Biomedical subjects

A Raz

Publications and source records attributed to A Raz.

At least 37 records · Page 2Linked to original sources

PubMed2001

On the role of cell surface carbohydrates and their binding proteins (lectins) in tumor metastasis.

This review focuses on the recent advances in investigations of the role of cell surface carbohydrates in tumor metastasis. It also summarizes the results of extensive studies of endogenous lectins, their structure, carbohydrate specificity and biological functions with the major emphasis on the significance of lectin-cell surface carbohydrate interactions in a metastatic process. Numerous data demonstrate that malignant transformation is associated with various and complex alterations in the glycosylation process. Some of these changes might provide a selective advantage for tumor cells during their progression to more invasive and metastatic phenotype. Cell glycosylation depends on the expression and function of various glycosyltransferases and glycosidases. Recently, transfection of genes encoding various glysosyltransferases gene in sense and antisense orientation helped to bring direct evidence that changes in cell surface carbohydrates are important for the metastatic behavior of tumor cells. Cell surface carbohydrates affect tumor cell interactions with normal cells or with the extracellular matrix during metastatic spread and growth. These interactions can be mediated via tumor cell carbohydrates and their binding proteins known as endogenous lectins. The family of the discovered endogenous lectins is rapidly expanding. The number of C-type lectins has reached 50 and at least 10 galectins have been identified. The biological significance of the endogenous lectins and their possible role in tumor growth and metastasis formation has started to unravel. Some lectins recognize the 'foreign' patterns of cell surface carbohydrates expressed by microorganisms and tumor cells, and play a role in innate and adaptive immunity. It was shown that lectins affect tumor cell survival, adhesion to the endothelium or extracellular matrix, as well as tumor vascularization and other processes that are crucial for metastatic spread and growth.

Animals↗

PubMed2001

Congenital short-bowel and malrotation: clinical presentation and outcome of six affected offspring in three related families.

Newborns with congenital short small bowel associated with malrotation and intestinal dysmotility have a uniformly bad prognosis. However, few long-term survivors have been reported, suggesting that the disorder is not invariably fatal. The majority of cases previously reported were familial. We report on six affected siblings in three related families. The aim of this report is to assess the mode of inheritance, the expression of this disorder, and to point to the correlation between the onset of gastrointestinal symptoms and the outcome.

Adolescent↗

PubMed2001

Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis.

Inhibition of lipid peroxidation contributes to the attenuation of macrophage cholesterol accumulation, foam-cell formation and atherosclerosis. Evidence suggests that nutritional antioxidants such as pomegranate juice (PJ) can contribute to the reduction of oxidative stress and atherogenesis. The goals of the present study were to determine whether such beneficial effects of PJ exist when supplemented to apolipoprotein E-deficient (E(0)) mice with advanced atherosclerosis and to analyze the antiatherosclerotic activity of a tannin-fraction isolated from PJ. Mice (4-mo-old) were supplemented with PJ in their drinking water for 2 mo and compared with age-matched placebo-treated mice, as well as to young (4-mo-old) control mice, for their mouse peritoneal macrophage (MPM) oxidative state, cholesterol flux and mice atherosclerotic lesion size. PJ supplementation reduced each of the proatherogenic variables determined in the present study compared with age-matched placebo-treated mice. It significantly induced serum paraoxonase activity and reduced MPM lipid peroxide content compared with placebo-treated mice and control mice. PJ administration to E(0) mice significantly reduced the oxidized (Ox)-LDL MPM uptake by 31% and MPM cholesterol esterification and increased macrophage cholesterol efflux by 39% compared with age-matched, placebo-treated mice. PJ consumption reduced macrophage Ox-LDL uptake and cholesterol esterification to levels lower than those in 4-mo-old, unsupplemented controls. PJ supplementation to E(0) mice with advanced atherosclerosis reduced the lesion size by 17% compared with placebo-treated mice. In a separate study, supplementation of young (2-mo-old) E(0) mice for 2 mo with a tannin fraction isolated from PJ reduced their atherosclerotic lesion size, paralleled by reduced plasma lipid peroxidation and decreased Ox-LDL MPM uptake. PJ supplementation to mice with advanced atherosclerosis reduced their macrophage oxidative stress, their macrophage cholesterol flux and even attenuated the development of atherosclerosis. Moreover, a tannin-fraction isolated from PJ had a significant antiatherosclerotic activity.

Animals↗

PubMed2001

A case report of olanzapine-induced hypersensitivity syndrome.

Hypersensitivity syndrome is defined as a drug-induced complex of symptoms consisting of fever, rash, and internal organ involvement. The hypersensitivity syndrome is well recognized as being caused by anticonvulsants. Olanzapine is an atypical antipsychotic agent whose side effects include sedation, weight gain, and increased creatinine kinase and transaminase levels. To date, there have been no reports of hypersensitivity syndrome related to this drug. A 34-year-old man developed a severe generalized pruritic skin eruption, fever, eosinophilia, and toxic hepatitis 60 days after ingestion of olanzapine. After termination of olanzapine treatment, the fever resolved, the skin rash was reduced, eosinophil count was reduced to normal, and the transaminase levels were markedly reduced. Clinical features and the results of skin and liver biopsies indicated that the patient developed hypersensitivity syndrome caused by olanzapine.

Adult↗

PubMed2001

Galectin-3 maintains the transformed phenotype of thyroid papillary carcinoma cells.

Galectin-3, a beta-galactoside-binding protein, is highly expressed in thyroid papillary carcinomas, while functional relevance of galectin-3 overexpression to the malignant phenotype remains elusive. In the present study we transfected galectin-3 antisense cDNA into the human thyroid papillary carcinoma cell line NPA which expresses an innately high level of galectin-3, and examined the effect of antisense inhibition of galectin-3 expression on the transformed phenotype. There was no difference in anchorage-dependent growth between the antisense clones and either the control or parental clones. In contrast, anchorage-independent growth and saturation density of the antisense clones were significantly suppressed compared to those of either the control or parental clones. These results demonstrate that overexpression of galectin-3 in thyroid papillary carcinoma cells is necessary for the maintenance of transformed phenotype, and suggest galectin-3 as a potential target for therapeutic interventions in the future.

Antigens, Differentiation↗

PubMed2001

Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells.

Galectin-3 is an endogenous beta-galactoside-binding protein with specificity for type I and II ABH blood group epitopes and poly-N-acetyllactosamine glycan-containing cell surface glycoproteins and is the major nonintegrin cellular laminin-binding protein. Galectin-3 is expressed at an elevated level in a wide range of neoplasms, and expression was shown to be associated in some tumor cell systems with metastases. Here we determined the functional consequence of blocking galectin-3 expression in highly malignant human breast carcinoma MDA-MB-435 cells. Inhibition of galectin-3 expression led to reversion of the transformed phenotype as determined by altered morphology, loss of serum-independent growth, acquisition of growth inhibition properties by cell contact, and abrogation of anchorage-independent growth. The blockage of galectin-3 expression led to a significant suppression of tumor growth in nude mice. These results provide direct evidence that galectin-3 expression is necessary for the maintenance of the transformed and tumorigenic phenotype of MDA-MB-435 breast carcinoma cells.

Animals↗

PubMed2001

Is pre-attentive processing compromised by prolonged wakefulness? Effects of total sleep deprivation on the mismatch negativity.

We investigated the potential influence of sustained wakefulness on pre-attentive capacities by recording the mismatch negativity (MMN), an electrophysiological manifestation associated with nonintentional detection of auditory oddball stimuli. The MMN was elicited by pitch deviants presented to both ears via earphones, at the beginning of a total sleep deprivation session (baseline), after 24 hr, and after 36 hr of continuous controlled wakefulness. A conspicuous MMN response was elicited at all three sessions. With time, however, a small yet significant gradual reduction in the MMN amplitude was evident. Whereas previous research suggested that controlled attention-demanding tasks are hampered by sleep deprivation, the balance of the present results suggests that passive (total) sleep deprivation may also bring about some degradation in the pre-attentive detection of environmental irregularities and as a consequence may disrupt the reflexive shift of attention induced by such events.

Acoustic Stimulation↗

PubMed2000

Phosphorylation of the beta-galactoside-binding protein galectin-3 modulates binding to its ligands.

The beta-galactoside-binding protein galectin-3 has pleiotropic biological functions and has been implicated in cell growth, differentiation, adhesion, RNA processing, apoptosis, and malignant transformation. Galectin-3 may be phosphorylated at N-terminal Ser(6), but the role of phosphorylation in determining interactions of this endogenous lectin with its ligands remains to be elucidated. We therefore studied the effect of phosphorylation on binding of galectin-3 to two of its reported ligands, laminin and purified colon cancer mucin. Human recombinant galectin-3 was phosphorylated in vitro by casein kinase I, and separated from the native species by isoelectric focusing for use in solid phase binding assays. Non-phosphorylated galectin-3 bound to laminin and asialomucin in a dose-dependent manner with half-maximal binding at 1.5 microg/ml. Phosphorylation reduced saturation binding to each ligand by >85%. Ligand binding could be fully restored by dephosphorylation with protein phosphatase type 1. Mutation of galectin-3 at Ser(6) (Ser to Glu) did not alter galectin ligand binding. Metabolic labeling or separation by isoelectric focusing confirmed the presence of phosphorylated galectin-3 species in vivo in the cytosol of human colon cancer cells from which ligand mucin was purified. Phosphorylation significantly reduces the interaction of galectin-3 with its ligands. The process by which phosphorylation modulates protein-carbohydrate interactions has important implications for understanding the biological functions of this protein, and may serve as an "on/off" switch for its sugar binding capabilities.

Antigens, Differentiation↗

PubMed2000

Firing patterns and correlations of spontaneous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine vervet model of parkinsonism.

To investigate the role of the basal ganglia in parkinsonian tremor, we recorded hand tremor and simultaneous activity of several neurons in the external and internal segments of the globus pallidus (GPe and GPi) in two vervet monkeys, before and after systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and development of parkinsonism with tremor of 5 and 11 Hz. In healthy monkeys, only 11% (20/174) of the GPe cells and 3% (1/29) of the GPi cells displayed significant 3-19 Hz oscillations. After MPTP treatment, 39% (107/271) of the GPe cells and 43% (26/61) of the GPi cells developed significant oscillations. Oscillation frequencies of single cells after MPTP treatment were bimodally distributed around 7 and 13 Hz. For 10% of the oscillatory cells that were recorded during tremor periods, there was a significant tendency for the tremor and neuronal oscillations to appear simultaneously. Cross-correlation analysis revealed a very low level of correlated activity between pallidal neurons in the normal state; 95.6% (477/499) of the pairs were not correlated, and oscillatory cross-correlograms were found in only 1% (5/499) of the pairs. After MPTP treatment, the correlations increased dramatically, and 40% (432/1080) of the cross-correlograms had significant oscillations, centered around 13-14 Hz. Phase shifts of the cross-correlograms of GPe pairs, but not of GPi, were clustered around 0 degrees. The results illustrate that MPTP treatment changes the pattern of activity and synchronization in the GPe and GPi. These changes are related to the symptoms of Parkinson's disease and especially to the parkinsonian tremor.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2000

Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein.

Phosphohexose isomerase (PHI) is a member of the ectoenzyme/exoenzyme family and plays a key role in both glycolysis and gluconeogenesis pathways. Upon secretion PHI acts as a cytokine with tumor autocrine motility factor (AMF), neuroleukin (NLK) and maturation factor (MF) functions. Signaling is initiated by its binding to a cell surface 78 kDa glycoprotein (gp78). However, since PHI protein is a 'leaderless' secretory protein, released from cells via a non-classical route(s), we questioned whether the molecule undergoes post-translation modification while retaining proper folding and maintaining intact enzymatic and motogenic activities. To address this, we have generated, expressed and isolated a recombinant human AMF (rhAMF). The rhAMF retained the biological activities of the native AMF, i.e., catalyzes phosphohexose isomerization and stimulated cell motility. Additionally, we show here that human PHI is phosphorylated at serine 185 by casein kinase II (CK II) and we provide experimental evidence suggesting that this phosphorylation is associated with secretion, thus providing insights for elucidating the intracellular signal transmission of cell response to stimulation by AMF/NLK/MF.

Amino Acid Sequence↗

PubMed2000

Decreased galectin-3 expression in prostate cancer.

BACKGROUND: Galectin-3 is a carbohydrate-binding protein whose level of expression has been shown to be correlated with metastatic potential in a number of different tumor types. The purpose of this investigation was to examine galectin-3 expression in several tumorigenic and nontumorigenic prostate cell lines and prostate tissue samples. METHODS: The expression of galectin-3 in cell lines and tissue samples was evaluated by tissue immunohistochemistry and Western blot analysis. RESULTS: Human cell lines PC-3M, PC-3, DU-145, PrEC-1, and MCF10A demonstrated the presence of galectin-3. Galectin-3 was not detected in TSU-pr1 and LNCaP by Western blot analysis. We furthered our studies by examining a series of human prostate tissue samples for expression of galectin-3. Overall, approximately 60-70% of the normal tissue examined demonstrated heterogenous expression of galectin-3. In stage II tumors, however, there was a dramatic decrease in galectin-3 expression in both PIN and tumor sections, with only 10.5% (2/19) of these samples expressing this protein. Stage III tumors also demonstrated a decreased expression of galectin-3, although this downregulation was not as dramatic, with 35% of PIN samples and 52% of tumor tissue expressing galectin-3 (P < 0.01). CONCLUSIONS: These data demonstrate that galectin-3 is downregulated in prostate cancer. The altered downregulation pattern of galectin-3 observed between tumor stages suggests different roles for galectin-3 in the progression of prostate cancer.

Antigens, Differentiation↗

PubMed2000

Expression of autocrine motility factor/phosphohexose isomerase in Cos7 cells.

Autocrine motility factor (AMF) is identical to the glycolytic enzyme phosphohexose isomerase (PHI) and overexpression of AMF/PHI is associated with tumor malignancy. In order to study the overexpression of AMF/PHI, an HA-tagged AMF construct was transiently transfected into Cos7 cells. Expression of a tagged AMF-HA allowed us to determine that over a period of 16 hours only a small amount (0.1-1%) of total cellular AMF-HA was secreted into the cell medium. Cell-associated AMF-HA was exclusively cytosolic as it could be completely extracted with Triton X-100 and concentrated within actin rich pseudopodial domains. Treatment of the cells with the glycolysis inhibitor oxamate disrupted the association of AMF-HA with actin concentrations demonstrating that glycolysis regulates the formation of these AMF/PHI-associated actin-rich protrusions. AMF/PHI is a well-characterized tumor cell secreted cytokine and we identify here an alternate intracellular function for this glycolytic enzyme/cytokine in cell motility.

Actins↗

PubMed2000

Electrospray/tandem mass spectrometry for quantitative analysis of lipid remodeling in essential fatty acid deficient mice.

A method utilizing electrospray ionization coupled with tandem mass spectrometry was developed as a facile and rapid method to identify and quantify lipid remodeling in vivo. Electrospray/tandem mass spectrometric analyses were performed on lipids isolated from liver tissue and resident peritoneal cells from essential fatty acid sufficient and deficient mice. Essential fatty acid deficiency was chosen as the paradigm to evaluate the methodology because it epitomizes the most extreme dietary means of altering fatty acid composition of virtually all cellular lipid species. Qualitative and quantitative changes were measured in the phospholipid and cholesterol ester species directly in the chloroform/methanol lipid extract without any prior chromatographic separation. Lipid remodeling in liver and peritoneal cells from essential fatty acid deficient mice was qualitatively similar in cholesterol ester, phosphatidylcholine, and phosphatidylethanolamine. The monoenoic fatty acids palmitoleic acid (16:1 n-7) and oleic acid (18:1 n-9) were increased markedly, whereas all n-6 and n-3 polyunsaturated fatty acids were nearly depleted in phospholipid and cholesterol ester species. The n-9 polyunsaturated fatty acid surrogate, Mead acid (20:3 n-9), substituted for arachidonic acid (20:4 n-6) and docosahexaenoic acid (22:6 n-3) in phospholipid, but not in cholesterol ester, species. Another notable difference was that adrenic acid (22:4 n-6) and docosapentaenoic acid (22:5 n-6), both metabolites of arachidonic acid, accumulated in phospholipid and cholesterol ester species of peritoneal cells, but not in liver cells, of essential fatty acid sufficient mice. The overall body of data presented illustrates the implementation of electrospray/tandem mass spectrometry as a method for facile and direct quantification of changes in lipid species during lipid metabolic studies.

Animals↗

PubMed2000

Acute local inflammation potentiates tumor growth in mice.

Chronic inflammation in humans has been implicated in the pathogenesis of several types of cancer. In animals, experimentally-induced tumor growth was found to be enhanced at sites of injury. However, a direct demonstration in vivo that an inflammatory agent applied locally at the tumor site can promote a switch into a highly proliferative state of tumor growth, has not yet been documented. The present work was designed to test, in a syngeneic primary tumor model in mice, whether a commonly used inflammatory agent, carrageenan, could cause acceleration of tumor growth and to investigate the cellular mechanisms mediating such a process. Local injection of carrageenan into a tissue site containing tumor cells produced an accelerated rate of tumor growth at that site which was characterized by a decreased percentage of apoptotic cells and an increased proportion of cells at the S and G2/M phases of the cell cycle. The pro-tumorigenic effect of carrageenan is dose-dependent and can be exerted at any time throughout the course of the tumor growth. Furthermore, the effect is prostaglandin-mediated since the cyclooxygenase inhibitor indomethacin totally abrogated it. Experiments with tumors cells in culture have shown that carrageenan actually inhibits cell proliferation as well as increases apoptosis. Thus, the tumor promoting effects of carrageenan in vivo appear to arise not from a direct effect on the tumor cells per se but rather through induction of host-dependent humoral/cellular responses that generate increased levels of prostanoids and pro-inflammatory cytokines that accelerate tumor growth. These data demonstrate for the first time that an acute, local inflammatory stimuli can induce accelerated tumor growth at the affected site and provide further support for a mechanism-based, anti-tumorigenic action of anti-inflammatory drugs.

Animals↗

PubMed2000

Heregulin regulation of autocrine motility factor expression in human tumor cells.

The exposure of cells to growth factors has been shown to induce cytoskeleton reorganization, leading to stimulation of cell motility and invasion. Heregulin beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 and human epidermal growth factor receptor 4 receptors, is a regulatory secretory polypeptide with a distinctive function in promoting motility and invasiveness of breast cancer cells. In addition to HRG, motility and invasiveness of tumor cells may also involve up-regulation of expression and function of the autocrine motility factor (AMF). Here we explored the possible involvement of AMF in the motility-promoting action of HRG in the MCF-7 breast cancer cell model system. We report that HRG increases the expression of AMF mRNA by 3-8-fold in an actinomycin D-sensitive manner and does not require de novo protein synthesis. The HRG-induced stimulation of AMF expression was inhibited by specific inhibitors of p42/44MAPK and p38MAPK kinases, but not by an inhibitor of the phosphatidylinositol 3'-kinase pathway. Other HRG-responsive human cell lines demonstrated that HRG does indeed significantly up-regulate AMF expression. Furthermore, HRG-stimulated increased motility was partially suppressed by inclusion of an anti-AMF antibody to breast cancer cells, suggesting that a HRG-mediated increase in cell motility may be mediated, at least in part, via induction of AMF. The present study is the first demonstration of AMF regulation by a growth factor and suggests a potential role for AMF in HRG regulation of breast cancer cell motility and a novel function of HRG as a regulator of motility factor expression.

Actins↗

PubMed2000

Galectin-3 induces endothelial cell morphogenesis and angiogenesis.

Increasing evidence suggests that carbohydrate-binding proteins play an essential role in tumor growth and metastasis. However, conflicting results on their function in the regulation of cell proliferation and differentiation during angiogenesis have been reported. We have examined the role of galectin-3 in the regulation of human umbilical vein endothelial cell proliferation, differentiation, migration, and neovascularization. Galectin-3, a carbohydrate-binding protein, with specificity for type 1 and 11 ABH blood group epitopes and polylactosamine glycan containing cell surface glycoproteins, is the major nonintegrin cellular laminin-binding protein. Because galectin-3 expression was shown to be associated in some tumor systems with metastasis, we questioned whether it induces endothelial cell morphogenesis. Here we show that galectin-3 affects chemotaxis and morphology and stimulates capillary tube formation of HUV-EC-C in vitro and angiogenesis in vivo. Endothelial cell morphogenesis is a carbohydrate-dependent process, as it is neutralized by specific sugars and antibodies. These findings demonstrate that endothelial cell surface carbohydrate recognition event(s) can induce a signaling cascade leading to the differentiation and angiogenesis of endothelial cells.

Animals↗

PubMed2000

Carbohydrate-recognition and angiogenesis.

Angiogenesis is required for the continual growth of the tumor and provides a gateway for cells to escape the confines of the primary tumor. Angiogenic stimulus triggers a cascade of functional responses leading to local basement membrane dissolution, endothelial cell migration, proliferation and microvessel morphogenesis. In this commentary, we review the significance of carbohydrate-binding proteins involved in angiogenesis. The importance of carbohydrate-recognition processes to angiogenesis stems from the observation that angiogenic factors like fibroblast growth factor family and vascular endothelial growth factors bind initially to the extracellular matrix proteoglycans before binding to their cognate receptors, and some of the adhesion molecules bind to glycoconjugates present on the surface of the endothelial cells. The possible significance of these interactions will be discussed.

Animals↗

PubMed2000

Intensity effect of active recovery from glycolytic exercise on decreasing blood lactate concentration in prepubertal children.

PURPOSE: Children's performance after intense exercise is known to recover faster than that of adults. However, very little is known about the physiological processes that differentiate children from adults in their recovery. The purpose of this study was to compare, in children, the decrease in blood lactate concentration ([La]) during various intensities of active recovery from highly intense exercise with that during passive recovery. METHODS: Subjects were 15 healthy, physically active, prepubertal, 9- to 11-yr-old boys (N = 8) and girls (N = 7). Subjects performed three 40-s cycling bouts at 150% peak oxygen consumption (VO2peak), with two 50-s rest intervals, followed by 2 min of passive recovery and 23 min of one of four randomly-assigned recovery levels: passive and 40%, 50%, and 60% VO2peak (RP, R40, R50, and R60, respectively). RESULTS: Mean values of peak [La] (by treatment) ranged between 9.9 +/- 1.5 and 10.8 +/- 2.0. Whereas HR and VO2 remained relatively higher, [La] decreased faster during all active recoveries compared with the passive mode. [La] during R60 was higher compared with [La] during R40. [La] was slightly higher in the first 10 min of R40 compared with R50, whereas from the 15th min onward, this difference was reversed. A similar pattern was seen in the boys and girls, separately. The calculated half-life of [La] was significantly higher during the passive compared with all three active recoveries, with no differences among the latter (22.0 +/- 5.0, 10.3 +/- 1.9, 10.5 +/- 2.2, and 11.5 +/- 2.1 min during RP, R40, R50, and R60, respectively). CONCLUSIONS: In summary, similar to the case in adults, the decrease in [La] after intense exercise in children is faster during active recovery compared with the passive mode. Further research is required to determine whether performance recovery parallels that of [La] in children and adults of both genders.

Age Factors↗