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)

Transforming growth factor-beta (TGF-beta) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-betas useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-beta has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-beta have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-beta activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.
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PMID:Medical applications of transforming growth factor-beta. 1593 Dec 80

Salvia miltiorrhiza (SM) has been used clinically in Asian countries to improve the microcirculation in the human body. Salvianolic acid B (Sal B), a pure compound extracted from SM, has been reported to be effective against fibrosis and ischemia-reperfusion injury, possibly through its anti-lipid peroxidation action. But the effect of Sal B on oral premalignant lesion and oral carcinogenesis remains unexplored. It is our interest to investigate the chemopreventive effect of Sal B on 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters with respect to angiogenesis. Seventy male Syrian golden hamsters were randomly divided into five groups, with two of 20 and three of 10. DMBA solution (0.5% in acetone) was applied topically to the left cheek pouch of male Syrian golden hamsters in Groups A and B, while animals in Group C were painted with acetone, three times a week for 6 weeks. For the next 18 weeks, animals in Groups B and D received Sal B daily (10 mg/kg body wt/day) by gavage, animals in Groups A and C received same volume of saline. Animals in Group E received no treatment and served as blank control. At the end of the experiment, animals were killed and tissue samples were collected for histopathological and immunohistochemical examinations. The results showed that Sal B significantly decreased the squamous cell carcinoma (SCC) incidence from 64.7 (11/17) to 16.7% (3/18) (P=0.004); angiogenesis was inhibited in dysplasia and SCC (P<0.01), with a simultaneous decrease in the immunostaining of hypoxia-inducible factor 1alpha and vascular endothelium growth factor protein (P<0.05). The results suggested that Sal B had inhibitory effect against the malignant transformation of oral precancerous lesion and such inhibition may be related to the inhibition of angiogenesis.
Carcinogenesis 2006 Apr
PMID:The preventive effect of salvianolic acid B on malignant transformation of DMBA-induced oral premalignant lesion in hamsters. 1628 60

Cyclooxygenase is an enzyme that catalyzes the first two steps in the biosynthesis of prostanoids. The constitutively expressed isoform COX-1 is regarded as a housekeeping enzyme that is responsible for the normal production of prostanoids. The inducible isoform COX-2, on the other hand, is transiently induced during inflammation by various stimuli. Increasing evidence has shown that COX-2 is not only implicated in inflammation but also in oncogenesis. Overexpression of COX-2 has been observed in a variety of tumors. Prostaglandins produced by COX-2 affect important processes in carcinogenesis, including angiogenesis, tissue invasion, metastasis and apoptosis. Several studies indicate that COX-2 is also involved in neurological disorders, like Alzheimer's disease, Parkinson's disease and ischemia, where COX-2 overexpression leads to neurotoxicity. Many aspects of the role of COX-2 in (patho)physiology, however, remain unclear. At present, COX-2 expression is determined by ex vivo laboratory analysis, but the results could be greatly affected by the instability of COX-2 mRNA and protein and by sampling errors. A noninvasive imaging method to monitor COX-2 expression, like positron emission tomography (PET) or single photon emission computed tomography (SPECT), could overcome this complication and may provide novel insights in the role of COX-2, especially in neurological disorders where repetitive sampling is not possible. Such a technique could also be applied to the in vivo evaluation of novel selective COX-2 inhibitors and in dose-escalation studies. This review will present an overview of the developments in the recently emerging field of COX-2 imaging.
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PMID:Imaging of cyclooxygenase-2 (COX-2) expression: potential use in diagnosis and drug evaluation. 1707 83

In contrast to vasculogenesis, angiogenesis is defined as the formation of new vessels from preexisting ones. Physiologically, this multistep process occurs in adults during the reproductive cycle and during pregnancy, pathophysiologically it can be found in wound healing, inflammation and carcinogenesis. The underlying mechanisms are vasodilatation and increasing permeability, destabilization of vessel walls and degradation of extracellular matrix, followed by the proliferation and migration of endothelial cells. Migrated endothelial cells form vascular tubes at sites of ischemia and these tubes are finally stabilized by pericytes and smooth muscle cells. This process is controlled by a complex interaction of angiogenic and angiostatic factors. In contrast to carcinogenesis, the role of angiogenesis for the pathogenesis and therapy of rheumatic diseases is less understood. Two examples for pathologically disturbed angiogenesis, rheumatoid arthritis and systemic sclerosis, are discussed in this review with respect to therapeutic options.
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PMID:[Angiogenesis. Possibilities for therapeutic intervention in rheumatic diseases]. 1749 16

Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme which catalyzes group heme into carbon monoxide, iron and bilirubin. In the recent years, HO-1 expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress. In this regard, induction of this enzyme has shown beneficial effects in several pathologic conditions, such as inflammatory processes, atherosclerosis, carcinogenesis, ischemia-reperfusion systems or degenerative diseases. Complex intracellular signalling cascades mediate the expression of HO-1 in response to external stimuli, Transcription factors, as nuclear factor E2-related factor-2, activator protein-1, and nuclear factor-kappa B, and some of their upstream kinases, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, or protein kinases A, C are responsible of the HO-1 gene expression. The purpose of this article is to review the increasing number of natural and synthetic molecules reported to induce HO-1 as additive mechanism responsible for their therapeutic effects; experimental and pathological conditions as well as possible signalling mechanism involved in HO-1 expression by this compounds are described. Controlled upregulation of this enzyme, or its catalytic activity, has shown antioxidant, anti-proliferative, anti-apoptotic and anti-inflammatory properties. For this reason, pharmacologic modulation of HO-1 system may represent an effective and cooperative strategy to intervene in several pathologic conditions.
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PMID:Inducers of heme oxygenase-1. 1828 74

Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell's ability to do work and control the intracellular Ca(2+) homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis.
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PMID:Mitochondria and energetic depression in cell pathophysiology. 1956 50

Reactive oxygen species (ROS) play key roles in many pathogenic processes, including carcinogenesis, inflammation, ischemia-reperfusion injury and signal transduction. Also, reactive nitrogen species (RNS) cause various biological events such as neurodegenerative disorders. Sensitive and specific detection methods for ROS and RNS in biological samples should be useful for elucidation of biological events both in vitro and in vivo. Fluorescent probes based on small organic molecules have become indispensable tools in modern biology because they provide dynamic information concerning the localization and quantity of biological molecules of interest, without the need of genetic engineering of the sample. In this review, we recount some recent achievements in the field of small molecular fluorescent probes. First, the probes for nitric oxide and peroxynitrite as RNS are introduced and the probes of hydroxyl radical, hydrogen peroxide, hypochlorous and singlet oxygen as ROS are discussed, based on the fluorescence off/on switching mechanisms including photoinduced electron transfer and spirocyclization processes, and with some applications for in vitro and in vivo systems.
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PMID:Bioimaging probes for reactive oxygen species and reactive nitrogen species. 1979 17

ABSTRACT Peroxynitrite is a reactive oxidant produced from nitric oxide ((.)NO) and superoxide anion (O(2)(.-)). It is produced by the body in response to environmental toxins, stress, ultraviolet light, ischemia/reperfusion, inflammation, etc. In vivo, peroxynitrite is formed in macrophages, endothelial cells, platelets, leukocytes, and neurons. It reacts with a variety of biomolecules including proteins, lipids, and DNA. We have investigated the photochemical addition of lysine to native DNA in view of its potential importance in the photo-cross-linking of histones to DNA in chromatin. Lysine-and arginine-rich histone H1 in nucleosome on modification by physical, chemical, or environmental agents forms histone-DNA adducts. We have characterized the photoadducts by absorption, fluorescence, and chromatographic methods. The UV absorption spectra of the DNA-lysine photoadduct showed hyperchromism, indicating structural distortions in DNA either due to single-strand breaks or opening of the double helix at the site of lysine conjugation. On peroxynitrite treatment, the melting temperature (T(m)) of the DNA-lysine adduct increased by 15 degrees C compared to the native DNA-lysine adduct. A decrease in the fluorescence intensity of the DNA-lysine photoadduct with respect to the modified adduct was observed. The gel filtration profile of the peroxynitrite-modified adduct was also found to be different from that of the native DNA and DNA-lysine photoadduct. Hence, the peroxynitrite-modified photoadduct may have important implications in toxicology, mutagenesis, and carcinogenesis.
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PMID:Biochemical Evaluation of Human DNA-Lysine Photoadduct Treated with Peroxynitrite. 2002 Aug 59

It is well known that human papillomaviruses (HPVs) involve in the pathogenesis of some specific carcinomas such as cervical cancer. Experimental and clinical studies have shown that early proteins E6 and E7 played the most important role in the cervical carcinogenesis. Early proteins E6 and E7 of HPV both are oncoproteins for they disable specific tumor suppressor proteins, p53 and pRb, and disturb apoptosis against carcinogenesis. Both p53 and pRb play an important role in regulating apoptosis and preventing cell immortalization, but they also mediate ischemia/reperfusion-associated apoptosis and give rise to ischemia-reperfusion injury (IRI). Several studies showed inhibition of apoptosis may provide promising approaches to ameliorating IRI in ischemia/reperfusion. Both small-molecule chemical inhibitor and siRNA against p53 block p53-dependent apoptosis and protect organ function from IRI. Similarly, inhibiting pRb can restrain ischemia/reperfusion-associated apoptosis. Based on these studies, we propose a novel hypothesis that early proteins E6 and E7 of HPV attenuate ischemia-reperfusion injury by inhibiting apoptosis and inactivating p53 and pRb. It is possible that the two oncoproteins can be used to protect organ function from ischemia-reperfusion injury in special clinical conditions such as organ transplant, stroke, cardiopulmonary bypass, and myocardial infarction.
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PMID:Early proteins E6 and E7 of human papillomavirus may attenuate ischemia-reperfusion injury. 2127 88

Cardiovascular diseases and cancer continue to be major causes of death worldwide, and despite intensive research only modest progress has been reached in reducing the morbidity and mortality of these awful diseases. Mitochondria are broadly accepted as the key organelles that play a crucial role in cell life and death. They provide cells with ATP produced via oxidative phosphorylation under physiological conditions, and initiate cell death through both apoptosis and necrosis in response to severe stress. Oxidative stress accompanied by calcium overload and ATP depletion induces the mitochondrial permeability transition (mPT) with formation of pathological, non-specific mPT pores (mPTP) in the mitochondrial inner membrane. Opening of the mPTP with a high conductance results in matrix swelling ultimately inducing rupture of the mitochondrial outer membrane and releasing pro-apoptotic proteins into the cytoplasm. The ATP level is the determining factor in deciding whether cells die through apoptosis or necrosis. Cardiac cells undergoing ischemia followed by reperfusion (IR) possess exactly the same conditions mentioned above to induce mPTP opening. Due to its critical role in cell death, inhibition of mPTP opening has been accepted as a major therapeutic approach to protect the heart against IR. In contrast to cardiac IR, cancer cells exhibit less sensitivity to pore opening which can be in part explained by increased expression of mPTP compounds/modulators and metabolic remodeling. Since the main goal of chemotherapy is to provoke apoptosis, mPT induction may represent an attractive approach for the development of new cancer therapeutics to induce mitochondria-mediated cell death and prevent cell differentiation in carcinogenesis. This review focuses on the role of the mPTP in cardiac IR and cancer, and pharmacological agents to prevent or initiate mPT-mediated cell death, respectively in these diseases.
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PMID:Targeting the mitochondrial permeability transition: cardiac ischemia-reperfusion versus carcinogenesis. 2147 6


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