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Biomedical subjects

E Rubin

Publications and source records attributed to E Rubin.

At least 127 records · Page 7Linked to original sources
PubMed1991

Chronic ethanol ingestion modifies liver microsomal phosphatidylserine inducing resistance to hydrolysis by exogenous phospholipase A2.

Chronic ethanol ingestion leads to the acquisition of a tolerance to membrane lipid disordering, a lowered partition coefficient to hydrophobic compounds and a resistance to the hydrolysis of the phospholipids by exogenous phospholipase A2. Anionic phospholipids have been implicated as being responsible for the resistance to lipid disordering and a number of modifications to these phospholipids are known to occur as a result of chronic ethanol-ingestion. In this study the basis of the resistance to phospholipase A2 in hepatic microsomes was investigated. It was found that chronic ethanol-induced modifications to each of the major phospholipid classes was responsible to some extent for the resistance to phospholipase A2, however, PS was particularly potent considering it is a compositionally minor constituent. The effect was interpreted as a reduced ability to activate the phospholipase A2 since PS acts as an essential activator of phospholipase A2 (along with PI). Fatty acid analysis revealed that the chronic ethanol-treatment resulted in a elevated level of docosahexaenoate with a parallel reduction in arachidonate in phosphatidylserine. Lipid packing and organization is important in the regulating the level of exogenous phospholipase A2 activity but the activity was not found to correlate with lipid order of different phosphatidylserine species. It is concluded that subtle differences in the molecular species arrangement or disposition around the enzyme may be responsible for the altered phospholipase A2 interaction with the membrane induced by chronic ethanol-treatment. One implication of this study is that other anionic phospholipid dependent membrane proteins, of which there are many known examples, may also be modified as a result of chronic ethanol-ingestion.

Alcoholism↗
PubMed1991

Maintenance of structural and functional characteristics of skeletal-muscle mitochondria and sarcoplasmic-reticular membranes after chronic ethanol treatment.

The effect of long-term ethanol intake on the structural and functional characteristics of rat skeletal-muscle mitochondria and sarcoplasmic reticulum was investigated. Functionally, skeletal-muscle mitochondria were characterized by a high respiratory control index and ADP/O ratio and a high State-3 respiration rate with different substrates. These parameters were not significantly different in preparations from control and ethanol-fed rats, except for a small increase in the rate of oxidation of alpha-oxoglutarate/malate in the latter. In submitochondrial particles from the two groups of animals there was no significant difference in cytochrome content, ATPase activity or the activity of respiratory-chain complexes. Mitochondrial membranes from untreated and ethanol-fed rats showed no difference in the baseline e.s.r. order parameter, and both preparations were equally sensitive to disordering by ethanol in vitro. Similarly, sarcoplasmic-reticulum preparations were not significantly affected by long-term ethanol feeding with respect to Ca2(+)-ATPase activity or in baseline order parameter and susceptibility to membrane disordering by ethanol in vitro. These membranes were also equally sensitive to degradation by exogenous phospholipase A2. Ethanol feeding did not alter the class composition of mitochondrial or sarcoplasmic-reticulum membrane phospholipids, nor the acyl composition of individual phospholipid classes. Specifically, the changes in acyl composition that characteristically occur in liver microsomal phosphatidylinositol and liver mitochondrial cardiolipin were not observed in the corresponding phospholipids from skeletal-muscle membranes. In experiments where membrane preparations from liver and skeletal muscle from the same ethanol-fed animals were compared, the liver membranes developed membrane tolerance, with the muscle membranes retaining normal sensitivity to disordering effects by ethanol. It is concluded that: (a) different tissues from the same animals differ in their susceptibility to ethanol; (b) the tissue-specific lack of development of membrane tolerance correlates with a lack of chemical changes in the phospholipids and with a retention of normal function of mitochondria and sarcoplasmic reticulum; (c) effects of chronic ethanol intake on muscle function are not due to a defect in the mitochondrial energy supply.

Adenosine Triphosphatases↗
PubMed1991

The effect of chronic ethanol consumption on the fatty acid composition of phosphatidylinositol in rat liver microsomes as determined by gas chromatography and 1H-NMR.

Cell membranes and vesicles composed of extracted phospholipids isolated from rats chronically-fed ethanol develop a resistance to disordering by ethanol in vitro (membrane tolerance) and a decreased partitioning of ethanol into the membranes. The anionic lipid phosphatidylinositol (PtdIns) is the only microsomal phospholipid from the ethanol-fed rats that confers tolerance to vesicles of microsomal phospholipids from control rats in a paradigm where phospholipid classes are sequentially swapped. To investigate the molecular basis of this adaptation, the fatty acid content of microsomal PtdIns extracted from the livers of rats chronically fed ethanol for 5 weeks and their calorically-matched controls was analyzed by gas-liquid chromatography (GLC) and 1H-NMR spectroscopy. Chronic ethanol consumption caused an 8.4% decrease in arachidonic acid [20:4(n - 6)], a 20.0% increase in oleic acid [18: 1(n - 9)] and a 47.1% increase in the quantitatively minor fatty acid [20:3(n - 6)]. 1H-NMR was used to quantitatively assay compositional changes in the delta 5 olefinic moiety of the acyl chains in PtdIns, an approach that should be broadly applicable to other lipid systems. After chronic ethanol feeding PtdIns had decreased delta 5 unsaturates (-7.9% NMR, -8.2% GLC) and a corresponding increase in delta 5 saturates (+5.4% NMR, +5.3% GLC). In the other phospholipids, chronic ethanol feeding caused alterations in the fatty acid compositions specific for each phospholipid. PtdIns was the only microsomal phospholipid that exhibited a significant decrease in both the polyunsaturate pool and the ratio of the total olefinic content to the saturated fatty acid content. The major adaptive response in rat liver microsomal PtdIns to chronic ethanol administration involves a decrease in arachidonic acid [20:4 (n - 6)], which is partly compensated for by increases in oleic acid [18:1(n - 9)] and eicosatrienoic acid [20:3 (n - 6)], resulting in a depressed unsaturation and polyunsaturation index. The decreased unsaturation at the delta 5 position may have special functional relevance, due to the proximity of this position to the membrane surface, where ethanol is believed to reside. Whether these acyl changes are merely coincident with, or causative of, membrane tolerance requires further elucidation.

Alcoholism↗
PubMed1991

Linkage analysis of low-density lipoprotein subclass phenotypes and the apolipoprotein B gene.

A common heritable phenotype has recently been identified which is characterized by a relative abundance of small, dense low-density lipoproteins (LDL), and mild elevations of plasma triglycerides and reductions in plasma high-density lipoproteins (HDL) cholesterol. This phenotype, designated LDL subclass phenotype B, has been associated with up to a three-fold increase in coronary disease risk. Complex segregation analysis in two large family studies has demonstrated that LDL subclass phenotype B is influenced by an allele at a single genetic locus with a population frequency of 0.25-0.3, and autosomal dominant inheritance, but with full penetrance only in males age 20 and over and in postmenopausal women. Since apolipoprotein B (apoB) is the principal protein component of LDL, linkage analysis was used to investigate possible linkage between the phenotype B phenotype and the apoB gene, using a variable number of tandem repeats site located 0.5 kb from the 3' end of the apoB gene. In 6 informative families including only family members in the penetrant classes, a total LOD score of -7.49 was found at a recombination fraction of 0.001. Thus, under the assumptions of the single gene model, it is unlikely that the apoB locus controls LDL subclass phenotype B.

Adult↗
PubMed1991

Inhibition by cocaine of excitation-contraction coupling in isolated cardiomyocytes.

The effects of cocaine on the Ca2+ fluxes responsible for excitation-contraction coupling were studied in isolated ventricular rat heart cells loaded with the fluorescent Ca2+ indicator fura-2. Ca2+ transients in response to electrical field stimulation were followed using a fluorescence ratio method in which excitation light was alternated with 5-ms resolution. The cardiomyocytes maintained a basal cytosolic Ca2+ concentration of approximately 70 nM, which increased to a peak of 450 nM in response to each electrical stimulus. The addition of cocaine (10 microM) to cells stimulated at 0.4 Hz decreased the magnitude of the electrically induced Ca2+ transients by 30 +/- 4% within 5 s. This inhibitory effect of cocaine was dose dependent, with a 50% reduction in the Ca2+ transient occurring at 40 microM cocaine. The effects of cocaine were not associated with any permanent cell damage and could be reversed by washing the cells free of the drug. Cytosolic Ca2+ increases in response to K(+)-induced depolarization of the cardiomyocytes were much less sensitive to cocaine than the electrically induced Ca2+ transients. In this respect the effects of cocaine were similar to the actions of lidocaine and tetrodotoxin but distinct from the effects of nitrendipine and verapamil. Cocaine had no effect on the caffeine-releasable Ca2+ pool in cardiomyocytes. These data demonstrate that cocaine directly inhibits the Ca2(+)-dependent steps of excitation-contraction coupling in heart muscle cells. Sarcolemmal Na+ channels represent a possible locus for this action of cocaine.

Animals↗
PubMed1991

The role of anionic phospholipids in membrane adaptation to ethanol.

In rats chronically fed-ethanol, liver microsomes and mitochondria, brain synaptosomes and reconstituted vesicles of their respective membrane phospholipids are resistant to disordering by ethanol in vitro (membrane tolerance) after 35 days of ethanol exposure. (Taraschi et al, 1986a; Rottenberg et al, 1981). Specific phospholipids from ethanol-fed rats, i.e. phosphatidylinositol (PI) from liver microsomes, cardiolipin (CL) from hepatic mitochondria and phosphatidylserine (PS) from brain synaptosomes confer tolerance to reconstituted vesicles of membrane phospholipids from control rats. In liver microsomes, PI was the only lipid that exhibited a significant decrease in both the polyunsaturate pool and the ratio of the total olefinic content to the saturated fatty acid content. The fatty acid composition of cardiolipin was perturbed by chronic ethanol administration as evidenced by a significant increase in oleic acid (18:1) and a significant decrease in linoleic acid (18:2). These alterations produced a more saturated cardiolipin with a decreased (4.4%) unsaturation index (UI) and a 60% reduction in the UI/saturated fatty acid index. These fatty acid modifications, which arise in response to long term ethanol ingestion, represent an adaptive shift in lipid metabolic pathways that do not appear to be (solely) responsible for membrane tolerance.

Alcoholism↗
PubMed1991

Activation of the c-jun protooncogene in human myeloid leukemia cells treated with etoposide.

The epipodophyllotoxin etoposide is an inhibitor of topoisomerase II. The effects of this agent on gene expression, particularly the transcriptional induction of genes implicated in growth control, are unknown. The present results demonstrate that etoposide induces expression of the c-jun protooncogene in HL-60 myeloid leukemia cells. This induction of c-jun expression was maximal at 3 hr and was transient. Similar findings were obtained in the human U-937 myeloid leukemia cell line. Nuclear run-on assays demonstrated that the induction of c-jun expression by etoposide is regulated at the transcriptional level. The results further demonstrate that etoposide-induced c-jun expression occurs in association with the appearance of c-fos transcripts. Moreover, the c-jun gene is induced by etoposide during periods of oligonucleosomal DNA cleavage, which is characteristic of programmed cell death. These findings suggest that transcriptional induction of c-jun expression represents a signaling pathway activated in the cellular response to etoposide-induced DNA damage.

DNA Damage↗
PubMed1990

Phospholipase C activation by ethanol in rat hepatocytes is unaffected by chronic ethanol feeding.

The activation of phosphoinositide-specific phospholipase C by ethanol was compared in hepatocytes isolated from ethanol-fed rats and from pair-fed control animals. Ethanol (100-300 mM) caused a dose-dependent transient increase in cytosolic free Ca2+ levels in indo-1-loaded hepatocytes from both groups of animals. The rate of Ca2+ increase was similar in hepatocytes from control and ethanol-fed rats, but the decay of the Ca2+ increase was somewhat slower in the latter preparation. The ethanol-induced Ca2+ increase caused activation of glycogen phosphorylase, with 50% response at 50 mM-ethanol and a maximal response at 150-200 mM-ethanol, not significantly different in hepatocytes from control and ethanol-fed animals. Ins(1,4,5)P3 formation in response to ethanol (300 mM) or vasopressin (2 nM or 40 nM) was also similar in the two preparations. It is concluded that long-term ethanol feeding does not lead to an adaptive response with respect to the ethanol-induced phospholipase C activation in rat hepatocytes. The ability of ethanol in vitro to decrease membrane molecular order in liver plasma membranes from ethanol-fed and control rats was measured by e.s.r. Membranes from ethanol-fed animals had a significantly lower baseline order parameter compared with control preparations (0.313 and 0.327 respectively), indicative of decreased membrane molecular order. Addition of 100 mM-ethanol significantly decreased the order parameter in control preparations by 2.1%, but had no effect on the order parameter of plasma membranes from ethanol-fed rats, indicating that the plasma membranes had developed tolerance to ethanol, similar to other membranes in the liver. Thus the membrane structural changes associated with this membrane tolerance do not modify the ethanol-induced activation of phospholipase C. The transient activation of phospholipase C by ethanol in hepatocytes may play a role in maintaining an adaptive phenotype in rat liver.

Alcoholism↗
PubMed1990

Ethanol withdrawal stimulates protein synthesis in rat pancreatic lobules.

Recent studies from our laboratory (Ponnappa et al. (1988) Biochim. Biophys. Acta 966, 390-402), indicate that in the pancreas of rats fed ethanol chronically, an overnight withdrawal of ethanol stimulated the rate of protein synthesis in vivo, whereas, during continuous ethanol ingestion, the rate of protein synthesis was the same as in the control group which did not receive ethanol. However, a stimulation of protein synthesis was also observed when isolated acini were prepared from the pancreas of continuously ethanol-fed rats. In the present studies, preparations of pancreatic lobules were used to further characterize the stimulatory effect observed in the ethanol-fed group. The rate of protein synthesis was studied in vitro by determining the rate of incorporation of [3H]leucine into proteins. Similar to in vivo observations, chronic ethanol feeding did not alter the rate of protein synthesis, but an overnight withdrawal of ethanol stimulated the rate of protein synthesis by 84%. The stimulation of protein synthesis reflected a general enhancement in the rate of synthesis of most of the digestive enzymes ranging from 60 to 110%. The maximal stimulation of protein synthesis occurred within 24 h of ethanol withdrawal and the rates rapidly decreased to control levels within 3 days. During the overnight ethanol withdrawal there was also a 30-40% decrease in the activities of most of the pancreatic digestive enzymes. This observation indicates that ethanol withdrawal also initiated the secretion and/or degradation of pancreatic digestive enzymes in vivo. The observation that the enhanced rate of protein synthesis can be observed in isolated acini but not in vivo or in lobular preparations from the continuously ethanol-fed rats indicates that the pancreas contains factors which supress this stimulatory effect of ethanol intake. The stimulation of protein synthesis, brought about either by ethanol withdrawal or by collagenase digestion of the tissue, may reflect the removal of such factors.

Alcoholism↗
PubMed1990

1H NMR dipolar echo decay spectroscopy: a sensitive probe of membrane structure.

The structural and motional properties of membrane lipids in various physical states and macroscopic organizations are elucidated by 1H NMR dipolar echo decay spectroscopy (DECODE). Multilamellar lipid dispersions in the gel (L beta') and liquid-crystalline (L alpha) states and a nonbilayer, hexagonal (HII) phase are readily distinguished, a dynamic profile within these phases is identified, and dipolar order parameters are obtained in the fluid phases. The method is suitable for any pulsed NMR spectrometer. DECODE provides the first depth-dependent assay of lipid order that does not rely on isotopic labeling or exogenous probe.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1990

The role of membrane skeletal-associated alpha-globin in the pathophysiology of beta-thalassemia.

The beta-thalassemic mouse provides a useful model for testing hypotheses about the pathophysiology in human beta-thalassemia. The clinical picture of these mice and their red blood cell deformability characteristics are quite similar to those observed in human beta-thalassemia intermedia. The creation of transgenic mice that express human beta-globin (beta s) has provided an opportunity to study the effect of increasing the non-alpha-globin chain production on the thalassemic phenotype. A small increase in beta-globin production produces transgenic mice that are healthier, have almost normal hemoglobin values, and whose red blood cell deformability is increased. We quantified and characterized the membrane skeletal-associated globin in normal, transgenic thal/sickle, and thalassemic mice and showed that only alpha-globin was associated with the membrane skeleton in the pathologic red blood cells, and that the degree of rigidity as measured in the rheoscope correlated directly and closely with the amount of membrane skeletal-associated globin in these abnormal red blood cells.

Alpha-Globulins↗
PubMed1990

Rats withdrawn from ethanol rapidly re-acquire membrane tolerance after resumption of ethanol feeding.

The time course for the re-acquisition of membrane tolerance to the disordering effects of ethanol in vitro has been determined for liver microsomes obtained from chronically ethanol-fed rats that were withdrawn from ethanol for 2-4 days (during which tolerance is lost) followed by resumption of ethanol feeding. Naive rats require 28-35 days of chronic ethanol feeding to develop membrane tolerance. Microsomal membranes regain partial sensitivity to ethanol disordering after 2-3 days of withdrawal and regain the complete sensitivity observed in membranes from untreated control rats after 4 days of withdrawal. The period of ethanol re-feeding required for the re-acquisition of membrane tolerance was dependent on the withdrawal period, with tolerance appearing sooner if the withdrawal period was shorter. The time course for the re-development of tolerance in previously tolerant animals was considerably faster (4-14 days) than in naive rats being administered the ethanol diet for the first time (35 days). Microsomes from rats that were withdrawn for 2 days (which retained partial tolerance) and then re-fed the ethanolic-diet required only 4 days to re-acquire membrane tolerance. Microsomes from rats withdrawn 3 days required 8 days and those withdrawn 4 days required 15 days for full tolerance to re-develop. The same time-course for the re-acquisition of membrane tolerance was observed in either intact microsomes or in liposomes prepared from extracted microsomal total phospholipids. Phosphatidylinositol (PI) has previously been reported to be responsible for conferring membrane tolerance to liver microsomes in ethanol-fed rats (Taraschi, T.F., Ellingson, J.S., Wu, A., Zimmerman, R. and Rubin, E. (1986) Proc. Natl. Acad. Sci. USA 83, 9398-9402). The time course for re-acquisition of membrane tolerance by liver microsomes following ethanol withdrawal and resumption of ethanol feeding correlated with the ability of PI to confer tolerance.

Animals↗
PubMed1990

Environmental diseases of the digestive system.

Environmental factors are important mediators of many diseases of the digestive system, defined as the alimentary tract and the accessory organs of digestion, the liver and pancreas. In this review, we principally focus on the action of chemical agents which are classified as (1) naturally occurring compounds, (2) occupational hazards, (3) therapeutic drugs, and (4) constituents of substances of abuse. In addition, the putative role of dietary habits in the pathogenesis of malignant diseases of the digestive system is discussed.

Alcohol Drinking↗
PubMed1990

Alcohol and membrane-associated signal transduction.

In recent years, ethanol has been shown to interact with membrane-associated signal transduction mechanisms which rely on the reaction of phospholipases with their phospholipid substrates in the membrane. In several cell and membrane preparations, ethanol activates the polyphosphoinositide-specific phospholipase C and triggers the complete battery of intracellular signalling responses that are characteristic for hormones acting through this pathway, including the formation of inositol-1,4,5-trisphosphate, the release of Ca2+ from intracellular storage sites with the consequent activation of cytosolic Ca2(+)-dependent enzymes, and the formation of diacylglycerol leading to the stimulation of protein kinase C. The activation of phospholipase C appears to be due to an interaction of ethanol with the intramembrane complex of receptor-G-protein-phospholipase C, presumably promoting the release of bound GDP and the binding of GTP to activate the G-protein which controls phospholipase C activity. In many intact cells, the phospholipase C is subject to a feedback inhibitory control by protein kinase C. In liver cells, ethanol also triggers this feedback inhibition, leading to a rapid decline in the phospholipase C activation; at the same time, ethanol also causes the desensitization of the response to vasopressin and other phospholipase C-linked agonists. At hormone concentrations in the physiological range, the heterologous desensitization by ethanol of the agonist-mediated phospholipase C activation may be a significant factor at ethanol concentrations that are readily attained in vivo. Further interaction of ethanol with the intracellular second messenger system is mediated through a hormone-sensitive phospholipase D. This enzyme uses phosphatidylcholine to generate phosphatidic acid which can be further converted to diacylglycerol. In the presence of ethanol the enzyme catalyzes the transphosphatidylation to phosphatidylethanol. It is not clear, however, under what conditions this process could affect the normal pattern of formation of second messenger molecules. After chronic ethanol intake, a tolerance can develop at the cellular level to the effects of ethanol on agonist-induced signal transduction processes. However, the mechanism by which this tolerance develops is currently a matter of conjecture. Studies on liver cells indicate that the activity of protein kinase C may play a role in the development of this type of tolerance to ethanol. A better understanding of the interaction of ethanol with these phospholipid-dependent signal transduction processes could point to mechanisms by which ethanol could interfere with physiological control mechanism in a variety of cells and tissues.

Alcoholism↗
PubMed1990

Patient-initiated mobile mammography: analysis of the patients and the problems.

Patient initiation of mammographic screening is one method of increasing compliance with screening mammography guidelines. A low-cost screening project using a mobile van was developed at the University of Alabama at Birmingham. Analysis of the first 2,099 patients revealed that the participants were generally white (92%), more likely to have had a previous mammogram than the norm (33% in this study vs 19% in a 1986 Gallup survey), and relatively high-risk (30% having a breast cancer risk factor). The cancer detection rate was 6.2 per 1,000 women screened, with a biopsy rate of 1.3% and a positive predictive value of 48%. More than half the cancers detected were in situ lesions or invasive carcinomas smaller than 1 cm. Our results suggest that low-cost mobile mammographic screening can operate at appropriate levels of sensitivity and specificity and is well accepted by participants. Such projects require considerable preliminary planning, significant financial and time commitment by the physicians involved, and meticulous follow-up. A mammography management software system was developed to facilitate tracking of patients for routine and diagnostic follow-up studies and rapid communication of results. Although most follow-up studies and biopsies were done in the community, resistance in the medical community was significant and is perhaps the greatest impediment to such screening endeavors.

Adult↗
PubMed1990

Cutaneous angiosarcoma of the breast 7 years after lumpectomy and radiation therapy.

A case of angiosarcoma of the skin of the breast is described in a woman 7 years after a primary breast carcinoma was treated by means of lumpectomy and irradiation. On mammograms, the angiosarcoma showed redevelopment of skin thickening and increase in breast density. Clinically, the skin showed patchy discoloration. Although there is an established association of angiosarcoma with lymphedema and therapeutic irradiation, there have been few other reports of this rare complication of local therapy for breast carcinoma. Recognition of the mammographic and clinical manifestations may help in the earlier diagnosis of additional cases.

Breast Neoplasms↗