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)

A little-noticed clinical report indicates that a low-fat, whole-food vegan diet, coupled with daily walking exercise, leads to rapid remission of neuropathic pain in the majority of type 2 diabetics expressing this complication. Concurrent marked improvements in glycemic control presumably contribute to this benefit, but are unlikely to be solely responsible. Consideration should be given to the possibility that improved blood rheology - decreased blood viscosity and increased blood filterability - plays a prominent role in mediating this effect. There is considerable evidence that neural hypoxia, secondary to impaired endoneurial microcirculatory perfusion, is a crucial etiologic factor in diabetic neuropathy; the unfavorable impact of diabetes on hemorheology would be expected to exacerbate endoneurial ischemia. Conversely, measures which improve blood fluidity would likely have a beneficial impact on diabetic neuropathy. There is indeed evidence that vegan diets, as well as exercise training, tend to decrease the viscosity of both whole blood and plasma; reductions in hematocrit and in fibrinogen may contribute to this effect. The fact that vegan diets decrease the white cell count is suggestive of an improvement in blood filterability as well; filterability improves with exercise training owing to an increase in erythrocyte deformability. Whether these measures influence the activation of leukocytes in diabetics - an important determinant of blood filterability - remains to be determined. There are various reasons for suspecting that a vegan diet can reduce risk for other major complications of diabetes - retinopathy, nephropathy, and macrovascular disease - independent of its tendency to improve glycemic control in type 2 patients. The vegan diet/exercise strategy represents a safe, 'low-tech' approach to managing diabetes that deserves far greater attention from medical researchers and practitioners.
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PMID:Favorable impact of a vegan diet with exercise on hemorheology: implications for control of diabetic neuropathy. 1232 13

Diabetic retinopathy is one of the most debilitating complications of diabetes mellitus. Despite major advances in understanding the pathogenesis of this disease and the efficacy of current therapies, diabetic retinopathy remains the leading cause of new-onset blindness among working-age people. The mainstay of current therapy, laser photocoagulation, is useful in preventing blindness and severe vision loss but is not often effective in restoring lost visual acuity. In addition, troublesome side effects and potentially serious complications may occur. Diabetic retinopathy is characterized by a progression of abnormalities. Nonproliferative retinopathy results from a series of biochemical and cellular changes that ultimately cause progressive retinal ischemia. The subsequent elaboration of growth factors in response to ischemia leads to the development of proliferative retinopathy, which is characterized by aberrant neovacularization of the retina-potentially leading to severe, irreversible visual loss. Increased retinal vascular leakage may also occur at any stage in this process, resulting in macular edema and possible progressive visual impairment. Although numerous biochemical factors are thought to play a role in the development of retinopathy, activation of protein kinase C (PKC), specifically the beta isoform of PKC (PKC beta), is implicated for both the early and late-stage manifestations of retinopathy. Studies suggest that orally administered LY333531, a beta-isoform specific PKC inhibitor, may be effective in ameliorating retinopathy progression, proliferation, and retinal vascular leakage. The status of ongoing clinical trials aimed at addressing the efficacy of PKC beta with regard to diabetes-induced retinal complications and perspectives on the role of PKC beta are presented.
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PMID:The potential role of PKC beta in diabetic retinopathy and macular edema. 1250 28

Macrophages are important participants in neovascularization. This study was designed to examine the role of the monocyte/macrophage chemotactic proteins, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP-1alpha) in a mouse model of oxygen-induced ischemic retinopathy and to determine whether the morphology and distribution of macrophages/microglia are concomitantly altered. The MCP-1, MIP-1alpha mRNA levels increased at 3 h after ischemia. MCP-1, MIP-1alpha, and vascular endothelial growth factor protein levels were also increased markedly and were maximal on days 1, 0.5, and 1, respectively, after ischemia. In situ hybridization showed that MCP-1 and MIP-1alpha were localized in the hypoxic inner retina. Immunostaining demonstrated that the macrophages/microglia in the retina had morphological changes with enlarged processes, and some were closely associated with neovascular tufts at postnatal day 17. Coadministration of the neutralizing antibodies against MCP-1 and MIP-1alpha inhibited retinal neovascularization by 30%. Our data suggest that MCP-1 and MIP-1alpha are involved in the induction of retinal neovascularization and play a role in the inflammation induced by the ischemic retinopathy, possibly by modulating or attracting macrophages/microglia.
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PMID:Role of MCP-1 and MIP-1alpha in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization. 1252 71

Ticlopidine, a thienopyridine that prevents the progression of diabetic retinopathy in humans, was recently shown to increase nitric oxide (NO) production in human neutrophils. The thienopyridine clopidogrel has been found to be clinically useful in the secondary prevention of thrombotic events. The aim of the present study was to evaluate the effect of clopidogrel on ischemic retinopathy in streptozotocin-diabetic rats and its influence on prostanoids and NO production. We compared nondiabetic rats and rats after 3 months of diabetes that were given three doses (1, 10 or 20 mg/kg per day p.o.) of ticlopidine or clopidogrel from the first day of diabetes. The variables recorded after 3 months of diabetes were platelet aggregation, thromboxane B(2) (TxB(2)) production, 6-keto-prostaglandin F(1)(alpha) (stable metabolite of prostacyclin), aortic NO, plasma nitrites/nitrates, and the percentage of the retinal surface occupied by horseradish peroxidase (HRP)-permeable vessels. In diabetic rats, platelet aggregation and thromboxane concentration were increased, and prostacyclin, NO and area occupied by HRP-permeable vessels were decreased. Ticlopidine and clopidogrel reduced the maximum extent of platelet aggregation in a dose-dependent manner: maximal inhibition with respect to untreated diabetic rats was 48.6% with ticlopidine and 66.6% with clopidogrel. Ticlopidine reduced thromboxane B(2) only at a dose of 20 mg/kg per day p.o. (47.4% inhibition) and clopidogrel at doses of 10 mg/kg per day (51% inhibition) or 20 mg/kg per day (51.7% inhibition). Aortic prostacyclin production did not change after treatment with either thienopyridine. Treatment with ticlopidine reduced the inhibition of NO production in untreated rats (89.6% inhibition) to 0.9%, and clopidogrel reduced inhibition to 30%. Treatment with ticlopidine or clopidogrel reduced the retinal nonperfused area from 86.8% inhibition in untreated rats to 45.6% and 25.3%, respectively. In conclusion, the early administration of thienopyridines in streptozotocin-diabetic rats partly prevented the appearance of diabetic retinal ischemia.
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PMID:Effects of clopidogrel and ticlopidine on experimental diabetic ischemic retinopathy in rats. 1259 63

Adenosine is a ubiquitous molecule that is produced predominantly by catabolism of adenosine triphosphate. Levels of this nucleoside increase dramatically with ischemia and elevated tissue activity. Adenosine levels are high in inner retina during retinal vascular development in postnatal dog. The source appears to be the ectoenzyme 5' nucleotidase, which is prominent at this time in the innermost process of Muller cells. One of the adenosine receptors, A(2A), is present on endothelial cell precursors, angioblasts, and endothelial cells in formed blood vessels in neonatal dog. These observations suggest that adenosine is important in retinal vascular development. Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity (ROP). The initial event in OIR is induced by exposure of the developing retina to high oxygen. Vascular development is halted and over 60% of the retinal vasculature is lost during this stage of the disease in dog, which is called vaso-obliteration. 5' nucleotidase is dramatically reduced during vaso-obliteration, resulting in a sharp decline in adenosine. When animals are returned to room air, the retina is hypoxic because of the lack of blood vessels, oxygen consumption is increased due to neuronal development, and systemic levels of oxygen have returned to normal. At this time, 5' nucleotidase activity and adenosine levels are elevated well beyond normal levels. This stage of OIR is the vasoproliferative stage and A(2A) expression and endothelial cell proliferation are very elevated compared to control animals. Florid preretinal neovascularization forms, which has high levels of adenosine and A(2A) receptors. Therefore, adenosine and its A(2A) receptor appear to be important in canine OIR. This work suggests that adenosine and its receptors may be a therapeutic target in OIR. This hypothesis is supported by recent studies in mouse (Mino et al., Invest. Ophthalmol. Vis. Sci. 42(13) (2001) 3320), which demonstrated that targeting one of the A(2) receptors can inhibit formation of neovascularization in OIR.
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PMID:Retinal vascular development and oxygen-induced retinopathy: a role for adenosine. 1259 25

Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.
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PMID:Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. 1470 18

Ischemia is a major stimulus for angiogenesis, a biological response mechanism that describes the formation of new blood vessels from existing vessels. An ischemic cell communicates with endothelial cells by soluble factors such as VEGF (vascular endothelial growth factor) and its receptors. A major transcriptional factor for VEGF is HIF-1 (hypoxia inducible factor). Proliferation of endothelial cells alone does not result in stable vascular tubes, this is only achieved by recruiting additional cells such as pericytes. The stabilisation and destabilisation of vessels, which are important prerequisites for vascular growth, are in a dynamic equilibrium which can be modified by additional growth factors such as angiopoietins. In this review we discuss some of the molecular mechanisms leading from ischemia to proliferative retinopathy with a special focus on retinopathy of prematurity and the closely related mouse model of hyperoxia-induced retinopathy. This model is very useful when developing new antiangiogenic therapies based on the increasing understanding of the molecular pathogenesis of ischemic proliferative retinopathy.
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PMID:[Angioproliferative retinal disease caused by ischemia]. 1274 2

In contrast to VEGF and its receptor VEGFR-2, PlGF and its receptor VEGFR-1 have been largely neglected and therefore their potential for therapy has not been previously explored. In this review, we describe the molecular properties of PlGF and VEGFR-1 and how this translates into an important role for PlGF in the angiogenic switch in pathological angiogenesis, by interacting with VEGFR-1 and synergizing with VEGF. PlGF was effective in the growth of new and stable vessels in cardiac and limb ischemia, through its action on different cell types (i.e. endothelial, smooth muscle and inflammatory cells and their precursors) that play a cardinal role in blood vessel formation. Accordingly, blocking its receptor VEGFR-1 with monoclonal antibodies (anti-VEGFR-1 mAb), expressed on al these cell types, successfully attenuated blood vessel formation during cancer, ischemic retinopathy and rheumatoid arthritis. In addition, while blocking this receptor was effective in reducing inflammatory disorders like atherosclerosis and rheumatoid arthritis, blocking the anti-angiogenic receptor VEGFR-2 was without effect. This indicates that in the latter diseases the beneficial effects of anti-VEGFR1 mAb were mainly due to its effect on inflammatory cells. Importantly, VEGFR-1 was also present on hematopoietic stem/progenitor cells, the precursors of inflammatory cells. Thus, these preclinical studies show proof-of-principle that PlGF and VEGFR-1 are promising therapeutic targets to treat angiogenesis and inflammation related disorders. Clinical trials will reveal whether this is also true for patients.
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PMID:Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. 1287 Dec 69

Retinopathy of prematurity (ROP) is an ischemia-induced proliferative retinopathy, which affects premature infants with low birth weight. It is a leading cause of visual impairment and blindness in children, and shares pathophysiological characteristics with other common ocular diseases such as diabetic retinopathy, central vein occlusion, and age-related macular degeneration. Pathologically similar inherited diseases such as Norrie disease suggest a possible genetic component in the susceptibility to ROP. The process of retinal neovascularization in ROP and in animal models of oxygen-induced retinopathy is complex, and involves angiogenic factors, such as vascular endothelial growth factor, and basement membrane components. Potential medical therapies for ROP, including modulators of angiogenic factors, inhibitors of basement membrane changes, endogenous inhibitors such as pigment epithelium derived factor, and anti-inflammatory drugs, have shown efficacy against neovascularization in several animal models. Some of these therapies are in clinical trials now for diabetic retinopathy and age-related macular degeneration, and in the future may prove efficacious for the treatment of ROP.
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PMID:Retinopathy of prematurity: molecular pathology and therapeutic strategies. 1293 Jan 59

We recently published the results of the Steno-2 study, which evaluated the benefits of intensified integrated behavior modification and targeted polypharmacy. The results provide abundant evidence that an ambitious treatment strategy is superior to a conventional one. The study involved 160 high-risk type 2 diabetic patients with microalbuminuria-a strong risk factor of both macrovascular and microvascular complications-aged 55.1 years, who were randomly assigned to a conventional or an intensive, multifactorial intervention for a period of 7.8 years. In the intensive group, a stepwise treatment plan was adopted involving both continuous lifestyle education and motivation and an ambitious goal-oriented pharmacological treatment of known modifiable risk factors. The conventional group was treated in accordance with national guidelines for type 2 diabetes with less stringent goals. The specific significant group differences in the degree of change in key clinical and biochemical variables at the end of the study were (in the intensive group): lower systolic and diastolic blood pressures, hemoglobin A(1c) (HbA(1c)), fasting serum total and low-density lipoprotein (LDL) cholesterol, fasting serum triglycerides, and 24-hour urine albumin excretion, as well as increased carbohydrate and decreased fat intake as percentage of total energy. There was no difference in weight gain between groups during follow-up and no other major side effects were reported. The primary end point was a macrovascular outcome: a composite of death from cardiovascular causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation for ischemia, or vascular surgery for peripheral arterial atherosclerosis. The differences between groups in surrogate end points translated into the following significant group differences in final clinical end points: 44% of patients in the conventional group had a cardiovascular event compared with 24% in the intensive group, ie, a relative risk reduction of about 50%. Also, the relative risk of nephropathy, retinopathy, and autonomic neuropathy (secondary end points) was diminished by about 60% in the intensively treated group. In conclusion, an intensified and goal-oriented multipronged approach to the treatment of type 2 diabetes reduces cardiovascular events, as well as nephropathy, retinopathy, and autonomic neuropathy, by about half. The challenge is to ensure that this experience is widely adopted in daily practice.
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PMID:Intensified multifactorial intervention and cardiovascular outcome in type 2 diabetes: the Steno-2 study. 1293 35


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