Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of the P-, L-, and E-selectins to sialyl Lewis(x) (sLe(x)) retards circulating leukocytes, thereby facilitating their attachment to the blood vessels of allografts. Whether the selectin inhibitor bimosiamose (BIMO; C(46)H(54)O(16) . 0.25 H(2)O [867.4 molecular weight]) inhibits the rejection process of kidney allografts in a rat model was examined. Rat recipients acutely rejected kidney allografts at a mean survival time of 8.8 +/- 0.75 d. An intravenous 7-d infusion by osmotic pump of 2.5, 5, 10, or 20 mg/kg BIMO extended kidney allograft survival to 11.5 +/- 2.2 d (P < 0.03), 25.4 +/- 11.4 d (P < 0.006), 37.4 +/- 13.6 d (P < 0.001), and 39.8 +/- 34.5 d (P < 0.01), respectively. Combination of BIMO with cyclosporine produced synergistic interactions, as documented by the combination index (CI) values of 0.34 to 0.43 (CI <1 is synergistic; CI = 1 is additive; and CI >1 is antagonistic). Similarly, BIMO interacted synergistically with sirolimus (CI = 0.64) and FTY720 (CI = 0.22). While the mechanism of immunosuppression was being analyzed, decreased infiltration of CD4(+), CD8(+), and macrophages on day 7 after grafting was observed. Multiple cytokines were also expressed, including IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-alpha, and IFN-gamma in kidney allografts on days 3, 5, and 7 after grafting, as measured by a ribonuclease protection assay. Furthermore, at similar time points, BIMO treatment reduced intragraft expression of P-selectin glycoprotein ligand-1, CX(3)CL1, CCL19, CCL20, and CCL2. Thus, BIMO blocks allograft rejection by reduction of intragraft expression of cytokines and chemokines.
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PMID:Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines. 1550 42

Recent studies from our laboratory demonstrate that TNF-alpha signaling contributes to the regulation of chondrocyte apoptosis and a lack of TNF-alpha signaling leads to a persistence of cartilaginous callus and delayed resorption of mineralized cartilage. This study examines how delays in the endochondral repair process affect the expression of specific mediators of proteolytic cartilage turnover and vascularization. Simple closed fractures were produced in wild type and TNF-alpha receptor (p55-/-/p75-/-)-deficient mice. Using ribonuclease protection assay (RPA) and microarray analysis, the expression of multiple mRNAs for various angiogenic factors and the metalloproteinase gene family were measured in fracture calluses. The direct actions of TNFalpha on the expression of specific angiogenic factors and metalloproteinases (MMPs) was examined in both cultured callus cells and articular chondrocytes to compare the effects of TNF-alpha in growth cartilage versus articular cartilage. MMPs 2, 9, 13, and 14 were quantitatively the most prevalent metalloproteases and all showed peaks in expression during the chondrogenic period. In the absence of TNF-alpha signaling, the expression of all of these mRNAs was reduced. The angiopoietin families of vascular regulators and their receptors were expressed at much higher levels than the VEGFs and their receptors and while the angiopoietins showed diminished or delayed expression in the absence of TNF-alpha signaling, VEGF and its receptors remained unaltered. The expression of vascular endothelial growth inhibitor (VEGI or TNFSF15) showed a near absence in its expression in the TNF-alpha receptor-deficient mice. In vitro assessment of cultured fracture callus cells in comparison to primary articular chondrocytes showed that TNF-alpha treatment specifically induced the expression of MMP9, MMP14, VEGI, and Angiopoietin 2. These results suggest that TNF-alpha signaling in chondrocytes controls vascularization of cartilage through the regulation of angiopoietin and VEGI factors which play counterbalancing roles in the induction of growth arrest, or apoptosis in endothelial cells. Furthermore, TNF-alpha appears to regulate, in part, the expression of two key proteolytic enzymes, MMP 9 and MMP14 that are known to be crucial to the progression of vascularization and turnover of mineralized cartilage. Thus, TNF-alpha signaling in healing fractures appears to coordinate the expression of specific regulators of endothelial cell survival and metalloproteolytic enzymes and is essential in the transition and progression of the endochondral phase of fracture repair.
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PMID:Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing. 1578 Sep 56

The host response during resolution of Pneumocystis murina infection following withdrawal of Dexamethasone (Dex) induced immunosuppression was analyzed. Mice were inoculated with P. murina and treated with Dex for 4 weeks. Treatment was stopped and mice were sacrificed at d1, d7, and d14. Control mice were treated in the same manner, but were inoculated with nonviable P. murina. P. murina was actively cleared from the lungs following withdrawal of Dex treatment. No P. murina was detected in control mice. Significantly more neutrophils, lymphocytes, macrophages, and eosinophils were recovered from the lungs of mice that had been infected with P. murina than from control mice at d7, but only neutrophils remained significantly elevated at d14. Significantly more CD4+ and CD8+ T cells were purified from the lungs of mice that had been infected with P. murina mice at d7 and d14. Cytokine levels were measured in lung lavage fluid by ELISA. TNF-alpha, IFN-gamma, IL-1, and IL-6 levels were higher in mice that had been inoculated with P. murina at all three time points. TNF-alpha and IL-1 levels did not change significantly following withdrawal of Dex treatment. Low levels of IL 6 were detected at d1, but increased significantly by d7 and d14. IFN-gamma levels peaked at d14. Chemokine message levels were measured in lung tissue by ribonuclease protection assay. MIP-1beta and IP-10 message increased between d1 and d7 and then decreased by d14. RANTES message levels increased from d1 to d7 and remained elevated at d14. Withdrawal of Dex induced immunosuppression from P. murina infected mice resulted in activation of many arms of the host response that lead to resolution of the infection.
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PMID:Resolution of Pneumocystis murina infection following withdrawal of corticosteroid induced immunosuppression. 1632 97

Neurocysticercosis is a parasitic infection of the human central nervous system caused by the cestode Taenia solium. The most common clinical manifestations of neurocysticercosis are seizures. Taenia crassiceps cysticercosis in mice has been used as an experimental model for T. solium cysticercosis. Granulomas surrounding murine cysticerci have striking immunopathological resemblance to human neurocysticercosis; early stage granulomas were able to induce seizures in a rodent model. To assess the role of proinflammatory cytokines in early stage granulomas, we isolated RNA from murine cysticercal granulomas and checked for cytokine expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ribonuclease (RNase) protection assays. Cytokine expression was compared with histological stages. Interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist, and tumor necrosis factor (TNF-alpha) were the major cytokines detected in all granulomas. Signals for IL-12, IL-18, and IL-6 RNA were not consistently detected and, when detected, were barely demonstrable. Expression of migration inhibitory factor (MIF), IL-6, IL-1alpha, TNF-alpha, and IL-18 was not significantly different between early and late-stage granulomas. Expression of IL-1beta, IL-1 receptor antagonist, and IL-12 p40 were higher in late, compared with early, stages. Thus, we demonstrated a broad range of cytokines in these granulomas. However, we did not document preferential expression of any proinflammatory cytokines in early stage granulomas. Thus, proinflammatory cytokines are not responsible for the seizures in the rodent model of neurocysticercosis.
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PMID:Proinflammatory cytokines in granulomas associated with murine cysticercosis are not the cause of seizures. 1699 90

The effect of exogenous RNA on many cellular functions has been studied in a variety of eukaryotic cells but there are few reports on macrophages. In the present study, it is demonstrated that cytoplasmatic RNA extracted from rat macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L-RNA, induced the release of TNF-alpha and IL-1 from monolayers of peritoneal resident macrophages. The activity of L-RNA was not altered by polymyxin B but was abolished by ribonuclease (RNase) pretreatment, indicating the absence of LPS contamination and that the integrity of the polynucleotide chain is essential for this activity. Both the poly A(-) and poly A(+) fractions obtained from L-RNA applied to oligo(dT)-cellulose chromatography induced TNF-alpha and IL-1 release. The L-RNA-induced cytokine release was inhibited by dexamethasone and seemed to be dependent on protein synthesis since this effect was abolished by cycloheximide or actinomycin-D. The LPS-stimulated macrophages, when pre-incubated with [5-(3)H]-uridine, secreted a trichloroacetic acid (TCA) precipitable material which was sensitive to RNase and KOH hydrolysis, suggesting that the material is RNA. This substance was also released from macrophage monolayers stimulated with IL-1beta but not with TNF-alpha, IL-6 or IL-8. The substance secreted ((3)H-RNA) sediments in the 4-5S region of a 5-20% sucrose gradient. These results show that L-RNA induces cytokine secretion by macrophage monolayers and support the idea that, during inflammation, stimulated macrophages could release RNA which may further induce the release of cytokines by the resident cell population.
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PMID:RNA from LPS-stirnulated macrophages induces the release of tumour necrosis factor-alpha and interleukin-1 by resident macrophages. 1847 60

A large number of trypsin inhibitors belonging to various types have been purified from different kinds of legumes. In this study, by using liquid chromatography, a Kunitz type trypsin inhibitor (KBTI) with a molecular weight of 20107.645 Da was purified from Korean large black soybeans. KBTI reduced the proteolytic activities of trypsin and alpha-chymotrypsin with the activity of approximately 8520 BAEE units/mg and approximately 24 BTEE units/mg, respectively. It showed high thermal stability (0-100 degrees C) as well as stability over a large range of pH values (pH 3-11). Furthermore, KBTI inhibited HIV-1 reverse transcriptase activity with an IC(50) value of 0.71 microM and induced the release of pro-inflammatory cytokines such as TNF-alpha, IL-1beta, IL-2 and interferon-gamma at the mRNA level. KBTI exerted weak antiproliferative activity toward CNE-2 and HNE-2 nasopharyngeal cancer cells, MCF-7 breast cancer cells, and Hep G2 hepatoma cells. KBTI was destitute of mitogenic, ribonuclease and antifungal activities.
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PMID:Thermostable Kunitz trypsin inhibitor with cytokine inducing, antitumor and HIV-1 reverse transcriptase inhibitory activities from Korean large black soybeans. 2015 65


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