bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Steroidogenic Acute Regulatory Protein in Cultured Schwann Cells and Its Regulation by cAMP
Authors: BENMESSAHEL Y. , GUENNOUN R. , CADEPOND F. , BAULIEU E. E. , SCHUMACHER M. , GROYER G.
Published: July 2009

Abstract: In steroidogenic cells the steroidogenic acute regulatory (StAR) protein plays a key role in the transport of cholesterol to the inner mitochondrial membrane, where the first step of steroidogenesis, the conversion of cholesterol to pregnenolone, takes place. cAMP is a known positive regulator of StAR gene expression and steroid biosynthesis in steroidogenic cells. As some steroids, such as progesterone, can also be synthesized de novo in the central and peripheral nervous systems and display neuroprotective and neurotrophic effects, we decided to verify the effect of cAMP on StAR gene expression in cultured Schwann cells. We observed that (1) in the presence of serum, forskolin, an agent known to elevate intracellular cAMP, induced both a morphological change and proliferation of cultured Schwann cells; (2) StAR mRNA and protein were expressed in Schwann cells; (3) unexpectedly, forskolin and 8 Br‐cAMP, a cell‐permeant analogue of cAMP, extinguishcd StAR gene expression; and (4) this response was similar in the presence or absence of serum.
Hepatic Insulin‐like Growth Factor‐I Binding Protein 3 Gene Expression in Rats with Endotoxic Shock: The Role of Glucocorticoids
Authors: PRIEGO T. , de CÁCERES I. IBAÑEZ , MARTÍN A. I. , VILLANÚA M. A. , LÓPEZ‐CALDERÓN A.
Published: July 2009

Abstract: The aim of this work was to study the role of glucocorticoids in the insulin‐like growth factor binding protein (IGFBP)‐3 response to endotoxin. Lipopolysaccharide (LPS) administration decreased IGFBP‐3 serum levels as well as hepatic IGFBP‐3 gene expression in both adrenalectomized and sham‐operated rats. These data suggest that the decrease in hepatic IGFBP‐3 gene expression induced by LPS is not mediated by glucocorticoids.
The F‐Actin Content of Multiple Myeloma Cells as a Measure of Their Migration
Authors: MENU ELINE , BRAET FILIP , TIMMERS MAARTEN , Van RIET IVAN , Van CAMP BEN , VANDERKERKEN KARIN
Published: July 2009

Abstract: One of the main characteristics of multiple myeloma (MM) cells is their specific homing and growth in the bone marrow (BM). For their homing, MM cells need chemotactic signals to be attracted towards the BM and to be activated. Profound knowledge of the different chemokines for MM cells and their signal transduction pathways is necessary to interfere in this process. We studied here an extra possible tool for the investigation of the different chemokines and their pathways. The 5T experimental mouse model was used to investigate the migration of MM cells towards BM stromal cells. We studied the changes of the F‐actin content in the 5TMM cells in the presence of BM stromal cell conditioned medium and we correlated this with their migratory capacity. F‐actin became polarized when the cells were migrating, in contrast to nonmigrating cells. This polarization could not only be seen by fluorescence and confocal laser scanning microscopy, but also could be quantified by fluorometry and flow cytometry. The correlation between the F‐actin content of the MM cells and their migration capacity thus makes its quantification a useful tool in studying their migratory behavior.
Induction of Cyclooxygenase‐2 in Ras‐Transformed Human Mammary Epithelial Cells Undergoing Apoptosis
Authors: NA HYE‐KYUNG , SURH YOUNG‐JOON
Published: July 2009

Abstract:COX‐2 expression has been reported to be elevated in several forms of human cancer. The presence of oncogenic ras has been associated with constitutive induction of COX‐2, which confers resistance to apoptosis. Contrary to the above notion, we have found that H‐ras‐transformed human breast epithelial (MCF10A‐ras) cells treated with the anticancer drug ET‐18‐O‐CH3exhibit an increased expression of COX‐2, while they still undergo apoptosis. To determine whether the induction of COX‐2 by ET‐18‐O‐CH3could contribute to apoptosis in MCF10A‐rascells, the selective COX‐2 inhibitor celecoxib (SC‐58635) was used. Celecoxib treatment attenuated ET‐18‐O‐CH3‐induced cell death. Taken together, the above findings suggest that COX‐2 up‐regulation does not necessarily confer the resistance to apoptosis inras‐transformed cells, but rather may sensitize these cells to apoptotic death.
Extracellular ATP Induces Phosphatidylserine Externalization Earlier than Nuclear Apoptotic Events in Thymocytes
Authors: COURAGEOT MARIE‐PIERRE , LEPINE SANDRINE , GIRAUD FRANCOISE , SULPICE JEAN‐CLAUDE
Published: July 2009

Abstract: The present study shows for the first time that ATPec induces a very early PS exposure in thymocytes and that this process can be induced in the absence of Ca2+ influx and caspase activation.
Involvement of Sphingosine in Dexamethasone‐Induced Thymocyte Apoptosis
Authors: LÉPINE SANDRINE , LAKATOS BORIS , MAZIERE PIERRE , COURAGEOT MARIE‐PIERRE , SULPICE JEAN‐CLAUDE , GIRAUD FRANCOISE
Published: July 2009

Abstract: It is generally accepted that ceramide plays an essential role in apoptosis. In this study we suggest that in thymocytes, dexamethasone‐induced apoptosis is mediated by sphingosine rather than ceramide, through the activation of an aSMase and a cerase in a caspase‐dependent manner.
β‐Amyloid Induces Oxidative DNA Damage and Cell Death through Activation of c‐Jun N Terminal Kinase
Authors: JANG JUNG‐HEE , SURH YOUNG‐JOON
Published: July 2009

Abstract: Oxidative stress induced by reactive oxygen species has been implicated in the pathophysiology of many neurodegenerative disorders including Alzheimer's disease (AD). In this study, we have investigated the molecular mechanisms underlying oxidative cell death induced by β‐amyloid, a neurotoxic peptide associated with senile plaques found in the brains of patients with AD. PC12 cells treated with β‐amyloid underwent apoptotic cell death as determined by characteristic morphological features, cleavage of poly(ADP‐ribose)polymerase, and positive in situ terminal‐end labeling (TUNEL). Furthermore, β‐amyloid treatment led to activation of c‐Jun N terminal kinase (JNK) and intracellular accumulation of ROS. In another experiment, β‐amyloid caused strand scission in φX174 DNA in the presence of ferrous iron. These findings suggest that production of ROS and subsequent activation of JNK play an important role in β‐amyloid‐induced apoptotic cell death.
Prodigiosin Induces Caspase‐9 and Caspase‐8 Activation and Cytochrome C Release in Jurkat T Cells
Authors: MONTANER BEATRIZ , PÉREZ‐TOMÁS RICARDO
Published: July 2009

Abstract: Prodigiosin (PG) is an active component of bacterial origin, with reported apoptotic effects. We examined the activation of caspases‐9, ‐8, and ‐3 in PG‐treated Jurkat cells in a dose‐response study. These caspases were activated in apoptotic cells, as judged by the appearance of cleavage products from procaspases, and cytochrome c (cyt c) was released to the cytosol. In addition, PG induced the cleavage of poly (ADP‐ribose) polymerase (PARP). This study demonstrates that the activation of caspases‐9, ‐8, and ‐3 mediates PG‐induced apoptosis.
Cigarette Smoke‐Induced Oxidative Stress and TGF‐β1Increase p21waf1/cip1Expression in Alveolar Epithelial Cells
Authors: MARWICK JOHN A. , KIRKHAM PAUL , GILMOUR PETER S. , DONALDSON KENNETH , MacNEE WILLIAM , RAHMAN IRFAN
Published: July 2009

Abstract:Sustained oxidative stress caused by cigarette smoking induces a chronic inflammatory response, resulting in the destruction of the alveolar cell wall characteristic of emphysema. The loss of tissue may involve the progressive depletion of epithelial cells through inhibition of proliferation leading to cell death. The cell cycle regulator p21waf1/cip1acts as a G1/S and G2/M phase checkpoint regulator. We hypothesize that cigarette smoke‐induced oxidative stress and transforming growth factor beta 1 (TGF‐β1) may inhibit cellular proliferation by p21waf1/cip1in type II alveolar epithelial cells (A549). A significant increase was observed in p21waf1/cip1mRNA expression in A549 cells by cigarette smoke condensate, H2O2, and TGF‐β1. In conclusion, cigarette smoke‐induced oxidative stress and TGF‐β1modulate expression of the cell cycle inhibitor p21waf1/cip1. This may be important in the growth arrest and cell survival of alveolar type II cells in the G1phase.
Inhibition of p38 MAP Kinase Corrects Biochemical and Neurological Deficits in Experimental Diabetic Neuropathy
Authors: AGTHONG SITHIPORN , TOMLINSON DAVID R.
Published: July 2009

Abstract: Diabetes is known to activate MAP kinase p38 in sensory neurons in both rats and patients. In vitro, activation of p38 in sensory neurons by combined glucose and oxidant stress causes cell damage or death. Consequently we tested the hypothesis that inhibition of MAP kinase p38 might prevent neuronal dysfunction in rats with experimental diabetes, such as the classical defect of slowed nerve conduction. Thus, treatment of streptozotocin‐diabetic rats with the p38 inhibitor SB239063 for the second half of a 12‐week diabetes protocol selectively prevented the nerve conduction deficit in sensory neurons. This implicates activation of MAP kinase p38 as an early step in the signal pathway to dysfunction in experimental diabetic neuropathy.
Chemopreventive Agents Induce Suppression of Nuclear Factor‐κB Leading to Chemosensitization
Authors: BHARTI ALOK C. , AGGARWAL BHARAT B.
Published: July 2009

Abstract: Nuclear factor‐κB (NF‐κB), a transcription factor, is present normally in the cytoplasm as an inactive heterotrimer consisting of p50, p65, and IκBα subunits. When activated, NF‐κB translocates to the nucleus as a p50‐p65 heterodimer. This factor regulates the expression of various genes that control apoptosis, viral replication, tumorigenesis, various autoimmune diseases, and inflammation. NF‐κB has been linked to the development of carcinogenesis for several reasons. First, various carcinogens and tumor promoters have been shown to activate NF‐κB. Second, activation of NF‐κB has been shown to block apoptosis and promote proliferation. Third, the tumor microenvironment can induce NF‐κB activation. Fourth, constitutive expression of NF‐κB is frequently found in tumor cells. Fifth, NF‐κB activation induces resistance to chemotherapeutic agents. Sixth, several genes involved in tumor initiation, promotion, and metastasis are regulated by NF‐κB. Seventh, various chemopreventive agents have been found to down‐regulate the NF‐κB activation. All these observation suggest that NF‐κB could mediate tumorigenesis and thus can be used as a target for chemoprevention and for the treatment of cancer. Agents that suppress NF‐κB activation can suppress the expression of genes involved in carcinogenesis and tumorigenesis in vivo.
Effects of Selected Ginsenosides on Phorbol Ester‐Induced Expression of Cyclooxygenase‐2 and Activation of NF‐κB and ERK1/2 in Mouse Skin
Authors: SURH YOUNG‐JOON , LEE JI‐YOON , CHOI KANG‐JU , KO SUNG‐RYONG
Published: July 2009

Abstract: Our previous studies have demonstrated that the methanol extract of heat‐processed Panax ginseng C.A. Meyer exerts antioxidative, antiinflammatory, and anti‐tumor‐promoting effects. In the present study, we examined the antiinflammatory effects of several ginsenosides (Rb1, Rc, Re, Rg1, Rg3) derived from P. ginseng. Topical application of each of these ginsenosides significantly attenuated ear edema induced by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). These ginsenosides also suppressed expression of cyclooxygenase‐2 (COX‐2) and activation of NF‐κB in the TPA‐treated dorsal skin of mice. Of the ginsenosides tested, Rg3 was found to be most effective in terms of inhibiting TPA‐induced ear edema, COX‐2 expression, and NF‐κB activation.
Proteasome Inhibitors Induce Cerebellar Granule Cell Death
Authors: PORCILE CAROLA , PICCIOLI PATRIZIA , STANZIONE SABRINA , BAJETTO ADRIANA , BONAVIA RUDY , BARBERO SIMONE , FLORIO TULLIO , SCHETTINIA GENNARO
Published: July 2009

Abstract: Many activities of neuronal cells, such as synaptic transmission, inflammation, neuroprotection, and neurotoxicity, are regulated by the activity of the transcription factor nuclear factor‐κB (NF‐κB). In resting cells, NF‐κB activity is present both in the cytoplasm, as an inducible‐inactive complex, and in the nucleus as a constitutive form. The activation of its inducible form is related to processing of IκB(s), which occurs through the proteasome. To understand whether NF‐κB is involved in the survival of cerebellar granule cells (CGCs) maintained under conditions of mild depolarization (25 mM KCl), these cells were treated with different proteasome inhibitors. The results presented show that these pharmacological tools reduce CGC survival with changes in nuclear morphology and induction of apoptosis. Furthermore, we demonstrate that PSI‐induced apoptosis is reverted by inhibitors of transcription and translation, as well as by specific caspase inhibitors. These issues are also associated with a redistribution of NF‐κB, in that a reduced amount of nuclear NF‐κB and an increased p65 cytoplasmic level have been observed. Finally, we propose that, at least in part, p65 metabolism could also be regulated by the ubiquitin‐proteasome complex. Altogether, the results presented define an important role for NF‐κB in maintainig CGC survival.
Transcription of the Human Prolactin Gene in Mammary Cells
Authors: BAUDHUIN A. , MANFROID I. , VAN DE WEERDT C. , MARTIAL J. A. , MULLER M.
Published: July 2009

Abstract: Expression of human prolactin in the mammary gland, one of the main target organs of this hormone, leads to the formation of an autocrine‐paracrine proliferative loop in this tissue. Involvement of prolactin in normal and neoplastic mammary development triggered the interest in transcriptional regulation of the human prolactin gene in mammary cells. Analysis of this regulation, and comparison to that in the pituitary, will contribute to a better understanding of mammary gland development and tumor formation. Here we present the first extensive analysis of the transcriptional regulation of the human prolactin gene in human mammary tumor cells.
Steroid Receptors in Various Glial Cell Lines Expression and Functional Studies
Authors: CADEPOND FRANÇOISE , MASSAAD CHARBEL , TROUSSON AMALIA , GRENIER JULIEN , GROYER GHISLAINE , BAULIEU ETIENNE , SCHUMACHER MICHAEL
Published: July 2009

Abstract: In glial cell lines from the central (CG4, C6) and peripheral (MSC80, CR3a1, and CR1b4) nervous systems, glucocorticoid receptor (GR) messenger RNA was clearly detected and was consistent with significant GR binding and transcriptional activity. Mineralocorticosteroid receptor mRNA was less abundant, with no corresponding binding and lack of transcriptional activity. Other steroid receptors were not significantly detected.
Glutathione in Defense and Signaling
Authors: DICKINSON DALE A. , FORMAN HENRY JAY
Published: July 2009

Abstract:The mechanisms of thiol metabolism and chemistry have particular relevance to both cellular defenses against toxicant exposure and to redox signaling. Here, we will focus on glutathione (GSH), the major endogenous low‐ molecular‐weight nonprotein thiol synthesizedde novoin mammalian cells. The major pathways for GSH metabolism in defense of the cell are reduction of hydroperoxides by glutathione peroxidases (GSHPx) and some peroxiredoxins, which yield glutathione disulfide (GSSG), and conjugation reactions catalyzed by glutathione‐S‐transferases. GSSG can be reduced to GSH by glutathione reductase, but glutathione conjugates are excreted from cells. The exoenzyme γ‐glutamyltranspeptidase (GGT) removes the glutamate from extracellular GSH, producing cysteinyl‐glycine from which a dipeptidase then generates cysteine, an amino acid often limiting forde novoGSH synthesis. Synthesis of GSH from the constituent amino acids occurs in two regulated, enzymatically catalyzed steps. The signaling pathways leading to activation of the transcription factors that regulate these genes are a current area of intense investigation. The elucidation of the signaling for GSH biosynthesis in human bronchial epithelial cells in response to 4‐hydroxynonenal (4HNE), an end product of lipid peroxidation, will be used as an example. GSH also participates in redox signaling through the removal of H2O2, which has the properties of a second messenger, and by reversing the formation of sulfenic acid, a moiety formed by reaction of critical cysteine residues in signaling proteins with H2O2. Disruption of GSH metabolism will therefore have major a impact upon function of cells in terms of both defense and normal physiology.
Possible Signaling by Glutathione and Its Novel Analogue through Potent Stimulation of Frontocortical G Proteins in Normal Aging and in Alzheimer's Disease
Authors: KARELSON E. , MAHLAPUU R. , ZILMER M. , SOOMETS U. , BOGDANOVIC N. , LANGEL Ü.
Published: July 2009

Abstract: In the frontal cortex (FC) of the normally aging human brain, glutathione (GSH) and its novel analogue, UPF1, stimulate G proteins more than in Alzheimer's disease (AD) FC. In normal aging and in AD, UPF1 is a more efficient stimulator of G proteins than GSH. In normal FC, both GSH and UPF1 stimulate G proteins, which mediate inhibitory signals to the cAMP system; while in AD, only UPF1 exhibits the same action. Stimulation of G proteins and coupled signaling by GSH antioxidant analogues, as potential signaling molecules, may ameliorate the oxidative impairments of neuronal signaling in AD.
Analysis ofin VivoEndothelial Cell Activation Applying RT‐PCR following Endothelial Cell Isolation by Laser Dissection Microscopy
Authors: ÁSGEIRSDÓTTIR S. A. , WERNER N. , HARMS G. , van den BERG A. , MOLEMA G.
Published: July 2009

Abstract:Laser dissection microscopy was applied to isolate endothelial cells from tumors obtained from mice treated with TNF‐α. RNA integrity was demonstrated from whole sections and dissected cells after acetone fixation and hematoxylin staining. RT‐PCR for GAPDH, CD31, VCAM‐1, ICAM‐1, and E‐selectin was successfully performed on these samples. These data demonstrate the feasibility of analyzing local endothelial cell responses in diseased tissues at the level of gene expression.
Cerebrovascular Pathology and Dementia in Autopsied Honolulu‐Asia Aging Study Participants
Authors: WHITE LON , PETROVITCH HELEN , HARDMAN JOHN , NELSON JAMES , DAVIS DARON G. , ROSS G. WEBSTER , MASAKI KAMAL , LAUNER LENORE , MARKESBERY WILLIAM R.
Published: July 2009

Abstract: Clinicopathologic data from 285 autopsies were analyzed. The decedents were long‐standing participants in the Honolulu‐Asia Aging Study, a prospective epidemiologic investigation of stroke, neurodegenerative diseases, and aging. We assessed the prevalence at death of four primary neuropathologic processes using specific microscopic lesions as indicators. An algorithm was developed to assign each decedent to one of six subsets, corresponding to pathologic dominance by microvascular lesions (14% of decedents), Alzheimer lesions (12%), hippocampal sclerosis (5%), cortical Lewy bodies (5%), codominance by two or more primary processes (9%), or without a dominant pathologic process recognized (55%). Definite or probable dementia had been identified in 118 of the decedents. The proportions of men in each subset identified as demented were (in the same order) 57%, 53%, 79%, 57%, 76%, and 25%. In this autopsied panel of older Japanese‐American men, the importance of microvascular lesions as a likely explanation for dementia was nearly equal to that of Alzheimer lesions. The cerebrovascular lesion type most essentially and inclusively related to dementia was multiple microinfarction.
Molecular and Functional Dissection of TGF‐β1‐Induced Cerebrovascular Abnormalities in Transgenic Mice
Authors: BUCKWALTER MARION , PEPPER JON‐PAUL , GAERTNER ROGER F. , EUW DOMINIQUE VON , LACOMBE PIERRE , WYSS‐CORAYA TONY
Published: July 2009

Abstract: Cerebrovascular abnormalities, such as reduced blood flow, microvascular fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's disease (AD). However, their etiology is poorly understood and it is unclear whether cerebrovascular changes contribute to functional impairments in the absence of neurodegeneration. In humans with AD, transforming growth factor‐β1 (TGF‐β1) mRNA levels in the midfrontal gyrus correlate positively with the relative degree of cerebrovascular amyloid deposition in that brain region, suggesting a possible role for TGF‐β1 in human cerebrovascular abnormalities. Transgenic mice overexpressing TGF‐β1 in astrocytes develop AD‐like cerebrovascular abnormalities, including perivascular astrocytosis, microvascular basement membrane thickening, and accumulation of thioflavin S‐positive amyloid in the absence of parenchymal degeneration. Mice overexpressing TGF‐β1 alone or in addition to human amyloid precursor protein (hAPP) show selective accumulation of human β‐amyloid (Aβ) in blood vessels and develop cerebral hemorrhages in old age. In 9‐month‐old TGF‐β1 transgenic mice, cerebral blood flow (CBF) in the limbic system was significantly less than in nontransgenic littermate controls. Aged TGF‐β1 mice also showed overall reduced cerebral glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction of TGF‐β1 in the brain results in structural and functional impairments reminiscent of those in AD cases with amyloid angiopathy.
Impact of Subcortical Ischemic Lesions on Behavior and Cognition
Authors: MORI ETSURO
Published: July 2009

Abstract: Both cerebrovascular disease and AD are common in the elderly. There are various types of underlying damage to tissue and vessels in vascular cognitive impairment, and the neural mechanisms producing cognitive impairment and the clinical picture are different among the subtypes. Among them, small subcortical infarcts disrupting cortico‐subcortical circuits and white matter lesions are the commonest types, and the combination of these two types of lesions might be more realistic than each pure form. Moreover, cognitive impairment of vascular origin may be superimposed on AD. Both vascular and degenerative mechanisms contribute to the development of cognitive impairment, especially in old age, whether they are two independent parallel processes or interacting pathologies. Subcortical small lesions involving the thalamus, caudate, and globus pallidus disrupt cortico‐subcortical circuits, resulting in cognitive dysfunction. Disruption of the frontal‐subcortical circuits leads to cognitive impairment with striking frontal lobe features, and disruption of the memory‐related circuits leads to amnesia. White matter changes, which are certainly related to chronic cerebral ischemia in some patients, are another issue. Patients with dementia and white matter changes may have either AD with cerebrovascular changes or a form of VaD, or a combination of these two etiologies. However, our series of studies have suggested that white matter changes in AD patients are superimposed phenomena of vascular origin and that white matter changes contribute to specific neurological and neuropsychiatric manifestations, but not to global cognitive impairment, which is more closely associated with the degenerative process.
Cerebrovascular Disease Is a Major Factor in the Failure of Elimination of Aβ from the Aging Human Brain
Authors: WELLER ROY O. , YOW HONG‐YEEN , PRESTON STEPHEN D. , MAZANTI INGRID , NICOLL JAMES A.R.
Published: July 2009

Abstract: Alzheimer's disease (AD) is characterized by the intracellular deposition of ubiquitinated tau and by the extracellular accumulation of soluble, insoluble, and fibrillary Aβ. Previous studies suggest that Aβ is normally eliminated from the brain along perivascular pathways that may become blocked in the aging brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD inhibits the elimination of Aβ from the aging human brain. Sections from 100 aged and AD brains were stained for Aβ by immunohistochemistry and by reticulin and Masson trichrome techniques. Early deposition of Aβ in brain parenchyma was related to individual arterial territories in the cortex. In areas of more extensive accumulation of Aβ, there was an inverse relationship between capillary amyloid angiopathy and plaques of Aβ. Thus, arterial territories with extensive capillary amyloid angiopathy were devoid of Aβ plaques, whereas in areas with abundant diffuse plaques there was no capillary amyloid angiopathy. Serial sections showed that cortical arteries feeding capillary beds with Aβ angiopathy were occluded by thrombus. We conclude that CVD inhibits the elimination of Aβ along capillary walls and changes the distribution of Aβ in the cerebral cortex. Loss of pulsations in thrombosed or arteriosclerotic arteries may thus abolish the motive force necessary for the drainage of Aβ and inhibit the elimination of Aβ. Therapies to increase elimination of Aβ in AD need to consider the effects of CVD on the elimination of Aβ from the aging human brain.
Vascular Basis of Alzheimer's Pathogenesis
Authors: de la TORRE J. C.
Published: July 2009

Abstract: Considerable evidence now indicates that Alzheimer's disease (AD) is primarily a vascular disorder. This conclusion is supported by the following evidence: (1) epidemiologic studies linking vascular risk factors to cerebrovascular pathology that can set in motion metabolic, neurodegenerative, and cognitive changes in Alzheimer brains; (2) evidence that AD and vascular dementia (VaD) share many similar risk factors; (3) evidence that pharmacotherapy that improves cerebrovascular insufficiency also improves AD symptoms; (4) evidence that preclinical detection of potential AD is possible from direct or indirect regional cerebral perfusion measurements; (5) evidence of overlapping clinical symptoms in AD and VaD; (6) evidence of parallel cerebrovascular and neurodegenerative pathology in AD and VaD; (7) evidence that cerebral hypoperfusion can trigger hypometabolic, cognitive, and degenerative changes; and (8) evidence that AD clinical symptoms arise from cerebromicrovascular pathology. The collective data presented in this review strongly indicate that the present classification of AD is incorrect and should be changed to that of a vascular disorder. Such a change in classification would accelerate the development of better treatment targets, patient management, diagnosis, and prevention of this disorder by focusing on the root of the problem. In addition, a theoretical capsule summary is presented detailing how AD may develop from chronic cerebral hypoperfusion and the role of critically attained threshold of cerebral hypoperfusion (CATCH) and of vascular nitric oxide derived from endothelial nitric oxide synthase in triggering the cataclysmic cerebromicrovascular pathology.
Vascular Changes in Iowa‐Type Hereditary Cerebral Amyloid Angiopathy
Authors: SHIN YOUNGAH , CHO HYUN SOON , REBECK G. WILLIAM , GREENBERG STEVEN M.
Published: July 2009

Abstract: Vascular dysfunction due to cerebral amyloid angiopathy (CAA) may contribute to cognitive impairment. The Iowa D694N amyloid precursor protein mutation, a recently identified cause of hereditary CAA with dementia, offers an opportunity to explore the anatomic basis of CAA‐related vascular dysfunction. Examination by immunolabeling and confocal microscopy demonstrated extensive loss of smooth muscle cells in affected segments as well as a perivascular inflammatory reaction of astrocytes and microglia. On 3‐D reconstruction, vessels appeared tortuous with twiglike projections that may represent areas of vascular degeneration. The observed changes in the Iowa brain suggest pathophysiologic mechanisms for vascular dysfunction in CAA and possible approaches to treatment of CAA‐related cognitive impairment.
Pathogenic Effects of Cerebral Amyloid Angiopathy Mutations in the Amyloid β‐Protein Precursor
Authors: Van NOSTRAND WILLIAM E. , MELCHOR JERRY P. , ROMANOV GALINA , ZEIGLER KELLY , DAVIS JUDIANNE
Published: July 2009

Abstract: Cerebral amyloid β‐protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. Several mutations have been identified within the Aβ region of the Aβ protein precursor (AβPP) gene that appear to enhance the severity of CAA. A new mutation has been identified within the Aβ region (D23N) of AβPP that is associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double‐mutant Aβ40 peptides rapidly assemble in solution to form fibrils compared to wild‐type Aβ40. Similarly, the E22Q Dutch and D23N Iowa Aβ40 peptides were found to induce robust pathologic responses in cultured human cerebrovascular smooth muscle (HCSM) cells, including elevated levels of cell‐associated AβPP, proteolytic breakdown of actin, and cell death. Double‐mutant E22Q/D23N Dutch/Iowa Aβ40 was more potent than either single‐mutant form of Aβ in causing pathologic responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of Aβ towards HCSM cells. Moreover, the presence of both CAA substitutions in the same Aβ peptide further enhances the fibrillogenic and pathogenic properties of Aβ. We also have generated transgenic mouse models to examine the effects of single and double CAA mutations in AβPP in vivo. Preliminary analysis of transgenic mouse brains indicates that expression of double‐mutant E22Q/D23N Dutch/Iowa AβPP leads to robust deposition of Aβ in a vascular‐weighted manner.
Clinical Features of CADASIL
Authors: ABE KOJI , MURAKAMI TETSURO , MATSUBARA ETSURO , MANABE YASUHIRO , NAGANO ISAO , SHOJI MIKIO
Published: July 2009

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary disease characterized by recurrent transient ischemic attacks, strokes, and vascular dementia. Various mutations in the Notch3 gene cause the disease, whereas the mechanism of how they cause the disorder remains unknown. We recently identified two Japanese CADASIL families with an R141C mutation. The mean age of onset was 44.6, and the main symptoms were recurrent strokes and progressive motor disturbances in extremities, as well as pseudobulbar palsy. Besides those in white matter and basal ganglia, ischemic lesions in temporal edge and corpus callosum were present on magnetic resonance images, which seemed to be characteristic of CADASIL. Moreover, in our cases, nocturnal arterial blood pressure fall was significantly lower in patients compared with control subjects, suggesting that it might be partly associated with ischemic lesions in deep white matter in CADASIL. We also compared Japanese and Caucasian CADASIL cases and found that dementia and pseudobulbar palsy were observed more frequently in Japanese patients, although typical migraine was rather rare. In the present study, we describe the clinical features of CADASIL, hoping to help reveal the mechanism of chronic ischemic brain diseases, including leukoaraiosis or Binswanger's disease.
Endothelial Cell Activation Is Associated with Cerebral White Matter Lesions in Patients with Cerebrovascular Disease
Authors: de LEEUW F‐E. , de KLEINE M. , FRIJNS C. J. M. , FIJNHEER R. , Van GIJN J. , KAPPELLE L. J.
Published: July 2009

Abstract: Cerebral MRI scanning frequently shows white matter lesions in elderly people. They are related to cognitive impairment and may result in dementia. Although vascular risk factors are associated with the presence of white matter lesions, the exact pathogenesis remains unclear. Animal studies have indicated involvement of endothelial cells in the pathogenesis of white matter lesions and possibly dementia. We investigated the relation between endothelial cell activation and white matter lesions in individuals with cerebrovascular disease. In 29 patients with an acute stroke (n= 11) or TIAs associated with a symptomatic internal carotid artery stenosis (n= 18), markers of endothelial cell activation such as intercellular adhesion molecule‐1 (sICAM‐1), vascular cell adhesion molecule‐1 (sVCAM‐1), sE‐selectin, and sP‐selectin were measured by means of ELISA. All individuals underwent 1.5‐T MRI scanning. White matter lesions were rated for the periventricular and the subcortical region separately. Individuals with severe periventricular white matter lesions had higher levels of sP‐selectin (245.5 ng/mL vs. 172.7 ng/mL, p= 0.01) and sVCAM‐1 (547.8 ng/mL vs. 454.0 ng/mL, p= 0.04) than those without. This association was only found in individuals with a symptomatic carotid artery stenosis. No such association was found for subcortical white matter lesions. We did not detect any relation between sICAM‐1 and sE‐selectin and white matter lesions. Endothelial cell activation may play a role in the pathogenesis of white matter lesions, especially in periventricular white matter. Possibly, this activation represents the influence of vascular factors on the cerebral endothelium as a prelude to increasingly severe small vessel disease.
The Unfolded Protein Response Is Involved in the Pathology of Alzheimer's Disease
Authors: KUDO TAKASHI , KATAYAMA TAIICHI , IMAIZUMI KAZUNORI , YASUDA YUKA , YATERA MISAKO , OKOCHI MASAYASU , TOHYAMA MASAYA , TAKEDA MASATOSHI
Published: July 2009

Abstract: The endoplasmic reticulum (ER) performs the synthesis, posttranslational modification, and proper folding of proteins. A variety of conditions can be ER stress, causing the accumulation of unfolding or misfolding proteins in the ER. Eukaryotic cells have three different mechanisms for dealing with an accumulation of unfolded proteins in the ER known as the unfolded protein response (UPR): transcriptional induction, translational attenuation, and degradation. This paper focuses on the relationship between UPR and the pathogenesis of AD. Our results indicate a new mechanism by which PS1 mutations may affect the sensing of ER stress. Experimental manipulation of IRE1, PERK, or eIF2α phosphorylation or GRP78 expression might allow the development of therapeutic strategies for FAD.
Cholesterol in Alzheimer's Disease and Tauopathy
Authors: BURNS MARK , DUFF KAREN
Published: July 2009

Abstract: Cholesterol has been implicated in the pathogenesis of amyloid plaques in Alzheimer's disease (AD) and in the formation of neurofibrillary pathology in Niemann‐Pick disease. Several epidemiology studies have implicated high cholesterol as a risk factor for AD and have shown that the use of cholesterol‐reducing agents (statins) can be protective against the disease. We and others have shown that cholesterol levels modulate the processing of the amyloid precursor protein (APP) both in vivo and in vitro, affecting the accumulation of A‐beta (Aβ) peptides that may directly impact the risk of AD. Mutations in the Niemann‐Pick C gene (NPC) result in deficient cholesterol transport/storage. Clinically, Niemann‐Pick disease causes a severe childhood lipidosis, with neurodegeneration characterized by the presence of AD‐type neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Studies of mouse models of NPC show that defects in cellular cholesterol trafficking are associated with enhanced generation of Aβ and the hyperphosphorylation of tau, further implicating the cholesterol homeostasis pathway as a risk factor for amyloidosis.
White Matter Lesions and Dementia MRI‐Pathological Correlation
Authors: UDAKA FUKASHI , SAWADA HIDEYUKI , KAMEYAMA MASAKUNI
Published: July 2009

Abstract: An MRI‐pathological correlation study was performed to determine the pathological background of white matter lesions depicted on MR images. The pathological findings were various combinations of myelin loss, axonal loss, scattered microinfarcts, astrogliosis, dilatation of perivascular space, and relative preservation of subcortical U‐fibers. Concerning the dilated perivascular space, we proposed a new classification according to the present study: (1) état criblé in the basal ganglia and the thalamus, (2) état criblé in the cerebral white matter, (3) enlarged perivascular space of the lenticulostriate arteries, and (4) état criblé in other sites. In conclusion, when effects of white matter lesions on cognitive function are to be evaluated, it is necessary to clarify tissues in at least three sequences: T2‐weighted, T1‐weighted, and FLAIR method.
Neuroprotective Effect of Apolipoprotein E against Ischemia
Authors: KITAGAWA KAZUO , MATSUMOTO MASAYASU , HORI MASATSUGU , YANAGIHARA TAKEHIKO
Published: July 2009

Abstract: Apolipoprotein E (APOE) deficiency has been shown to worsen neuronal injuries after cerebral ischemia. However, the molecular mechanism underlying the protective effect of APOE remains uncertain, even though several mechanisms including excitotoxicity, free radicals, and apoptosis have been cited as causes of selective neuronal vulnerability in cerebral ischemia. In the present study, we compared the vulnerability of cultured neurons prepared from APOE‐knockout mice upon exposure to glutamate, hydrogen peroxide, and staurosporine. No significant difference in cell viability was observed after exposure to glutamate or staurosporine between APOE‐deficient and wild‐type mice. However, exposure to hydrogen peroxide significantly increased the level of cell death in APOE‐deficient mice compared with that in wild‐type mice. In the adult mice, after transient forebrain ischemia for 12 min, APOE‐deficient mice showed more neuronal death than wild‐type mice. Pretreatment of APOE‐deficient mice with vitamin E for 2 months markedly reduced neuronal death caused by ischemia. The results suggested that APOE exerted the neuroprotective effect against ischemia through its antioxidant action, but not through mitigation of glutamate toxicity or blocking of apoptosis.
Responses to Donepezil in Alzheimer's Disease and Parkinson's Disease
Authors: MORI SATORU
Published: July 2009

Abstract: Alzheimer's disease is the most common cause of dementia, but Parkinson's disease also shows dementia in the later stages. Donepezil is a cholinesterase inhibitor used for the treatment of Alzheimer's disease. Variable responses to this drug suggest that Alzheimer's disease is clinically heterogeneous. In the clinical trial of tacrine, a first developed cholinesterase inhibitor, three cases markedly improved and, several years later, they were pathologically confirmed as dementia with Lewy bodies (DLB). In recent years, another cholinesterase inhibitor, rivastigmine, has also been reported to be effective for patients with DLB by a placebo‐controlled, double‐blind, multicenter study. Parkinson's disease with dementia, which is known to fulfill the pathological criteria of DLB, also shows a favorable response to donepezil. In some cases, not only does cognitive function improve, but also parkinsonism. Both DLB and Parkinson's disease with dementia show characteristic CBF patterns: While the parietal and temporal lobes are involved in Alzheimer's disease, the occipital lobe is additionally affected in these diseases. Alzheimer's disease and Parkinson's disease have been considered discrete disease entities. However, viewed from the aspects of response to donepezil treatment and CBF patterns, both diseases overlapped. A brain SPECT may be a useful tool to detect such treatable conditions.
Treatment of Vascular Dementia
Authors: OKAMOTO KOICHI , TANAKA MAKOTO , KONDO SUSUMU
Published: July 2009

Abstract: We report positron emission tomography (PET) findings of our patients with vascular dementia, asymptomatic cerebral infarction, and chronic cerebral circulatory insufficiency. According to the PET studies, it was suggested that frontal lobe hypoperfusion and hypometabolism play important roles in dementia caused by cerebral infarctions. It was also suggested that patients with subjective complaints associated with asymptomatic strokes and patients with chronic cerebral circulatory insufficiency already exhibited decreased cerebral circulation. Since therapeutic approaches to vascular dementia after its development are limited, active control of risk factors and prevention of recurrent stroke during the developmental process of vascular dementia are important. We review recent situations in prevention and treatment of vascular dementia.
The Role of the National Center for Research Resources at the National Institutes of Health
Authors: HAYWARD ANTHONY R.
Published: July 2009

Abstract: Lymphatic research has infrastructure needs ranging from the nursing support provided by General Clinical Research Centers to training grants for future clinician investigators. Both have high priority in the activities currently funded by the Division of Clinical Research at NCRR. Further into the future, the therapeutic development networks and embryonic stem cells resources that are currently being developed should seem equally to have been essential resources.
Tissue Engineering of the Lymphatic System
Authors: NIKLASON LAURA E. , KOH JENNIFER , SOLAN AMY
Published: July 2009

Abstract: The field of tissue engineering has seen tremendous expansion in the last decade. In the last several years, tissue‐engineering strategies to treat diseases of skin, cartilage, bone, bladder, blood vessel, tendon, and other tissues have been described. However, tissue‐engineering approaches to treat diseases of the lymphatic system are currently nonexistent. We propose that acellular tissues, either native or engineered, could be exploited as a platform for the study of lymphatic biology, and for lymphatic tissue engineering. While speculative, this type of experimental model system could prove powerful for dissecting molecular and cellular events surrounding tumor invasion of lymphatics, as well as lymphangiogenesis. Scaffolds seeded with genetically engineered lymphatic cells could also be implanted to repopulate lymphatic vasculature. In the future, the lymphatic system will surely be added to the list of tissues and organs that prove amenable to tissue‐engineering therapies.
The Pathogenesis of Filarial Lymphedema
Authors: LAMMIE PATRICK J. , CUENCO KAREN T. , PUNKOSDY GEORGE A.
Published: July 2009

Abstract: Our understanding of the pathogenesis of filarial lymphedema, although evolving, is still limited. Recurrent bacterial infections play a major role in the progression of lymphedema to elephantiasis, but the host and parasite factors that trigger disease development are not known. Field studies in Haiti show that lymphedema and host responses to parasite antigens cluster in families, consistent with the hypothesis that host genes influence lymphedema susceptibility. The recent recognition that filarial parasites harbor the endosymbiotic bacteria, Wolbachia, also raises questions about the potential contribution of the inflammatory response to Wolbachia antigens to lymphedema development. In this review, we discuss potential risk factors for lymphedema and try to integrate these in a model of pathogenesis.
De Novo Lymph Node Formation in Chronic Inflammation of the Human Leg
Authors: OLSZEWSKI WALDEMAR L.
Published: July 2009

Abstract: Organized lymphoid tissue is the first line of antigenic defense. Recruited by antigen located in the non‐lymphoid tissues, the infiltrating lymphocytes often organize themselves as follicle‐like structures that contain germinal centers, similar to those in secondary lymphoid follicles of lymph nodes. These extranodal tertiary lymphoid follicles are found in various autoimmune diseases. We investigated 153 patients with protracted lymph stasis of the lower limb, caused by lymphatic damage incurred through soft tissue bacterial inflammation or mechanical trauma of soft tissues and bones. In 10% of patients with post‐inflammatory, and in 25% with post‐traumatic lymph stasis, “newly‐formed” lymph nodes were detected by means of lymphoscintigraphy. They were located along the large calf and thigh veins. Although scattered nodes are normally detected in these areas, the number and total mass of visualized nodes substantially exceeded those seen in healthy subjects. The calculated surface area of “newly formed” nodes attained 50‐70% of the area of ipsilateral inguinal nodes. Histological evaluation of nodal biopsy specimens in three such patients revealed, in one, a lymph node structure without differentiation into cortical and medullary areas, and in a second, a follicle‐like structure within a dilated lymph vessel. Lymph clot removed from another dilated vessel contained a lymphocyte/dendritic cell aggregate. The “newly formed” nodes likely originate from primordial lymphoid follicles and/or lymphoid cell aggregates formed in response to chronic stimulation by microbial products and self‐antigens from the damaged tissues. Detection of “newly‐formed” lymph nodes in the limb is evidence of an ongoing inflammatory process and requires appropriate therapy.
Proteomic Technologies to Study Diseases of the Lymphatic Vascular System
Authors: LEAK LEE V. , PETRICOIN EMANUEL F. , JONES MICHAEL , PAWELETZ CLOUD P. , ARDEKANI ALI M. , FUSARO VINCENT A. , ROSS SALLY , LIOTTA LANCE A.
Published: July 2009

Abstract: Now that the human genome has been mapped, a new challenge has emerged: deciphering the various products of individual genes. Consequently, new proteomic technologies are being developed to monitor and identify protein function and interactions responsible for the total activities of the cell. The application of these new proteomic technologies to study cellular activities, will lead to a faster sample throughput and increased sensitivity for the detection of individual proteins, thus providing major opportunities for the discovery of new biomarkers for the early detection of protein alterations associated with the progression of the disease state.
Analysis of Malignancy‐Associated DNA Changes in the Nuclei of Buccal Epithelium in the Pathology of the Thyroid and Mammary Glands
Authors: KLYUSHIN D. A. , PETUNIN YU. I. , ANDRUSHKIW R. I. , BORODAY N. V. , GANINA K. P.
Published: July 2009

Abstract: The object of the investigation reported in this paper was to study, from the point of view of statistical and geometric theory of pattern recognition, the DNA optical density distribution peculiarities in the interphase nuclei of buccal epithelium present in the pathology of the thyroid and mammary glands. Two new indices to characterize this distribution (ratio of modal class volumes and relief index) are proposed. It is shown that in malignant neoplasms of the thyroid and mammary glands the changes in the nuclei of buccal epithelium are characterized by an increase in the optical density of DNA over a range from 0.15 to 0.30 in conventional units of measure, as compared with its values in benign pathological processes. The sensitivity of the proposed criterion for diseases of the thyroid gland is equal to 76.2% and the specificity is equal to 85.8%. For diseases of the mammary gland (excluding IDLC) we have discovered that the sensitivity of the method is equal to 94.29% and its specificity equal to 90.91%. In diseases of the mammary gland (including IDLC) we have discovered that the sensitivity of the method is equal to 71.42% and its specificity is equal to 90.91%.