Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80098 (monocyte chemoattractant protein)
 1,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelium releases multiple mediators, not only regulators of vasomotor function but also important physiological and pathophysiological inflammatory mediators. Endothelial dysfunction is caused by chronic exposure to various stressors such as oxidative stress and modified low-density lipoprotein (LDL) cholesterol, resulting in impaired nitric oxide (NO) production and chronic inflammation. Biomechanical forces on the endothelium, including low shear stress from disturbed blood flow and hypertension, are also important causes of endothelial dysfunction. These processes seem to be augmented in patients with diabetes. In states of insulin resistance and in type 2 diabetes insulin signalling is impaired. Increased vascular inflammation, including enhanced expression of interleukin- 6 (IL-6), vascular cellular adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein (MCP- 1) are observed, as is a marked decrease in NO bioavailability. Furthermore, hyperglycaemia leads to increased formation of advanced glycation end products (AGE), which quench NO and impair endothelial function. In summary, during the development of diabetes a number of biochemical and mechanical factors converge on the endothelium, resulting in endothelial dysfunction and vascular inflammation. In the presence of insulin resistance, these processes are potentiated and they provide a basis for the macrovascular disease seen in diabetes.
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PMID:The endothelium and vascular inflammation in diabetes. 1765 40

Activation of nuclear factor (NF)-kappaB is mediated by signal-induced phosphorylation of IkappaBalpha, subsequent IkappaBalpha degradation, and then translocation of unbound NF-kappaB to the nucleus. Termination of gene expression occurs when IkappaBalpha binds NF-kappaB subunits (Rel A) in the nucleus. Leptomycin B specifically inhibits export of IkappaBalpha and the inactive IkappaBalpha/Rel A complex via the nuclear export protein exportin 1. We hypothesized that inhibition of IkappaBalpha nuclear export would increase nuclear IkappaBalpha and attenuate NF-kappaB inflammatory gene expression in pulmonary microvascular endothelial cells. We found that inhibition of exportin 1 causes nuclear accumulation of both endogenous NF-kappaB (Rel A) and IkappaBalpha. IL-1beta causes nuclear accumulation of NF-kappaB (Rel A) but does not increase nuclear IkappaBalpha. Inhibition of exportin 1 before IL-1beta prevented an increase in the nuclear ratio of NF-kappaB (Rel A) to IkappaBalpha and decreases NF-kappaB DNA binding. Furthermore, inhibition of exportin 1 attenuates IL-1beta-induced phosphorylation of IkappaBalpha without affecting IkappaB kinase phosphorylation. Lastly, inhibition of exportin 1 attenuates monocyte chemoattractant protein, IL-8, and intercellular adhesion molecule expression in response to IL-1beta stimulation. We suggest that the decrease in cell activation due to exportin 1 inhibition is a result of termination of NF-kappaB DNA binding due to increased concentration of IkappaBalpha in the nucleus.
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PMID:Exportin 1 inhibition attenuates nuclear factor-kappaB-dependent gene expression. 1769 24

Tumor necrosis factor (TNF)-alpha is central to the endometriotic disease process. TNF-alpha receptor signaling regulates epithelial cell secretion of inflammation and invasion mediators. Because epithelial cells are a disease-inducing component of the endometriotic lesion, we explored the response of 12Z immortalized human epithelial endometriotic cells to TNF-alpha. This report reveals the impact of disruption of established TNF-alpha-induced signaling cascades on the expression of biomarkers of inflammation and epithelial-mesenchymal transition (EMT) from endometriotic epithelial cells. Note that we show the molecular potential of soluble TNF-R1 [TNF binding protein (TBP)] and a panel of small molecule kinase inhibitors to block endometriotic gene expression directly. The TNF-alpha receptor is demonstrated to signal through IkappaB kinase complex (IKK) 2 > IkappaB > nuclear factor kappaB, extracellular signal-regulated kinase > mitogen-activated protein kinase kinase (MEK), p38, and phosphatidylinositol 3-kinase (PI3K) > Akt1/2. TNF-alpha induces the expression of transcripts for inflammatory mediators interleukin (IL)-6, IL-8, regulated on activation normal T cell expressed and secreted, TNF-alpha, granulocyte macrophage-colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)-1 and also invasion mediators matrix metalloproteinase (MMP)-7, MMP-9, and intracellular adhesion molecule-1. Indeed, TBP inhibits the TNF-alpha-induced expression of all the above endometriotic genes in 12Z endometriotic epithelial cells. The secretion of IL-6, IL-8, GMCSF, and MCP-1 by TNF-alpha is blocked by TBP. Interestingly, MEK, p38, and IKK inhibitors block TNF-alpha-induced IL-8, IL-6, and GM-CSF secretion and 12z invasion, whereas the PI3K inhibitors do not. The only inhibitor to block MCP-1 expression is the p38 inhibitor. Last, TBP, MEK inhibitor, or p38 inhibitor also block cell surface expression of N-cadherin, a marker of mesenchymal cells. Taken together, these results demonstrate that interruption of TNF-alpha-induced signaling pathways in human endometriotic epithelial cells results in decreased expression and secretion of biomarkers for inflammation, EMT, and disease progression.
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PMID:Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. 1825 6

Histophilus somni is a gram-negative coccobacillus that causes respiratory and reproductive disease in cattle. The hallmark of systemic H. somni infection is diffuse vascular inflammation that can lead to an acute central nervous system disease known as thrombotic meningoencephalitis. Previously, we demonstrated that H. somni and its lipooligosaccharide (LOS) activate bovine platelets, leading to expression of P selectin, CD40L, and FasL. Because activated platelets have been reported to induce endothelial cell cytokine production and adhesion molecule expression, we sought to determine if bovine platelets induce proinflammatory and procoagulative changes in bovine pulmonary artery endothelial cells. Endothelial cells were incubated with platelets activated with adenosine diphosphate, H. somni, or H. somni LOS. Incubation with activated bovine platelets significantly increased expression of in adhesion molecules (intercellular adhesion molecule 1, E selectin) and tissue factor, as measured by flow cytometry, real-time polymerase chain reaction, and Western blot analysis. Activated platelets also up-regulated expression of endothelial cell IL-1beta, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1alpha as determined by real-time polymerase chain reaction and an IL-1beta enzyme-linked immunosorbent assay. An interesting and surprising finding was that bovine platelets activated by H. somni or its LOS were internalized by bovine endothelial cells as visualized by transmission electron microscopy. This internalization seemed to correlate with endothelial cell activation and morphological changes indicative of cell stress. These findings suggest that activated platelets might play a role in promoting vascular inflammation during H. somni infection.
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PMID:Platelet activation by Histophilus somni and its lipooligosaccharide induces endothelial cell proinflammatory responses and platelet internalization. 1838 89

Vascular adhesion protein-1 (VAP-1) is an endothelial cell adhesion molecule involved in leukocyte recruitment. Leukocytes and, in particular, macrophages play an important role in the development of choroidal neovascularization (CNV), an integral component of age-related macular degeneration (AMD). Previously, we showed a role for VAP-1 in ocular inflammation. Here, we investigate the expression of VAP-1 in the choroid and its role in CNV development. VAP-1 was expressed in the choroid, exclusively in the vessels, and colocalized in the vessels of the CNV lesions. VAP-1 blockade with a novel and specific inhibitor significantly decreased CNV size, fluorescent angiographic leakage, and the accumulation of macrophages in the CNV lesions. Furthermore, VAP-1 blockade significantly reduced the expression of inflammation-associated molecules such as tumor necrosis factor (TNF) -alpha, monocyte chemoattractant protein (MCP) -1, and intercellular adhesion molecule (ICAM) -1. This work provides evidence for an important role of VAP-1 in the recruitment of macrophages to CNV lesions, establishing a novel link between VAP-1 and angiogenesis. Inhibition of VAP-1 may become a new therapeutic strategy in the treatment of AMD.
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PMID:Vascular adhesion protein-1 blockade suppresses choroidal neovascularization. 1843 61

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

To assess the influence of unknown factors in endotoxemia, a conditioned medium, achieved by the stimulation of THP1 monocytes with lipopolysaccharide (LPS) [4h], was used for the stimulation of human umbilical vein endothelial cells (HUVECs) [16h]. SVEP1, KIAA0247, and SRPX2 were selected after microarray analysis. To study their possible functions, siRNAs of SVEP1, KIAA0247, or SRPX2 were used for the transfection of HUVECs and cells were stimulated with conditioned medium [16h]. Inhibition of SVEP1 expression resulted in an increase of soluble intercellular adhesion molecule (sICAM) 1 (10%) and soluble E-selectin (sE-selectin) (19%). Inhibition of SRPX2 led to an increase of sICAM (11%) and sE-selectin (14%). KIAA0247 negative HUVECs showed a decrease in monocyte chemoattractant protein (MCP) 1 of 16%. SVEP1 and SRPX2 seemed to act as regulators of ICAM1 and E-selectin shedding and influence the expression of membrane bound adhesion molecules.
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PMID:Characterization of SVEP1, KIAA, and SRPX2 in an in vitro cell culture model of endotoxemia. 2023 27

1. The novel nuclear factor (NF)-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) is a derivative of the antibiotic epoxyquinomicin C from Amycolatopsis sp. that has been found to inhibit tumour necrosis factor (TNF)-alpha-induced activation of NF-kappaB by suppressing nuclear translocation of NF-kappaB. The aim of the present study was to determine the effects of DHMEQ on interferon (IFN)-gamma- and histamine-activated NCTC 2544 keratinocytes. 2. Keratinocytes were stimulated or not with 200 U/mL IFN-gamma and 10(-4) mol/L histamine in the absence or presence of different concentrations of DHMEQ (1, 5 and 10 microg/mL) or hydrocortisone (10(-5) mol/L), which was used as a reference anti-inflammatory drug. After 48 h, each sample was tested for the presence of intercellular adhesion molecule (ICAM)-1 by western blot analysis, as well as for the release of monocyte chemoattractant protein (MCP)-1, RANTES and interleukin (IL)-8 using specific sandwich ELISAs. To verify the effect of DHMEQ on cell viability of non-stimulated NCTC 2544 keratinocytes, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used. 3. The results showed that 10 microg/mL DHMEQ potently inhibited ICAM-1 production (by 50%), as well as the release of MCP-1 (to 25% of control), RANTES (to 5% of control) and IL-8 (to 2% of control). The results of the MTT assay indicated that DHMEQ has no effect on cell viability. 4. In conclusion, DHMEQ inhibits the IFN-gamma- and histamine-induced activation of the keratinocyte cell line NCTC 2544. The anti-inflammatory effects of DHMEQ could be exploited by applying the drug topically alone or in combination with sub-toxic concentrations of anti-inflammatory drugs to producer a synergistic effect.
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PMID:Dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, prevents inflammatory injury induced by interferon-gamma and histamine in NCTC 2544 keratinocytes. 2033 59

Methamphetamine (MA) dependence causes serious cognitive impairments that can persist during abstinence and negatively affect recovery outcomes. Evidence suggests that immune factors, such as cytokines, chemokines, and cellular adhesion molecules, contribute to MA-induced immune dysfunction, neuronal injury, and persistent cognitive impairments, yet the role of MA-induced brain inflammation remains unclear. To address this question, we used a cross-species, translational approach. Thirty-two male C57BL/6J mice were administered MA (1 mg/kg) or saline subcutaneously for seven consecutive days. Mice were euthanized at 72 h or 3 weeks after the last drug dose, and blood and brain samples were collected. In addition, 20 adults in remission from MA dependence and 20 non-dependent controls completed neuropsychological assessments and a blood draw. Multiplex assays were used to measure cytokine, chemokine, and intercellular adhesion molecule (ICAM-1) expression in mouse and human samples. A number of significant MA-induced changes in neuroimmune factors were observed. Of particular interest were the chemokine monocyte chemoattractant protein 1 (MCP-1) and the cellular adhesion molecule ICAM-1, which were similarly increased in the plasma of MA exposed mice as well as humans. In human participants, MA-induced changes in the cytokine and chemokine milieu were accompanied by increased cognitive impairments. Mice showing MA-induced changes in peripheral immune molecule expression also had significant brain-region specific changes in pro-inflammatory cytokines, chemokines, and ICAM-1. This cross-species, translational study suggests that chronic CNS immune dysregulation may in part contribute to the longlasting neuropsychiatric consequences of MA dependence.
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PMID:Methamphetamine causes persistent immune dysregulation: a cross-species, translational report. 2095 17

Evidence from animal models of trauma and hemorrhage has suggested that the gut plays an active role in the pathogenesis of systemic inflammatory responses and multiple organ dysfunction syndrome. The aim of the present study was to seek evidence for gut-derived signals in man in a group of eight patients undergoing elective abdominal aortic reconstruction, a procedure that is associated with sterile tissue injury, controlled colonic ischemia as a consequence of aortic cross-clamping, and a significant risk of developing systemic inflammation and multiple organ dysfunction syndrome. Despite the presence of a marked systemic inflammatory response (IL-6, IL-18, monocyte chemoattractant protein 1, and IL-8) and a gut-derived inflammatory signal (IL-6), we could find no evidence that gut-derived pathogen DNA was present in the central or mesenteric circulation, and we could find no evidence that either central or mesenteric plasma samples could induce apoptotic or necrotic cell death in human umbilical vein endothelial cells in vitro. Similarly, we could find no evidence of adhesion molecule upregulation in the endothelial monolayers exposed to central or mesenteric plasma sampled at any time point during surgery. There was, however, evidence of an increase in the expression of RAGE (receptor for advanced glycation end products) by endothelial cells following exposure to mesenteric venous, but not central, plasma sampled during maximum ischemia. In conclusion, during sterile tissue injury and controlled colonic ischemia-reperfusion in man, there is a marked systemic proinflammatory response, which is in part gut derived, in the absence of evidence for the presence of toxic endothelial factors or gut-derived microorganisms in the central or mesenteric circulations.
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PMID:Investigation of systemic and mesenteric inflammatory signaling and gut-derived endothelial toxicity in patients undergoing high-risk abdominal aortic surgery. 2155 85


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