Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In light of the involvement of tumor-associated macrophages (TAM) in the promotion of tumor growth and metastasis, strategies to prevent TAM recruitment within the tumor microenvironment are currently under investigation. The recent observation that angiostatin reduces macrophage infiltration in an atherosclerosis model prompted our laboratory to further explore the use of human plasminogen angiostatin (hK1-3) protein as a macrophage modulatory agent. We demonstrate that hK1-3 blocks migration of murine peritoneal macrophages (91% decrease, P<0.00005) and human monocytes (85% decrease, P<0.05) in vitro. Cell viability of hK1-3-treated cells is not affected, as determined by fluorochrome-labeled inhibitors of caspase-propidium iodide (FLICA/PI) flow cytometry analysis. Furthermore, confocal microscopy of phalloidin-stained cells reveals that hK1-3 leads to disruption of actin filopodia/lamellipodia in human monocytes and induces distinct podosome accumulation in mature differentiated macrophages. Paradoxically, we observed a 3.5-fold increase in secretion and a 3- to 5.5-fold increase in gelatinolytic activity of macrophage-produced matrix metalloproteinase-9, which we suggest is a cellular response to compensate for the dominant static effect of hK1-3 on actin. We also demonstrate that hK1-3 induces the phosphorylation of extracellular signal-regulated kinase (ERK1/2) in human monocytes. hK1-3-mediated macrophage immobilization has the potential to be exploited therapeutically in pathological conditions associated with cellular hypoxia, such as cancer and atherosclerosis.
 ...
PMID:Angiostatin inhibits monocyte/macrophage migration via disruption of actin cytoskeleton. 1762 68

It is rarely considered that age-related common vascular co-morbidities may affect therapeutic outcomes of antiangiogenic therapy in cancer. Indeed, the accepted model of human disease consists of 4- to 8-week-old (young) tumor-bearing, but otherwise healthy, experimental mice, yet human cancers are diagnosed and treated in later decades of life when atherosclerosis and vascular diseases are highly prevalent. Here we present evidence that tumor growth and angiogenesis are profoundly altered in mice affected by natural aging and with genetically induced atherosclerosis (in ApoE(-/-) mice). Thus, transplantable tumors (Lewis lung carcinoma and B16F1) grew at higher rates in young (4 to 8 weeks old) ApoE(+/+) and ApoE(-/-) nonatherosclerotic syngeneic recipients than in their old (12 to 18 months old) or atherosclerotic (old/ApoE(-/-)) counterparts. These age-related changes were paralleled by reduced tumor vascularity, lower expression of tumor endothelial marker 1, increased acute tumor hypoxia, depletion of circulating CD45(-)/VEGFR(+) cells, and impaired endothelial sprouting ex vivo. Exposure of tumor-bearing mice to metronomic therapy with cyclophosphamide exerted antimitotic effects on tumors in young hosts, but this effect was reduced in atherosclerotic mice. Collectively, our results suggest that vascular aging and disease may affect tumor progression, angiogenesis, and responses to therapy.
 ...
PMID:Atherosclerosis and vascular aging as modifiers of tumor progression, angiogenesis, and responsiveness to therapy. 1782 92

Angiogenesis, the growth of new blood vessels from preexisting ones, is a necessary component of embryogenesis, wound healing, and the proliferative phase of the female reproductive cycle. Angiogenesis also plays a critical role in important pathologic processes such as cancer and cardiovascular complications. In addition, clinical, laboratory, and pharmacologic evidence has shown a link between angiogenesis, coagulation, hemostasis, and thrombosis in the settings of these pathologies. Recent studies in our laboratory revealed that thrombin has a significant stimulatory effect on angiogenesis. This effect of thrombin is independent of fibrin formation and can be attributed mainly to the activation of protease-activated receptor-1 (PAR-1). PAR-1 is widely expressed in vascular cells and is involved in cardiovascular complications such as atherosclerosis, restenosis, and neointimal formation. It is also expressed in many cancer cells contributing to induction of tumor growth and metastasis. In this review, we will summarize our present-day understanding of the role of thrombin and PAR-1 in angiogenesis and the potential therapeutic utility of targeting PAR-1 in angiogenesis-related disease, such as atherosclerosis, restenosis, and cancer.
 ...
PMID:Inhibition of angiogenesis by small-molecule antagonists of protease-activated receptor-1. 1800 Jul 95

Lactosylceramide is a ubiquitously present glycosphingolipid in mammalian tissues and has been implicated in cell proliferation, adhesion, migration and angiogenesis. This glycosphingolipid is synthesized by Golgi-localized enzyme LacCer synthase. According to recent nomenclature and gene mapping studies, two LacCer synthases beta1,4GalT-V and beta1,4GalT-VI have been identified and characterized. In addition, beta1,4GalT-V has been implicated in the synthesis of N-glycans of cell surface glycoproteins. During the past two decades data have accumulated suggesting that the cellular level of LacCer can be regulated by various growth factors, cytokines, lipids, lipoproteins and hemodynamic factors, such as fluid shear stress, by altering the activity of LacCer synthase. An interesting feature is that a nuclear regulating factor (SP1) plays a critical role in transcriptional regulation of this enzyme in cancer cells. Moreover, in human umbilical vein endothelial cells, NF-kappaB has been also shown to regulate this enzyme which, in turn, regulates the gene/protein expression of platelet endothelial cell adhesion molecule, intercellular cell adhesion molecule and angiogenesis. Since new blood supply via formation of capillaries is critical in tumor growth, metastasis, and atherogenesis, these findings expand the role of enzyme in these pathologies. Additional studies are warranted to understand the molecular and biochemical basis of how LacCer synthases are regulated. These studies will facilitate advances in discovery of drugs which mitigate diseases, such as atherosclerosis and cancer due to an aberrant regulation of these LacCer synthases.
 ...
PMID:Regulation of lactosylceramide synthase (glucosylceramide beta1-->4 galactosyltransferase); implication as a drug target. 1839 21

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-alpha signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-beta signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial-mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.
 ...
PMID:Role of platelet-derived growth factors in physiology and medicine. 1848 17

Factor VIIa (FVIIa)-induced signal transduction is strongly dependent on cellular surface expression of Tissue Factor (TF) and Protease Activated Receptors (PARs). FVIIa signals primarily through PAR2. This contrasts to thrombin which signals primarily via PAR1 and does so without the assistance of a co-receptor, but by binding to an exosite on PAR1. Various TF:FVII-mediated cellular activities are now well documented and have indicated possible links to inflammation, atherosclerosis, angiogenesis, tissue repair, tumor growth and metastasis. Further knowledge about cellular responses induced by coagulation factors has been obtained by gene-expression profiling of MDA-MB-231 cells stimulated with FVIIa or alternatively with PAR1 or PAR2 agonist peptides. These studies and qPCR measurements of the transcription of selected genes in these and other carcinoma cell lines have provided new information about gene expression induced by PAR activation, the gene repertoire induced by TF:FVIIa via PAR2, and how it differs from that induced via PAR1 by thrombin.
 ...
PMID:Microarray studies of factor VIIa-activated cancer cells. 1869 91

Platelets are highly reactive components of the circulatory system, which exert not only haemostatic activity but also contribute to the modulation of various pathological conditions including inflammation, atherosclerosis and cancer metastasis through the release of cytokines, chemokines and the presentation of several adhesion molecules. During cancer metastasis, the formation of platelet-tumor cell aggregates in the circulation facilitates immune evasion and the microvascular arrest of tumor cells at distant sites. Several adhesion molecules, such as integrins and glycoproteins, were shown to be involved in this process. Recent findings indicate that P-selectin is another main mediator of platelet-tumor cell interactions. Other effects of activated platelets on cancer progression are associated with a release of platelet-derived factors stimulating tumor growth and angiogenesis. Any interference in platelet-tumor cell interactions resulted in attenuation of cancer metastasis. The well recognized, albeit not fully characterized function of platelets during cancer progression defines platelets as potential targets for cancer therapy. Specifically, the rapid expression of P-selectin on the cell surface of activated platelets and its strong association with metastasis provide a rationale for P-selectin inhibition as an antimetastatic treatment.
 ...
PMID:The role of platelet activation in tumor metastasis. 1869 63

PDGF (platelet derived growth factor) has been shown to play an important role in tumorigenesis, tumor growth, atherosclerosis and inflammation and other various pathologic settings. PDGF-B chain gene is 92% homologous to v-sis oncogene of the simian sarcoma virus. Thus PDGF-B gene is also called c-sis proto-oncogene. This report provides 3 TFOs (triplex-forming oligonucleotides) to inhibit the expression of c-sis/PDGF-B gene. The results from gel mobility shift analysis,in vitro transcription, DNase I footprinting and protein binding assays demonstrate that the TFOs we designed can form sequence-specific stable triplex with the target, and can effectively suppress the downstream gene transcription and inhibit transcription factors binding. They can be used for preparation of drugs to inhibit tumor growth and for the therapy of atherosclerosis, inflammation, etc.
 ...
PMID:In vitro triplex formation and functional analysis of TFOs designed against human c-sis/PDGF-B proto-oncogene. 1876 92

Angiogenesis is a general term describing formation of new tube-like microvessel sprouts that are the size of capillary blood vessels. Angiogenesis is fundamental in key stages of embryonic development, organ formation, and wound repair and is also involved in the development and progression of a variety of pathological conditions, including cancer (tumor growth and metastasis), cardiovascular disease, diabetic retinopathy, age-related macular degeneration, atherosclerosis, and rheumatoid arthritis. Because of its diverse roles in key physiological and pathological processes, angiogenesis is an important area of medical research, with a considerable number of angiogenic and anti-angiogenic drugs currently undergoing clinical trials. Cost-effective and efficient screening for potential lead compounds is therefore of prime importance. However, screening methodologies vary in their physiological relevance depending on how faithfully critical aspects of angiogenesis are represented. Cell-based in vitro angiogenesis assays are important tools for screening, which in many cases rely on imaging microscopy to ascertain drug effects. Unfortunately, such screens can be hampered by poorly defined biology, slow image acquisition by manual or semiautomated hardware, and slow data analysis by non-dedicated software. This article describes use of a 96-well microplate in vitro angiogenesis screening system as part of an integrated workflow, comprising (1) setting up the biology in a three-dimensional physiologically relevant system, (2) acquiring a series of image slices ("stacks") using an automated z-stage instrument, (3) collapsing the image stack series into sets of two-dimensional images, (4) segmenting objects of interest, and (5) analyzing the segmentation patterns in order to obtain statistically relevant data.
 ...
PMID:Angiogenesis: an improved in vitro biological system and automated image-based workflow to aid identification and characterization of angiogenesis and angiogenic modulators. 1903 50

Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11betaHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11betaHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity.
 ...
PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. 1934 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>