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Biomedical subjects

M Brook

Publications and source records attributed to M Brook.

At least 19 recordsLinked to original sources
PubMed2001

Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38.

The stability of cyclooxygenase 2 (Cox-2) mRNA is regulated positively by proinflammatory stimuli acting through mitogen-activated protein kinase (MAPK) p38 and negatively by anti-inflammatory glucocorticoids such as dexamethasone. A tetracycline-regulated reporter system was used to investigate mechanisms of regulation of Cox-2 mRNA stability. Dexamethasone was found to destabilize beta-globin-Cox-2 reporter mRNAs by inhibiting p38. This inhibition occurred at the level of p38 itself: stabilization of reporter mRNA by a kinase upstream of p38 was blocked by dexamethasone, while stabilization by a kinase downstream of p38 was insensitive to dexamethasone. Inhibition of p38 activity by dexamethasone was observed in a variety of cell types treated with different activating stimuli. Furthermore, inhibition of p38 was antagonized by the anti-glucocorticoid RU486 and was delayed and actinomycin D sensitive, suggesting that ongoing glucocorticoid receptor-dependent transcription is required.

3' Untranslated Regions↗
PubMed2001

Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability.

Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-alpha) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-alpha mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-alpha 3' untranslated region. The p38 pathway is required for the induction of TNF-alpha RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-alpha gene expression at a posttranscriptional level.

3' Untranslated Regions↗
PubMed2000

Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade.

The translation of tumour necrosis factor alpha (TNFalpha) mRNA is regulated by the stress-activated protein kinase p38, which also controls the stability of several pro-inflammatory mRNAs. The regulation of TNFalpha gene expression in a mouse macrophage cell line RAW264.7 was re-examined using an inhibitor of stress-activated protein kinases. Stimulation of these cells with bacterial lipopolysaccharide resulted in stabilisation of TNFalpha mRNA, which was reversed by specific inhibition of p38. An adenosine/uridine-rich element from the TNFalpha 3' untranslated region conferred p38-sensitive decay in a tetracycline-regulated mRNA stability assay. Therefore the p38 pathway also controls TNFalpha mRNA turnover.

3' Untranslated Regions↗
PubMed1999

p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes.

p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown that the pyridinyl imidazole SB 203580, which inhibits it, blocks the interleukin-1 induction of cyclooxygenase-2 (COX-2) and matrix metalloproteinase 1 and 3 mRNAs in fibroblasts. Here we explore the role of p38 MAPK in the response of human monocytes to LPS. 0.1 microM SB 203580 significantly inhibited the LPS induction of COX-2 and tumor necrosis factor protein and mRNAs. The activity of MAPK-activated protein kinase-2 (a substrate of p38 MAPK) in the cells was commensurately reduced. Some isoforms of c-jun N-terminal kinase (which is also activated by LPS) are sensitive to SB 203580; the inhibitor had little effect on monocyte c-jun N-terminal kinases up to 2 microM. We investigated the mechanism of inhibition of COX-2 induction. Transcription (measured by a nuclear run-on assay) was 60% inhibited by SB 203580 (2 microM). Importantly, we found that p38 MAPK was essential for stabilizing COX-2 mRNA: when cells stimulated for 4 h with LPS were treated with actinomycin D, COX-2 mRNA decayed slowly. Treatment of stimulated cells with 2 microM SB 203580 caused a rapid disappearance of COX-2 mRNA, even with actinomycin D present. We conclude p38 MAPK plays a role in the transcription and stabilization of COX-2 mRNA.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1998

A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA.

The mechanism by which p38 mitogen-activated protein kinase (MAPK) regulates the induction of cyclooxygenase (COX)-2 by interleukin-1 (IL-1) has been investigated in HeLa cells. SB 203580, an inhibitor of p38 MAPK, in the range 0.1-1 microM inhibited IL-1-stimulated PGE2 (but not arachidonic acid) release and this was associated with inhibition of induction of COX-2 protein and mRNA. IL-1 stimulated COX-2 transcription in HeLa cells about 2-fold as judged by both reporter gene and nuclear run-on assays. The inhibitor had no significant effect on this. However, in cells previously stimulated with IL-1 it caused rapid destabilisation of COX-2 mRNA independently of on-going transcription. The results suggest a novel function for p38 MAPK in the regulation of mRNA stability.

Arachidonic Acids↗
PubMed1998

The effects of inhaled nitric oxide on postoperative pulmonary hypertension in infants and children undergoing surgical repair of congenital heart disease.

UNLABELLED: The role of inhaled nitric oxide in the immediate post-bypass period after surgical repair of congenital heart disease is uncertain. In a controlled, randomized, double-blind study, we tested the hypothesis that inhaled nitric oxide (NO) would reduce pulmonary hypertension immediately after surgical repair of congenital heart disease in 40 patients with preoperative evidence of pulmonary hypertension (mean pulmonary arterial pressure [MPAP] exceeding 50% of mean systemic arterial pressure [MSAP]). Patients were then followed in the intensive care unit (ICU) to document the incidence of severe pulmonary hypertension. Of the patients, 36% (n = 13) emerged from bypass with MPAP > 50% MSAP. In these patients, inhaled NO reduced MPAP by 19% (P = 0.008) versus an increase of 9% in the placebo group. No effect on MPAP was observed in patients emerging from bypass without pulmonary hypertension (n = 23). Inhaled NO was required five times in the ICU, always in the patients who had emerged from cardiopulmonary bypass with pulmonary hypertension (5 of 13 [38%] versus 0 of 23). We conclude that, in infants and children undergoing congenital heart surgery, inhaled NO selectively reduces MPAP in patients who emerge from cardiopulmonary bypass with pulmonary hypertension and has no effect on those who emerge without it. IMPLICATIONS: In a randomized double-blind study, inhaled nitric oxide selectively reduced pulmonary artery pressures in pediatric patients who developed pulmonary hypertension (high blood pressure in the lungs) immediately after cardiopulmonary bypass and surgical repair.

Administration, Inhalation↗
PubMed1995

Factors determining reopening of the ductus arteriosus after successful clinical closure with indomethacin.

OBJECTIVE: To examine the role of ductus arteriosus (DA) constriction and loss of luminal blood flow in producing permanent closure of the DA in human infants. METHODS: We studied 77 newborn infants (gestational age, 23 to 33 weeks) with asymptomatic patent ductus arteriosus (PDA), who had "complete clinical closure" (defined as the disappearance of all PDA signs) after treatment with indomethacin (three doses within 36 hours). All infants had an echocardiogram 24 to 36 hours after the last dose of indomethacin. They were then followed for the development of ductus reopening. RESULTS: Despite the absence of clinical signs, 18 (23%) of 77 infants still had some residual luminal blood flow according to their echocardiograms. The failure to obliterate luminal blood flow completely was directly related to the infant's postnatal age when treatment was begun and to the amount of fluid administered before treatment. Subsequently the DA reopened in 16 (21%) of 77 infants. As predicted, infants with residual luminal blood flow after indomethacin treatment had a higher rate of subsequent clinical reopening than did those with no luminal flow. In addition, immature infants had a significantly higher reopening rate than did more mature infants. The increased risk of reopening in immature infants was seen even when indomethacin caused complete obliteration of ductus luminal blood flow. CONCLUSION: The DA of immature infants is resistant to the constriction-induced ischemic damage that is necessary for subsequent permanent closure of the vessel.

Ductus Arteriosus↗
PubMed1990

Pay equity.

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Female↗
PubMed1989

Students' preferences for male or female counselors for social and educational problems.

Fifty-eight male and 66 female junior high school students were examined to determine their preferences for sex of counselor under personal/social and educational hypothetical counseling situations. Girls demonstrated a definite same-sex preference for both counseling situations, while boys preferred male counselors for personal/social counseling and had opposite-sex preferences for educational counseling. Implications of the findings are discussed in light of earlier contradictory results from research on college students.

Achievement↗
PubMed1969

Vitamin C supplementation in the elderly: a 17-month trial in an old persons' home.

Seventeen months' supplementation of the diet with vitamin C in elderly residents in an old persons' home failed to show any changes in sublingual lesions, which on histological examination proved to be aneurysmal dilatations of the venules. Nine months' supplementation of 40 to 80 mg. daily of vitamin C was necessary before the white-cell vitamin levels reached that found in younger people. There was a marked individual variation in response.

Aged↗