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

Interferons inhibit cell growth in normal and tumor-derived cells. The molecular basis of interferons antiproliferative activity remains to be defined. Using subtraction hybridization, a human melanoma differentiation associated gene, mda-20, has been identified that is down-regulated by treatment with interferon. Sequence analysis indicates that mda-20 is human ribosomal protein L23a (rp L23a). The mRNA levels of rp L23a and growth are diminished in a variety of human tumor cell lines following treatment with human fibroblast interferon, interferon-beta (IFN-beta). Expression of rp L23a is also reduced in human melanoma cells treated with human leukocyte (IFN-alpha) and immune (IFN-gamma) interferons, but not by growth inhibition resulting from serum starvation. These findings suggest that growth suppression alone is not sufficient to reduce rp L23a expression. Instead, reduced rp L23a mRNA results from biochemical changes mediated by interferons. Ectopic expression of an antisense rp L23a sequence in human HeLa cervical carcinoma cells results in a reduction in colony formation indicating a direct antiproliferative effect by inhibiting rp L23a expression. The mechanism underlying inhibition in rp L23a expression in IFN-beta-treated cells may involve antisense rp L23a RNA. These results suggest that rp L23a may be one of the target molecules involved in mediating growth inhibition by interferon.
 ...
PMID:Suppression of human ribosomal protein L23A expression during cell growth inhibition by interferon-beta. 905 44

The expression of the angiotensin II type 2 (AT2) receptor is developmentally and growth regulated. In cultured R3T3 cells, expression of this receptor is markedly induced at the confluent state and with serum deprivation. In this study we demonstrated that the removal of serum from culture media resulted in the induction of apoptosis in these cells and the addition of angiotensin II further enhanced apoptosis. We have previously identified an interferon regulatory factor (IRF) binding motif in the mouse AT2 receptor gene promoter region. In this report, we observed that serum removal increased IRF-1 expression, with a rapid and transient decrease of IRF-2. To prove that the changes in IRFs after serum removal mediated apoptosis and up-regulated AT2 receptor, we transfected antisense oligonucleotides for IRF-1 or IRF-2 into R3T3 cells and observed that IRF-1 antisense oligonucleotide attenuated apoptosis and abolished the up-regulation of AT2 receptor. IRF-2 antisense oligonucleotide pretreatment did not affect the onset of apoptosis after serum removal; instead, it increased AT2 receptor binding and enhanced angiotensin II-mediated apoptosis. Taken together, these results suggest that increased IRF-1 after serum starvation contributes to the induction of apoptosis and that increased IRF-1 up-regulates the AT2 receptor expression after serum starvation, resulting in enhanced angiotensin II-mediated apoptosis.
 ...
PMID:Interferon regulatory factor-1 up-regulates angiotensin II type 2 receptor and induces apoptosis. 911 58

Toxoplasma gondii is an obligate intracellular parasite that is a common opportunistic pathogen of the central nervous system in AIDS patients. Gamma interferon (IFN-gamma) alone or in combination with interleukin-1 (IL-1), IL-6, or tumor necrosis factor alpha significantly inhibits the growth of T. gondii in murine astrocytes, suggesting these are important nonimmune effector cells in the brain. Inhibition was found to be independent of a nitric oxide-mediated or tryptophan starvation mechanism. Both reactive oxygen intermediates and iron deprivation are IFN-gamma-mediated mechanisms known to operate against intracellular parasites in other cell types. Astrocytes generated from mice genetically deficient in the production of reactive oxygen intermediates (phox(-/-) mice) were found to inhibit growth of T. gondii when stimulated with IFN-gamma alone or in combination with other cytokines. The reactive oxygen inhibitor catalase and the reactive oxygen scavengers mannitol and thiourea failed to reverse the IFN-gamma-induced inhibition of T. gondii in astrocytes. These data indicate that IFN-gamma-induced inhibition in astrocytes is independent of reactive oxygen intermediates. IFN-gamma-induced inhibition could not be reversed by the addition of iron salts, ferric citrate, ferric nitrate, or ferric transferrin. Pretreatment of astrocytes with desferrioxamine also did not induce the inhibition of T. gondii. These data indicate that the mechanism of IFN-gamma inhibition was not due to iron deprivation. IFN-gamma had no effect on T. gondii invasion of astrocytes, but inhibition of growth and loss of tachyzoite vacuoles were evident in IFN-gamma-treated astrocytes by 24 h after invasion. Overall, these data suggest that IFN-gamma-activated astrocytes inhibit T. gondii by an as-yet-unknown mechanism.
 ...
PMID:Investigation into the mechanism of gamma interferon-mediated inhibition of Toxoplasma gondii in murine astrocytes. 1081 94

The interferon (IFN)-induced, double-stranded (ds)RNA-activated serine-threonine protein kinase, PKR, is a key mediator of the antiviral activities of IFNs. In addition, PKR activity is also involved in regulation of cell proliferation, apoptosis, and signal transduction. In virally infected cells, dsRNA has been shown to bind and activate PKR kinase function. Implication of PKR activity in normal cellular processes has invoked activators other than dsRNA because RNAs with perfectly duplexed regions of sufficient length that are able to activate PKR are absent in cellular RNAs. We have recently reported cloning of PACT, a novel protein activator of PKR. PACT heterodimerizes with PKR and activates it by direct protein-protein interaction. Overexpression of PACT in mammalian cells leads to phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2alpha), the cellular substrate for PKR, and leads to inhibition of protein synthesis. Here, we present evidence that endogenous PACT acts as a protein activator of PKR in response to diverse stress signals such as serum starvation, and peroxide or arsenite treatment. Following exposure of cells to these stress agents, PACT is phosphorylated and associates with PKR with increased affinity. PACT-mediated activation of PKR leads to enhanced eIF2alpha phosphorylation followed by apoptosis. Based on the results presented here, we propose that PACT is a novel stress-modulated physiological activator of PKR.
 ...
PMID:PACT, a stress-modulated cellular activator of interferon-induced double-stranded RNA-activated protein kinase, PKR. 1098 89

Toxoplasma gondii is an obligate intracellular parasite that infects a wide variety of nucleated cells in its numerous intermediate hosts, including humans. Much interest has focused on the ability of gamma interferon (IFN-gamma)-activated macrophages to prevent intracellular replication, but some other cells (e.g., fibroblasts, endothelial cells, microglial cells, astrocytes, enterocytes and retinal pigment cells) can also be activated to induce this inhibition of proliferation. Dendritic cells are generally known to be involved in the induction of immune responses, but no previous study had investigated the possibility that dendritic cells may act as effector cells of this system. Our results show that IFN-gamma-activation inhibits the replication of T. gondii in dendritic cells, with the inhibition being dose dependent. Neither nitrogen derivatives nor tryptophan starvation appears to be involved in the inhibition of parasite replication by IFN-gamma. Experiments with oxygen scavengers indicate that intracellular T. gondii replication is oxygen dependent. Our findings suggest that, in addition to their essential role in stimulating the immune system, dendritic cells probably act as effector cells in the first line of defense against pathogen invasion.
 ...
PMID:Dendritic cells as effector cells: gamma interferon activation of murine dendritic cells triggers oxygen-dependent inhibition of Toxoplasma gondii replication. 1195 72

One of the key mediators of the antiviral and antiproliferative actions of interferon is double-stranded-RNA-dependent protein kinase (PKR). PKR activity is also involved in the regulation of cell proliferation, apoptosis and signal transduction. We have recently identified PACT, a novel protein activator of PKR, as an important modulator of PKR activity in cells in the absence of viral infection. PACT heterodimerizes with PKR and activates it by direct protein-protein interactions. Endogenous PACT acts as an activator of PKR in response to diverse stress signals, such as serum starvation and peroxide or arsenite treatment, and is therefore a novel, stress-modulated physiological activator of PKR. In this study, we have characterized the functional domains of PACT that are required for PKR activation. Our results have shown that, unlike the N-terminal conserved domains 1 and 2, the third conserved domain of PACT is dispensable for its binding of double-stranded RNA and inter action with PKR. However, a deletion of domain 3 results in a loss of PKR activation ability, in spite of a normal interaction with PKR, thereby indicating that domain 3 plays an essential role in PKR activation. Purified recombinant domain 3 could also activate PKR efficiently in vitro. Our results indicate that, although dispensable for PACT's high-affinity interaction with PKR, the third motif is essential for PKR activation. In addition, domain 3 and eukaryotic initiation factor 2alpha both interact with PKR through the same region within PKR, which we have mapped to lie between amino acid residues 318 and 551.
 ...
PMID:The C-terminal, third conserved motif of the protein activator PACT plays an essential role in the activation of double-stranded-RNA-dependent protein kinase (PKR). 1198 96

The progressive deterioration in nutrition status frequently seen in cancer patients is often referred to as cancer cachexia. Unlike starvation, in which fat stores from adipose are depleted and protein is spared from skeletal muscle, neither fat nor protein is spared in cachexia. Cachexia affects nearly half of cancer patients, causing the clinical manifestations of anorexia, muscle wasting, weight loss, early satiety, fatigue, and impaired immune response. Cachexia does not only impede the response to chemotherapy but also is a major cause of morbidity and mortality. According to clinical studies, increasing caloric intake does not necessarily reverse cachexia. The pathophysiology of cachexia involves more complex mechanisms than simply caloric deficiency. The process appears to be mediated by circulating catabolic factors, either secreted by the tumor alone or in concert with host-derived factors, such as tumor necrosis factor-alpha (TNF-alpha), interleukins (IL-1 and IL-6), interferon (IFN-y), and leukemia inhibitory factor (LIF). The successful reversal of this process will require in-depth knowledge of the mechanisms involved, which will then enable the development of effective pharmacologic interventions that may not only improve quality of life, but more importantly, improve survival among cancer patients.
 ...
PMID:The cancer cachexia syndrome: a review of metabolic and clinical manifestations. 1620 77

Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic beta-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-gamma/TNF-alpha, whose synergism is a major cause for beta-cell destruction in type I diabetes. HIT-T15 beta-cells expressed ghrelin but not ghrelin receptor (GRLN-R), which binds acylated ghrelin (AG) only. However, both unacylated ghrelin (UAG) and AG recognized common high-affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Galpha(s) protein and prevented serum starvation- and IFN-gamma/TNF-alpha-induced apoptosis. Antighrelin antibody enhanced apoptosis in either the presence or absence of serum but not cytokines. AG and UAG even up-regulated intracellular cAMP. Blockade of adenylyl cyclase/cAMP/protein kinase A signaling prevented the ghrelin cytoprotective effect. AG and UAG also activated phosphatidyl inositol 3-kinase (PI3K)/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted the ghrelin antiapoptotic effect. Furthermore, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E beta-cells, which express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Noteworthy, both peptides inhibited cytokine-induced NO increase in either HIT-T15 or INS-1E cells. Finally, they induced cell survival and protection against apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also UAG and AG binding sites. Our data demonstrate that AG and UAG promote survival of both beta-cells and human islets. These effects are independent of GRLN-R, are likely mediated by AG/UAG binding sites, and involve cAMP/PKA, ERK1/2, and PI3K/Akt.
 ...
PMID:Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. 1706 44

Famine and viral infection, as well as interferon therapy have been reported to increase the risk of developing bipolar disorder. In addition, almost 100 polymorphic genes have been associated with this disease. Several form most of the components of a phosphatidyl-inositol signalling/AKT1 survival pathway (PIK3C3, PIP5K2A, PLCG1, SYNJ1, IMPA2, AKT1, GSK3B, TCF4) which is activated by growth factors (BDNF, NRG1) and also by NMDA receptors (GRIN1, GRIN2A, GRIN2B). Various other protein products of genes associated with bipolar disorder either bind to or are affected by phosphatidyl-inositol phosphate products of this pathway (ADBRK2, HIP1R, KCNQ2, RGS4, WFS1), are associated with its constituent elements (BCR, DUSP6, FAT, GNAZ) or are downstream targets of this signalling cascade (DPYSL2, DRD3, GAD1, G6PD, GCH1, KCNQ2, NOS3, SLC6A3, SLC6A4, SST, TH, TIMELESS). A further pathway relates to endoplasmic reticulum-stress (HSPA5, XBP1), caused by problems in protein glycosylation (ALG9), growth factor receptor sorting (PIK3C3, HIP1R, SYBL1), or aberrant calcium homoeostasis (WFS1). Key processes relating to these pathways appear to be under circadian control (ARNTL, CLOCK, PER3, TIMELESS). DISC1 can also be linked to many of these pathways. The growth factor pathway promotes protein synthesis, while the endoplasmic reticulum stress pathway, and other stress pathways activated by viruses and cytokines (IL1B, TNF, Interferons), oxidative stress or starvation, all factors associated with bipolar disorder risk, shuts down protein synthesis via control of the EIF2 alpha and beta translation initiation complex. For unknown reasons, oligodendrocytes appear to be particularly prone to defects in the translation initiation complex (EIF2B) and the convergence of these environmental and genomic signalling pathways on this area might well explain their vulnerability in bipolar disorder.
 ...
PMID:Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability. 1723 88

Malnutrition compromises immune function, resulting in reduced resistance to infection. Recent animal and human studies have suggested that leptin is capable of modulating the immune response and that its levels, which are regulated by nutritional status, fall rapidly during starvation. Leptin deficiency is associated with impaired cell-mediated immunity, an increased incidence of infectious disease and an associated increase in mortality. The purpose of this study was to examine the effect of leptin on activation and cytokine production in peripheral blood T cells from malnourished children. The data obtained in the present study demonstrate that leptin produced an increase in the percentage of CD4(+) and CD8(+) cells producing interleukin (IL)-2 and interferon (IFN)-gamma in 24-h cultures. Moreover, leptin decreased the percentage of CD4(+) and CD8(+) cells producing IL-4 and IL-10, and enhanced activation of circulating T cells when co-stimulated by phorbol 12-myristate 13 acetate (PMA)-ionomycin. Leptin enhanced the expression of activation markers CD69 and CD25 in both CD4(+) and CD8(+) cells after 5 h of stimulation. In conclusion, the results obtained show that leptin modulates CD4(+) and CD8(+) cell activation towards a T helper 1 (Th1) phenotype by stimulating the synthesis of IL-2 and IFN-gamma. In contrast, leptin decreases IL-4 and IL-10 production. Moreover, leptin enhanced the expression of CD69 and CD25 on CD4(+) and CD8(+) cells after stimulation with PMA-ionomycin.
 ...
PMID:Effect of leptin on activation and cytokine synthesis in peripheral blood lymphocytes of malnourished infected children. 1735 47


<< Previous 1 2 3 4 Next >>