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Biomedical subjects

F Reichsman

Publications and source records attributed to F Reichsman.

14 recordsLinked to original sources
PubMed2000

Secreted frizzled-related protein-1 binds directly to Wingless and is a biphasic modulator of Wnt signaling.

Secreted Frizzled-related protein-1 (sFRP-1) contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzleds. To facilitate the biochemical and biological analysis of sFRP-1, we developed a mammalian recombinant expression system that yields approximately 3 mg of purified protein/liter of conditioned medium. Using this recombinant protein, we demonstrated that sFRP-1 and Wg (wingless) interact in enzyme-linked immunosorbent and co-precipitation assays. Surprisingly, a derivative lacking the cysteine-rich domain retained the ability to bind Wg. Cross-linking experiments performed with radioiodinated sFRP-1 provided definitive evidence that sFRP-1 and Wg bind directly to each other. Besides detecting a cross-linked complex consistent in size with 1:1 stoichiometry of sFRP-1 and Wg, we also observed a larger complex whose size suggested the presence of a second sFRP-1 molecule. The formation of both complexes was markedly enhanced by an optimal concentration of exogenous heparin, emphasizing the potential importance of heparan-sulfate proteoglycan in Wnt binding and signaling. sFRP-1 exerted a biphasic effect on Wg activity in an armadillo stabilization assay, increasing armadillo level at low concentrations but reducing it at higher concentrations. These results provide new insights about the Wnt binding and biological activity of sFRPs.

Animals↗
PubMed2000

Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice.

Syndecan-1 is a cell-surface, heparan-sulphate proteoglycan (HSPG) predominantly expressed by epithelial cells. It binds specifically to many proteins, including oncoproteins. For example, it induces the assembly of a signalling complex between FGF ligands and their cognate receptors. But so far there has been no direct evidence that this proteoglycan contributes to tumorigenesis. Here we have examined the role of syndecan-1 (encoded by Sdc1) during mammary tumour formation in response to the ectopic expression of the proto-oncogene Wnt1. We crossed syndecan-1-deficient mice with transgenic mice that express Wnt1 in mammary gland (TgN(Wnt-1)1Hev; ref. 2). Ectopic Wnt-1 expression induces generalized mammary hyperplasia, followed by the development of solitary tumours (median time 22 weeks). We show that in Sdc1-/- mice, Wnt-1-induced hyperplasia in virgin mammary gland was reduced by 70%, indicating that the Wnt-1 signalling pathway was inhibited. Of the 39 tumours that developed in a test cohort of mice, only 1 evolved in the Sdc1-/- background. In addition, we show that soluble syndecan-1 ectodomain purified from mouse mammary epithelial cells stimulates the activity of a Wnt-1 homologue in a tissue culture assay. Our results provide both genetic and biochemical evidence that syndecan-1 can modulate Wnt signalling, and is critical for Wnt-1-induced tumorigenesis of the mouse mammary gland.

Animals↗
PubMed1996

Glycosaminoglycans can modulate extracellular localization of the wingless protein and promote signal transduction.

Wingless, the Drosophila homologue of the proto-oncogene Wnt-1, encodes a secreted glycoprotein that regulates differentiation and proliferation of nearby cells. Here we report on the biochemical mechanism(s) by which the wingless signal is transmitted from cell to cell. When expressed in S2 cells, the majority (approximately 83%) of secreted wingless protein (WG) is bound to the cell surface and extracellular matrix through specific, noncovalent interactions. The tethered WG can be released by addition of exogenous heparan sulfate and chondroitin sulfate glycosaminoglycans. WG also binds directly to heparin agarose beads with high affinity. These data suggest that WG can bind to the cell surface via naturally occurring sulfated proteoglycans. Two lines of evidence indicate that extracellular glycosaminoglycans on the receiving cells also play a functional role in WG signaling. First, treatment of WG-responsive cells with glycosaminoglycan lyases reduced WG activity by 50%. Second, when WG-responsive cells were preincubated with 1 mM chlorate, which blocks sulfation, WG activity was inhibited to near-basal levels. Addition of exogenous heparin to the chlorate-treated cells was able to restore WG activity. Based on these results, we propose that WG belongs to the group of growth factor ligands whose actions are mediated by extracellular proteoglycan molecules.

Animals↗
PubMed1995

Two distinct ATP receptors activate calcium entry and internal calcium release in bovine chromaffin cells.

ATP, an established neurotransmitter, causes elevation of cytosolic Ca2+ and catecholamine secretion when applied to chromaffin cells in the intact adrenal gland. The ATP-induced rise in Ca2+ is due both to release from internal stores and to entry across the plasma membrane. The latter source of Ca2+ causes secretion; the primary role of Ca2+ released from internal stores remains undetermined. In this article, we have studied the nucleotide specificity for activating the two types of Ca2+ increases. The agonist potency order for the increase in fluorescence from fura-2-loaded chromaffin cells due to release of Ca2+ from internal stores is ATP = UTP > ADP > 2-methylthio-ATP, alpha, beta-methylene ATP, identifying the receptor as a P2u purinoceptor. The potency order for secretion is 2-methylthio-ATP > ATP > alpha, beta-methylene ATP, ADP, UTP, placing the receptor in the P2Y subtype. Thus, two distinct receptors are responsible for Ca2+ release and secretion. Agonists were more effective in the absence of extracellular Mg2+, suggesting that ATP uncomplexed with divalent cations binds preferentially to both receptors. The low response of both receptors to ADP distinguishes them from the ATP receptor on these cells that inhibits voltage-dependent Ca2+ current and secretion.

Adenosine Diphosphate↗
PubMed1991

Muscle protein changes following eccentric exercise in humans.

This study characterized changes in the protein composition of human muscle tissue after eccentric exercise. Four subjects performed 70 maximum eccentric, isokinetic actions of the forearm flexors with one arm. The other arm served as control. A biopsy of the biceps muscle of each arm was taken 2 days after exercise when muscles were very sore (mean = 8.0; 1 = normal; 10 = very, very sore), and muscle damage was documented by a mean decrease of 0.2 radians in the relaxed elbow angle. Proteins from the biopsy tissue were solubilized in a high ionic strength buffer containing several proteolytic inhibitors. Protein concentrations of the extracts were determined and identical amounts loaded onto sodium dodecyl sulfate (SDS) polyacrylamide gels (7.5, 12.5, and 17.5%). Densitometric analysis of the Coomassie brilliant blue stained gels revealed alterations in the amounts of three protein bands in the exercised tissue relative to the control. These changes were in the linear portion of the graph of absorbance versus protein amount. Wilcoxon's signed rank test showed the first two of the following bands to increase significantly in amount (P less than 0.062). The average percentage changes [mean (SEM)] for these bands were 63 (21), 39 (5), and 82 (35). The corresponding molecular weights determined from known standards were 76300 (860), 33200 (310), and 12000 (80) daltons, respectively. These changes imply that the increased synthesis, decreased degradation, or some combination thereof, of these three proteins may be necessary for the repair or regeneration response to exercise-induced muscle damage.

Arm↗
PubMed1990

The effect of ethanol on exercise-induced muscle damage.

The effect of ethanol ingestion on exercise-induced muscle damage was examined. It has been reported that a reduced leakage of muscle proteins was found when alcohol was ingested prior to exercise. The results of that study were confounded by repeating the same exercise using the same muscle groups; the alcohol treatment was always given on the second exercise bout so that the reduced protein leakage may be due to a rapid training effect. The present study was designed to control for rapid training effect when examining the effects of ethanol ingestion on exercise-induced protein leakage from muscle. Also, this study examined the effect of acute ethanol ingestion on other indicators of muscle damage: force generation, muscle stiffness and muscle soreness. Ten women subjects performed two similar exercise regimens, one with each arm, separated by at least 10 days. Alcohol was ingested prior to exercising one arm and a nonalcoholic beverage ingested prior to exercising the contralateral arm. The exercises resulted in increased serum creatine kinase activity (p less than .05) and muscle pain (p less than .01), and decreased range of motion (p less than .01) and strength (p less than .01), indicating muscle damage. There was no significant difference between the alcohol and nonalcohol conditions for any criterion measure. It was concluded that acute ingestion of alcohol has no effect on several indicators of exercise-induced muscle damage.

Adult↗
PubMed1988

Effects of shoe type on cardiorespiratory responses and rearfoot motion during treadmill running.

Running kinematics and physiological responses to high intensity submaximal treadmill running in training shoes and racing flats were evaluated. Eight women (mean age = 21.9 yr) completed a peak VO2 test on the treadmill (mean peak VO2 = 49.2 ml.kg-1.min-1). In two subsequent testing sessions, subjects completed 15-min runs at a speed corresponding to 90% of peak VO2 (range = 9.9-13.4 km.hr-1) while wearing training shoes and racing flats (balanced order assignment). No significant time effect or time by shoe condition interaction was observed for the rearfoot motion variables. Maximum rearfoot angle and total rearfoot motion averaged 42% and 13.9% higher, respectively, for the racing flat (P less than 0.05). There were significant increases over time for VO2, VE, HR, and RPE, indicating an increase in cardiorespiratory response and the perception of effort over the course of the 15-min run. Thus, metabolic and perceptual indications of fatigue at the end of the run emerged but were not accompanied by rearfoot motion changes in either running shoe. These results indicate that rearfoot motion is a function of shoe design and did not change during 15 min of high intensity running.

Adult↗
PubMed1975

Teaching psychosomatic medicine to medical students, residents and postgraduate fellows.

The teaching objectives of a psychosomatic program are discussed--in particular, to teach skills and methods of observation; to help students to acquire information about mind-body relationships in health and disease; to help future practitioners develop the capacity for clinical reasoning which includes psychological and social considerations; to effect modifications in attitudes and behavior towards patients and their families; and to present to students the model of a physician who has a major interest and considerable competence in two areas of medicine--the psychosocial and the physical-physiologic-biochemical. A description of the general organization of the liaison service is presented, and the specific aspect of teaching programs for medical students, medical interns and residents, psychiatric residents, and liaison fellows are outlined. Implications for the future of liaison teaching are mentioned.

Curriculum↗