Ca v 2.3 density was variable among similar-sized spine heads and did not correlate with the density in the parent dendrite, implying that spines are individual calcium compartments operating autonomously from their parent dendrites.
Background: Neuronally LRP1-deficient mice show severe neurological signs and symptoms. Results: Neuronal LRP1 is cleaved by ␥-secretase and regulates NMDA-dependent signaling and protein turnover. Conclusion: LRP1 modulates postsynaptic protein complexes and thus has the potential to influence synaptic transmission. Significance: This might explain why neuronal LRP1 is essential in vivo and shed light on its genetic association with neurodegenerative disease (i.e. Alzheimer disease).
Low density lipoprotein receptor-related protein 1 (LRP1) is indispensable for embryonic development. Comparing different genetically engineered mouse models, we found that expression of Lrp1 is essential in the embryo proper. Loss of LRP1 leads to lethal vascular defects with lack of proper investment with mural cells of both large and small vessels. We further demonstrate that LRP1 modulates Gi-dependent sphingosine-1-phosphate (S1P) signaling and integrates S1P and PDGF-BB signaling pathways, which are both crucial for mural cell recruitment, via its intracellular domain. Loss of LRP1 leads to a lack of S1P-dependent inhibition of RAC1 and loss of constraint of PDGF-BB-induced cell migration. Our studies thus identify LRP1 as a novel player in angiogenesis and in the recruitment and maintenance of mural cells. Moreover, they reveal an unexpected link between lipoprotein receptor and sphingolipid signaling that, in addition to angiogenesis during embryonic development, is of potential importance for other targets of these pathways, such as tumor angiogenesis and inflammatory processes.
Insulin degludec is a new-generation long-acting insulin analog that has stable and ultra-long glucose-lowering effects, as demonstrated using the euglycemic clamp technique.1,2 It has recently been approved for the treatment of diabetes in Europe and Japan. Insulin degludec is a soluble dihexamer preparation that forms stable soluble multihexamers after subcutaneous injection. These multihexamers are retained at the injection site for a short period of time before entering the blood stream in a slow and sustained manner by gradual dissolution with releasing monomers. They also bind with albumin via a fatty acid side chain at the injection site and in the blood, increasing the duration of the action. It has been reported that the frequency of nocturnal hypoglycemia was significantly lower in patients treated with insulin degludec than in patients treated with insulin glargine if overall glycemic control was equal.3-5 However, in the Food and Drug Administration review, 6 the advantageous effects of insulin degludec in nocturnal hypoglycemia were not apparent when patients with type 1 diabetes were analyzed alone or when the definition of the nighttime period was changed from 0:01-5:59 to 21:59-5:59 or to 0:01-7:59. Therefore, it is unclear whether insulin degludec is associated with a lower frequency of nocturnal hypoglycemia compared to insulin glargine. In addition, in a clamp study of The study presents a comparison of the glucose-lowering effects, glycemic variability, and insulin doses during treatment with insulin degludec or insulin glargine. Methods: In this open-label, single-center, 2-way crossover study, 13 Japanese diabetic outpatients in the insulin-dependent state on basal-bolus therapy were assigned to receive either insulin glargine followed by insulin degludec, or insulin degludec followed by insulin glargine. Basal insulin doses were fixed in principle, and patients self-adjusted their bolus insulin doses. Seventy-two-hour continuous glucose monitoring was performed 2 weeks after switching the basal insulin. Results: Mean blood glucose (mg/dL) was not significantly different between insulin degludec and insulin glargine over 48 hours (141.8 ± 35.2 vs 151.8 ± 43.3), at nighttime (125.6 ± 40.0 vs 124.7 ± 50.4), or at daytime (149.3 ± 37.1 vs 163.3 ± 44.5). The standard deviation (mg/dL) was also similar (for 48 hours: 48.9 ± 19.4 vs 50.3 ± 17.3; nighttime: 18.7 ± 14.3 vs 13.7 ± 6.7; daytime: 49.3 ± 20.0 vs 44.3 ± 17.7). Other indices of glycemic control, glycemic variability, and hypoglycemia were similar for both insulin analogs. Total daily insulin dose (TDD) and total daily bolus insulin dose (TDBD) were significantly lower with insulin degludec than with insulin glargine (TDD: 0.42 ± 0.20 vs 0.46 ± 0.22 U/ kg/day, P = .028; TDBD: 0.27 ± 0.13 vs 0.30 ± 0.14 U/kg/day, P = .036). Conclusions: Insulin degludec and insulin glargine provided effective and stable glycemic control. Insulin degludec required lower TDD and TDBD in this population of patients.
We report on a 3 year old girl with acute promyelocytic leukemia (APL) with cerebral infarction due to disseminated intravascular coagulation (DIC) at initial presentation. She was hospitalized because of unconsciousness and petechiae on the chest wall and extremities. Cerebral ischemia and infarction were found on computed tomography scan and magnetic resonance imaging. Peripheral bood content was hemoglobin 7.3 g/dL, white blood cells 1.0 × 103cells/μL (31% blasts) and platelet count was 12 × 103cells/μL. Fragmented erythrocytes were frequently observed on May‐Giemsa stained blood smears. Bone marrow aspirates showed normal cellularity, with 60.4% blasts, containing faggot cells. The blasts were positive for peroxidase. Therapy was begun; however, the patient died 1 week after admission.
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