Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is a chronic inflammatory disease, which is positively and negatively regulated by T helper (Th) 1 and Th2 lymphocytes, respectively. Recent findings indicate that suppressive oligodeoxynucleotides (ODNs) expressing TTAGGG motifs selectively reduce Th1 cytokine production and have been proven effective at blocking the development of organ-specific autoimmune diseases. In the current research, we hypothesized that suppressive ODNs may alter the development of atherosclerosis. Eight-week-old homozygous ApoE(-/-) male mice were injected with 300 mug ODNs A151 (TTAGGG) or nonspecific ODNs 1612. Atherosclerotic lesion sizes were dramatically reduced by ODNs A151, but not by nonspecific ODNs. MCP-1 and VCAM-1, which are the key inflammatory factors in atherogenesis, were significantly attenuated by the suppressive ODNs A151. In the splenic lymphocytes, FACS analysis showed ODNs A151 reduced the percentage of IFN-gamma-producing Th1 cells and slightly increased the percentage of IL-4-producing Th2 cells, indicating that suppressive ODNs skewed the Th1/Th2 balance toward Th2 inflammation in vivo. Furthermore, ODNs A151 down-regulated the phosphorylation of STAT1 and STAT4 and suppressed up-regulation of T-bet, a signal modulator for Th1, and didn't impact GATA-3 and STAT6, which are associated with a Th2 phenotype. Consistent with this in vivo observation, ELISA analysis demonstrated that ODNs A151 suppressed Th1 cytokines IFN-gamma and TNF-alpha, and augmented Th2 cytokines IL-4 and IL-10 in vitro. This study provides the first experimental evidence that suppressive ODNs inhibit the development of atherosclerosis through inhibition of the STAT1/4 and T-bet pathways, which further modulate the Th1/Th2 balance in vivo.
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PMID:Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE(-/-) mice through modulation of Th1/Th2 balance. 1859 76

Using multiplex technology, the authors investigated the laboratory and biologic variation of a panel of cytokines (interleukin (IL)-1a, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, interferon-inducible protein-10, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha) over 18 months and their relations to cardiovascular disease risk factors, hormone therapy, and weight loss. Data were obtained from the Woman On the Move through Activity and Nutrition (WOMAN) Study, a randomized clinical trial investigating the effect of nonpharmacologic interventions on subclinical atherosclerosis among overweight, postmenopausal women in Pennsylvania. The present analysis (February 2002-August 2005) comprised 290 women aged 52-62 years (mean age = 57 years). Most of the cytokines were detectable in a majority of the samples, and the between-individual biologic variation was greater than the within-individual biologic and laboratory variation. There was little association between use of hormone therapy at baseline or change in hormone therapy by 18 months and cytokine levels. Weight loss was associated with a decrease in levels of IL-1 receptor antagonist, IL-6, and C-reactive protein. The results suggest that a wide panel of cytokines may be measured simultaneously from one sample. There is large unexplained variability in cytokine levels that is probably due to genetic-environmental associations.
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PMID:Epidemiology of cytokines: the Women On the Move through Activity and Nutrition (WOMAN) Study. 1857 36

Endothelial cells are maintaining atherosclerotic signaling mediated by Extracellular Regulated Kinases 1 and 2 (ERK). Signaling gets activated upon stimulation of G protein-coupled receptors mediated by G(q) and G(i/o) proteins subjected to regulation by RGS proteins. The goal of the study was to delineate the specificity of RGS proteins modulating induced ERK phosphorylation. We used stimulated HUVEC, silenced specifically RGS proteins and compared assessed ERK 1/2 activation with immunohistochemical stainings on atherosclerotic plaques. Increased ERK phosphorylation was detected upon stimulation with Phenylephrine (2.6+/-0.1 times over basal), Endothelin-1 (1.8+/-0.2), Dopamine (5.1+/-0.2), TNF (9.8+/-0.7) or IL-4 (3.1+/-0.3). RGS silencing increased activation of ERK 1/2: Phen (RGS3, 5), ET-1 (RGS3, 4), Dopa (RGS3), TNF (RGS2, 3, 4) or IL-4 (RGS2, 3, 4). Immunohistochemically, increased ERK activation was detected on atherosclerotic plaques. This data supports the role of RGS proteins on ERK activation in human atherosclerosis which identifies RGS proteins as new therapeutical targets.
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PMID:Role of endogenous RGS proteins on endothelial ERK 1/2 activation. 1897 18

Introduction to bioorganic chemistry by Prof. Kanaoka at the entrance of my research works affects greatly throughout the life afterward. Chemical modification studies of enzyme proteins taught me quality of chemical reactions. For example, triethyloxonium fluoroborate (Et3O+ BF4(-)), a Meerwein reagent, selectively reacted with a particular carboxyl group (Asp-177) in the substrate binding site of trypsin, even though the reaction was performed in aqueous solution. A series of ion channel studies intoxicate me how exciting the science works are. Purification of sodium channel protein from electric eels initiated the collaboration work to reveal total primary structure of the molecule, as an inaugurating work of ion channel molecules. Photoaffinity labeling proved to be an efficient method to elucidate ligand binding sites, such as TTX binding site within the sodium channel and the sites for calcium anatagonists in L-type calcium channels. Encounter with CD36 molecule expands our works to more pathobiochemical field. We revealed CD36, a class B scavenger receptor, is related to development of atherosclerosis by phagocytosis of ox-LDL in macrophages and even matured adipocytes. In microglia, however, CD36 plays clearance role of oligomeric beta-amyloid peptides in IL-4 activated type-2 microglia, suggesting the activation of type-2 microglia may be useful for developing a new method to treat or prevent from Alzheimer's disease.
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PMID:[Seeking "Etwas Neues"--from bioorganic chemistry to Alzheimer's disease]. 1898 99

Imaging or drug delivery tools for atherosclerosis based on the plaque biology are still insufficient. Here, we attempted to identify peptides that selectively home to atherosclerotic plaques using phage display. A phage library containing random peptides was ex vivo screened for binding to human atheroma tissues. After three to four rounds of selection, the DNA inserts of phage clones wer sequenced. A peptide sequence, CRKRLDRNC, was the most frequently occurring one. Intravenously injected phage displaying the CRKRLDRNC peptide was observed to home to atherosclerotic aortic tissues of low-density lipoprotein receptor-deficient (Ldlr-/-) mice at higher levels than to normal aortic tissues of wild-type mice. Moreover, a fluorescein- or radioisotope-conjugated synthetic CRKRLDRNC peptide, but not a control peptide, homed in vivo to atherosclerotic plaques in Ldlr(-/-) mice, while homing of the peptide to other organs such as brain was minimal. The homing peptide co-localized with endothelial cells, macrophages and smooth muscle cells a mouse and human atherosclerotic plaques. Homology search revealed that the CRKRLDRNC peptide shares a motif of interleukin-receptor (IL-4) that is critical for binding to its receptor. The peptide indeed co-localized with IL-4 receptor (IL-4R) at atherosclerotic plaques. Moreover, the peptide bound to cultured cells expressing IL-4R on the cell surface and the binding was inhibited by the knock-down of IL-4R. These results show that the CRKRLDRNC peptide homes to atherosclerotic plaques through binding to IL-4R as its target and may be a useful tool for selective drug delivery and molecular imaging of atherosclerosis.
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PMID:Phage display selection of peptides that home to atherosclerotic plaques: IL-4 receptor as a candidate target in atherosclerosis. 1901 27

Chlamydia pneumoniae is an obligate intracellular Gram-negative bacterium with a unique biphasic developmental cycle that can cause persistent infections. In humans, Chlamydia causes airway infection and has been implicated in chronic inflammatory diseases, such as asthma and atherosclerosis. In addition, recent studies demonstrated that patients with severe periodontitis can harbor C. pneumoniae, which can increase the risk for a host inflammatory response with weighty clinical sequelae. Previous studies have established that periodontal pathogenic bacteria (i.e. Gram-negative bacteria) can induce the synthesis and release of cytokines and other inflammatory mediators in human gingival fibroblasts. HGF are resident cells of the periodontium that respond to receptor stimulation by producing a variety of substances including cytokines and growth factors. Our results demonstrate that after 48 hr of incubation with viable C. pneumoniae HGF showed a proliferative response, as seen by both colorimetric MTT assay and direct cell count (30% and 35%, respectively). In addition, HGF incubated with viable or UV light-inactivated C. pneumoniae organisms showed an increase in the levels of IL-6 and IL-10, but not IL-4; on the contrary, HGF infected with heat-killed bacteria did not show a significant production of any of the cytokines considered. In conclusion, the present study suggests that C. pneumoniae may modulate the expression of IL-6 and IL-10 by human gingival fibroblasts. Further studies are warranted to clarify the molecular mechanisms of C. pneumoniae in the regulation of cytokine expression by host cells and to elaborate the relevant clinical implications.
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PMID:Chlamydia pneumoniae induces interleukin-6 and interleukin-10 in human gingival fibroblasts. 1903 53

Mast cell development is an important component of atopic and chronic inflammatory diseases such as asthma, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. In this study, we found that IL-4 and IL-10 were produced constitutively in cultures of developing mast cells, correlating with mast cell purity. Deletion of either gene increased mast cell numbers and Fc epsilon RI expression during culture in IL-3 + stem cell factor (SCF). By adding exogenous IL-4 and IL-10 to bone marrow (BM) cultures containing IL-3 + SCF, we found that IL-4 + IL-10 suppressed mast cell development through mechanisms not used by either cytokine alone. IL-4 + IL-10 elicited a rapid cell death coincidental with reduced Kit receptor expression and signaling and enhanced mitochondrial damage and caspase activation. IL-4 or IL-10 costimulation, unlike either cytokine alone, altered mast cell ontogeny to yield predominantly macrophages in cultures that typically produce mast cells. This effect was observed consistently with unseparated BM cells, purified mouse BM stem cells, and erythrocyte-depleted human umbilical cord blood cells. These experiments demonstrated a major role for Stat6 and Stat3, but not the Stat3-induced transcriptional repressor Ets variant gene 3. Genetic background was also a critical factor, as BALB/c-derived BM cells were completely resistant to IL-10-mediated killing and expressed lower levels of IL-10R. Collectively, these results support the theory that IL-4 and IL-10 function as endogenous regulators of mast cell progenitor development, consistent with a role in immune homeostasis. Loss of this homeostasis, perhaps via genetic polymorphism, could contribute to the etiology of mast cell-associated disease.
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PMID:Endogenous suppression of mast cell development and survival by IL-4 and IL-10. 1922 15

Studies of human native C-reactive protein (nCRP) in mice have shown effects ranging from proatherogenic, to antiatherogenic, to no effect. It is likely that these disparities are related to (a) the use, in some studies, of contaminated nCRP, or to (b) variation in CRP levels associated with either its episodic administration or the use of CRP-transgenic mice. In our study, 12-week-old male apolipoprotein E-deficient (apoE (-/-)) mice, maintained on a Western diet, received azide- and endotoxin-free nCRP (n = 23) or placebo (n = 23) continuously via osmotic pumps (20.4 microg/day) for 4 weeks. CRP-treated and control mice developed similar atherosclerotic lesions in whole aortas (nCRP: 10.4 +/- 4.7% vs. controls: 11.7 +/- 4.4%, P = 0.76) and aortic roots (nCRP: 65.0 +/- 7.8% vs. controls: 64.7 +/- 9.7%, P = 0.94). No differences were observed in macrophage or T-lymphocyte infiltrates and there was no meaningful change in VCAM-1 or IL-6 expression, in the levels of soluble VCAM-1, or in circulating proinflammatory (IL-1 beta, IL-6, IL-12p40, IL-12p70, TNF-alpha, and INF-gamma), or anti-inflammatory (IL-4 and IL-10) cytokines. We conclude that continuous infusion of uncontaminated nCRP in apoE (-/-) mice is not associated with increased atherosclerosis, does not alter systemic or local inflammation, and does not affect endothelial activation. These observations suggest that alternative approaches to study CRP (perhaps using different pentraxins in the mouse model or using a rabbit model instead of a mouse model) are needed to evaluate the effects of pentraxins on atherosclerosis.
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PMID:Continuously-infused human C-reactive protein is neither proatherosclerotic nor proinflammatory in apolipoprotein E-deficient mice. 1935 57

Flaxseed and its components may improve cardiovascular health because of their numerous attributes. Flaxseed contains 35% of its mass as oil, of which 55% is alpha-linolenic acid (ALA). Flax meal, which is devoid of oil, contains the lignan secoisolariciresinol diglucoside (SDG). Flaxseed, flaxseed with very low ALA, flaxseed oil, flax lignan complex (FLC), and SDG reduce the development of hypercholesterolemic atherosclerosis by 46%, 69%, 0%, 73%, and 34%, respectively, in the rabbit model. FLC and SDG slow the progression of atherosclerosis but have no effect in regression of atherosclerosis. Suppression of atherosclerosis by flaxseed is the result of its lignan content and not the result of ALA content. Suppression of atherosclerosis is associated with lowering of serum lipids and antioxidant activity. Effects of flaxseed on serum lipids in experimental animals are variable from no change to slight reduction. Flaxseed oil does not affect serum lipids, except for a slight reduction in serum triglycerides. Lignan in general reduces serum total cholesterol and low-density lipoprotein cholesterol and raises serum high-density lipoprotein cholesterol. SDG and its metabolites have antioxidant activity. Flaxseed and flaxseed oil do not have antioxidant activity except they suppress oxygen radical production by white blood cells. Flaxseed oil/ALA has variable effects on inflammatory mediators/markers (interleukin [IL]-1beta, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, interferon-gamma, C-reactive protein, and serum amyloid A). Doses of ALA less than 14 g/d do not affect inflammatory mediators/markers, but 14 g/d or greater reduce inflammatory mediators/markers. Flaxseed oil decreases soluble vascular cell adhesion molecule-1 but has no effect on soluble intracellular adhesion molecule-1, soluble E-selectin, and monocyte colony-stimulating factor. Flaxseed has variable effects on IL-6, high-sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1. FLC reduces plasma levels of C-reactive protein but has no effects on IL-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, or monocyte chemoattractant protein. Flaxseed has a very small hypotensive effect, but flaxseed oil does not lower blood pressure. However, SDG is a very potent hypotensive agent. Flaxseed oil decreases platelet aggregation and increases platelet activating inhibitor-1 and bleeding time. Flaxseed and FLC have no effect on the hemopoietic system. SDG is a potent angiogenic and antiapoptotic agent that may have a role in cardioprotection in ischemic heart disease. In conclusion, flaxseed, FLC, and SDG, but not flaxseed oil, suppress atherosclerosis, and FLC and SDG slow progression of atherosclerosis but have no effect on regression. Flaxseed oil suppresses oxygen radical production by white blood cells, prolongs bleeding time, and in higher doses suppresses serum levels of inflammatory mediators and does not lower serum lipids.
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PMID:Flaxseed and cardiovascular health. 1956 81

YKL-39 is a Glyco_18 domain containing chitinase-like protein which is currently recognized as a biomarker for the activation of chondrocytes and the progress of the osteoarthritis in human. YKL-39 was identified as an abundantly secreted protein in primary culture of human articular chondrocytes. Two biological activities of YKL-39 might contribute to the disease progression. One is the induction of autoimmune response and second is the participation in tissue remodeling. Other mammalian chitinase-like proteins including chitotriosidase, SI-CLP, YKL-40 and YM1 are expressed by macrophages in various pathological conditions. In contrast, YKL-39 was never reported to be produced by macrophages. We used in vitro model of human monocyte-derived macrophage differentiation to analyse regulation of YKL-39 expression. Expression of YKL-39 was examined by real-time RT-PCR. CD14+ MACS sorted human monocytes differentiated for 6 days under different stimulations including IFNgamma, IL-4, dexamethasone and TGF-beta. We found that both IL-4 and TGF-beta have weak stimulatory effect on YKL-39 expression in all donors tested (3.2 +/- 1.7 fold, p = 0.006 and 6.3 +/- 3.1 fold, p = 0.014 respectively). However the combination of IL-4 and TGF-beta had strong stimulatory effect on the expression of YKL-39 in all analysed individual macrophage cultures (34 +/- 36 fold, p = 0.05). IFN-gamma did not show statistically significant effect of YKL-39 mRNA expression. Presence of dexamethasone almost completely abolished the stimulatory effects of IL-4 and TGF-beta. In summary, we show here for the first time, that human cells of monocyte origin are able to produce YKL-39. Maturation of monocyte derived macrophages in the presence of Th2 cytokine IL-4 and TGF-beta leads to the strong activation of YKL-39 expression. Thus elevated levels of YKL-39 observed during chronic inflammations can not be attributed solely to the activity of chondrocytes. In perspective, YKL-39 might serve as a useful biomarker to detect macrophage-specific response in pathologies like tumour, atherosclerosis and Alzheimer disease.
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PMID:Expression of Osteoarthritis Marker YKL-39 is Stimulated by Transforming Growth Factor Beta (TGF-beta) and IL-4 in Differentiating Macrophages. 1957 92


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