Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathological features of multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system, support an autoimmune etiology. Strong evidence has been provided for a potential functional defect of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) in patients with relapsing-remitting MS. More recently, alterations in homeostatic parameters related to the development and function of naive and memory-like Tregs were discovered in MS patients. In this review, we evaluate the evidence for disturbed Treg homeostasis in MS and discuss the role of potential compensatory mechanisms in the chronic disease phase. Better insights into the processes underlying the compromised immune regulation in MS patients will be important to understand the potential of Treg-based therapies.
Trends Mol Med 2010 Feb
PMID:Disturbed regulatory T cell homeostasis in multiple sclerosis. 2015 85

The British Isles have a very cloudy climate and as a result receive fewer hours of clear sunlight than most other industrial regions. The majority of people in these islands have low blood levels of vitamin D [25(OH)D] all year round. Few food products are fortified with vitamin D in the UK and the government does not recommend any vitamin D supplement for most adults in the UK. Diseases associated with vitamin D insufficiency such as cancer, heart disease, diabetes (types 1 and 2) and multiple sclerosis are more frequent in the UK, and particularly in Scotland, than in many other European countries and some, such as multiple sclerosis and diabetes (types 1 and 2), are increasing in incidence. Present knowledge suggests that the risk of some chronic diseases could be reduced if vitamin D intake or sun exposure of the population were increased. Yet policy and public health recommendations of the UK government and its agencies (e.g. the Health Protection Agency, the Food Standards Agency) and of Cancer Research UK have failed to take full account of established and putative benefits of vitamin D and/or sunshine. The epidemic of chronic disease in the UK, which is associated with and caused at least in part by vitamin D insufficiency, has not been adequately recognized by these agencies, and too often measures taken by them have been misguided, inappropriate or ineffective.
Mol Nutr Food Res 2010 Aug
PMID:Sunlight robbery: a critique of public health policy on vitamin D in the UK. 2044 Jun 94

The role of cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins in various pathological processes, including angiogenesis, thrombosis, inflammation, apoptosis, cell migration, and proliferation is well documented. These processes can lead to both acute and chronic disease states such as ocular diseases, metastasis, unstable angina, myocardial infarction, stroke, osteoporosis, a wide range of inflammatory diseases, vascular remodeling, and neurodegenerative disorders. A key success in this field was identification of the role of platelet glycoprotein (GP)IIb/IIIa in the prevention and diagnosis of various thromboembolic disorders. The use of soluble adhesion molecules as potential diagnostic markers for acute and chronic leukocyte, platelet, and endothelial cell insult is becoming increasingly common. The development of various therapeutic and diagnostic candidates based on the key role of CAMs, with special emphasis on integrins in various diseases, as well as the structure-function aspects of cell adhesion and signaling of the different CAMs and ECM are highlighted.
Methods Mol Biol 2010
PMID:Adhesion molecules: potential therapeutic and diagnostic implications. 2061 23

Infection with the protozoan parasite Trypanosoma cruzi, the agent of Chagas disease, is characterised by a variable clinical course - from symptomless cases to severe chronic disease with cardiac and/or gastrointestinal involvement. The variability in disease outcome has been attributed to host responses as well as parasite heterogeneity. In this article, we review studies indicating the importance of immune responses as key determinants of host resistance to T. cruzi infection and the pathogenesis of Chagas disease. Particular attention is given to recent studies defining the role of cognate innate immune receptors and immunodominant CD8+ T cells that recognise parasite components - both crucial for host-parasite interaction and disease outcome. In light of these studies we speculate about parasite strategies that induce a strong and long-lasting T-cell-mediated immunity but at the same time allow persistence of the parasite in the vertebrate host. We also discuss what we have learned from these studies for increasing our understanding of Chagas pathogenesis and for the design of new strategies to prevent the development of Chagas disease. Finally, we highlight recent studies employing a genetically engineered attenuated T. cruzi strain as a vaccine shuttle that elicits potent T cell responses specific to a tumour antigen and protective immunity against a syngeneic melanoma cell line.
Expert Rev Mol Med 2010 Sep 15
PMID:The endless race between Trypanosoma cruzi and host immunity: lessons for and beyond Chagas disease. 2084 Jul 99

Biologically reactive intermediates are formed following metabolism of xenobiotics, and during normal oxidative metabolism. These reactive species are electrophilic in nature and are capable of forming stable adducts with target proteins. These covalent protein modifications can initiate processes that lead to acute tissue injury or chronic disease. Recent advancements in mass spectrometry techniques and data analysis has permitted a more detailed investigation of site-specific protein modifications by reactive electrophiles. Knowledge from such analyses will assist in providing a better understanding of how specific classes of electrophiles produce toxicity and disease progression via site-selective protein-specific covalent modification. Hydroquinone (HQ) is a known environmental toxicant, and its quinone-thioether metabolites, formed via the intermediate generation of 1,4-benzoquinone (1,4-BQ), elicit their toxic response via the covalent modification of target proteins and the generation of reactive oxygen species. We have utilized a model protein, cytochrome c, to guide us in identifying 1,4-BQ- and 1,4-BQ-thioether derived site-specific protein modifications. LC-MS/MS analyses reveals that these modifications occur selectively on lysine and glutamic acid residues of the target protein, and that these modifications occur within identifiable "electrophile binding motifs" within the protein. These motifs are found within lysine-rich regions of the protein and appear to be target sites of 1,4-BQ-thioether adduction. These residues also appear to dictate the nature of post-adduction chemistry and the final structure of the adduct. This model system will provide critical insight for in vivo adduct hunting following exposure to 1,4-BQ-thioethers, but the general approaches can also be extended to the identification of protein adducts derived from other classes of reactive electrophiles.
Methods Mol Biol 2011
PMID:Utilization of LC-MS/MS analyses to identify site-specific chemical protein adducts in vitro. 2097 62

Essential hypertension is a chronic cardiovascular disease that effects over 50 million people in the United States. It is a complex pathophysiological state that is primarily characterized by a sustained elevation in blood pressure (BP). If untreated, this chronically elevated BP can affect major target organs of the body including the heart, kidney, brain, and vascular system. As a consequence of the sustained high BP, there is an increased risk of mortality and morbidity that is characterized by myocardial infarction, congestive heart failure, stroke, end-stage renal failure, and peripheral vascular disease (1-3). Because hypertension is basically an asymptomatic disease, it confounds effective treatment and makes compliance a major issue in the treatment of this disease. Pharmacological agents currently utilized have to be administered daily in an attempt to control BP, and there are no agents available to cure essential hypertension. Thus, more effective therapeutic intervention is required in order to have a significant impact in alleviating this chronic disease and its lethal cardiovascular sequel.
Methods Mol Med 2001
PMID:Systemic Delivery of aTransgene in Intact Animals by a Retroviral Vector. 2133 10

For a technique often now referred to as "the backbone of public health," it is curious how only recently surveillance has come to be recognized as important. As soon as recording of disease events began, so of course did surveillance, but the first application of the term to "the ongoing scrutiny of disease" is thought to have been by Langmuir (1) in the 1950s. The use of the term has helped to focus attention on it as a technique and a discipline in its own right, and there are now books devoted to the subject (2,3). The technique is also being applied increasingly to chronic disease (2).
Methods Mol Med 2001
PMID:Surveillance of meningococcal disease in europe. 2133 53

Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.
Curr Mol Med 2011 Jun
PMID:microRNAs in the regulation of adipogenesis and obesity. 2150 21

Liver fibrosis is a chronic disorder that is characterized by an alteration of the balance between fibrogenesis and fibrinolysis, which results in accumulation of excessive amounts of extracellular matrix (ECM) and distortion of the normal liver architecture. The activation and transformation of quiescent hepatic stellate cells (HSCs) into myofibroblast-like cells constitute a major mechanism for the increased production of ECM in the liver. The nuclear receptor farnesoid X receptor (FXR) shows potent antifibrotic activity in HSCs and protects animals in rodent models of liver fibrosis. However, the detailed mechanism remains incompletely understood. In this study, we report that treatment with 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064), a synthetic FXR ligand, led to up-regulation of microRNA-29a (miR-29a) in HSCs isolated from wild-type mice, rats, and humans but not from FXR(-/-) mice. miR-29a seems to play an inhibitory role in the regulation of ECM production because of the following: 1) transfection of HSCs with miR-29a mimic resulted in drastic down-regulation of the mRNA expression of several genes that encode ECM proteins; and 2) miR-29a significantly inhibited the expression of a reporter expression plasmid that contains the 3'-untranslated region of the corresponding ECM genes. Our results suggest that miR-29a is a FXR target gene because miR-29a promoter activity was significantly increased by pharmacologic or genetic activation of FXR. Functional analysis of human miR-29a promoter identified an imperfect inverted repeat spaced by one nucleotide DNA motif, inverted repeat-1 (5'-AGGTCAcAGACCT-3'), as a likely FXR-responsive element that is involved in miR-29a regulation. Our study uncovers a new mechanism by which FXR negatively regulates the expression of ECM in HSCs.
Mol Pharmacol 2011 Jul
PMID:Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells. 2151 16

Obesity is a chronic disease of multifactorial origin and can be defined as an increase in the accumulation of body fat. Adipose tissue is not only a triglyceride storage organ, but studies have shown the role of white adipose tissue as a producer of certain bioactive substances called adipokines. Among adipokines, we find some inflammatory functions, such as Interleukin-6 (IL-6); other adipokines entail the functions of regulating food intake, therefore exerting a direct effect on weight control. This is the case of leptin, which acts on the limbic system by stimulating dopamine uptake, creating a feeling of fullness. However, these adipokines induce the production of reactive oxygen species (ROS), generating a process known as oxidative stress (OS). Because adipose tissue is the organ that secretes adipokines and these in turn generate ROS, adipose tissue is considered an independent factor for the generation of systemic OS. There are several mechanisms by which obesity produces OS. The first of these is the mitochondrial and peroxisomal oxidation of fatty acids, which can produce ROS in oxidation reactions, while another mechanism is over-consumption of oxygen, which generates free radicals in the mitochondrial respiratory chain that is found coupled with oxidative phosphorylation in mitochondria. Lipid-rich diets are also capable of generating ROS because they can alter oxygen metabolism. Upon the increase of adipose tissue, the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), was found to be significantly diminished. Finally, high ROS production and the decrease in antioxidant capacity leads to various abnormalities, among which we find endothelial dysfunction, which is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide (NO), and an increase in endothelium-derived contractile factors, favoring atherosclerotic disease.
Int J Mol Sci 2011
PMID:Inflammation, oxidative stress, and obesity. 2168 73


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