The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1 Neovascularization (angiogenesis) is also implicated in the pathogenesis of a number of disorders These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis1,2 A strong correlation has been noted between density of microvessels in primary breast cancers and their nodal metastases and patient survival3 Similarly, a correlation has been reported between vascularity and invasive behavior in several other tumors4–6

The biology of vascular endothelial growth factor

▪ Abstract At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxid...

Nitric oxide and macrophage function

Objective. —To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake. Data Sources. —MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels. Study Selection and Data Extraction. —Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations. Data Synthesis. —Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-μmol/L tHcy increment is 1.6(95% confidence interval [Cl], 1.4 to 1.7) for men and 1.8 (95% Cl, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-μmol/L tHcy increment) is 1.5 (95% Cl, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 μg/d) reduces tHcy levels by approximately 4 μmol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13 500 to 50 000 CAD deaths annually could be avoided; fortification of food had the largest impact. Conclusions. —A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements. ( JAMA . 1995;274:1049-1057)

https://jamanetwork.com/journals/jama/articlepdf/389728/jama_274_13_028.pdf

A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes

Vascular endothelial growth factor (VEGF) is a highly specific mitogen for vascular endothelial cells. Five VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene. These isoforms differ in their molecular mass and in biological properties such as their ability to bind to cell-surface heparan-sulfate proteoglycans. The expression of VEGF is potentiated in response to hypoxia, by activated oncogenes, and by a variety of cytokines. VEGF induces endothelial cell proliferation, promotes cell migration, and inhibits apoptosis. In vivo VEGF induces angiogenesis as well as permeabilization of blood vessels, and plays a central role in the regulation of vasculogenesis. Deregulated VEGF expression contributes to the development of solid tumors by promoting tumor angiogenesis and to the etiology of several additional diseases that are characterized by abnormal angiogenesis. Consequently, inhibition of VEGF signaling abrogates the development of a wide variety of tumors. The various VEGF forms bind to two tyrosine-kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1), which are expressed almost exclusively in endothelial cells. Endothelial cells express in addition the neuropilin-1 and neuropilin-2 coreceptors, which bind selectively to the 165 amino acid form of VEGF (VEGF165). This review focuses on recent developments that have widened considerably our understanding of the mechanisms that control VEGF production and VEGF signal transduction and on recent studies that have shed light on the mechanisms by which VEGF regulates angiogenesis.

Vascular endothelial growth factor (VEGF) and its receptors

L'invention concerne des methodes et des compositions associees a l'identification et a l'utilisation d'informations genetiques provenant de la batterie de genes d'IL-1, telles que des informations de structure et d'organisation de nouveaux genes de type IL-1 isoles dans le locus d'IL-1, ainsi que des polymorphismes et des haplotypes associes compris dans ces genes. L'invention permet ainsi d'etendre le repertoire des informations genetiques utiles disponibles provenant du locus d'IL-1, lequel contient les genes d'IL-1α, d'IL-1β et d'IL-RN deja identifies, d'ou la possibilite de predire les phenotypes associes a IL-1 (par ex., les risques accrus ou reduits de developper une maladie inflammatoire), et de traiter les phenotypes inflammatoires associes aux haplotypes d'IL-1.

Batterie de genes d'il-1 et polymorphismes et haplotypes inflammatoires associes

La presente invention concerne des proteines de liaison au PRLR. L'invention concerne specifiquement des anticorps qui sont des anticorps chimeres, a greffe de CDR et humanises. Les anticorps preferes presentent une grande affinite pour hPRLR et neutralisent l'activite de hPRLR in vitro et in vivo . Un anticorps selon l'invention peut etre un anticorps de pleine longueur ou une partie de cet anticorps se liant a un antigene. L'invention concerne egalement des procedes de fabrication et des procedes d'utilisation des anticorps de l'invention. Les anticorps selon l'invention ou les fragments d'anticorps de ceux-ci sont utiles pour detecter hPRLR et pour inhiber l'activite de hPRLR, par exemple chez un sujet humain atteint d'un trouble dans lequel l'activite de hPRLR est nefaste. En outre, l'invention concerne des conjugues medicament-anticorps anti-PRLR (ADC).

Protéines de liaison au récepteur de la prolactine et utilisations de celles-ci

La presente invention porte sur des proteines isolees, en particulier des anticorps monoclonaux, qui se lient et neutralisent la proteine RGM A. De facon specifique, ces anticorps ont l'aptitude d'inhiber la liaison de la RGM A a son recepteur et/ou ses corecepteurs. Ces anticorps ou parties de ceux-ci de l'invention sont utiles pour detecter la RGM A et pour inhiber l'activite de la RGM A, par exemple chez un etre humain souffrant d'un trouble comprenant, mais sans y etre limite, la sclerose en plaques, le traumatisme du cerveau d'un mammifere, la lesion de la moelle epiniere, l'accident vasculaire cerebral, les maladies neurodegeneratives et la schizophrenie.

Anticorps monoclonaux dirigés contre la protéine rgm a et ses utilisations

PROBLEM TO BE SOLVED: To provide a nucleic acid for a recombinant protein expression in mammalian cell culture.SOLUTION: Disclosed is an expression vector comprising (a) OriP origin of replication derived from Epstein-Barr virus (EBV); (b) a SV40 origin of replication; (c) an insertion site for inserting a gene of interest; (d) s cytomegalovirus (CMV) promoter operably linked to the insertion site, wherein the OriP origin of replication is bound by a trans-acting EBNA1 replication initiation factor which is not encoded by the expression vector, or the SV40 origin of replication is bound by a trans-acting SV40 T antigen which is not encoded by the expression vector. The episomal vectors promote high protein production in mammalian cells expressing the SV40 T Ag or Epstein-Barr virus nuclear antigen (e.g., COS7 or HEK293-6E cells).

Chung-Ming Hsieh

Papers

Batterie de genes d'il-1 et polymorphismes et haplotypes inflammatoires associes

Protéines de liaison au récepteur de la prolactine et utilisations de celles-ci

Anticorps monoclonaux dirigés contre la protéine rgm a et ses utilisations

Improved mammal expression vector and use thereof

Prostaglandin-E2 bindende Proteine und ihre Verwendung