gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site.

gamma-Secretase is an unusual protease with an intramembrane catalytic site that cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor. Genetic and biochemical studies have identified four membrane proteins as components of gamma-secretase: heterodimeric presenilin composed of its N- and C-terminal fragments, nicastrin, Aph-1, and Pen-2. Here we demonstrated that certain compounds, including protein kinase inhibitors and their derivatives, act directly on purified gamma-secretase to selectively block cleavage of APP- but not Notch-based substrates.

Structure-activity relationship study of novel necroptosis inhibitors.

Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling necrosis. It can be induced in a FADD-deficient variant of human Jurkat T cells treated with TNF-alpha. 5-(1H-Indol-3-ylmethyl)-2-thiohydantoins and 5-(1H-indol-3-ylmethyl)hydantoins were found to be potent necroptosis inhibitors (called necrostatins).

Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells.

Ischemia causes kidney tubular cell damage and abnormal renal function. The kidney is capable of morphological restoration of tubules and recovery of function. Recently, it has been suggested that cells repopulating the ischemically injured tubule derive from bone marrow stem cells.

Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in men.

Background: Emerging evidence suggests a possible role of lycopene in the primary prevention of cardiovascular disease (CVD).

Objective: We examined whether plasma lycopene concentrations in the Physicians' Health Study were associated with CVD in a prospective, nested, case-control design.

Design: Baseline blood samples were collected starting in 1996.

Methotrexate-induced bullous acral erythema in a child.

Chemotherapy induced acral erythema (CIAE) is an uncommon and dramatic reaction to high-dose chemotherapy. It is characterized by symmetrical, well-demarcated, painful erythema of the palms and soles which may progress to bullae formation and desquamation. Prompt recognition and discrimination from more serious conditions such as graft-vs-host disease or toxic epidermal necrolysis is essential.

The stomach mesenchymal transcription factor Barx1 specifies gastric epithelial identity through inhibition of transient Wnt signaling.

Inductive interactions between gut endoderm and the underlying mesenchyme pattern the developing digestive tract into regions with specific morphology and functions. The molecular mechanisms behind these interactions are largely unknown. Expression of the conserved homeobox gene Barx1 is restricted to the stomach mesenchyme during gut organogenesis.

Pathological changes in acute coronary syndromes: the role of statin therapy in the modulation of inflammation, endothelial function and coagulation.

Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD), their acute presentations as acute coronary syndromes (ACS) and the role of LDL cholesterol. In particular there is clear evidence that atherosclerosis is far from being a process that leads to an amorphous flow limiting lesion on an angiogram, but rather involves a complex interplay between the endothelium, inflammatory cells and the coagulation cascade occurring throughout the coronary vascular bed. While a culprit flow limiting lesion may be effectively treated by a drug eluting stent or coronary bypass surgery, this will have little impact on the global molecular processes that determine recurrent plaque instability at non-culprit sites.

Structure-activity relationship study of novel tissue transglutaminase inhibitors.

Thieno[2,3-d]pyrimidin-4-one acylhydrazide derivatives were discovered as moderately potent inhibitors of TGase 2 (tissue transglutaminase) utilizing a fluorescence-based assay that measured TGase 2 catalyzed incorporation of the dansylated Lys derivative alpha-N-Boc-Lys-CH(2)-CH(2)-dansyl into the protein substrate N,N-dimethylated-casein. A SAR study revealed that the acylhydrazide thioether side-chain and the thiophene ring were critical to inhibitory activity.

Troponins in acute coronary syndromes.

Cardiac troponins have replaced creatine kinase-MB as the preferred biomarker for establishing the diagnosis of myocardial infarction (MI). Expert recommendations set the diagnostic decision-limit for each assay at the 99th percentile of troponin levels in an apparently healthy reference population, which due to a lack of standardization, will vary depending upon the manufacturer. Among patients presenting with an acute coronary syndrome (ACS), even low-level elevations of cardiac troponin T or I correlate with higher risk of death and recurrent ischemic events compared to patients with levels of troponin below the decision limit.

Gastrointestinal stromal tumors (GISTs).

Purpose Of Review: Gastrointestinal stromal tumors (GISTs) have recently been the subject of considerable clinical and experimental interest. This focus is based on the recognition that GISTs characteristically have uncontrolled activation of the KIT protein, a transmembrane tyrosine kinase receptor involved in cell survival, development, and proliferation. The clinical application of imatinib mesylate, a selective inhibitor of the KIT kinase activity, has provided a novel molecularly targeted therapy for these tumors.

Effects of a verbenachalcone derivative on neurite outgrowth, inhibition of caspase induction and gene expression.

A verbenachalcone derivative was synthesized and shown to protect N2a cells from caspase induction caused by serum starvation and to enhance the effect of NGF on neurite outgrowth in PC12 cells. As an initial investigation of the compound's mechanism(s) of action, we performed differential gene expression profiling in PC12 cells using oligonucleotide ( approximately 10,000 gene probes) microarrays. Gene expression patterns were compared in the presence of NGF (2 and 50 ng/mL) and NGF (2 ng/mL) plus the verbenachalcone derivative.

Development of chronic daily headache: a clinical study.

We studied the development of chronic daily headache in 258 headache practice patients, 50 men and 208 women. Chronic daily headache was defined as headaches occurring at least 5 days per week for at least 1 year. Twenty-two percent of the patients had daily headaches from the onset, and 78% initially experienced intermittent headaches.

Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage.

Research on Alzheimer's disease led to the identification of a novel proteolytic mechanism in all metazoans, the presenilin/gamma-secretase complex. This unique intramembrane-cleaving aspartyl protease is required for the normal processing of Notch, Jagged, beta-amyloid precursor protein (APP), E-cadherin, and many other receptor-like proteins. We recently provided indirect evidence of gamma-secretase activity at the cell surface in HeLa cells following inhibition of receptor-mediated endocytosis.

Induction of angiogenesis by heat shock protein 90 mediated by protein kinase Akt and endothelial nitric oxide synthase.

Objective: A specific inhibitor of heat shock protein 90 (Hsp90), 17-AAG, has been shown to inhibit tumor growth through cell cycle arrest, differentiation, or apoptosis. Because angiogenesis is important for tumor growth, we hypothesize that inhibition of angiogenesis by 17-AAG may mediate some of its antitumor effects.

Methods And Results: Because protein kinase Akt and endothelial nitric oxide synthase (eNOS) are critical for angiogenesis, we studied the effects of 17-AAG on the phosphorylation and expression of Akt and eNOS in human umbilical vein endothelial cells.

Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection.

Objective: Rho-kinase activity is increased in cardiovascular diseases and in patients with cardiovascular risk factors. However, it is not known whether inhibition of Rho-kinase could lead to cardiovascular protection and, if so, by what mechanism.

Methods And Results: In human endothelial cells, the Rho-kinase inhibitor, hydroxyfasudil (HF) (1 to 100 micromol/L), increased Akt serine-473 phosphorylation within 15 minutes, leading to a 2.

Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet.

Amyloid beta (Abeta) protein immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). Here we show that Caribbean vervet monkeys (Chlorocebus aethiops, SK) develop cerebral Abeta plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Abeta peptide over 10 months.

Aldosterone in the development and progression of renal injury.

Background: The renin-angiotensin-aldosterone system (RAAS) contributes to hypertension and nephropathy. Until recently, aldosterone either has not been considered or has been considered a relatively minor component of the process-a contribution that could be negated with angiotensin-converting enzyme (ACE) inhibition or angiotensin receptor blockade.

Methods: A Medline search was performed to identify relevant literature describing the role of aldosterone in the pathogenesis of renal dysfunction.

Troponins in acute coronary syndromes.

Delivering superior clinical specificity and sensitivity for myocardial necrosis, cardiac troponin has replaced creatine kinase-MB as the preferred biomarker for establishing the diagnosis of myocardial infarction. On the basis of expert recommendations, present convention sets the diagnostic decision-limit for each assay at the 99th percentile of troponin levels in an apparently healthy reference population. Owing to a lack of standardization between different assays, this level, corresponding to the 99th percentile, will vary depending upon the manufacturer.

Genome-wide linkage analysis of longitudinal phenotypes using sigma2A random effects (SSARs) fitted by Gibbs sampling.

The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the familial aggregation and evidence for linkage to change in systolic blood pressure (SBP) over time.

Distance from the coronary ostium to the culprit lesion in acute ST-elevation myocardial infarction and its implications regarding the potential prevention of proximal plaque rupture.

Background: Shorter distances from the coronary ostia to culprit lesions have been associated with a higher incidence of adverse outcomes in ST elevation acute myocardial infarction (STEMI). As drug-eluting stents are associated with low rates of restenosis and formation of a stable intima, we sought to develop a mathematical model to estimate how far down the coronary artery a drug-eluting stent would have to be placed to theoretically mitigate the risk of proximal plaque rupture.

Objectives And Methods: Distances from the ostia to the end of the culprit lesions were planimetered in 1,914 patients from the TIMI 14, INTEGRITI, FASTER and ENTIRE/TIMI 23 trials.

Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex.

Gamma-secretase is a member of a new class of proteases with an intramembrane catalytic site and cleaves numerous type I membrane proteins, including the amyloid beta-protein precursor (APP) and the Notch receptor. Biochemical and genetic studies have identified four membrane proteins as components of gamma-secretase: a heterodimeric form of presenilin (PS), composed of its N- and C-terminal fragments (PS-NTF and PS-CTF, respectively), a highly glycosylated, mature form of nicastrin (NCT), Aph-1, and Pen-2. However, it is unclear how these components interact physically with each other and assemble into functional complexes.