Biomedical subjects

M L Sherman

Publications and source records attributed to M L Sherman.

At least 37 records · Page 2Linked to original sources

PubMed1992

Involvement of reactive oxygen intermediates in the induction of c-jun gene transcription by ionizing radiation.

Previous work has demonstrated that the cellular response to ionizing radiation includes transcriptional activation of the c-jun gene. The signaling events responsible for this response, however, remain unclear. The present studies have examined the effects of ionizing radiation on c-jun expression in a variant of HL-60 cells, designated HL-525, which is deficient in protein kinase C (PKC)-mediated signal transduction. The results demonstrate that these cells express low levels of PKC alpha and PKC beta transcripts and exhibit an attenuated induction of c-jun expression following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). In contrast, HL-525 cells respond to ionizing radiation with an increase in c-jun mRNA which is more pronounced than that in wild-type HL-60 cells. These cells similarly respond to ionizing radiation with increased expression of the jun-B, jun-D, c-fos, and fos-B genes. Nuclear run-on assays demonstrate that X-ray-induced c-jun expression in HL-525 cells is regulated by increases in the rate of c-jun gene transcription. Moreover, mRNA stability studies in irradiated HL-525 cells demonstrate that the half-life of c-jun transcripts is prolonged compared to that in wild-type cells. Studies with N-acetyl-L-cysteine (NAC), an antioxidant, suggest that X-ray-induced transcriptional activation of the c-jun gene is mediated at least in part through the formation of reactive oxygen intermediates (ROIs). In this context, H2O2 also induced c-jun expression in HL-525 cells, and this effect was inhibited by NAC.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Nucleus↗

PubMed1992

Transcriptional regulation of cytokine expression by diethyldithiocarbamate in human HL-60 promyelocytic leukemia cells.

Diethyldithiocarbamate (DDTC) is an investigational agent used to ameliorate chemotherapy- or radiotherapy-induced myelosuppression. We studied the effects of DDTC on the regulation of hematopoietic cytokine production in human myeloid cells. The results demonstrated that DDTC decreases proliferation of human HL-60 promyelocytic leukemia cells in a concentration-dependent manner. DDTC treatment also increased interleukin-alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor (TNF) expression in these cells. Similar findings were obtained in normal human peripheral blood monocytes. Peak induction of these cytokines occurred 6-12 hr after exposure to DDTC; levels returned to those in control cells by 24-48 hr in HL-60 cells. This effect was specific for IL-1 and TNF in that there was no detectable increase in IL-3, macrophage colony-stimulating factor or granulocyte/macrophage colony-stimulating factor RNA expression. Transcriptional run-on analysis demonstrated that exposure to DDTC increased the rate of TNF gene transcription in HL-60 cells. These data suggest that the myeloprotective effects of DDTC may be mediated, at least in part, by the induction of TNF, IL-1 alpha, and IL-1 beta.

Cytokines↗

PubMed1992

Functional expression of the macrophage colony-stimulating factor receptor in human THP-1 monocytic leukemia cells.

Macrophage colony-stimulating factor (M-CSF) is required for the proliferation, differentiation, and activation of monocytes. High-affinity receptors for M-CSF are encoded by the c-fms proto-oncogene. In the present study, we show that c-fms transcripts are detectable in human THP-1 myeloid leukemia cells. Furthermore, radiolabeled 125I-M-CSF is rapidly internalized into THP-1 cells and then degraded intracellularly. The results also show that treatment of THP-1 cells with M-CSF is associated with the activation of protein kinase C (PKC) and the induction of tumor necrosis factor (TNF) gene expression. TNF transcript levels were low to undetectable in uninduced THP-1 cells, reached maximal levels by 1 hour of exposure to M-CSF, and returned to those of control cells by 24 hours. Transcriptional run-on analysis showed that a low level of TNF transcription is detectable in untreated THP-1 cells, and M-CSF treatment increased the rate of TNF transcription. Pretreatment of THP-1 cells with pertussis toxin inhibited the increase in PKC activity but not the induction of TNF transcripts by M-CSF. Moreover, exposure of THP-1 cells to inhibitors of protein kinase activity blocked the increase in TNF messenger RNA. These findings suggest that at least two M-CSF-mediated signaling pathways exist in THP-1 cells and that the induction of TNF may be regulated by a protein kinase-dependent mechanism distinct from PKC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1992

Factors affecting the dose response to oxytocin for labor stimulation.

For nearly 40 years synthetic oxytocin has been used for labor stimulation by titrating dosage rate to uterine contractions. We used a computerized data base to determine variables affecting the dose response to oxytocin in 1773 pregnancies. Statistically important predictors of required oxytocin dosage included cervical dilatation, parity, and gestational age. Maternal body surface area was found to be associated with a higher oxytocin dosage in women undergoing induction of labor. However, the broad range of the statistical confidence intervals precluded prediction of a given pregnancy's oxytocin requirement.

Dose-Response Relationship, Drug↗

PubMed1992

Birth weight threshold for postponing preterm birth.

OBJECTIVE: The study was designed to determine the birth weight threshold at which obstetric efforts intended to delay delivery might potentially improve rates of neonatal morbidity and mortality among pregnancies delivered after spontaneous preterm labor or rupture of the membranes. STUDY DESIGN: We studied 1147 singleton infants with birth weights between 1000 and 2499 gm and whose only complication was spontaneous preterm labor or preterm rupture of the membranes. The Mantel-Haenszel chi 2 statistic was used to evaluate trends for neonatal mortality and several indexes of morbidity. RESULTS: The birth weight threshold for neonatal mortality was 1600 gm (p < 0.001). For neonatal morbidity the threshold was between 1600 and 1900 gm (p < 0.008). CONCLUSION: Aggressive obstetric attempts to prevent preterm birth for infants whose weights exceed 1900 gm offers few apparent potential benefits.

Birth Weight↗

PubMed1992

Maternal and perinatal effects of hypertension at term.

This study sought to determine if selected maternal and fetal outcomes in term singleton pregnancies complicated by hypertension during labor differed from those without this complication. All pregnancies delivered at Parkland Memorial Hospital, Dallas, Texas, during 1986 were ascertained using a computerized database. A total of 11,812 term singleton pregnancies ended in delivery during the study period; 1,392 (12%) were complicated by hypertension. Women with a total of 1,383 of these hypertensive pregnancies presented to the hospital with a live fetus. Hypertension was diagnosed in 984 (19%) of the 5,060 primiparous and 399 (6%) of the 6,752 parous women. Hypertension during labor in term singleton pregnancies is associated with increased maternal risks because of the potential complications associated with interventions necessary for successful management. Moreover, hypertension in such pregnancies also increases the perinatal mortality rate. However, this increased rate results from a higher likelihood that fetal death will occur prior to the patient's presentation to the hospital. The risk of fetal morbidity and mortality appears to be low in the hypertensive woman with a term pregnancy admitted to the hospital with a live fetus.

Cesarean Section↗

PubMed1992

Chorioamnionitis: a harbinger of dystocia.

The impact of chorioamnionitis on the course of labor is controversial. Some clinicians believe the infection has stimulatory effects, whereas others suspect inhibitory influences. Two hundred sixty-six pregnancies with chorioamnionitis requiring labor stimulation with oxytocin were matched to uninfected women for maternal age, race, parity, gestational age, oxytocin dosage regimen, indication for labor stimulation, type of labor stimulation, cervical dilatation at initiation of oxytocin, and time for rupture of membranes to initiation of labor stimulation. Chorioamnionitis diagnosed before oxytocin infusion was associated with shorter oxytocin initiation-to-delivery intervals (4.3 versus 5.6 hours; P = .04) and had no significant impact on the cesarean rate compared with matched controls. In contrast, pregnancies complicated by chorioamnionitis detected late in labor were associated with markedly longer oxytocin initiation-to-delivery intervals (12.6 versus 7.9 hours; P less than .0001) and a fourfold increase in cesarean for dystocia compared with matched controls (40 versus 10%; P less than .0001). Thus, the impact of chorioamnionitis on the course of labor can be divided into two clinical presentations. That diagnosed before labor stimulation does not increase the use of cesarean, whereas that diagnosed after oxytocin stimulation may be a sign of abnormal labor, as it was associated with a marked increase in abdominal delivery for dystocia.

Adult↗

PubMed1992

High- versus low-dose oxytocin for labor stimulation.

The number of cesarean births for dystocia has increased dramatically in the United States. Central to the management of dystocia is correction of ineffective labor by oxytocin administration, and contemporary obstetric practice is to stimulate labor with a low-dose oxytocin regimen. We prospectively compared a low-dose oxytocin regimen (1-mU/minute dosage increments) with a high-dose regimen (6-mU/minute dosage increments) in 2788 consecutive singleton cephalic pregnancies. The low-dose regimen was used first for 5 months in 1251 pregnancies, and the high-dose regimen in 1537 pregnancies during the subsequent 5 months. Indications for oxytocin stimulation were divided into augmentation (N = 1676) and induction (N = 1112). Labor stimulation was more than 3 hours shorter (P less than .0001) with the high-dose oxytocin regimen and associated with a reduction in neonatal sepsis (0.2 versus 1.3%; P less than .01). Uterine hyperstimulation was more common (55 versus 42%; P less than .0001) with the high-dose regimen, but no adverse fetal effects were observed. High-dose augmentation resulted in significantly fewer forceps deliveries (12 versus 16%; P = .03) and fewer cesareans for dystocia (9 versus 12%; P = .04). Similarly, failed induction was less frequent with high-dose compared with low-dose oxytocin (14 versus 19%; P = .05). Although the high-dose induction regimen was associated with a significantly increased cesarean incidence for fetal distress (6 versus 3%; P = .05), the incidence of umbilical artery cord blood acidemia was not increased in this subset. Induction of labor with high-dose oxytocin is problematic because of risk-benefit considerations. Although induction failed less frequently with the high-dose regimen, cesarean for fetal distress was performed more frequently. In contrast, high-dose oxytocin to augment ineffective spontaneous labor minimized the number of cesareans done for dystocia.

Adult↗

PubMed1992

Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis.

The infiltration of monocytes into the vascular wall and their transformation into lipid-laden foam cells characterizes early atherogenesis. Macrophages are also present in more advanced human atherosclerotic plaques and can produce many mediators that may contribute to lesion formation and progression. Macrophage colony-stimulating factor (MCSF) enhances the proliferation and differentiation of monocyte progenitors and is required for the survival and activation of mature monocytes and macrophages. The authors therefore examined the expression of the MCSF gene in cultured human vascular endothelial (EC) and smooth muscle cells (SMC) as well as in atheromatous lesions from rabbits and humans. Growth arrested EC and SMC contain a low level of MCSF mRNA. Bacterial lipopolysaccharide (LPS), recombinant human interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor alpha (TNF alpha) induced MCSF mRNA accumulation in a concentration-dependent manner in both EC and SMC. These stimuli induced large increases in MCSF mRNA with peak induction between 4-8 hours after treatment. LPS, IL-1 alpha, and TNF alpha stimulated EC and SMC also showed increased fluorescent antibody staining for MCSF protein and released immunoreactive MCSF in a time-dependent manner. In contrast, phorbol 12-myristate 13-acetate (PMA) was a less potent inducer of MCSF gene expression and iron-oxidized low-density lipoproteins (ox-LDL) did not increase consistently MCSF mRNA or the synthesis and secretion of immunoreactive protein. Northern analysis of mRNA isolated from the atheromatous aorta of rabbits fed a 1% cholesterol diet for 10 weeks showed elevated MCSF mRNA compared with controls. Immunostaining of atheromatous arterial lesions of rabbits demonstrated MCSF protein in association with intimal SMC as well as macrophages. Furthermore, polymerase chain reaction (PCR) analysis of MCSF mRNA in human atheromata showed higher levels than found in nonatherosclerotic arteries and veins. Since the authors found no mRNA for the MCSF receptor, c-fms, in cultured EC or SMC macrophages are likely the primary target for MCSF within atheromatous vessels. The authors therefore investigated the effects of MCSF on monocyte functions related to foam cell development. Treatment of cultured human monocytes with recombinant human MCSF (10(3) U/ml, 72 hr) led to the accumulation of mRNA for the acetyl-LDL (scavenger) receptor and apolipoprotein E (apo E). These studies establish that vascular EC and SMC produce substantial MCSF in response to a variety of stimuli. The local production of MCSF during atherogenesis may contribute to macrophage survival and proliferation or activate specific macrophage functions such as expression of the scavenger receptor and secretion of apo E.

Animals↗

PubMed1991

Inhibition of protein kinase C is associated with a decrease in c-myc expression in human myeloid leukemia cells.

Treatment of human myeloid leukemic cells with phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with activation and then partial down-regulation of protein kinase C activity. Previous work has suggested that the activation of protein kinase C by TPA contributes to the decrease in c-myc expression during differentiation of these cells. The present studies demonstrate that the decline in c-myc mRNA levels following exposure of HL-60 cells to TPA is preceded by an increase in expression of this gene. In contrast, exposure of HL-60 cells to inhibitors of protein kinase C activity is associated with down-modulation of c-myc expression. Similar findings have been obtained in U-937 myeloid leukemia cells. Taken together, these findings suggest that phorbol esters have a biphasic effect on c-myc expression. Whereas the activation of protein kinase C by phorbol esters may be associated with an increase in c-myc gene expression, the subsequent partial down-regulation of kinase activity may initiate a cascade of events resulting in the down-modulation of c-myc expression.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Tumor necrosis factor gene expression is mediated by protein kinase C following activation by ionizing radiation.

Tumor necrosis factor (TNF) production following X-irradiation has been implicated in the biological response to ionizing radiation. Protein kinase C (PKC) is suggested to participate in TNF transcriptional induction and X-ray-mediated gene expression. We therefore studied radiation-mediated TNF expression in HL-60 cells with diminished PKC activity produced by either pretreatment with protein kinase inhibitors or prolonged 12-O-tetradecanoylphorbol-13-acetate treatment. Both treatments resulted in attenuation of radiation-mediated TNF induction. Consistent with these results, we found no detectable induction of TNF expression following X-irradiation in the HL-60 variant deficient in PKC-mediated signal transduction. The rapid activation of PKC following gamma-irradiation was established using an in vitro assay measuring phosphorylation of a PKC specific substrate. A 4.5-fold increase in PKC activity occurred 15 to 30 s following irradiation, which declined to baseline at 60 s. Two-dimensional gel electrophoresis of phosphoproteins extracted from irradiated cells demonstrated in vivo phosphorylation of the PKC specific substrate Mr 80,000 protein at 45 s following X-irradiation. These findings indicate that signal transduction via the PKC pathway is required for the induction of TNF gene expression by ionizing radiation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Effects of hexamethylene bisacetamide on induction of monocytic differentiation of human U-937 myeloid leukemia cells.

The present studies have examined the effects of hexamethylene bisacetamide (HMBA) on the human U-937 monocytic cell line. HMBA treatment was associated with: (1) decreases in U-937 cell proliferation, (2) increases in nonspecific esterase activity and cell surface antigen expression consistent with monocytic differentiation, (3) decreases in c-myc gene expression, and (4) induction of tumor necrosis factor (TNF) transcripts. Treatment of U-937 cells with HMBA was also associated with increases in phospholipase A2 activity and increases in the release of arachidonic acid and its metabolites. Dexamethasone, an agent previously shown to inhibit monocytic differentiation, had no detectable effect on the down-regulation of c-myc, but blocked the induction of TNF expression. Taken together, the results demonstrate that HMBA induces monocytic differentiation of U-937 cells and that this effect is sensitive, in part, to dexamethasone.

Acetamides↗

PubMed1991

Regulation of jun-B expression by a cyclic AMP (cAMP)-dependent mechanism in human myeloid cells.

The present studies have examined the regulation of the jun-B early response gene by cyclic AMP (cAMP)-dependent signaling pathways. The 2.0-kb jun-B transcript was at low but detectable levels in uninduced human HL-60 myeloid leukemia cells. In contrast, treatment with 1 mmol/L8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP) in the presence of isobutylmethylxanthine, an inhibitor of cAMP-dependent phosphodiesterase, was associated with increases in jun-B transcripts that were maximal by 1 hour and then decreased to near pretreatment levels by 6 hours. Similar findings were obtained with 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPT-cAMP) and N6,2'-0-dibutyryladenosine 3',5'-cyclic monophosphate (dBt-cAMP). jun-B transcripts were also increased with other agents that increase intracellular cAMP levels, such as prostaglandin E2 (PGE2) and forskolin. Moreover, inhibition of cAMP-dependent protein kinase by the isoquinolinesulfonamide H-8 blocked 8-Br-cAMP-induced increases in jun-B expression. The results of nuclear run-on assays demonstrate that treatment of HL-60 cells with PGE2, forskolin, 8-Br-cAMP, and dBt-cAMP is associated with increases in the rate of jun-B transcription. The present findings also demonstrate that the related jun-D gene is similarly regulated by a cAMP-dependent pathway. Taken together, these findings suggest that stimulation of cAMP-dependent protein kinase is involved in the induction of jun gene expression in myeloid leukemia cells.

Bone Marrow↗

PubMed1991

Biological consequences of gene regulation after ionizing radiation exposure.

Ionizing radiation is a ubiquitous environmental mutagen and carcinogen widely used in cancer therapy. However, little is known about the induction of cellular signaling events and specific gene expression after radiation exposure. We review the accumulating evidence that ionizing radiation induces signal transduction pathways involving activation of protein kinase C and a program of genetic events that may contribute to the biological effects of x rays.

Base Sequence↗

PubMed1991

Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and JUN.

The cellular response to ionizing radiation includes growth arrest and DNA repair followed by proliferation. Induction of immediate early response genes may participate in signal transduction preceding these phenotypic responses. We analyzed mRNA expression for different classes of immediate early genes (JUN, EGR1, and FOS) after cellular x-irradiation. Increased expression of the EGR1 and JUN genes was observed within 0.5-3 hr following x-ray exposure. Preincubation with cycloheximide was associated with superinduction of JUN and EGR1 in x-irradiated cells. Inhibition of protein kinase C activity by prolonged stimulation with phorbol 12-myristate 13-acetate or the protein kinase inhibitor H7 prior to irradiation attenuated the increase in EGR1 and JUN transcripts. FOS expression was not coregulated with that of EGR1 following x-irradiation, suggesting a distinct regulatory pathway of this gene as compared with its regulation following serum and phorbol ester. These data implicate the EGR1 and JUN proteins as signal transducers during the cellular response to radiation injury and suggest that this effect is mediated in part by a protein kinase C-dependent pathway.

Cell Line↗

PubMed1991

Mechanisms of X-ray-mediated protooncogene c-jun expression in radiation-induced human sarcoma cell lines.

c-jun is a protooncogene associated with neoplastic transformation and is transcriptionally induced by ionizing radiation. To examine the possible mechanisms of radiation-induced c-jun transcription, we analyzed RNA from human tumor cell lines RIT-3 and STSAR-5 following x-irradiation in the presence of protein kinase inhibitors, or the absence of serum and calcium. Protooncogene c-jun expression increased several fold following irradiation of these radiation-induced human sarcoma cell lines. The expression of c-jun was not altered following irradiation in conditioned medium containing serum as compared to that of cells in serum free medium. Depletion of PKC by prolonged TPA treatment resulted in inhibition of c-jun expression. In addition, nonspecific protein kinase inhibitors, staurosporin and H7 attenuated c-jun expression, whereas the analogue of ATP (sangivamycin) did not. Furthermore, the selective inhibitor of cAMP dependent protein kinase HA 1004 did not alter radiation-mediated c-jun induction. These data indicate that ionizing radiation exposure results in c-jun induction which is dependent upon the activation of PKC. Protein kinase C activation and the subsequent expression of the protooncogene c-jun by ionizing radiation may further define the molecular mechanisms of radiation-induced neoplastic transformation.

Enzyme Activation↗

PubMed1991

Regulation of tumor necrosis factor gene expression by ionizing radiation in human myeloid leukemia cells and peripheral blood monocytes.

Previous studies have demonstrated that ionizing radiation induces the expression of certain cytokines, such as TNF alpha/cachectin. However, there is presently no available information regarding the molecular mechanisms responsible for the regulation of cytokine gene expression by ionizing radiation. In this report, we describe the regulation of the TNF gene by ionizing radiation in human myeloid leukemia cells. The increase in TNF transcripts by x rays was both time- and dose-dependent as determined by Northern blot analysis. Similar findings were obtained in human peripheral blood monocytes. Transcriptional run-on analyses have demonstrated that ionizing radiation stimulates the rate of TNF gene transcription. Furthermore, induction of TNF mRNA was increased in the absence of protein synthesis. In contrast, ionizing radiation had little effect on the half-life of TNF transcripts. These findings indicate that the increase in TNF mRNA observed after irradiation is regulated by transcriptional mechanisms and suggest that production of this cytokine by myeloid cells may play a role in the pathophysiologic effects of ionizing radiation.

Cell Line↗

PubMed1991

Ionizing radiation induces expression and binding activity of the nuclear factor kappa B.

Recent studies have demonstrated that treatment of mammalian cells with ionizing radiation is associated with activation of gene expression. Although the signal transduction pathways stimulated by ionizing radiation remain unclear, our previous findings indicate that radiation induces specific genes at the transcriptional level. The present work has examined the effects of ionizing radiation on the transcription factor NF-kappa B. The results demonstrate that ionizing radiation activates DNA binding of nuclear factor (NF)kappa B. This effect was detectable at 2 grays (Gy) and reached a maximum at 5-20 Gy. At a dose of 20 Gy, the increase in NF-kappa B binding activity was maximal at 2-4 h and then declined to pretreatment levels. The results also demonstrate that ionizing radiation transiently increases NF-kappa B mRNA levels. However, the finding that induction of NF-kappa B binding to DNA occurs in the presence of cycloheximide indicates that ionizing radiation activates preexisting NF-kappa B protein. NF-kappa B exists as a cytoplasmic protein before activation. Thus, our results suggest that ionizing radiation induces transduction pathways which include cytoplasmic signaling events.

Base Sequence↗