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

La presente invention concerne des proteines de liaison isolees, par exemple des anticorps ou les parties de ces anticorps se liant a des antigenes, qui se lient au facteur alpha de necrose tumorale (TNF-α), par exemple au TNF-α humain, ainsi que des molecules et des compositions associees a base d'anticorps. La presente invention concerne en outre des compositions pharmaceutiques comprenant ces anticorps, ainsi que des methodes therapeutiques et diagnostiques reposant sur l'utilisation desdits anticorps.

Agents de liaison immunologique dirigés contre le tnf

Protéines de liaison dll4 thérapeutiques

La presente invention concerne des proteines isolees, notamment des anticorps monoclonaux, particulierement des anticorps humanises CDR-greffes, qui se lient a une proteine RAGE. Specifiquement, ces anticorps presentent la capacite d’inhiber la liaison d’un RAGE a ses differents ligands. Les anticorps ou des parties de ceux-ci decrits dans la presente invention sont utiles pour le traitement d’une maladie ou d’un trouble caracterise par ou induit par des ligands physiopathologiques des RAGE, par exemple des proteines mal pliees telles que l’amyloide β et les produits terminaux de glycation avancee.

Chung-Ming Hsieh

Papers

Agents de liaison immunologique dirigés contre le tnf

Protéines de liaison dll4 thérapeutiques

Anticorps contre le récepteur des produits terminaux de glycation avancée (rage) et leurs utilisations

Doppelt spezifische il-1a/il-1b-antikörper

Monoklonale antikörper gegen das rgm-a-protein und verwendungen davon