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Biomedical subjects

D Stern

Publications and source records attributed to D Stern.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid beta-peptide.

Insights into factors underlying causes of familial Alzheimer's disease (AD), such as mutant forms of beta-amyloid precursor protein and presenilins, and those conferring increased risk of sporadic AD, such as isoforms of apolipoprotein E and polymorphisms of alpha2-macroglobulin, have been rapidly emerging. However, mechanisms through which amyloid beta-peptide (Abeta), the fibrillogenic peptide most closely associated with neurotoxicity in AD, exerts its effects on cellular targets have only been more generally outlined. Late in the course of AD, when Abeta fibrils are abundant, non-specific interactions of amyloid with cellular elements are likely to induce broad cytotoxicity. However, early in AD, when concentrations of Abeta are much lower and extracellular deposits are infrequent, mechanisms underlying cellular dysfunction have not been clearly defined. The key issue in elucidating the means through which Abeta perturbs cellular properties early in AD is the possibility that protective therapy at such times may prevent cytotoxicity at a point when damage is still reversible. This brief review focusses on two cellular cofactors for Abeta-induced cellular perturbation: the cell surface immunoglobulin superfamily molecule RAGE (receptor for advanced glycation endproducts) and ABAD (Abeta binding alcohol dehydrogenase). Although final proof for the involvement of these cofactors in cellular dysfunction in AD must await the results of further in vivo experiments, their increased expression in AD brain, as well as other evidence described below, suggests the possibility of specific pathways for Abeta-induced cellular perturbation which could provide future therapeutic targets.

Alcohol Dehydrogenase↗
PubMed2000

Protein kinase C-beta and oxygen deprivation. A novel Egr-1-dependent pathway for fibrin deposition in hypoxemic vasculature.

Fibrin deposition is a salient feature of hypoxemic vasculature and results from induction of tissue factor. Such tissue factor expression in an oxygen deficient environment is driven by the transcription factor Early Growth Response (Egr)-1. Using homozygous null mice for the protein kinase C beta-isoform gene (PKCbeta null), PKCbeta is shown to be upstream of Egr-1 in this oxygen deprivation-mediated pathway for triggering procoagulant events. Whereas wild-type mice exposed to hypoxia (6%) displayed a robust increase in tissue factor transcripts and antigen, and vascular fibrin deposition, PKCbeta null animals showed a markedly blunted response. Consistent with a central role for Egr-1 in hypoxia-induced expression of tissue factor, PKCbeta null mice subjected to oxygen deprivation displayed at most a minor elevation in Egr-1 transcripts, antigen, and intensity of the gel shift band by electrophoretic mobility shift assay, compared with normoxic animals. These data firmly establish PKCbeta as a trigger for events leading to induction of Egr-1 and tissue factor under hypoxic conditions, and provide insight into a biologic cascade whereby oxygen deprivation recruits targets of PKCbeta and Egr-1, thereby amplifying the cellular response.

Animals↗
PubMed2000

Discovery of a Color-selected Quasar at z = 5.50.

We present observations of RD J030117+002025, a quasar at z=5.50 discovered from deep, multicolor, ground-based observations covering 74 arcmin2. This is the most distant quasar or active galaxy currently known. The object was targeted as an R-band dropout, with RAB>26.3 (3 sigma limit in a 3&arcsec; diameter region), IAB=23.8, and zAB=23.4. The Keck/Low-Resolution Imaging Spectrometer spectrum shows broad Lyalpha/N v lambda1240 emission and sharp absorption decrements from the highly redshifted hydrogen forests. The fractional continuum depression due to the Lyalpha forest is DA=0.90. RD J030117+002025 is the least luminous high-redshift quasar known (MB approximately -22.7).

Journal Article↗
PubMed2000

Regulation of plastid rDNA transcription by interaction of CDF2 with two different RNA polymerases.

The plastid genome is known to be transcribed by a plastid-encoded prokaryotic-type RNA polymerase (PEP) and by a nucleus-encoded phage-type RNA polymerase (NEP). The spinach plastid rrn operon promoter region harbours three different, overlapping promoters. Two of them are of the prokaryotic type. The third promoter is a non-consensus-type NEP promoter. We separated three different transcriptional activities from spinach chloroplasts: PEP, the phage-type RNA polymerase NEP-1, and a third, hitherto undescribed transcriptional activity (NEP-2). NEP-2 specifically transcribes the rrn operon in the presence of the transcription factor CDF2. CDF2 was previously shown to recruit PEP to the rrn promoter to repress transcription. Together, our results suggest the existence of a third RNA polymerase in plastids and a mechanism of rDNA transcriptional regulation that is based on the interaction of the transcription factor CDF2 with two different transcriptional systems.

Blotting, Western↗
PubMed2000

Endothelial monocyte activating polypeptide II induces endothelial cell apoptosis and may inhibit tumor angiogenesis.

Endothelial monocyte activating polypeptide II (EMAP-II) is a tumor-derived cytokine with potent effects on endothelial cells in vitro and in vivo including upregulation of tissue factor and the sensitization of human melanoma to systemic TNF treatment via its effects on the tumor vasculature. We investigated the effects of EMAP-II on tumor growth, angiogenesis, vasculogenesis, and apoptosis. EMAP-II inhibited endothelial cell proliferation, vasculogenesis, and neovessel formation. In vivo growth of human melanoma lines expressing high amounts of EMAP-II demonstrated slower growth, smaller tumors, and increased amounts of tumor necrosis than those expressing lower amounts of EMAP-II. EMAP-II induced endothelial-cell-specific apoptosis via a pathway that includes upregulation of the Fas-associated death domain and downregulation of Bcl-2. EMAP-II appears to have important effects on angiogenesis and may play a role in regulating tumor vascular growth.

3T3 Cells↗
PubMed2000

Identification of the initiation codon for the atpB gene in Chlamydomonas chloroplasts excludes translation of a precursor form of the beta subunit of the ATP synthase.

The chloroplast atpB gene of Chlamydomonas reinhardtii, which encodes the beta subunit of the ATP synthase, contains three in-frame ATGs that are candidate translation initiation codons. An earlier study revealed that the N terminus of the assembled beta subunit maps at the +2 position with respect to the second in-frame methionine codon (Fiedler et al. 1995). Using chloroplast transformation, we have examined the possibility that either of the two additional in-frame ATG codons is competent for translation initiation. We provide evidence that translation of atpB is initiated exclusively at the second ATG codon. We conclude that the beta subunit is not synthesized with an N-terminal leader before its assembly into a functional ATP synthase complex.

5' Untranslated Regions↗
PubMed2000

Atherosclerosis and diabetes: the RAGE connection.

Diabetes mellitus begins as a disorder of glucose metabolism that progressively compromises the function of virtually every organ system as the secondary complications inexorably develop. The quality of life for patients with diabetes is diminished by the consequences of these complications. Accelerated and aggressive atherosclerosis is the greatest cause of morbidity and mortality with diabetes, emphasizing the importance of determining underlying mechanisms. This review highlights the role of the multiligand receptor for advanced glycation endproducts (RAGE) and two of its ligands, advanced glycation endproducts (AGEs) and S100/calgranulins, in the pathogenesis of atherosclerosis associated with diabetes. The results of the studies reviewed herein suggest that RAGE is a potential therapeutic target for macrovascular disease in diabetes.

Animals↗
PubMed2000

Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis.

Accumulation of fibrils composed of amyloid A in tissues resulting in displacement of normal structures and cellular dysfunction is the characteristic feature of systemic amyloidoses. Here we show that RAGE, a multiligand immunoglobulin superfamily cell surface molecule, is a receptor for the amyloidogenic form of serum amyloid A. Interactions between RAGE and amyloid A induced cellular perturbation. In a mouse model, amyloid A accumulation, evidence of cell stress and expression of RAGE were closely linked. Antagonizing RAGE suppressed cell stress and amyloid deposition in mouse spleens. These data indicate that RAGE is a potential target for inhibiting accumulation of amyloid A and for limiting cellular dysfunction induced by amyloid A.

Amyloid↗
PubMed2000

Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor kB (NF-kB) activation.

Mutated transthyretin (TTR) fibrils are associated with the pathology of familial amyloidotic polyneuropathy (FAP), in which extracellular amyloid deposits lead to degeneration of cells and tissues, in particular neurons of the peripheral nerve. Here we present evidence that the receptor for advanced glycation end products (RAGE), previously associated with Alzheimer's disease, acts as a selective cell surface acceptor site for both soluble and fibrillar TTR. Immunohistochemical studies demonstrating increased expression of RAGE in FAP tissues suggested the relevance of this receptor to TTR-induced fibrillar pathology. In vitro studies using soluble RAGE showed saturable specific interaction with soluble and fibrillar TTR with a K(d) of approximately 120 nM. However, no binding was observed when soluble TTR was combined with retinol-binding protein, which represents the form in which TTR normally circulates in plasma. Specific binding of TTR to RAGE-transfected Chinese hamster ovary cells (which was completely blocked by anti-RAGE) was observed, confirming that RAGE could mediate TTR binding to cellular surfaces. RAGE-dependent activation of nuclear transcription factor kB (NF-kB) by TTR fibrils was shown in PC-12 cells stably transfected to overexpress the receptor. Furthermore, FAP nerves showed up-regulation of p50, one of the NF-kB subunits, when compared with age-matched controls. From these observations we predict that, in vivo, the presence of TTR fibrils associated with cellular surfaces of FAP patients, by contributing to NF-kB activation, leads to the pathogenesis of neurodegeneration. Further insights into the consequences of the interaction of fibrillar TTR with RAGE may therefore provide a better understanding of neurodegeneration associated with FAP.

Animals↗
PubMed2000

beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1.

In patients with amyloid beta-related cerebrovascular disorders, e.g. , Alzheimer's disease, one finds increased deposition of amyloid peptide (Abeta) and increased presence of monocyte/microglia cells in the brain. However, relatively little is known of the role of Abeta in the trafficking of monocytes across the blood-brain barrier (BBB). Our studies show that interaction of Abeta(1-40) with monolayer of human brain endothelial cells results in augmented adhesion and transendothelial migration of monocytic cells (THP-1 and HL-60) and peripheral blood monocytes. The Abeta-mediated migration of monocytes was inhibited by antibody to Abeta receptor (RAGE) and platelet endothelial cell adhesion molecule (PECAM-1). Additionally, Abeta-induced transendothelial migration of monocytes were inhibited by protein kinase C inhibitor and augmented by phosphatase inhibitor. We conclude that interaction of Abeta with RAGE expressed on brain endothelial cells initiates cellular signaling leading to the transendothelial migration of monocytes. We suggest that increased diapedesis of monocytes across the BBB in response to Abeta present either in the peripheral circulation or in the brain parenchyma may play a role in the pathophysiology of Abeta-related vascular disorder.

Adult↗
PubMed1999

NICMOS Imaging of the Dusty Microjansky Radio Source VLA J123642+621331 at z = 4.424.

We present the discovery of a radio galaxy at a likely redshift of z=4.424 in one of the flanking fields of the Hubble Deep Field (HDF). Radio observations with the Very Large Array and MERLIN centered on the HDF yielded a complete sample of microjansky radio sources, of which about 20% have no optical counterpart to I</=25 mag. In this Letter, we address the possible nature of one of these sources through deep Hubble Space Telescope near-infrared camera and multiobject spectrometer (NICMOS) images in the F110W (J110) and F160W (H160) filters. VLA J123642+621331 has a single emission line at 6595 Å, which we identify with Lyalpha at z=4.424. We argue that this faint (H160=23.9 mag), compact (re approximately 0&farcs;2), red (I814-K=2.0) object is most likely a dusty, star-forming galaxy with an embedded active nucleus.

Journal Article↗
PubMed1999

N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression.

Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure, N(epsilon)-(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-kappaB and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component.

Animals↗
PubMed1999

Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells.

Neovascularization is essential for growth and spread of primary and metastatic tumors. We have identified a novel cytokine, endothelial-monocyte activating polypeptide (EMAP) II, that potently inhibits tumor growth, and appears to have antiangiogenic activity. Mice implanted with Matrigel showed an intense local angiogenic response, which EMAP II blocked by 76% (P < 0.001). Neovascularization of the mouse cornea was similarly prevented by EMAP II (P < 0.003). Intraperitoneally administered EMAP II suppressed the growth of primary Lewis lung carcinomas, with a reduction in tumor volume of 65% versus controls (P < 0.003). Tumors from human breast carcinoma-derived MDA-MB 468 cells were suppressed by >80% in EMAP II-treated animals (P < 0.005). In a lung metastasis model, EMAP II blocked outgrowth of Lewis lung carcinoma macrometastases; total surface metastases were diminished by 65%, and of the 35% metastases present, approximately 80% were inhibited with maximum diameter <2 mm (P < 0.002 vs. controls). In growing capillary endothelial cultures, EMAP II induced apoptosis in a time- and dose-dependent manner, whereas other cell types were unaffected. These data suggest that EMAP II is a tumor-suppressive mediator with antiangiogenic properties allowing it to target growing endothelium and limit establishment of neovasculature.

Animals↗
PubMed1999

RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.

S100/calgranulin polypeptides are present at sites of inflammation, likely released by inflammatory cells targeted to such loci by a range of environmental cues. We report here that receptor for AGE (RAGE) is a central cell surface receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Blockade of EN-RAGE/RAGE quenches delayed-type hypersensitivity and inflammatory colitis in murine models by arresting activation of central signaling pathways and expression of inflammatory gene mediators. These data highlight a novel paradigm in inflammation and identify roles for EN-RAGEs and RAGE in chronic cellular activation and tissue injury.

Amino Acid Sequence↗
PubMed1999

Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis.

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid beta peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders.

Animals↗