Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This workshop intended to perform a "state-of-the art" of current research on adhesion molecules in various pathophysiologies, and to determine pharmacological targets. Indeed, recent important progress concerning the cellular and molecular physiology of adhesion molecules led to the development of various integrin antagonists in several domains, like cardiovascular disease, inflammation and cancer. Integrins play a major role in numerous process like embryonic development, tumor growth and metastasis, apoptosis, hemostasis, leucocyte recruitment and activation, and bone resorption. The development of integrin antagonists is well advanced in the cardiovascular domain, since the first marketed drug (abciximax, Reopro) is an antibody directed against the GPIIb/IIIa complex (integrin alpha IIb/beta 3) involved in the final pathway of platelet aggregation. Another active domain of research in pharmacology is 'cardioprotection', i.e. the prevention of cardiac damages induced by the reperfusion of the coronary bed after an ischemia secondary to thrombolysis, angioplasty, of coronary bypass. The pharmacological targets of these antagonists are integrins involved in various process like leucocyte and platelet adhesion and endothelial function. Other potential indications in the cardiovascular field are restenosis after angioplasty, and atherosclerosis.
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PMID:[Cell adhesion molecules and pharmacologic applications. Round Table No 3 at Giens XIII]. 980 7

The management of advanced digestive endocrine tumors is often challenging. Liver metastases are usually diffuse at the time of diagnosis, and surgical resection is rarely feasible. Objective response rates with systemic chemotherapy are disappointing. Arterial hypervascularization of most liver metastases from digestive endocrine tumors argues in favor of hepatic arterial chemoembolization (HACE). It is assumed that embolization-induced ischemia sensitizes tumor cells to cytotoxic drugs, whose tumor concentrations are increased by blood flow slowing down. The aims of HACE are: (1) to control otherwise untractable hormone-related symptoms, particularly the carcinoid syndrome (>50% urinary 5-HIAA decrease: 57-91%) and insulinoma-related life-threatening hypoglycemias; (2) to inhibit tumor growth (objective response rates: 33-80%; mean duration: 6-42.5 months), and (3) to improve patients' survival. The postembolization syndrome, usually mild and transient, is the commonest side effect. Major extrahepatic complications are rare. In conclusion, HACE seems to be an attractive alternative treatment for diffuse (unresectable) and progressive metastases confined to the liver in patients with digestive endocrine tumors, mainly following unsuccessful systemic chemotherapy. Further studies assessing the long-term results of HACE and comparing it to other treatments, particularly systemic chemotherapy, are needed.
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PMID:Hepatic arterial chemoembolization in the management of advanced digestive endocrine tumors. 1094 Jun 92

Angiogenesis, the process of new vessel growth, is necessary for many normal physiological and pathological processes such as tumor growth, wound healing and ischemia. We have recently examined in vitro and in vivo the ability of two potent angiogenic compounds, SIKVAV (a peptide derived from the alpha chain of laminin-1) and Neuropeptide Y (NPY) to revascularize ischemic tissue. These compounds were tested in an ex vivo capillary sprouting angiogenesis assay that uses rat aortic rings. Both NPY and SIKVAV in the presence of VEGF, stimulated the formation of long sprouts at concentrations of 1 ng NPY (0.2 pmol/L) and 100 micrograms SIKVAV. In comparison very little sprouting occurred in the control rings and 50 ng of VEGF alone was required to induce equivalent number of sprouts as NPY. SIKVAV and NPY were further tested in vivo in a rat hindlimb ischemic model. Both compounds (500 micrograms SIKVAV and 10 ng of NPY) were embedded in the rat hind limb following unilateral ligation of the femoral artery 1 cm proximal to the adductor hiatus. After two weeks control peptides show little or no revascularization of the hindlimb distal to the ligation; however, both SIKVAV and NPY demonstrated a two-fold increase in new vessels in the region proximal to the ligation. Histological sections of latex perfused hindlimb demonstrated that ligated limbs had very few latex-filled dermal capillaries. Limbs treated with SIKVAV and NPY, however, demonstrated normal distribution in the dermal capillary beds. These data indicate that both SIKVAV and NPY are potent angiogenic factors that show promising potential clinical application to the revascularization of ischemic tissue.
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PMID:Revascularization of ischemic tissues with SIKVAV and neuropeptide Y (NPY). 1094 62

With adequate medical management the midgut carcinoid tumor generally is an indolent malignancy associated with substantial life expectancy and appreciable life quality, even in the presence of liver metastases and significant tumor burden. Abdominal complications may occur in this entity of carcinoids owing to entrapment of intestines and encasement of mesenteric vessels by mesenteric metastases and associated marked mesenteric fibrosis. This may be the cause of abdominal pain, disabling diarrhea, weight loss to the extent of malnutrition, and eventually the risk of death with acute or chronic intestinal obstruction or intestinal gangrene. Operative removal of the mesentericointestinal lesion is often indicated to prevent or treat these complications but may be technically difficult when mesenteric metastases extend in the vicinity of major vessels in the mesenteric root. At laparotomy 56 patients with advanced midgut carcinoids underwent removal of the mesenteric tumor with a method for preserving the mesenteric vessels. This was feasible by mobilizing and releasing the right colon and mesenteric root from posterior adhesions, identifying the mesenteric artery below the pancreas, and free-dissecting this artery on the tumor capsule in the mobilized mesentery. Dissection was successful even with tumors initially judged inoperable unless tumor growth completely surrounded the mesenteric vessels or extended retroperitoneally. One patient was subjected to distal intestinal artery bypass. Symptom relief was been substantial and often of long duration after mesenteric tumor removal in patients who prior to surgery often had threatening intestinal ischemia. Patients with advanced midgut carcinoids may benefit markedly from dissectional removal of mesenteric tumors, which (conceivably better than conventional wedge resection) preserves the length of the remaining intestine.
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PMID:Method for dissection of mesenteric metastases in mid-gut carcinoid tumors. 1103 14

The formation of new blood vessel is essential for a variety of physiological processes like embryogenesis and the female reproduction as well as wound healing and neovascularization of ischemic tissue. Major progress in understanding the underlying mechanisms regulating blood vessel growth has offered novel therapeutic options in the treatment of a variety of diseases including ischemic cardiovascular disorders. Vasculogenesis and angiogenesis are the mechanisms responsible for the development of the blood vessels. Angiogenesis refers to the formation of capillaries from preexisting vessels in the embryo and adult organism. While pathologic angiogenesis includes the role of post-natal neovascularization in the pathogenesis of arthritis, diabetic retinopathy, and tumor growth and metastasis, therapeutic angiogenesis, either endogenously or in response to administered growth factors, includes the development of collateral blood vessels in tissue ischemia. Preclinical studies established that angiogenic growth factors could promote collateral artery development in animal models of peripheral and myocardial ischemia. Subsequent clinical trials using gene transfer of naked DNA encoding for VEGF for the treatment of critical limb and myocardial ischemia documented the safety and clinical benefit of this novel therapeutic approach. Several objective methods indicated marked improvement in collateral vessel development. Vasculogenesis describes the development of new blood vessels from in situ differentiating endothelial cells. Recently considered to be restricted to embryogenesis, there exists now striking evidence that endothelial progenitor cells (EPC) circulate also in adult peripheral blood able to participate in ongoing neovascularization. Different cytokines and growth factors have a stimulatory effect on these bone-marrow derived EPC. Granulocyte macrophage colony stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) mobilize EPC from the bone marrow into the peripheral circulation. While their endogenous contribution to postnatal neovascularization needs to be documented, the iatrogenic expansion and mobilization of EPC might represent an effective means to augment the resident population of endothelial cells (ECs). This kind of cell therapy for tissue regeneration in ischemic cardiovascular diseases opens a novel and challenging clinical option besides or in addition to the use of growth factors in gene therapy.
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PMID:[Angiogenesis and vasculogenesis. Therapeutic strategies for stimulation of postnatal neovascularization]. 1107 19

Vasculogenesis and angiogenesis are the processes responsible for the development of the circulatory system during embryonic and adult life. Vasculogenesis occurs during embryogenesis while angiogenesis refers to blood vessel formation from any preexisting vasculature. Postnatal angiogenesis resumes during reproduction, wound healing, and ischemia. Excess blood vessel formation may contribute to initiating and maintaining many diseases such as chronic inflammatory disorders, tumor growth, restenosis, and atherosclerosis. In contrast. insufficient blood vessel formation is responsible for tissue ischemia, as in coronary artery disease. An increasing number of patients with advanced coronary artery disease remain symptomatic despite maximal interventional, surgical or medical treatment. Ideally, they would benefit most from additional arterial blood supply to ischemic areas of myocardium. Therapeutic angiogenesis, the ability to induce the growth of new blood vessels, is one of the most intriguing new frontiers in interventional cardiology for this growing patient group. Several approaches are currently undergoing intensive experimental investigations or have already entered early clinical trials involving either local angiogenic peptide administration or the transfection of angiogenic genes. Gene therapy for therapeutic myocardial angiogenesis is the most promising synthesis of two emerging technologies. In the following article, we will review the fundamental pathophysiological concepts of gene-based angiogenic therapy, the technical approaches and delivery systems, and the results of the first clinical trials. We will also discuss the controversies and unresolved issues of this new revascularization therapy.
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PMID:Gene therapy for myocardial angiogenesis: has it come of age? 1112 68

Cathepsin D (CD) and cathepsin E are representative lysosomal and nonlysosomal aspartic proteinases, respectively, and play an important role in the degradation of proteins, the generation of bioactive proteins, antigen processing, etc. Recenty, several lines of evidence have suggested the involvement of these two enzymes in the execution of neuronal death pathways induced by aging, transient forebrain ischemia, and excessive stimulation of glutamate receptors with excitotoxins. CD has also been shown to mediate apoptosis induced by various stimuli and p53-dependent tumor suppression. To gain more insight into in vivo functions of CD, mice deficient in this enzyme were generated. The mutant animals showed a progressive atrophy of the intestinal mucosa, a massive destruction of lymphoid organs, and a profound accumulation of ceroid lipofuscin, and developed a phenotype resembling neuronal ceroid lipofucinosis, suggesting that CD is essential for proteolysis of proteins regulating cell growth and tissue homeostasis. It has also been shown that CD molecules secreted from human prostate carcinoma cells are responsible for the generation of angiostatin, a potent endogenous inhibitor of angiogenesis, suggesting its contribution to the prevention of tumor growth and angiogenesis-dependent growth of metastases. Interestingly, pro-CD from human breast carcinoma cells showed a significantly lower angiostatin-generating activity than that from prostate carcinoma cells. Since deglycosylated CD molecules from both carcinoma cells showed a low angiostatin-generating activity, this discrepancy appeared to be attributed to the difference in the carbohydrate structures of CD molecules between the two cell types and to contribute to their potency to prevent tumor growth and metastases.
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PMID:New functional aspects of cathepsin D and cathepsin E. 1121 63

Interleukin-12 and tumor necrosis factor (TNF)-alpha promote T-helper (Th) 1 responses and cellular immunity, whereas IL-10 suppresses Th1 activities and stimulates Th2 and humoral immune responses. Recent evidence indicates that glucocorticoids, norepinephrine, epinephrine, histamine, and adenosine inhibit the production of human IL-12 and TNF-alpha, whereas they do not affect or even stimulate the production of IL-10. Through this mechanism these neuroendocrine mediators may cause a selective suppression of Th1 responses and a Th2 shift rather than generalized Th suppression. The substantial Th2-driving force of endogenous stress mediators, as well as histamine and adenosine, can be amplified to a great extent during certain conditions and may play a role in increased susceptibility of the organism to various infections that are normally cleared by Th1 responses. In addition, conditions that contribute to a substantial increase or decrease of local or systemic concentrations of these mediators via modulation of IL-12, TNF alpha/IL-10 balance may also play a role in induction, expression, and progression of certain autoimmune diseases, allergic/atopic reactions, and tumor growth. These conditions include: acute or chronic stress; cessation of chronic stress or chronic hypoactivity of the stress system; severe exercise; serious surgical procedures or traumatic injuries; major burns; severe ischemia or hypoxia; pregnancy and the postpartum period. Thus, better understanding of the neuroendocrine regulation of IL-12, TNF-alpha/IL-10 balance might help the development of new therapeutic strategies for the treatment of Th1- and Th2-mediated human diseases.
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PMID:Neuroendocrine regulation of IL-12 and TNF-alpha/IL-10 balance. Clinical implications. 1126 24

Formation of new blood vessels in the adult animal (i.e., angiogenesis) is an important event for tissue repair and for tumor growth and metastasis. Angiogenesis involves the migration and proliferation of endothelial cells. We have investigated the role of the growth suppressor p27(Kip1) (p27) on endothelial cell function in vitro and angiogenesis in vivo. We have generated Ad-TetON, a replication-deficient adenovirus that constitutively expresses the reverse tet-responsive transcriptional activator, and Ad-TRE-p27, which drives expression of p27 under the control of the tet response element. Western blot analysis demonstrated doxycycline-dependent overexpression of p27 in human umbilical vein endothelial cells (HUVECs) coinfected with Ad-TetON and Ad-TRE-p27, which resulted in a marked inhibition of DNA replication and cell migration in vitro. Inducible overexpression of p27 in cultured HUVECs inhibited the formation of tubelike structures and, when applied in a murine model of hind limb ischemia, reduced hind limb blood flow recovery and capillary density. These findings thus underscore a novel role of p27 in regulating endothelial cell migration in vitro and angiogenesis in vivo, suggesting a novel anti-angiogenic therapy based on inducible p27 overexpression.
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PMID:Overexpression of p27(Kip1) by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis. 1153 67

We have recently reported that nicotine has angiogenic effects, which appear to be mediated through non-neuronal nicotinic acetylcholine receptors (nAChRs). Here, we describe the endogenous cholinergic pathway for angiogenesis. In an in vitro angiogenesis model, increasing concentrations of the nonselective nAChR antagonist mecamylamine completely and reversibly inhibited endothelial network formation. Although several nAChR isoforms are expressed on endothelial cells (ECs), a similar inhibition was only obtained with the selective alpha7-nAChR antagonist alpha-bungarotoxin, whereas other selective antagonists did not result in significant inhibition of network formation. alpha7-nAChR was upregulated during proliferation, by hypoxia in vitro, and by ischemia in vivo. The nAChR-induced network formation was partially dependent on VEGF, was completely dependent on the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, and finally resulted in NF-kappaB activation. In vivo, pharmacological inhibition of nAChR as well as genetic disruption of alpha7-nAChR expression significantly inhibited inflammatory angiogenesis and reduced ischemia-induced angiogenesis and tumor growth. Our results suggest that nAChRs may play an important role in physiological and pathological angiogenesis. To our knowledge, this is the first description of a cholinergic angiogenic pathway, and it suggests a novel avenue for therapeutic modulation of angiogenesis.
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PMID:A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors. 1218 47


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