Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we showed that starvation of HL-60 promyelocytic leukemia cells for a single essential amino acid induced irreversible differentiation into more mature monocyte-like cells. Although not an essential amino acid, glutamine is important in the growth of normal and neoplastic cells. The glutamine analogue, alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) inhibits several glutamine-utilizing enzymes and therefore depletes cells of certain metabolic end products. The current study was designed to examine in vitro the effects of acivicin on growth and differentiation of several established human myeloid leukemia cell lines, including the HL-60 cell line, and of freshly isolated cells from patients with acute nonlymphocytic leukemia (ANLL). Four-day culture of HL-60 cells with acivicin at concentrations of 0.1 to 10.0 micrograms/mL (0.56 to 56 nmol/L) decreased cell growth by 33% to 88% as compared with untreated control cells. Viability of cells was greater than 92% for untreated cells and 93% to 41% for acivicin-treated cells. Cells treated with acivicin differentiated along a monocytic pathway as shown by increased H2O2 production and alpha-naphthyl butyrate esterase (NSE) content. Differentiation was time and dose dependent, and was irreversible. Changes in H2O2 production and NSE content were partially abrogated by co-culture with 10 mmol/L exogenous cytidine and guanosine but not by co-culture with other nucleosides or glutamine. At these concentrations of acivicin, differentiation was associated with expression of the N-formyl-methyl-leucyl-phenylalanine-receptor (FMLP-R) on 8% to 29% of cells as compared with 8% for control cells. Acivicin potentiated the differentiating effects of interferon-gamma, tumor necrosis factor, dihydroxyvitamin D3, dimethylsulfoxide, and retinoic acid. Culture of cells from the U937 (monoblastic), K562 (erythroleukemia), and KG-1 (myeloblastic) cell lines resulted in decreased growth and viability, but not consistently in differentiation. Acivicin decreased survival of freshly isolated ANLL cells and increased their H2O2 production and NSE content. These results suggest that the glutamine analogue acivicin may be useful as a differentiating agent with antileukemia activity in patients with ANLL.
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PMID:Monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells induced by the glutamine antagonist acivicin. 279 Jan 98

The effect of human recombinant interferon-gamma (IFN-gamma) on Toxoplasma gondii in cultured human fibroblasts is predominantly parasitostatic. This effect is dependent upon the induction in the host cell of a potent indoleamine 2,3-dioxygenase that converts tryptophan to N-formylkynurenine. This product is, in turn, degraded to kynurenine by a formamidase. Within 24 h of treatment with IFN-gamma most of the tryptophan originally present in the medium is converted to these products together with some minor metabolites. When added to the medium of infected cultures at concentrations equimolar to the tryptophan content, neither N-formylkynurenine nor kynurenine suppresses the growth of T. gondii, although at higher concentrations they are effective. The medium of uninfected cultures treated with IFN-gamma for 24 h has no effect on the growth of T. gondii, when transferred to fresh cultures provided that the residual IFN-gamma is first removed by ultrafiltration or neutralized with a specific monoclonal antibody. Thus minor metabolites produced from tryptophan in response to IFN-gamma and excreted into the medium are not parasitostatic. When cultures treated with IFN-gamma for 24 h are incubated with medium that contains [3H]tryptophan, the radioactive amino acid is converted to N-formylkynurenine and kynurenine as rapidly as it enters the cell. This degradation not only results in a very low intracellular concentration of tryptophan but also produces intracellular concentrations of tryptophan metabolites that are significantly higher than the tryptophan concentration in control cells. However, it is unlikely that either metabolite reaches intracellular concentrations that are sufficient to suppress the growth of the parasite. The parasitostatic effect of IFN-gamma is most likely to result from the starvation of T. gondii for tryptophan.
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PMID:Interferon-gamma suppresses the growth of Toxoplasma gondii in human fibroblasts through starvation for tryptophan. 309 59

Anorexia, net proteolysis of skeletal muscle and consumption of body fat are hallmarks of the cachexia syndrome associated with chronic disease states. While inanition contributes to cachexia, this wasting diathesis has little in common with simple starvation. The cachexia syndrome is characterized by progressive weight loss and depletion of lean body mass in excess to that resulting from comparable caloric restriction. Accelerated mobilization and consumption of host protein stores from peripheral tissues occurs to support gluconeogenesis and acute phase protein synthesis [1, 2]. In contrast, simple starvation is associated with a relative sparing of lean tissue with the preferential consumption of fat. While the clinical manifestations of cachexia are readily apparent, identification of the specific mechanisms responsible for the development of cachexia remains an enigma. In recent years, interest has focused on the role that the immune system plays in the development of cachexia. Investigators initially hypothesized that the chronic production of two inflammatory cytokines, tumour necrosis factor alpha (TNF alpha) and/or interleukin-1 (IL-1), could explain the host non-specific responses resulting in cachexia [3-5]. Other pro-inflammatory cytokines, including interleukin-6 (IL-6) [6, 7] and interferon-gamma [8, 9], have been more recently proposed to be involved in this complex process. Although no consensus exists for the exclusive role of any one cytokine in the pathogenesis of cachexia, there is growing acceptance that the progression of cachexia results in part from the inappropriate release of one or more pro-inflammatory cytokines [10, 11]. In the present review, the current role of TNF alpha as a mediator of cachexia is examined.
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PMID:Tumor necrosis factor and cachexia: a current perspective. 788 18

Flow cytometry with the specific monoclonal antibody (MoAb) L31 was used to analyse the expression of HLA class I heavy chains not bound with beta 2-microglobulin (beta 2m) by neuroblastoma (NB) cell lines IMR-32 and LA-N-1. The cells, which express barely detectable amounts of beta 2m-free (L31-positive molecules) and beta 2m-complexed HLA class I antigens (W6.32- and BBM.1-reactive molecules), expressed MHC class I molecules not bound to light chains upon differentiation with either retinoic acid or serum starvation. The expression was not accompanied by an increase of surface heterodimers. Conversely, recombinant interferon-gamma (rIFN-gamma) treatment led IMR-32 and LA-N-1 cells to almost exclusively express beta 2m-complexes HLA class I heavy chains. Surface beta 2m-free MHC class I molecules displayed a molecular mass of approximately 45 kDa and did not bind exogenously added beta 2m. No changes in the synthesis of either HLA class I and beta 2m mRNAs or of L31 proteins were observed in differentiated NB cells, thus suggesting that the surface exposure of unusual HLA class I antigens is regulated post-translationally. These findings indicate that, in addition to activated lymphocytes, the surface expression of beta 2m-free class I heavy chains is a feature of other cell types, such as NB cells.
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PMID:Expression of beta 2m-free HLA class I heavy chains in neuroblastoma cell lines. 831 64

Although neuronal cells are a major target of phorbol ester action, the activity of the various protein kinase C (PKC) isoenzymes have not been studied in detail in human neuroblasts. Differentiation of the LAN-5 human neuroblastoma cell line by interferon-gamma (IFN-gamma) is accompanied by a twofold increase in PKC activity. Since PKC is a multigene family, we investigated which isoforms were expressed in control and differentiated cells, and which of these isoenzymes is involved in neuronal differentiation. We found that: (1) PKC activity is higher in differentiated than in undifferentiated cells; (2) RT-PCR analysis showed the expression of mRNA for PKC alpha, -gamma, -delta, -epsilon and -zeta and the absence of mRNA for beta in untreated LAN-5 cells; (3) Western blot evaluation with PKC isoform-specific antibodies showed the same pattern of PKC expression in non-differentiated cells; (4) Expression of PKC epsilon mRNA was significantly enhanced by IFN-gamma-induced differentiation, while the other isoforms were not affected; (5) Differentiation of LAN-5 cells with IFN-gamma or retinoic acid induced overexpression of the PKC epsilon protein, while inhibition of cell proliferation by fetal calf serum starvation was without effect. These findings suggest that expression of PKC epsilon isoform is tightly coupled with neuronal differentiation and may play a role in the maintenance of the differentiated state.
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PMID:Protein kinase C isoenzymes in human neuroblasts. Involvement of PKC epsilon in cell differentiation. 848 77

KFR1, a mitogen-activated protein (MAP) kinase identified in the African trypanosome, Trypanosoma brucei, is a serine protein kinase capable of phosphorylating the serine residues in histone H-1, myelin basic protein, and beta-casein. It phosphorylates four proteins with estimated molecular masses of 22, 34, 46, and 90 kDa from the T. brucei bloodstream-form lysate in vitro. KFR1 bears significant sequence similarity to the yeast MAP kinases KSS1 and FUS3 but cannot functionally complement the kss1/fus3 yeast mutant. It is encoded by a single-copy gene in the diploid T. brucei, and only one of the two alleles can be successfully disrupted, suggesting an essential function of KFR1 in T. brucei. KFR1 activity is present at a much enhanced level in the bloodstream form of T. brucei when compared with that in the insect (procyclic) form. This enhanced activity can be eliminated in vitro by the treatment with protein phosphatase HVH2 known to act specifically on MAP kinases. It can also be decreased in the bloodstream form of T. brucei by serum starvation but induced specifically by interferon-gamma. The production of interferon-gamma in the mammalian host is known to be triggered by T. brucei infection, and this cytokine, as has been reported, promotes the proliferation of T. brucei in the mammalian blood. Since none of these phenomena can be observed in the procyclic form of T. brucei, activation of KFR1 is most likely involved in mediating the interferon-gamma-induced proliferation of T. brucei in the mammalian host.
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PMID:Interferon-gamma activation of a mitogen-activated protein kinase, KFR1, in the bloodstream form of Trypanosoma brucei. 909 33

Toxoplasma gondii is an obligate intracellular parasite that infects a wide variety of nucleated cells in its numerous intermediate hosts including man. The oral route is the natural portal of entry of T. gondii. Ingested organisms are released from cysts or oocysts within the gastrointestinal tract and initially invade the intestinal epithelium. We show that T. gondii invades and proliferates in cultured primary rat enterocytes, obtained with an original procedure. Activation of the enterocytes with rat recombinant interferon-gamma (IFN-gamma) inhibits T. gondii replication, the inhibition being dose dependent. Neither nitrogen and oxygen derivatives nor tryptophan starvation appear to be involved in the inhibition of parasite replication by IFN-gamma. Experiments using Fe2+ salt, carrier and chelator indicate that intracellular T. gondii replication is iron dependent, suggesting that IFN-gamma-treated enterocytes inhibit T. gondii replication by limiting the availability of intracellular iron to the parasite. Our data show that enterocytes probably play a major role on mucosal surfaces as a first line of defence against this coccidia, and possibly other pathogens, through an immune mechanism. The results suggest that limiting the availability of iron could represent a broad antimicrobial mechanism through which the activated enterocytes exert control over intracellular pathogens.
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PMID:Interferon-gamma-activated primary enterocytes inhibit Toxoplasma gondii replication: a role for intracellular iron. 976 36

Asparagine linked (N-linked) glycosylation is an important modification of recombinant proteins, because the attached oligosaccharide chains can significantly alter protein properties. Potential glycosylation sites are not always occupied with oligosaccharide, and site occupancy can change with the culture environment. To investigate the relationship between metabolism and glycosylation site occupancy, we studied the glycosylation of recombinant human interferon-gamma (IFN-gamma) produced in continuous culture of Chinese hamster ovary cells. Intracellular nucleotide sugar levels and IFN-gamma glycosylation were measured at different steady states which were characterized by central carbon metabolic fluxes estimated by material balances and extracellular metabolite rate measurements. Although site occupancy varied over a rather narrow range, we found that differences correlated with the intracellular pool of UDP-N-acetylglucosamine + UDP-N-acetylgalactosamine (UDP-GNAc). Measured nucleotide levels and estimates of central carbon metabolic fluxes point to UTP depletion as the cause of decreased UDP-GNAc during glucose limitation. Glucose limited cells preferentially utilized available carbon for energy production, causing reduced nucleotide biosynthesis. Lower nucleoside triphosphate pools in turn led to lower nucleotide sugar pools and reduced glycosylation site occupancy. Subsequent experiments in batch and fed-batch culture have confirmed that UDP-sugar concentrations are correlated with UTP levels in the absence of glutamine limitation. Glutamine limitation appears to influence glycosylation by reducing amino sugar formation and hence UDP-GNAc concentration. The influence of nucleotide sugars on site occupancy may only be important during periods of extreme starvation, since relatively large changes in nucleotide sugar pools led to only minor changes in glycosylation.
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PMID:Metabolic effects on recombinant interferon-gamma glycosylation in continuous culture of Chinese hamster ovary cells. 1009 45

We investigated the effects of acute starvation on mitogen-induced T-cell activation and Th1/Th2 cytokine responses in rheumatoid arthritis (RA) patients. Ten RA patients with active disease underwent a 7-day fast followed by a 2-week refeeding period. Immunological, hormonal, laboratory and clinical evaluations were carried out on days 0, 7 and 21. Using flow cytometry, mitogen-stimulated T-cell activation was assessed in fresh heparinised blood via analysis of CD69 expression. Production of Th1 (interferon-gamma) and Th2 (interleukin-4, IL-4) cytokines was also assessed by ELISA. The 7-day fast significantly decreased the erythrocyte sedimentation rate, C-reactive protein level, joint count, morning stiffness, body weight, CD4+ and CD8+ counts and CD69+ expression on mitogen stimulated CD4+ lymphocytes. A significant increase in mitogen-induced IL-4 production after fasting was found. The fast markedly reduced serum leptin and insulin-like growth factor-1 concentrations. No significant differences occurred in serum cortisol or prolactin before and after fasting. Decreases in CD4+ lymphocyte activation during fasting correlated with decreases in body weight. Our results suggest that the clinical and laboratory improvements in fasting RA patients may be attributed to decreased CD4+ T-cell activation and an increase in the number and/or function of IL-4-producing Th2 cells. Factors associated with loss of body weight during acute starvation appear to have an inhibitory effect on CD4+ lymphocyte activation.
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PMID:Decreased CD4+ lymphocyte activation and increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation. 1052 54

Malnutrition compromises immune function, reducing resistance to infection. We examine whether the decrease in leptin induced by starvation increases susceptibility to lipopolysaccharide (LPS)- and tumor necrosis factor (TNF)-induced lethality. In mice, fasting for 48 hours enhances sensitivity to LPS. Decreasing the fasting-induced fall in leptin by leptin administration markedly reduced sensitivity to LPS. Although fasting decreases basal leptin levels, LPS treatment increased leptin to the same extent as in fed animals. Fasting increased basal serum corticosterone; leptin treatment blunted this increase. Fasting decreased the ability of LPS to increase corticosterone; leptin restored the corticosterone response to LPS. Serum glucose levels were decreased in fasted mice and LPS induced a further decrease. Leptin treatment affected neither basal glucose nor that after LPS. LPS induced a fivefold greater increase in serum TNF in fasted mice, which was blunted by leptin replacement. In contrast, LPS induced lower levels of interferon-gamma and no differences in interleukin-1beta in fasted compared to fed animals; leptin had no effect on those cytokines. Furthermore, fasting increased sensitivity to the lethal effect of TNF itself, which was also reversed by leptin treatment. Thus, leptin seems to be protective by both inhibiting TNF induction by LPS and by reducing TNF toxicity.
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PMID:Reduced leptin levels in starvation increase susceptibility to endotoxic shock. 1079 89


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