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)

Since increases in muscle strength are proportional to increases in the cross-sectional diameter of the muscles being trained, the body must convert greater than normal amounts of amino acids available to it to increase size in athletes in training. When androgens became available in the 1930's they were used primarily to restore positive nitrogen balance in victims of starvation. Anabolic steroids, which were developed to avoid unwanted effects of androgens, were first given to weight lifters, but football players and weight throwers were soon using them. From 1965 to 1977, 25 clinical studies were published dealing with the administration of an anabolic-androgenic steroid to adult human males for evaluating changes in strength and, in 10 of these studies, in maximum oxygen consumption. In 12 of these studies, improvements were claimed from the use of these steroids; in the other 13 no improvements were observed. Other studies have shown that in healthy adult males these steroids reduce testosterone and gonadotrophin output, which reduces spermatogenesis. Alterations of normal liver function have been found in up to 80% of persons treated with C17-alkylated testosterone derivatives. Peliosis hepatitis, with liver failure and death, and fatal liver cancer have also been reported in adults so treated. Reliable methods for detecting anabolic steroids in the urine are now used in certain international competitions. Testing, announced bans, and disqualifications have not been effective in controlling the use of the drugs. The best hope for doing so lies in continuing education of athletes and their supervisors.
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PMID:Anabolic steroids are fool's gold. 626 3

The cytotoxicity of 5-FUra has been related to its incorporation into RNA. In a model of secondary liver cancer in the rat, the incorporation of 5-FUra into the acid-soluble fraction, RNA and DNA of several normal tissues and an adenocarcinoma of the colon transplanted to the liver was determined. A therapeutic labelled dose of the drug was infused via the hepatic artery for 2 hr and the rats killed 1 hr later. Half of the rats were starved overnight before treatment. The incorporation of 5-FUra into liver and intestinal RNA increased at starvation. It was unchanged in kidney and bone marrow. The incorporation into tumor RNA decreased insignificantly. The incorporation into tumor RNA was significantly higher than in hepatic, intestinal, and renal RNA at ad libitum feeding. This difference disappeared at overnight starvation.
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PMID:Relation between the incorporation of 5-fluorouracil into liver carcinoma and normal tissue RNA at hepatic arterial administration in the rat is altered by overnight starvation. 768 58

Mutations in the tumor suppressor p53 are a common event in hepatocellular carcinoma (HCC). Because HCCs typically occur in livers with chronic injury and impaired function, we have explored the role of wild-type p53 in regulating the growth and differentiation of Hep 3B hepatoma cells, a p53-negative line derived from a liver cancer. Stable Hep 3B cell lines were generated in which inducible p53 was introduced using either a temperature-sensitive mutant (p53val135) or a tamoxifen-regulated p53-estrogen receptor chimera (p53-mERtm-pBabepuro). In both cell lines, induction of transcriptionally active p53 was confirmed by assessing several p53 targets: Mdm2 protein, p21waf1 mRNA and protein, and the cyclin G promoter. Despite marked induction of p21waf1, cells with active p53 failed to undergo growth arrest, which is probably due to the presence of a non-functional retinoblastoma protein (pRb) in these cells. Apoptosis also was not observed, even after prolonged (48 h) serum starvation or exposure to cisplatinum. Lack of apoptosis was correlated with unchanged bax mRNA levels following p53 induction. Additionally, albumin mRNA levels remained unchanged, and there was no change in basal transactivation of a reporter containing the promoter of the haptoglobin gene, encoding an acute phase protein. This suggests that growth arrest may be required to promote liver-specific gene expression. Overall, our data demonstrate that introduction of transcriptionally active p53 does not alter the malignant, dedifferentiated phenotype of Hep 3B hepatoma cells. Hence, not all cancer cells are equally responsive to the re-activation of wild-type 53. The ability of a cancer cell to undergo p53-mediated phenotypic alterations may depend on the retention of functional downstream effector pathways.
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PMID:Resistance to p53-mediated growth arrest and apoptosis in Hep 3B hepatoma cells. 923 78

We investigated whether changes in apoptosis and cell proliferation induced by starvation and refeeding in rat liver may contribute to the initiation mechanism of liver cancer by 20 mg/kg of diethylnitrosamine (DENA). Rats were starved for 4 d, then refed and given 20 mg/kg of DENA after 1 d of refeeding. Rat livers were examined before and after DENA treatment to measure DNA loss and synthesis, the number of the placental form of glutathione S-transferase (P-GST) positive cells and their turnover. Four days of starvation depressed cell replication, as indicated by the labeling index (LI), and induced apoptosis, as shown by the decay of total DNA radioactivity and apoptotic index (AI, TUNEL technique). After 1 d of refeeding, AI significantly decreased and LI remained low, indicating that a high percentage of S phase cells was not required for the DNA damage due to 20 mg/kg of DENA. DENA induced apoptosis and the AI after 20 mg/kg of DENA was 3% in refed rats vs. 1% in fully-fed rats 5 d after DENA (P </= 0.05). Putative-initiated P-GST-positive hepatocytes appeared after administration of 20 mg/kg in refed rats, and they showed a higher LI (6%) than the surrounding P-GST-negative cells 3 d after DENA (LI = 2%; P </= 0.01), while very few P-GST-positive cells were found in fully-fed rats. These data indicate that starvation-induced cell loss and the subsequent refeeding trigger cell proliferation that gives a selective advantage to the cells initiated by 20 mg/kg of DENA to grow in the livers of refed rats.
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PMID:Apoptosis and cell proliferation are involved in the initiation of liver carcinogenesis by a subnecrogenic dose of diethylnitrosamine in refed rats. 1061 75

We hypothesized that the tolerance for nutrient deprivation as well as angiogenesis might be an important factor for tumor progression under hypovascular conditions. When normal human fibroblasts were subjected to extreme nutrient starvation by culturing in a medium without serum, glucose, and amino acids, cells died within 24 h. When substituted with liver cancer cell lines HepG2, Hep3B, HLE, and HuH-7, cell death occurred within 36 h. In contrast, four of six pancreas cancer cell lines, PANC-1, AsPC-1, BxPC-1, and KP-3, survived for remarkably longer periods; >50% of the cells survived, even after starvation for 48 h. Among three gastric cancer cell lines, MKN28, MKN45, and MKN74, only the most poorly differentiated MKN45 cells survived >36 h. More than 50% of the cells in colon cancer cell lines SW480, WiDr, and DLD-1 survived after 36 h, and the most undifferentiated SW480 cell line survived longest. We examined the possible involvement of PKB/Akt expression in the survival of various cell lines under nutrient starvation conditions. High expression of PKB/Akt was found to be associated with tolerance for nutrient starvation. When Akt antisense RNA expression vectors were introduced into PANC-1 cells, the tolerance was partially but significantly diminished by vectors for Akt1 and Akt2 but not Akt3. Because elimination of the tolerance might serve as a new strategy for cancer therapy, several compounds were tested for this purpose, and troglitazone, an insulin sensitizer, as well as LY294002, a phosphatidylinositol 3-kinase inhibitor, were found to kill PANC-1 cells only under nutrient starvation conditions.
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PMID:Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. 1108 46

As tumors grow and invade beyond their homeostatic limits, the tumor cells are subjected to insufficient nutrient and oxygen supplies because of excessive demand for nutrition and oxygen, and insufficient vascularization. We therefore hypothesized that tolerance to nutrient deprivation as well as angiogenesis may be critical in some malignancies, including pancreatic cancers, which are seen to be a hypovascular tumor. In this study, we assessed the effect of AMP-activated protein kinase (AMPK), which plays a major role in protecting cells from metabolic stresses, on tumor biology under nutrient-deprived condition. Whereas hepatic cancer cells had mostly died within 48 h during glucose deprivation, most pancreatic cancer cells survived more than 48 h. The tolerance to glucose deprivation tended to correlate with the cells level of expression of AMPK alpha1 and alpha2. The introduction of AMPK antisense RNA expression vectors into pancreas cancer cell lines, PANC-1 and AsPC-1, significantly diminished their tolerance to glucose deprivation, and the stable transfection of AMPK antisense into PANC-1 cells inhibited tumor growth in nude mice. These findings indicate that AMPK expression contributes to tolerance to nutrient starvation in cancer cells. We propose AMPK as a new target for therapeutic strategies to suppress tumor growth and invasion.
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PMID:Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. 1220 20

Amino acid transporter B(0)/ASC transporter 2 (ATB(0)/ASCT2) is responsible for most glutamine uptake in human hepatoma cells. Because this transporter is not expressed in normal hepatocytes, we hypothesized that its expression is necessary for growth of human liver cancer cells. To test this hypothesis, Sloan Kettering hepatoma (SK-Hep) cells were stably transfected with an inducible 1.3-kb ATB(0)/ASCT2 antisense RNA expression plasmid under the transcriptional control of mifepristone, a synthetic steroid. Induced antisense RNA expression in monolayer cultures decreased ATB(0)/ASCT2 mRNA levels by 73% and glutamine transport rates by 65% compared with controls after 24 h, leading to a 98% decrease in cell number after 48 h. Cellular death was attributable to apoptosis based on cellular blebbing, caspase-3 activation, vital dye and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and poly-(ADP-ribose) polymerase (PARP) cleavage. Transporter knockdown also markedly increased activities of caspases-2 and -9, marginally enhanced caspase-8 activity, and dramatically increased ASCT1 mRNA levels, presumably as a futile compensatory response. Apoptosis elicited via transporter silencing was not attributable to the double-stranded RNA-dependent protein kinase R (PKR) pathway. For comparison, glutamine deprivation also caused apoptotic cell death but with slower temporal kinetics, stimulated caspases-2 and -3 but not caspases-8 or -9 activities, and led to considerable PARP cleavage. Thus ASCT2 suppression exerts proapoptotic effects transcending those of glutamine starvation alone. We conclude that ATB(0)/ASCT2 expression is necessary for SK-Hep cell growth and viability and suggest that it be further explored as a selective target for human hepatocellular carcinoma.
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PMID:Inducible antisense RNA targeting amino acid transporter ATB0/ASCT2 elicits apoptosis in human hepatoma cells. 1456 74

CD133/Prominin-1 is a pentaspan transmembrane protein that has been frequently used as a biomarker for cancer stem cells, although its biological function is unclear. The aim of our study was to explore the intrinsic functions of CD133 membrane protein in hepatoma cells during autophagy, apoptosis, tumorigenesis and cell survival through expression or downregulation of CD133. In this study, CD133 was found to be dynamically released from plasma membrane into cytoplasm in both of complete medium(CM) and low glucose medium (LGM), and LGM promoted this translocation. Expression of CD133 enhanced autophagic activity in LGM, while silencing CD133 attenuated this activity in HCC LM3 and Huh-7 cells, suggesting that CD133 is associated with autophagy. Immunofluorescence and time-lapsed confocal techniques confirmed that CD133 was associated with autophagy marker, microtubule-associated protein light chain3 (LC3) and lysosome marker during the glucose starvation. We further found that Huh-7 cells with stable expression of shCD133 (Huh-7sh133) impaired the ability of cell proliferation and formation of xenograft tumors in the NOD/SCID mice. Although loss of CD133 did not affect the rates of glucose uptake in Huh-7con and Huh-7sh133 cells under the CM, Huh-7sh133 cells obviously died fast than Huh-7con cells in the LGM and decreased the rate of glucose uptake and ATP production. Furthermore, targeting CD133 by CD133mAb resulted in cell death in HepG2 cells, especially in the LGM, via inhibition of autophagic activity and increase of apoptosis. The results demonstrated that CD133 is involved in cell survival through regulation of autophagy and glucose uptake, which may be necessary for cancer stem cells to survive in tumor microenvironment.
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PMID:CD133/prominin-1-mediated autophagy and glucose uptake beneficial for hepatoma cell survival. 2343 59

Liver cancer stem cells (LCSCs) can drive and maintain hepatocellular carcinoma (HCC) growth, metastasis, and recurrence. Therefore, they are potentially responsible for the poor prognosis of HCC. Oxygen and nutrient deficiencies are common characteristics of the tumor microenvironment. However, how LCSCs adapt to oxygen- and nutrient-deprived conditions is unclear. Here, we used immunofluorescent staining and flow cytometry analysis to show that CD133+ cells were significantly enriched after hypoxia and nutrient starvation (H/S) in the human HCC cell line Huh7. Sorted CD133+ cells showed higher survival, less apoptosis, and possess higher clonogenic ability under H/S compared to the CD133- population. Under H/S, electron microscopy revealed more advanced autophagic vesicles in CD133+ cells. Additionally, CD133+ cells had higher autophagy levels as measured by both RT-qPCR and Western blotting. CD133+ cells had more accumulated GFP-LC3 puncta, which can be detected by fluorescence microscopy. The autophagic inhibitor chloroquine (CQ) significantly increased apoptosis and decreased the clonogenic capacity of CD133+ cells under H/S. Pre-culturing in H/S enhanced the sphere-forming capacity of CD133+ cells. However, CQ significantly impaired this process. Therefore, autophagy is essential for LCSCs maintenance. CD133+ cells were also found to have a higher tumor-forming ability in vivo, which could be inhibited by CQ administration. Collectively, our results indicate that the involvement of autophagy in maintenance of CD133+ LCSCs under the oxygen- and nutrient-deprived conditions that are typical of the tumor microenvironment in HCC. Therefore, autophagy inhibitors may make LCSCs more sensitive to the tumor microenvironment and be useful in improving anti-cancer treatments.
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PMID:Autophagy contributes to the survival of CD133+ liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment. 2387 69

Hyperammonemia and severe amino acid imbalances play central role in hepatic encephalopathy (HE). In the article is demonstrated that the main source of ammonia in cirrhotic subjects is activated breakdown of glutamine (GLN) in enterocytes and the kidneys and the main source of GLN is ammonia detoxification to GLN in the brain and skeletal muscle. Branched-chain amino acids (BCAA; valine, leucine, and isoleucine) decrease due to activated GLN synthesis in muscle. Aromatic amino acids (AAA; phenylalanine, tyrosine, and tryptophan) and methionine increase due to portosystemic shunts and reduced ability of diseased liver. The effects on aminoacidemia of the following variables that may affect the course of liver disease are discussed: nutritional status, starvation, protein intake, inflammation, acute hepatocellular damage, bleeding from varices, portosystemic shunts, hepatic cancer, and renal failure. It is concluded that (1) neither ammonia nor amino acid concentrations correlate closely with the severity of liver disease; (2) BCAA/AAA ratio could be used as a good index of liver impairment and for early detection of derangements in amino acid metabolism; (3) variables potentially leading to overt encephalopathy exert substantial but uneven effects; and (4) careful monitoring of ammonia and aminoacidemia may discover important break points in the course of liver disease and indicate appropriate therapeutic approach. Of special importance might be isoleucine deficiency in bleeding from varices, arginine deficiency in sepsis, and a marked rise of GLN and ammonia levels that may appear in all events leading to HE.
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PMID:Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy. 2522 Aug 75


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