UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.
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PMID:Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. 1290 15

Most epidemiological surveys in the Italian population, have concentrated on areas of northern and central Italy. The incidence of the first-ever ischemic and hemorrhagic strokes in a well-defined population of the province of Foggia, a rural area of southern Italy, over a 3-year period has been investigated, to compare the occurrence of stroke by type in this and other areas. A retrospective study in a local health district (USL FG3) in the province of Foggia was conducted and all cases of first-ever cerebral infarction (CI) and intracerebral hemorrhage (ICH) in the local population (41 269) from January 1, 1993 to December 31, 1995 have been investigated. Case ascertainment was performed by a chart review in the two local hospitals and examination of death certificates. General practitioners were also asked to report on non-hospitalized cases suffering a stroke during the study period. Patients with recurrent stroke, unclassifiable stroke, transient ischemic attacks and subarachnoid hemorrhage were excluded. Risk factors for stroke and 30-day mortality were investigated. The rates were standardized to the Italian population (57 138 489, 1991 census). During the 3-year study period, 202 patients had a first-ever ischemic or hemorrhagic stroke (66 in 1993, 69 in 1994 and 67 in 1995). Of these, 174 (86.1%) had cerebral ischemia, accounting for 57, 60 and 57 cases in the three index years. The overall crude annual incidence of CI and ICH was 1.60, 1.67 and 1.62 of 1000 for 1993, 1994 and 1995, respectively. The corresponding standardized incidences rates were 2.0, 2.10 and 2.06 of 1000. The rate was 0.11 in patients <55 years of age, and 1.97, 7.01, 13.52, and 25.34 at ages 55-64, 65-74, 75-84, and 85+ years for the entire period; the 30-day mortality was 27.2, 21.7, and 15% for 1993, 1994, and 1995, respectively. Hypertension (45.9%), diabetes (26.4%) and atrial fibrillation (16.6%) were the most common risk factors. The incidence of CI and ICH was similar to that of most other Italian studies. It was constant during the 3-year period, and mostly involved older people.
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PMID:Incidence of first-ever ischemic and hemorrhagic stroke in a well-defined community of southern Italy, 1993-1995. 1294 Aug 39

One third of cases of cerebral ischemia have no clear etiology. A humoral response to the atherosclerotic plaques components beta2-glycoprotein l (beta2-gpl) and heat-shock proteins (Hsp) might be involved in the pathogenesis of stroke. This case-control study includes a complete profile of anti-beta2-gpl antibodies and testing of IgG antibodies to the 60/65 kilodaltons (kDa) Hsp in stroke patients. Ninety-three patients with acute ischemic stroke and 93 controls were evaluated for age, sex, race, hypertension, smoking, previous cardiopathy, diabetes mellitus, hypercholesterolemia and previous history of cerebral ischemia. lgG/lgM/lgA anticardiolipin (aCL) and anti-beta2-gpl antibodies, as well as lgG antibodies to human 60 kDa Hsp and to Mycobacterium bovis 65 kDa Hsp, were detected by immunoassay. Adjusted odds ratios (OR) were calculated by logistic regression. The adjusted OR for IgA anti-beta2-gpl antibodies was 4.6 (90%Cl 1.5 to 14.3; p = 0.025). The non-adjusted OR for IgG antibodies to Hsp 60 was 26.1. The adjusted OR for IgG antibodies to Hsp 65 was 3.2 (90%Cl 1.2 to 8.3; p = 0.044). The adjusted OR for lgG to any Hsp (60 or 65) was 4.8 (90%Cl 1.9 to 12.1; p = 0.006). This study demonstrates that elevated IgA anti-beta2-gpl and lgG anti-Hsp 60/65 antibodies are associated with increased risk of ischemic stroke. The association occurred independently of other risk factors. This humoral response might link autoimmunity, thrombophilia and atherosclerosis in stroke patients.
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PMID:Antibodies to the atherosclerotic plaque components beta2-glycoprotein I and heat-shock proteins as risk factors for acute cerebral ischemia. 1459 78

Despite the great technical advancement of mass spectrometry, this technique has contributed in a limited way to the discovery and quantitation of specific/precocious markers linked to free radical-mediated diseases. Unsaturated aldehydes generated by free radical-induced lipid peroxidation of polyunsaturated fatty acids, and in particular 4-hydroxy-trans-2 nonenal (HNE), are involved in the onset and progression of many pathologies such as cardiovascular (atherosclerosis, long-term complications of diabetes) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and cerebral ischemia). Most of the biological effects of HNE are attributed to the capacity of HNE to react with the nucleophilic sites of proteins and peptides (other than nucleic acids), to form covalently modified biomolecules that can disrupt important cellular functions and induce mutations. By considering the emerging role of HNE in several human diseases, an unequivocal analytical approach as mass spectrometry to detect/elucidate the structure of protein-HNE adducts in biological matrices is strictly needed not only to understand the reaction mechanism of HNE, but also to gain a deeper insight into the pathological role of HNE. This with the aim to provide intermediate diagnostic biomarkers for human diseases. This review sheds focus on the "state-of-the-art" of mass spectrometric applications in the field of HNE-protein adducts characterization, starting from the fundamental early studies and discussing the different MS-based approaches that can provide detailed information on the mechanistic aspects of HNE-protein interaction. In the last decade, the increases in the accessible mass ranges of modern instruments and advances in ionization methods have made possible a fundamental improvement in the analysis of protein-HNE adducts by mass spectrometry, and in particular by matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) tandem mass spectrometry. The recent developments and uses of combined analytical approaches to detect and characterize the type/site of interaction have been highlighted, and several other aspects, including sample preparation methodologies, structure elucidation, and data analysis have also been considered.
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PMID:Mass spectrometry for detection of 4-hydroxy-trans-2-nonenal (HNE) adducts with peptides and proteins. 1513 38

In secondary prevention, reduction of the risk of recurrent ischemic stroke might be expected with statins if a correlation can be established between hyperlipidemia and ischemic stroke or some specific ischemic stroke/TIA subtypes. However, such correlation remains controversial, and more particularly with the etiologic stroke/TIA subtypes. Few studies have evaluated the plasma lipid profile in different ischemic stroke subtypes, and notably in lacunar infarctions and cardioembolic strokes. The objectives of this case-control study was to determine (1) which cholesterol fractions is associated with large vessel disease (LVD), small vessel disease (SVD), and cardioembolic disease (CED); (2) whether hypertriglyceridemia is related more to any particular stroke subtype; and (3) whether the lipid profile is different between LVD and SVD which are both responsible for atherothrombotic cerebral ischemia. From a cohort of 485 patients, were selected 240 consecutive cases with ischemic stroke (n = 182) or transient ischemic attack (n = 58) due to a single etiology. The levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglycerides (TG) were measured in 61 patients with LVD, in 65 with SVD, and in 114 with CED, and compared with age- and sex-matched control subjects. Additional analysis was performed to compare the lipid profile between LVD and SVD after adjustment for other risk factors. Compared to controls, the total-C level was significantly higher in patients with SVD (p = 0.005) and LVD (p = 0.018). A significant increase in the LDL-C level (p < 0.004) and a significant decrease in the HDL-C level (p = 0.001) were only observed in the LVD patients. The three stroke subtypes showed higher TG levels than the controls (CED, p = 0.037; SVD, p < 0.001; LVD, p = 0.014). The plasma lipid profile was similar in the SVD and LVD subtypes except for HDL-C, which was significantly lower in LVD than in SVD (p = 0.047). Logistic regression adjusted for confounders showed that decreased HDL-C (p = 0.020), and smoking (p = 0.019) were significant discriminative factors for LVD vs. SVD. In conclusion, this controlled study shows that hypertriglyceridemia is commonly found in patients with ischemic cerebrovascular disease whatever the etiologic subtype, whereas hypercholesterolemia is related more to SVD and LVD. In addition to hypertension and diabetes, hypercholesterolemia may also be involved in the etiology of SVD and differs from LVD by a lower decrease in HDL-C.
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PMID:Lipids in ischemic stroke subtypes. 1514 57

The objective of the present study was to examine the role of the angiotensin II type 1 receptor (AT(1)-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT(1)-R antagonist candesartan (0.5 mg.kg(-1).day(-1)) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats (n = 189) were divided into five groups: normal control, diabetes, MCAO, diabetes + MCAO, and diabetes + MCAO + candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91(phox) and p22(phox) mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91(phox) and p22(phox) mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91(phox) and p22(phox), decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT(1)-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.
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PMID:Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. 1514 62

The major neuropathological lesions defining Alzheimer's disease (AD) include neurofibrillary tangles and amyloid plaques, which are mainly composed of abnormally phosphorylated tau and amyloid-beta (A beta), respectively. Numerous neuropathological and neuroimaging studies indicate that at least one-third of AD cases are complicated by some degree of vascular pathology, whereas in a similar proportion of patients clinically diagnosed with vascular dementia, AD pathology is also present. Many classical vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have recently been shown also to increase the risk of AD. Growing evidence suggests that vascular pathology lowers the threshold for the clinical presentation of dementia at a given level of AD-related pathology and potentially directly promotes AD lesions such as A beta plaques. Cerebral ischemia, chronically up-regulates expression of the amyloid precursor protein (APP), which is the precursor to the amyloid beta peptide and damages the blood-brain barrier (BBB), affecting A beta peptide clearance from the brain. Recognition of the importance of these vascular risk factors for AD-related dementia and their treatment will be beneficial not only for preventing cardiac, cerebral, and peripheral complications of vascular disease, but also will likely have a direct impact on the occurrence of sporadic AD in older subjects. In this paper, we review some of the links between vascular risk factors and AD pathology and present data on the direct effect of ischemia on cognitive function and A beta deposition in a mouse model of AD.
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PMID:Links between the pathology of Alzheimer's disease and vascular dementia. 1517 82

Mitochondria play a critical role in the pathogenesis of cerebral ischemia. Acute hyperglycemia has been shown to activate the mitochondria-initiated cell death pathway after an intermediate period of ischemia. The objective of the present study was to determine if diabetic hyperglycemia induced by streptozotocin activates the cell death pathway after a brief period of global ischemia. Five minutes of global ischemia was induced in nondiabetic and diabetic rats. Brain samples were collected after 30 min, 6 h, 1, 3, and 7 days of recirculation as well as from sham-operated controls. Histopathological examination in the hippocampal CA1, CA3, hilus, and dentate gyrus regions, as well as in the cortical and thalamic areas, showed that neuronal death in diabetic animals increased compared to nondiabetic ischemic controls. Neuronal damage maturation occurred after 7 days of recovery in nondiabetic rats, while it was shortened to 3 days of recovery in diabetic animals. Western blot analyses revealed that release of cytochrome c markedly increased after 1 and 3 days of reperfusion in diabetic rats. Caspase-3 activation was evident in the nuclear fraction of the cortex of diabetic rats after 3 days recovery and it was preceded by activation of caspase-9, but not activation of caspase-8. Electron microscopy demonstrated that chromatin condensation and mitochondrial swelling were features of the diabetes-mediated ischemic neuronal damage. However, no apoptotic bodies were observed in any sections examined. These results suggest that a brief period of global ischemia in diabetic animals activates a neuronal cell death pathway involving cytochrome c release, caspase-9 activation, and caspase-3 cleavage, all of which are most likely initiated by early mitochondria damage.
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PMID:Activation of cell death pathway after a brief period of global ischemia in diabetic and non-diabetic animals. 1524 41

After immediate intervention for cerebral infarction or transient ischemic attack (TIA), the primary goal is secondary prevention of future cerebral ischemia and prevention of complications related to the initial ischemic event. The goals of the diagnostic evaluation are to (1) determine potential contributing mechanisms (cardioembolic, large-vessel disease of the extracranial and intracranial vessels, small-vessel disease, coagulation defects, and cryptogenic), (2) identify contributing risk factors (hypertension, hyperlipidemia, tobacco use, diabetes), and (3) complete the evaluation in a cost-effective and safe manner. We provide a sequential approach to the diagnostic evaluation of cerebral infarction or TIA to optimize diagnostic yield of testing, minimize cost and potential harm to the patient, and provide information that will change management. This systematic approach focuses on 6 important questions: (1) Are the symptoms consistent with a cerebral infarction or TIA (versus nonischemic pathology)? (2) Where does the ischemic event localize? (3) What etiologies and mechanisms of cerebral infarction and TIA are possible? (4) What is the prevalence of each potential etiology? (5) What treatments are available for this etiology? (6) What tests and studies are useful to evaluate this etiology?
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PMID:Evaluation and management of transient ischemic attack and minor cerebral infarction. 1530 38

Cerebrovascular risk represents a progressive and evolving concept owing to the particular distribution of risk factors in patients with ischemic stroke and in light of the newest stroke subtype classifications that account for pathophysiological, instrumental, and clinical criteria. Age represents the strongest nonmodifiable risk factor associated with ischemic stroke, while hypertension constitutes the most important modifiable cerebrovascular risk factor, confirmed by a host of epidemiological data and by more recent intervention trials of primary (HOT, Syst-Eur, LIFE) and secondary (PROGRESS) prevention of stroke in hypertensive patients. To be sure, a curious relationship exists between stroke and diabetes. Although the Framingham Study, The Honolulu Heart Program, and a series of Finnish studies reported a linear relationship between improved glucose metabolism and cerebral ischemia, the clinical and prognostic profile of diabetic patients with ischemic stroke remains to be fully understood. Our group, on the basis of TOAST classification--a diagnostic classification of ischemic stroke developed in 1993 that distinguishes five different clinical subtypes of ischemic stroke: large-artery atherosclerosis (LAAS), cardioembolic infarct (CEI), lacunar infarct (LAC), stroke of other determined origin (ODE), and stroke of undetermined origin (UDE), and now extensively used in clinical and scientific context--analysed the prevalence of cerebrovascular risk factors and the distribution of TOAST subtypes in more 300 patients with acute ischemic stroke in two consecutives studies that reported the significant association between diabetes and the lacunar subtype and a better clinical outcome for diabetic patients, most likely related to the higher prevalence of the lacunar subtype. Well-confirmed are the roles of cigarette smoking, atrial fibrillation, and asymptomatic carotid stenosis as cerebrovascular risk factors. Particularly interesting seems to be the function of inflammation markers (CRP, TNF-alpha, IL-1 beta, ISPs) as potential risk factors. Still elusive remains the association between cholesterol serum levels and stroke, on the basis of the epidemiological data regarding this causative relationship, confirmed only by the results of intervention trials (4S, LIPID, CARE, HPS, ASCOT). Ultimately, cerebrovascular risk appears peculiar owing to the unique relationship between some modifiable risk factors (mainly diabetes and cholesterol) and the possible preferential association with stroke subtypes and specific cerebrovascular risks.
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PMID:Cerebrovascular risk factors and clinical classification of strokes. 1563 Jun 37

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