Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.4 (ribonuclease)
6,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological studies have indicated that exposure to elevated levels of particulate matter exacerbates several pulmonary diseases, including asthma, bronchitis, and viral infections. Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in infants and may lead to the development of asthma in childhood. To determine whether particle exposure modulates the immune response to RSV, eight-week-old female BALB/c mice received an intratracheal (i.t.) instillation of either 40 micro g ultrafine carbon black (CB) particles or vehicle. The following day, mice were i.t. instilled with either 106 pfu RSV or uninfected media. End points were examined 1, 2, 4, 7, and 10 days during RSV infection. Compared with RSV alone, tumor necrosis factor-alpha (TNF-alpha) protein was reduced in the bronchoalveolar lavage fluid (BALF) on days 1 and 2 of infection; there was also a reduction in BALF lymphocyte numbers on day 4, which correlated with reductions in both IFN-gamma-inducible protein (IP-10), lymphotactin, and IFN-gamma mRNAs in the lungs of RSV + CB mice. Multiprobe ribonuclease protection assays of RSV + CB lung tissue showed no changes in the RSV-associated chemokines regulated upon activation, normal T cell expressed and secreted (RANTES), eotaxin, monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein (MIP)-1 alpha or MIP-1 beta. Viral titers in RSV + CB mice were lower than RSV on days 2-4 of infection. By day 7 of infection, however, neutrophil numbers, proinflammatory cytokine mRNA expression, and protein levels of TNF-alpha and the Th2 cytokine interleukin (IL)-13 were increased in the lungs of RSV + CB mice, indicating an exacerbation of infection. These data indicate that preexposure to ultrafine particles induces an inflammatory milieu promoting allergic immune responses rather than IFNgamma production necessary for microbial defense.
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PMID:Effect of preexposure to ultrafine carbon black on respiratory syncytial virus infection in mice. 1266 Mar 65

Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.
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PMID:Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism. 1269 8

Leptin is a 16-kDa hormone with an array of biologic actions. We, and others, have demonstrated that leptin is critical to the development of liver fibrogenesis both in vitro and in the lean littermates of ob/ob mice exposed to carbon tetrachloride (CCl(4)). Controversy exists as to whether leptin can act as a direct cytokine in the development of increased collagen expression, and whether ob/ob mice are resistant to potential injury from CCl(4). Here, we provide evidence that strongly suggests that leptin acts to increase nascent production of mRNA for the alpha2(I) collagen gene based upon ribonuclease protection analysis (RPA). Actinomycin D, but not cyclohexamide, or the pan-neutralizing antibody to transforming growth factor beta one (TGFbeta1), significantly diminished the effect of leptin on total alpha2(I) collagen mRNA levels. Further evidence that leptin acts directly on HSCs to alter gene expression in liver wounding is demonstrated by enhanced binding of phosphorylated signal transduction and activator of transcription factor 3 (pStat3) to a cis-inducible element (SIE) oligonucleotide by electrophoretic mobility shift assay (EMSA). This consensus sequence is responsible for production of a critical collagen transcription factor, AP-1. Finally, we have demonstrated from the ob/ob mouse model that these animals are at least as sensitive to CCl(4) as their respective lean animals as assessed by serum alanine aminotransferase (ALT) measurements. Taken together, the current data provide a continued framework that leptin is a profibrogenic cytokine and plays a key role in liver fibrosis.
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PMID:Leptin induces increased alpha2(I) collagen gene expression in cultured rat hepatic stellate cells. 1270 94

Astrocytes may be infected with the human immunodeficiency virus type 1 (HIV-1) or exposed to the HIV protein gp120, yet their role in the pathogenesis of HIV dementia is largely unknown. To characterize the effects of HIV on astrocytic transcription, microarray analysis and ribonuclease protection assays (RPA) were performed. Infection of astrocytes by HIV or treatment with gp120 had differential and profound effects on gene transcription. Of the 1153 oligonucleotides on the immune-based array, the expression of 108 genes (53 up; 55 down) and 82 genes (32 up; 50 down) were significantly modulated by gp120 and HIV infection respectively. Of the 1153 oligonucleotides on the neuro-based array, 58 genes (25 up; 33 down) and 47 genes (17 up; 30 down) were significantly modulated by gp120 and HIV infection respectively. Chemokine and cytokine induction occurred predominantly by HIV infection, whereas gp120 had no significant effect. These results were confirmed by RPA. The authors conclude that profound alterations of astrocytic function occur in response to HIV infection or interaction with viral proteins, suggesting that astrocytes may play an important role in the pathogenesis of HIV dementia.
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PMID:Differential transcriptional regulation by human immunodeficiency virus type 1 and gp120 in human astrocytes. 1277 19

Interactions between neurotransmitters and immunomodulators within the central nervous system may be functionally relevant for communication between the immune system and the brain. Previous studies indicate that cytokines such as interleukin-1 (IL-1) alter activity of the serotonergic system at multiple levels. This study tested the hypothesis that serotonergic activation modulates cytokine mRNA expression in brain. Serotonergic activation was induced by injecting rats intraperitoneally (i.p.) prior to dark onset with the serotonin precursor L-5-hydroxytryptophan (5-HTP; 100 mg/kg). Cytokine mRNA expression in discrete brain regions at selected time points was determined by means of ribonuclease protection assay. Plasma corticosterone concentrations were also measured to determine if the hypothalamic-pituitary-adrenal axis is activated in response to this treatment, which potentially could exert feedback regulating cytokine message expression in brain. Plasma corticosterone was elevated for 4 h after 5-HTP administration. At this time IL-1alpha mRNA expression was reduced in the hippocampus, hypothalamus, and brainstem, and IL-1beta mRNA was reduced in the hippocampus. Six hours after 5-HTP injection, IL-1beta mRNA increased in the hypothalamus. These results show that activation of the serotonergic system affects cytokine message expression in rat brain, possibly by actions of corticosterone.
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PMID:Serotonergic activation stimulates the pituitary-adrenal axis and alters interleukin-1 mRNA expression in rat brain. 1289 55

Fumonisin B1 (FB1), a mycotoxin, is a potent inhibitor of ceramide synthase, and produces organ-, species-, and even gender-specific toxic responses in animals. The hepatotoxic response of FB1 in mice involves accumulation of free sphingoid bases and induction of inflammatory cytokines including tumor necrosis factor alpha (TNFalpha). The FB1-induced hepatotoxic responses were reduced in mice lacking TNFalpha receptor (TNFR) 1 or TNFR2. However, the hepatotoxicity was exacerbated in mice lacking TNFalpha. We therefore investigated the modulation of various other apoptotic signaling factors in TNFalpha-knockout (TKO) mice compared to wild-type (WT) strain after repeated daily subcutaneous injections of 2.25 mg/kg FB1 treatment for 5 days. Expression of various signaling genes in liver was evaluated by ribonuclease protection assay. Expression of CD95-ligand (FasL) was more than doubled in TKO animals after FB1 whereas it was unaltered in the WT group. FB1 did not alter CD95 expression in either strain; however, expressions of TRAIL, and downstream signaling factors FADD, TRADD, and caspase 8 were higher in FB1-treated TKO mice than in the corresponding WT animals. The TKO strain had a higher constitutive expression of apoptotic factors except CD95L. In addition to the CD95 and TNFalpha systems, the expression of apoptotic molecules bcl-2, b-myc, c-myc, bax, max, mad and IL1alpha was induced by FB1 in TKO mice to a greater extent than in WT animals; many of these factors also had a higher constitutive expression in TKO animals than WT mice. Results indicated that FB1 can induce CD95 modulated signaling when TNFalpha is absent. Differential constitutive expression of apoptotic genes in TKO mice may explain their increased sensitivity to FB1. These results are important in characterizing the modulating effect of TNFalpha on apoptotic signaling and in explaining the unexpected sensitivity of mice lacking this cytokine in response to hepatotoxic xenobiotics.
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PMID:Increased expression of CD95-ligand and other apoptotic signaling factors by fumonisin B1, a hepatotoxic mycotoxin, in livers of mice lacking tumor necrosis factor alpha. 1459 19

Exposure to low molecular weight (LMW) chemicals in the workplace has been linked to a variety of respiratory effects. Within the LMW chemicals, one of the major classes involved in these effects are the acid anhydrides. The immunological basis of respiratory hypersensitivity involves CD4+ cells. By virtue of their induction of cytokines typical of CD4+ T-helper type 2 (Th2) cells-interleukin (IL)-4, 10, and 13-respiratory sensitizers may be identified and differentiated from contact sensitizers which induce Th1 cytokines (IL-2 and IFN-gamma). Our previous work suggested that the ribonuclease protection assay (RPA) was useful in identifying the respiratory sensitizer, trimellitic anhydride (TMA), based on quantitative differences in Th2 cytokine mRNA as compared to the contact sensitizer dinitrochlorobenzene (DNCB). Therefore, the purpose of the studies described in this report was to expand the chemicals tested in the RPA. To this end, four acid anhydrides with known respiratory sensitization potential, TMA, maleic anhydride (MA), phthalic anhydride (PA) and hexahydrophthalic anhydride (HHPA), were tested. Although previously determined to induce immunologically equivalent responses in a local lymph node assay (LLNA), the initial dose chosen (2.5%) failed to induce Th2 cytokine mRNA expression. To determine if the lack of cytokine expression was related to dose, LLNAs were conducted at higher doses for each of the anhydrides. The highest doses evaluated (four- to six-fold higher than those used in the initial RPA) gave equivalent proliferative responses for the various anhydrides and were used for subsequent RPA testing. At these higher doses, significant increases in Th2 versus Th1 cytokine mRNA were observed for all anhydrides tested. These results suggest that the RPA has the potential to serve as a screen for the detection of LMW airway sensitizing chemicals. However, the basis for selecting immunologically equivalent doses may require some modification.
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PMID:Identifying airway sensitizers: cytokine mRNA profiles induced by various anhydrides. 1459 59

Chemokines have been implicated in the pathogenesis of many inflammatory processes, including bronchopulmonary dysplasia in mechanically ventilated premature infants. We hypothesized that early expression of the proinflammatory cytokine, tumor necrosis factor alpha (TNFalpha), would be followed by later expression of the downstream chemokine, Grobeta, in the oxygen-injured newborn lung. Reverse transcriptase-polymerase chain reaction (RT-PCR) and ribonuclease protection assay (RPA) were used to assess TNFalpha and Grobeta mRNA expression in lung RNA samples from newborn rabbits exposed to > 95% O2 for 8-9 days, followed by 60% O2 for a further 2-4 weeks or from control rabbits exposed to air. Four lung samples per condition were collected every 2 days from day 0 to day 14, and at days 22 and 36. Rabbit alveolar macrophages (AM) stimulated in vitro with bacterial lipopolysaccharide served as positive controls ( n = 8). Grobeta mRNA expression in rabbit lung samples increased with oxygen exposure until day 8, then returned toward baseline levels. This corresponded to previously described elevations in neutrophil number in the lungs. TNFalpha mRNA expression in lung samples was below the limit of detection by RPA and showed no upregulation in hyperoxic lung samples by RT-PCR. TNFalpha activity was assessed in lung lavage ( n = 2 samples per condition per time) using an L929 cell line bioassay and was not increased in hyperoxic animals. The expression of Grobeta mRNA without antecedent or concurrent TNFalpha mRNA expression or activity makes it unlikely that Grobeta in the hyperoxic newborn rabbit lung is elaborated in response to a stimulus by TNFalpha.
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PMID:Effects of hyperoxia on tumor necrosis factor alpha and Grobeta expression in newborn rabbit lungs. 1474 38

Endothelial cells are the primary targets of circulating immune and inflammatory mediators. We hypothesize that interleukin-18, a proinflammatory cytokine, induces endothelial cell apoptosis. Human cardiac microvascular endothelial cells (HCMEC) were treated with interleukin (IL) 18. mRNA expression was analyzed by ribonuclease protection assay, protein levels by immunoblotting, and cell death by enzyme-linked immunosorbent assay and fluorescence-activated cell sorter analysis. We also investigated the signal transduction pathways involved in IL-18-mediated cell death. Treatment of HCMEC with IL-18 increases 1) NF-kappaB DNA binding activity; 2) induces kappaB-driven luciferase activity; 3) induces IL-1beta and TNF-alpha expression via NF-kappaB activation; 4) inhibits antiapoptotic Bcl-2 and Bcl-X(L); 5) up-regulates proapoptotic Fas, Fas-L, and Bcl-X(S) expression; 6) induces fas and Fas-L promoter activities via NF-kappaB activation; 7) activates caspases-8, -3, -9, and BID; 8) induces cytochrome c release into the cytoplasm; 9) inhibits FLIP; and 10) induces HCME cell death by apoptosis as seen by increased annexin V staining and increased levels of mono- and oligonucleosomal fragmented DNA. Whereas overexpression of Bcl-2 significantly attenuated IL-18-induced endothelial cell apoptosis, Bcl-2/Bcl-X(L) chimeric phosphorothioated 2'-MOE-modified antisense oligonucleotides potentiated the proapoptotic effects of IL-18. Furthermore, caspase-8, IKK-alpha, and NF-kappaB p65 knockdown or dominant negative IkappaB-alpha and dominant negative IkappaB-beta or kinase dead IKK-beta significantly attenuated IL-18-induced HCME cell death. Effects of IL-18 on cell death are direct and are not mediated by intermediaries such as IL-1beta, tumor necrosis factor-alpha, or interferon-gamma. Taken together, our results indicate that IL-18 activates both intrinsic and extrinsic proapoptotic signaling pathways, induces endothelial cell death, and thereby may play a role in myocardial inflammation and injury.
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PMID:Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. 1496 May 79

Our objective was to determine the effect of ovine interferon-tau (IFN-tau) on prolactin receptor (PRL-R) gene expression in the ovine endometrium. IFN-tau is an embryonic cytokine which, via its paracrine anti-luteolytic activity, plays a critical role in maternal recognition of pregnancy in ruminants. Using ribonuclease protection assay procedures, we compared endometrial PRL-R mRNA levels in ewes that were intrauterine injected with either 2 mg bovine serum albumin or 2 mg recombinant ovine IFN-tau on day 10 of the oestrous cycle (day 0 = day of oestrus). IFN treatment significantly increased the abundance of both the long and short forms of PRL-R mRNA in the ovine uterus, but had no effect on the long:short form ratio. In situ hybridization experiments revealed that the increase in abundance of PRL-R mRNA in the uterus was localized to the glandular compartment of the endometrium. In pregnant ewes, a similar increase in PRL-R mRNA abundance was found to occur in ovine endometrium on days 14-15 post conception. Collectively, these data provided strong evidence that IFN-tau modulates the level of lactogenic hormone receptor mRNA in the ovine uterus. Whether the effect of IFN-tau on PRL-R expression is mediated directly or influenced, at least in part, by progesterone remains to be elucidated.
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PMID:Interferon-tau upregulates prolactin receptor mRNA in the ovine endometrium during the peri-implantation period. 1523 67


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