Gene/Protein Disease Symptom Drug Enzyme Compound
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This chapter describes protocols for two-dimensional (2D) gel electrophoresis (isoelectric focusing [IEF] followed by sodium-dodecyl sulfate (SDS)-polyacrylamide gel electro-phoresis [PAGE]), staining of gels with the fluorescent dye Sypro Ruby, 2D gel image analysis, peptide mass fingerprint (PMF) analysis using matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF) mass spectrometry (MS), liquid chromatography (LC)-tandem mass spectrometry (MS/MS), Western blot analysis of protein oxidations, and mass spectrometric mapping of sites of protein oxidations. Many of these methods were used to identify proteins affected in rat brain following ingestion of grape seed extract (GSE), a dietary supplement touted for anti-oxidant activity. Although beneficial actions in cell and animal models of chronic disease have been described for GSE, it has not been shown whether specific proteins were affected, or the nature of the effects. Applying 2D gel proteomics technology allowed discovery of proteins targeted by GSE without a priori knowledge of which one(s) might be affected. The newer 2D blue native (BN) electrophoresis methodology, which resolves protein complexes in a nondenaturing first dimension and then the components of these complexes in a denaturing second dimension, is discussed as a complementary approach. Analysis of protein oxidations and protein-protein interactions have special relevance to aging-related research, since oxidative stress and altered protein interactions may be at the heart of aging-related diseases. Finally, quality control issues related to implementation of high throughput technologies are addressed, to underscore the importance of minimizing bias and randomizing human and technical error in generating large datasets that are expensive and time-consuming to repeat.
Methods Mol Biol 2007
PMID:2D gel proteomics: an approach to study age-related differences in protein abundance or isoform complexity in biological samples. 1763 92

Epidemiological evidence suggests a role for tea catechins in reduction of chronic disease risk. However, stability of catechins under digestive conditions is poorly understood. The objective of this study was to characterize the effect of common food additives on digestive recovery of tea catechins. Green tea water extracts were formulated in beverages providing 4.5, 18, 23, and 3.5 mg per 100 mL epicatechin (EC), epigallocatechin (EGC), epigallocatechin-gallate (EGCG), and epicatechin-gallate (ECG), respectively. Common commercial beverage additives; citric acid (CA), BHT, EDTA, ascorbic acid (AA), milk (bovine, soy, and rice), and citrus juice (orange, grapefruit, lemon, and lime) were formulated into finished tea beverages at incremental dosages. Samples were then subjected to in vitro digestion simulating gastric and small intestinal conditions with pre- and post-digestion catechin profiles assessed by HPLC. Catechin stability in green tea was poor with <20% total catechins remaining post-digestion. EGC and EGCG were most sensitive with less, not double equals 10% recovery. Teas formulated with 50% bovine, soy, and rice milk increased total catechin recovery significantly to 52, 55, and 69% respectively. Including 30 mg AA in 250 mL of tea beverage significantly (p<0.05) increased catechin recovery of EGC, EGCG, EC, and ECG to 74, 54, 82, and 45% respectively. Juice preparation resulted in the highest recovery of any formulation for EGC (81-98%), EGCG (56-76%), EC (86-95%), and ECG (30-55%). These data provide evidence that tea consumption practices and formulation factors likely impact catechin digestive recovery and may result in diverse physiological profiles.
Mol Nutr Food Res 2007 Sep
PMID:Common tea formulations modulate in vitro digestive recovery of green tea catechins. 1768 97

Alzheimer's disease (AD) is a syndrome caused by a few uncommon mutations that lead to early-onset disease, occurs in adults with Down's syndrome, but is by far most commonly seen as a late-onset disease with multiple risk factors but no causative factors yet identified. Emerging data suggests a chronic disease model for AD with latency, prodrome, and dementia stages together lasting decades. Free radical damage to lipids in brain is one pathogenic process of AD that may be quantified with F(2)-isoprostanes (IsoPs). Whereas brain and cerebrospinal fluid (CSF) F(2)-IsoPs are reproducibly elevated in AD patients at both dementia and prodromal stages of disease, plasma and urine F(2)-IsoPs are not reproducibly increased in AD patients. CSF F(2)-IsoPs may be used to assist in diagnosis and aid in objective assessment of disease progression and response to therapeutics in patients with AD.
J Mol Neurosci 2007 Sep
PMID:F(2)-isoprostanes as biomarkers of late-onset Alzheimer's disease. 1790 55

The role of cell adhesion molecules (CAM) and extracellular matrix proteins (ECM) in various pathological processes including angiogenesis, thrombosis, apoptosis, cell migration & proliferation are 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 is evident from the potential role of the platelet GPIIb/IIIa integrin in the prevention and diagnosis of various thromboembolic disorders. Additionally, the use of soluble adhesion molecules as potential diagnostic markers for acute and chronic leukocyte, platelet, and endothelial cellular insult are increasingly utilized. The development of various therapeutic and diagnostic candidates based on the key role of CAM, with special emphasis on integrins in various diseases as well as the structure-function aspects of cell adhesion and signaling of the different CAM and ECM are highlighted.
Mol Biotechnol 2008 Jan
PMID:Cell adhesion molecules: potential therapeutic & diagnostic implications. 1809 89

The sirtuin 1 protein (SIRT1) is a member of the class III NAD+-dependent histone deacetylases, which are also referred to as the 'sirtuins'. The sirtuins and silent information regulator 1 (SIRT1) in particular, are known to play a role in the response to DNA damage, metabolism, longevity and carcinogenesis. SIRT1 regulates different cellular processes such as proliferation, differentiation and apoptosis through deacetylation of important regulatory proteins such as p53, FOXO3a and NFkappaB. A number of different modifiers of SIRT1 expression and activity have been discovered and even food and cosmetic additives (e.g. resveratrol and dihydrocoumarin) have been suggested to either activate or inhibit the activity of human SIRT1. We screened a panel of 18 different drugs which are frequently used in everyday clinical practice with regard to their influence on cell survival and SIRT1 expression in freshly isolated peripheral blood mononuclear cells (PBMCs) from young and healthy volunteers. In this context, we identified L-thyroxin, insulin and sodium nitroprusside to be potent activators of human SIRT1 expression. In addition, treatment of PBMCs with sodium nitroprusside was associated with a significant cellular lifespan extension, while L-thyroxin and insulin were unable to prolong lifespan, suggesting that isolated upregulation of SIRT1 is in fact insufficient to promote longevity. These findings have an important impact on the long-term use of a number of frequently used clinical agents in the treatment of chronic disease with respect to aging and carcinogenesis.
Int J Mol Med 2008 Feb
PMID:Aging and anti-aging: unexpected side effects of everyday medication through sirtuin1 modulation. 1820 89

Diabetes mellitus is a chronic disease characterized by an overproduction of reactive oxygen species, which perturbs zinc metabolism and promotes the onset of cardiovascular disease (CVD) in diabetic patients. Metallothioneins (MT) are cysteine-rich metal-binding proteins which, by means of their antioxidant and zinc-buffering properties, might prevent the development of diabetic cardiovascular complications. A recent investigation shows that a polymorphism (+647 A/C) in the human MT-1A gene, affects the intracellular zinc ion release (iZnR) from the proteins and is associated with longevity in Italian population. The aim of the present study is to assess the involvement of +647 A/C and +1245 A/G MT1A polymorphisms with the susceptibility to type 2 diabetes (DM2) and cardiovascular complications. The study included 694 old individuals: 242 old healthy controls, 217 DM2 patients without clinical evidence of CVD (DNC) and 235 diabetic patients with diagnosis of CVD (DCVD). +647 A/C MT1A polymorphism, but not the second SNP, was associated with DM2. C allele carriers were more prevalent in DNC and DCVD patients than in control group (OR=1.37, p=0.034; OR=1.54, p=0.002, respectively). C+ carriers was associated with higher glycemia and glycosylated hemoglobin in DCVD patients, but not in DNC or control subjects. No differences in plasma zinc, but a modulation of MT levels and iZnR in PBMCs were observed in DCVD cohort when related to +647 A/C MT1A polymorphism. In summary, this work provides novel evidence on the association of the +647 A/C MT1A polymorphism with DM2. Moreover, C+ carriers in DCVD patients presented a worse glycemic control, a reduced iZnR and a higher MT levels, suggesting a possible role of MT in diabetic cardiovascular complications.
Mol Genet Metab 2008 May
PMID:+647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications. 1832 46

Transforming growth factor-beta (TGF-beta) signalling is induced in liver as a consequence of damage and contributes to wound healing with transient activation, whereas it mediates fibrogenesis with long-term up-regulation in chronic disease. Smad-dependent TGF-beta effects are blunted by antagonistic Smad7, which is transcriptionally activated as an immediate early response upon initiation of TGF-beta signalling in most cell types, thereby providing negative feedback regulation. Smad7 can be induced by other cytokines, e.g. IFN-gamma, leading to a crosstalk of these signalling pathways. Here we report on a novel mouse strain, denoted S7DeltaE1, with a deletion of exon I from the endogenous smad7 gene. The mice were viable and exhibited normal adult liver architecture. To obtain insight into Smad7-depend-ent protective effects, chronic liver damage was induced in mice by carbon tetrachloride (CCI4) administration. Subsequent treatment, elevated serum liver enzymes indicated enhanced liver damage in mice lacking functional Smad7. CCI4-dependent Smad2 phosphorylation was pronounced in S7DeltaE1 mice and accompanied by increased numbers of alpha-smooth muscle actin positive 'activated' HSCs. There was evidence for matrix accumulation, with elevated collagen deposition as assessed morphometrically in Sirius red stained tissue and confirmed with higher levels of hydroxyproline in S7DeltaE1 mice. In addition, the number of CD43 positive infiltrating lymphocytes as well as of apoptotic hepatocytes was increased. Studies with primary hepatocytes from S7DeltaE1 and wild-type mice indicate that in the absence of functional Smad7 protein, hepatocytes are more sensitive for TGF-beta effects resulting in enhanced cell death. Furthermore, S7DeltaE1 hepatocytes display increased oxidative stress and cell damage in response to CCI4, as measured by reactive oxygen species production, glutathione depletion, lactate dehydrogenase release and lipid peroxidation. Using an ALK-5 inhibitor all investigated CCI4 effects on hepatocytes were blunted, confirming participation of TGF-beta signalling. We conclude that Smad7 mediates a protective effect from adverse TGF-beta signalling in damaged liver, re-iterating its negative regulatory loop on signalling.
J Cell Mol Med 2008 Oct
PMID:Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice. 1826 71

Cardiovascular disease remains the most common cause of death in the developed world and is predicted by the World Health Organization to kill approximately 20 million people worldwide each year until at least 2015. In light of these figures, work on producing superior tools for clinical use in the cardiovascular field is intensive. As proteins are the primary effectors of cellular function, a significant majority of this work focuses on the role of proteins in the cardiovascular system in physiological and pathological states in order to outline both mechanisms and markers of disease. One of the most effective ways to investigate these on a global basis is through proteomic analysis, which allows for broad spectrum screening of cellular protein or peptide complements during cardiovascular pathogenesis. Furthermore, specific technologies are now available to screen animal model or human blood samples for novel, improved markers of chronic disease states, such as atherosclerosis or for earlier indicators of acute myocardial stress, including ischemia/reperfusion injury and heart failure. This review summarizes current literature on the key aspects of proteomics and peptidomics related to clinical cardiovascular science.
Mol Cell Proteomics 2008 Oct
PMID:The role of proteomics in clinical cardiovascular biomarker discovery. 1866 14

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there are few therapeutic regimens that influence the underlying pathogenic phenotypes. However, of the currently available therapies, exercise training is considered to be one of the best candidates for amelioration of the pathological phenotypes of AD. Therefore, we directly investigated exercise training to determine whether it was able to ameliorate the molecular pathogenic phenotypes in the brain using a neuron-specific enolase (NSE)/Swedish mutation of amyloid precursor protein (APPsw) transgenic (Tg) mice as a novel AD model. To accomplish this, Non-Tg and NSE/ APPsw Tg mice were subjected to exercise on a treadmill for 16 weeks, after which their brains were evaluated to determine whether any changes in the pathological phenotype-related factors had occurred. The results indicated (i) that amyloid beta-42 (Abeta-42) peptides were significantly decreased in the NSE/APPsw Tg mice following exercise training; (ii) that exercise training inhibited the apoptotic biochemical cascades, including cytochrome c, caspase-9, caspase-3 and Bax; (iii) that the glucose transporter-1 (GLUT-1) and brain-derived neurotrophic factor (BDNF) proteins induced by exercise training protected the neurons from injury by inducing the concomitant expression of genes that encode proteins such as superoxide dismutase-1 (SOD-1), catalase and Bcl-2, which suppress oxidative stress and excitotoxic injury; (iv) that heat-shock protein-70 (HSP-70) and glucose-regulated protein-78 (GRP-78) were significantly increased in the exercise (EXE) group when compared to the sedentary (SED) group, and that these proteins may benefit the brain by making it more resistant to stress-induced neuron cell damage; (v) and that exercise training contributed to the restoration of normal levels of serum total cholesterol, insulin and glucose. Taken together, these results suggest that exercise training represents a practical therapeutic strategy for human subjects suffering from AD. Moreover, this training has the potential for use in new therapeutic strategies for the treatment of other chronic disease including diabetes, cardiovascular and Parkinson's disease.
Int J Mol Med 2008 Oct
PMID:Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer's disease in an NSE/APPsw-transgenic model. 1881 61

Acute insulin resistance can develop following critical illness and severe injury, and the mortality of critically ill patients can be reduced by intensive insulin therapy. Thus, compensating for the insulin resistance in the clinical care setting is important. However, the molecular mechanisms that lead to the development of acute injury/infection-associated insulin resistance are unknown, and the development of acute insulin resistance is much less studied than chronic disease-associated insulin resistance. An animal model of injury and blood loss was utilized to determine whether acute skeletal muscle insulin resistance develops following injury, and surgical trauma in the absence of hemorrhage had little effect on insulin-mediated signaling. However, following hemorrhage, there was an almost complete loss of insulin-induced Akt phosphorylation in triceps, and severely decreased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1. The severity of insulin resistance was similar in triceps and extensor digitorum longus muscles, but was more modest in diaphragm, and there was little change in insulin signaling in cardiac muscle following hemorrhage. Since skeletal muscle is an important insulin target tissue and accounts for much of insulin-induced glucose disposal, it is important to determine its role in injury/infection-induced hyperglycemia. This is the first report of an acute development of skeletal muscle insulin signaling defects. The presented data indicates that the defects in insulin signaling occurred rapidly, were reversible and more severe in some skeletal muscles, and did not occur in cardiac muscle.
Mol Med
PMID:Acute, muscle-type specific insulin resistance following injury. 1900 15


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