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)

The c-Jun N-terminal kinases (JNKs), which are essential regulators of physiological and pathological processes, are involved in several diseases including diabetes, atherosclerosis, stroke, and Parkinson's and Alzheimer's diseases. Inhibition of JNKs suppresses pathological features of these diseases but the many physiological functions of these enzymes argue against the use of sustained, systemic, nonspecific inhibition in the treatment of these diseases. For example, deletion of the gene that encodes JNK1 prevents insulin resistance but disrupts neuronal cytoarchitecture and initiates the pathology of Alzheimer's disease. Thus, it is not sufficient to inhibit selectively either JNKs or individual isoforms of JNK. Instead, the aim is to inhibit the damaging actions of JNK. This can be achieved using peptides that selectively block molecular domains of individual JNK signaling complexes (exclusively) that form under pathological conditions. To date, peptide inhibitors of JNK have been successful in protecting against ischemia-induced brain damage and insulin resistance following obesity. In this review, we discuss novel pharmacological strategies to inhibit JNK and the limitations of these strategies.
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PMID:Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage. 1605 42

Peripheral vascular disease (PVD) is very prevalent in the United States and is part of a global vascular problem. PVD patients have a heightened inflammatory state and are at high risk of death from acute cardiovascular problems rather than from progression of PVD. Modifiable risk factors for PVD include smoking, hypertension, diabetes, hyperlipidemia, elevated high sensitivity C-reactive protein, obesity, and the metabolic syndrome. Symptomatic treatment of claudication includes smoking cessation, exercise, cilostazol, statins, and revascularization with percutaneous or surgical therapy. Antithrombotic therapy with aspirin or clopidogrel is important to reduce cardiovascular events but does not affect symptoms of claudication. Patients with rest limb ischemia or ulceration should be revascularized to minimize the chance of limb loss. Percutaneous revascularization is not without significant complications, however, and future research needs to focus on inflammation, thrombosis, and restenosis in the PVD patient. Finally, new devices that tackle difficult lesions, drug-eluting stents, and pharmacologic agents that reduce global atherosclerosis are on the horizon and are likely to become critical components in the management of the PVD patient.
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PMID:Evidence-based management of peripheral vascular disease. 1610 78

There is little objective to guide the therapy of patients with diastolic heart failure. Because of the similarities of pathophysiology abnormalities in diastolic and systolic heart failure, it is a reasonable inference to suggest that the proven therapy for systolic heart failure may also be of benefit in patients with diastolic heart failure. Treatment of underlying or exacerbating conditions in diastolic heart failure, such as hypertension, left ventricular hypertrophy, ischemia, diabetes, anemia, obesity and pulmonary disease is an important means of managing diastolic heart failure. Control of systolic blood pressure is effective in improving and preventing the development of diastolic heart failure. Treatment of diastolic heart failure is most effective when it is associated with hypertension. Production of systolic arterial pressure acutely reduces pulmonary congestion, ischemia, and chronically may lead to regression of left ventricular hypertrophy. Patients with diastolic heart failure in the absence of hypertension are very difficult to treat.
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PMID:Therapy for diastolic heart failure. 1611 17

Since the end of the 1980s, key discoveries have been made which have significantly revived the scientific interest in a cell organelle, which has been studied continuously and with steady success for the last 100 years. It has become increasingly evident that mitochondrial dysfunction contributes to a variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Moreover, since the middle of the 1990s, mitochondria, the 'power house' of the cell, have also become accepted as the cell's 'arsenals' reflecting their increasingly acknowledged key role during apoptosis. Based on these recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of 'Mitochondrial Medicine' as a whole new field of biomedical research. Targeting of biologically active molecules to mitochondria in living cells will open up avenues for manipulating mitochondrial functions, which may result in the selective protection, repair or eradication of cells. This review gives a brief synopsis over current strategies of mitochondrial targeting and their possible therapeutic applications.
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PMID:Mitochondrial pharmaceutics. 1612 Mar 57

Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.
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PMID:Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. 1621 Oct 35

Mitochondrial dysfunction contributes to a large variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Increasing pharmacological efforts toward therapeutic interventions have been made leading to the emergence of "Mitochondrial Medicine" as a new field of biomedical research. The identification of molecular mitochondrial drug targets in combination with the development of methods for selectively delivering biologically active molecules to the site of mitochondria will eventually launch a multitude of new therapies for the treatment of mitochondria-related diseases, which are based either on the selective protection, repair, or eradication of cells. Yet, while tremendous efforts are being undertaken to identify new mitochondrial drugs and drug targets, the development of mitochondria-specific drug carrier systems is lagging behind. To ensure a high efficiency of current and future mitochondrial therapeutics, delivery systems need to be developed, which are able to selectively transport biologically active molecules to and into mitochondria within living human cells. In this study we present the first data demonstrating that conventional liposomes can be rendered mitochondria-specific via the attachment of known mitochondriotropic residues to the liposomal surface.
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PMID:Mitochondriotropic liposomes. 1619 27

We propose that inadequate sympathetic bias and Th2 bias in the uterine environment contributes to the formation of fibroids, independent of the sex steroid status. We also propose that fibroids represent a modern maladaptation that partly results from decreasing exposure to seminal fluid, which contains catecholalmines, transforming growth factor beta1 (TGFbeta1), aldosterone, prostaglandins, and other factors that shift the uterine environment to sympathetic and T helper (Th)2 bias. Lower risk of fibroids is associated with pre-menarche, post-menopause, pregnancy, exposure to contraceptives, smoking, earlier age of first pregnancy, shorter interval since last pregnancy, higher parity, and non-obesity. These associations are currently attributed to alterations of sex steroids. However, the association may also be explained by the observation that pre-menarche, post-menopause, pregnancy, and smoking represent periods of sympathetic and Th2 bias. Furthermore, use of contraceptives, early age of first pregnancy, short interval since last pregnancy, high parity, abnormal pap smear, and non-obesity may represent surrogates for increased sexual activity and increased exposure to seminal fluid. Catecholalmines, aldosterone, TGF, and prostaglandins are among the seminal fluid components that promote sympathetic and Th2 bias. Vasectomized copulations protect against fibroids, an observation that undermines the steroid hypothesis and supports our hypothesis. The putative mechanism of action of uterine artery embolization (UAE) for fibroid treatment is starvation of blood supply, but the extensive collaterals that protect uterine perfusion would presumably also buffer against fibroid hypoperfusion. Instead, the sympathetic and Th2 responses to UAE-related ischemia may contribute to fibroid regression. A potential explanation for the association of fibroids with intrauterine devices may be a Th1 cell-mediated immune response to the foreign body, which may also enhance the contraceptive effect. Novel methods of preventing and treating fibroids by promoting sympathetic and Th2 shift through natural, pharmacologic, and neuromodulatory means are envisioned. Fibroids are likely a modern dysfunction given the high Darwinian fitness cost of fibroid-related infertility, and may be attributable to reduced intercourse frequency. Fibroids have been observed among animals in captivity that are presumably reproductively isolated.
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PMID:Sympathetic and T helper (Th)2 bias may ameliorate uterine fibroids, independent of sex steroids. 1621 89

Rhabdomyolysis is an uncommon event in bariatric surgery. It can be caused by ischemia, crush injury, alcohol ingestion and drug intake, and as a consequence renal failure can develop. A few reports indicate that patients undergoing bariatric surgical intervention are at risk for rhabdomyolysis. A super-obese male (BMI 52 kg/m2) is reported, who underwent laparoscopic biliopancreatic diversion with duodenal switch (BPD/DS). Operative time was 265 minutes, and the BPD/DS operation was uneventful. Post-operatively, the patient complained of pain in both hips and the left shoulder, and suffered oliguria. He was treated with fluids (isotonic saline), bicarbonate, and mannitol. Despite this, he developed renal failure, which subsequently required hemodialysis. The patient died from arrhythmia and cardiac arrest on the 8th postoperative day. Obese patients undergoing bariatric surgery are at risk of rhabdomyolysis. Prolonged compression of the muscles during the surgical intervention, in long laparoscopic procedures, predisposes to this complication.
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PMID:Rhabdomyolysis after biliopancreatic diversion with duodenal switch. 1625 2

Obesity is associated with increased cardiovascular morbidity and amortality. Endothelial dysfunction, involved in the pathogenesis of cardiovascular events, has been demonstrated in obese patients with invasive techniques requiring artery catheterization. The aim of our investigation was to evaluate, with a non-invasive method readily employable on clinical grounds, impaired vasodilatation and its relationship with insulin resistance in uncomplicated obesity. 15 uncomplicated obese subjects (BMI = 36.6 +/- 3.2) and 10 lean controls (BMI = 22.9 +/- 1.25) were enrolled in this study. All subjects underwent measurement of endothelium-dependent (FBFr) vasodilatation by forearm venous occlusion pletysmography after increasing times of ischemia, and measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (M index), by fasting glucose and insulin (HOMA-IR) and by oral glucose tolerance test (ISI index). Endothelium-independent (N-FBFr) vasodilatation was assessed as well. The FBFr was markedly blunted in obese patients versus lean controls (30 s: 2.12 +/- 0.34 vs. 3.63 +/- 0.22, P < 0.01; 60 s: 2.34 +/- 0.42 vs. 3.82 +/- 0.53, P < 0.01; 180 s: 3.20 +/- 0.45 vs. 7.15 +/- 0.35, P < 0.01; 300 s: 4.08 +/- 0.94 vs. 14.1 +/- 0.82, P < 0.001). The N-FBFr was not different in the two groups. High correlation was found between M index and FBFr at all ischemia times. HOMA-IR and ISI were not related with FBFr. The non-invasive evaluation of endothelial dysfunction by a simple and reliable method based on venous occlusive plethysmography shows high correlation between impaired endothelium-dependent vasodilatation and insulin resistance in uncomplicated obesity. This non-invasive test of endothelial function may be routinely performed in the assessment of cardiovascular risk in uncomplicated obesity.
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PMID:Non-invasive evaluation of endothelial dysfunction in uncomplicated obesity: relationship with insulin resistance. 1643 62

Considerable experimental and clinical data indicate that sex has an important influence on cardiovascular physiology and pathology. This report integrates selected literature with new data from the Women's Ischemia Syndrome Evaluation (WISE) on vascular findings in women with ischemic heart disease (IHD) and how these findings differ from those in men. A number of common vascular disease-related conditions are either unique to (e.g., hypertensive disorders of pregnancy, gestational diabetes, peripartum dissection, polycystic ovarian syndrome, etc.) or more frequent (e.g., migraine, coronary spasm, lupus, vasculitis, Raynaud's phenomenon, etc.) in women than men. Post-menopausal women more frequently have many traditional vascular disease risk conditions (e.g., hypertension, diabetes, obesity, inactivity, and so on), and these conditions cluster more frequently in them than men. Considerable evidence supports the notion that, with these requisite conditions, women develop a more severe or somewhat different form of vascular disease than men. Structurally, women's coronary vessels are smaller in size and appear to contain more diffuse atherosclerosis, their aortas are stiffer (fibrosis, remodeling, and so on), and their microvessels appear to be more frequently dysfunctional compared with men. Functionally, women's vessels frequently show impaired vasodilator responses. Limitations of existing data and higher risks in women with acute myocardial infarction, need for revascularization, or heart failure create uncertainty about management. A better understanding of these findings should provide direction for new algorithms to improve management of the vasculopathy underlying IHD in women.
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PMID:Some thoughts on the vasculopathy of women with ischemic heart disease. 1645 68


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