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PubMedDate not supplied

Methionine starvation modulates the efficacy of cisplatin on human breast cancer in nude mice.

There are few agents with activity against metastatic breast cancer. We therefore exploited the elevated methionine dependence of tumors to develop a selective and effective therapy against metastatic breast and other cancers. Methionine starvation leads to depleted methionine levels in cells, modifies methylation reactions, lowers glutathione levels and alters folate distribution and leads to a tumor-selective cell cycle arrest in late-S/G2. These effects present the opportunity for methionine depletion to modulate the efficacy of a number of different classes of chemotherapeutic drugs. This report demonstrates that methionine depletion can strongly modulate the efficacy of cisplatin against the MX-t human breast carcinoma cell line when grown in nude mice. The tumor-bearing nude mice were subjected to a methionine-free diet and were additionally treated with cisplatin i.p. at one mg/kg once a week for 3 weeks. The MX-t tumor was relatively resistant to both methionine starvation and cisplatin alone but was very sensitive to the combination of methionine starvation and cisplatin with a 32.1% T/C ratio. The intratumoral platinum concentration was higher in combination with methionine starvation than cisplatin alone, possibly accounting for at least part of the modulating effect of methionine depletion. Future studies will focus on methionine depletion via the enzyme methioninase to modulate cisplatin as well as other classes of chemotherapeutic agents in order to develop a new approach to the treatment of cancer.

Animals↗

PubMed1997

Accumulation of Ade+ reversions in isoauxotrophic stains of Saccharomyces cerevisiae allelic in RAD6 during adenine starvation.

A comparative method based on an analysis of accumulation of starvation-induced Ade+ reversions and cell death during adenine starvation was developed and exploited for estimating the role of RAD6 in the starvation-induced reversions. It was shown that inactivation of RAD6 function in Saccharomyces cerevisiae markedly enhances the accumulation of Ade+ reversions, and therefore it is likely that this gene is taking part in maintaining the low level of starvation-induced mutations in yeast cells.

Adenine↗

PubMed1965

REGULATION OF XANTHINE DEHYDROGENASE IN CHICK LIVER. EFFECT OF STARVATION AND OF ADMINISTRATION OF PURINES AND PURINE NUCLEOSIDES.

1. The xanthine-dehydrogenase activity of chick liver, expressed per mg. of nitrogen, is increased during starvation. 2. Administration of inosine and possibly of adenine has a comparable effect on the xanthine dehydrogenase, and also induces an elevation of the total quantity of enzyme. Hypoxanthine, xanthine, guanine, xanthosine, guanosine and adenosine are ineffective. Cortisone is equally ineffective. 3. The administration of puromycin abolishes the effect of inosine and reduces that of starvation. It is concluded that inosine induces an increased synthesis of xanthine dehydrogenase, whereas during starvation the enzyme is spared with respect to other liver proteins. 4. The hypothesis is formulated that chick-liver xanthine dehydrogenase is an adaptive enzyme, its activity being regulated by inosine or by one of its metabolites.

Adenine↗

PubMed1990

Dietary nucleotides reverse malnutrition and starvation-induced immunosuppression.

The requirement of dietary nucleotide sources for maximal helper T-cell function has been demonstrated. The effect of dietary nucleotide restriction was tested during two forms of nutritional stress: starvation and protein malnutrition. In the starvation model, mice were fed chow diet, nucleotide free or nucleotide free supplemented with 0.25% yeast RNA, for at least 4 weeks. The animals were then starved for 5 days, at which time they were killed and mitogen assays were performed using spleen cells. Animals previously maintained on the nucleotide-free diet supplemented with RNA showed a significant increase in spontaneous concanavalin A and phytohemagglutinin-stimulated blastogenesis. Protein malnutrition was induced by feeding Balb/c mice a protein-free diet for 7 to 10 days. These mice then received either the protein-free diet, the nucleotide-free diet, or the nucleotide-free diet supplemented with 0.25% yeast RNA. Popliteal lymph node assays were then performed. The chow diet, nucleotide-free diet, and nucleotide-free diet supplemented with 0.25% yeast RNA led to a restoration of body weight, but only the chow and supplemented diets restored significant popliteal lymph node immune reactivity. These studies using starvation and protein-malnutrition models clearly indicate the nutritional role of nucleotides in the maintenance and restoration of the immune response.

Animals↗

PubMed1999

Ubiquitinated aldolase B accumulates during starvation-induced lysosomal proteolysis.

We have previously shown that stress-induced protein degradation requires a functional ubiquitin-activating enzyme and the autophagic-lysosomal pathway. In this study, we examined the occurrence of ubiquitin-protein conjugates that form during nutrient starvation. Kidney and liver epithelial cells respond to nutrient stress by enhancing autophagy and protein degradation. We have shown that this degradative response was more dramatic in nondividing cultures. In addition, the onset of autophagy was suppressed by pactamycin, cycloheximide, and puromycin. We observed an accumulation of ubiquitinated proteins coincident with the degradative response to amino acid starvation. The stress-induced protein ubiquitination was not affected by cycloheximide, indicating that protein synthesis was not required. The ubiquitinated proteins were localized to the cytosol and subcellular fractions enriched with autophagosomes and lysosomes. The incorporation of the ubiquitinated proteins into autolysosomes was dramatically reduced by 3-methyladenine, an inhibitor of autophagy. The evidence suggests that ubiquitinated proteins are sequestered by autophagy for degradation. We next set out to identify those primary ubiquitinated proteins at 60 kDa and 68 kDa. Polyclonal antibodies were prepared against these proteins that had been immunopurified from rat liver lysosomes. The antibodies prepared against those 68 kDa proteins also recognized a 40 kDa protein in cytosolic fractions. Internal amino acid sequences obtained from two cyanogen bromide fragments of this 40 kDa protein were shown to be identical to sequences in liver fructose1,6-bisphosphate aldolase B. Anti-Ub68 antibodies recognized purified aldolase A and aldolase B. Conversely, antibodies prepared against aldolase B recognized the 40 kDa aldolase as well as four to five high molecular weight forms, including a 68 kDa protein. Finally, we have shown that the degradation of aldolase B was enhanced during amino acid and serum starvation. This degradation was suppressed by chloroquine and 3-methyladenine, suggesting that aldolase B was being degraded within autolysosomes. We propose that aldolase B is ubiquitinated within the cytosol and then transported into autophagosomes and autolysosomes for degradation during nutrient stress.

Adenine↗

PubMed1977

The ontogeny of plasma osmolality and intravascular volume maintenance during short-term starvation in rats.

Body fluid deviations were examined in albino rats of both genders between 30 and 100 days of age during food deprivation. Plasma volume declined with age in free-feeding control groups. Hypovolemia induced by starvation (4 days) was more intense in 30- to 60-day-old animals than in 80- and 100-day groups. Plasma ismolality concentration of control groups indicated increases with age leveling off after 60 days. The initiation of drinking during fasting was accompanied by physiologically significant elevations in plasma osmolality over ad libitum concentrations at each age tested. In a second experiment, repeated exposure to short periods of food deprivation (2 days) during development resulted in the maintenance of intravascular fluid at control volumes. Longer periods (4 days) of deprivation did not result in savings of intravascular volume loss evidenced during starvation. These results suggest that rats compensate for hypovolemia induced by short-term starvation when provided experience with food restriction during development.

Animals↗

PubMed1978

Influence of age and short-term starvation on the ATPase activity in the developing rat brain.

Na+-K+-stimulated and Mg++-dependent ATPase activities were investigated in the developing cerebral cortex, subcortical structures, and medulla oblongata of rats as was the effect of 24-hr lasting starvation and thirst on those enzyme activities. We found (a) a developmental increase of these ATPase activities in the developing rat brain with the maximum in the cerebral cortex and with the minimum in the medulla oblongata; (b) a decrease of the ratio of these enzyme activities, which was near unity in adult animals; (c) an increase of ATPase activities in the cerebral cortex and subcortical formations of young rats under starvation conditions followed by a decrease of the Mg++/Na+-K+-ATPase activity ratios in these structures; and (d) a decrease of these activities, especially in the cerebral cortex, and an increase of the activity ratios in adult animals under starvation conditions.

Age Factors↗

PubMed1984

The effect of temperature and starvation on the clearance of bacteria from the bloodstream of rainbow trout (Salmo gairdneri Richardson).

The blood clearance of 51Cr-labeled heat-killed Salmonella pullorum was generally biphasic and exponential for each phase. Starvation had little significant effect on this pattern, although the rate of first phase clearance was probably slower. Raising the water temperature from 8 degrees C to 18 degrees C enhanced the rate of clearance of the second phase to almost exactly double that at 8 degrees C. At 18 hr postinoculation, the spleen contained much more radioactivity per gm than any other tissue. This finding is in marked contrast to earlier work that showed that at 1 hr postinoculation, the kidney contained the most, and it suggests that redistribution of bacteria occurred. The most distinct effect of temperature stress on tissue localization of bacteria was in the heart: A rising temperature stress caused increased numbers of bacteria to localize within the heart. Less clear-cut changes were also seen in other tissues with different treatments. With the possible exception of starvation effecting a slower first phase clearance rate, we have been unable to demonstrate that the vascular clearance mechanisms, including the reticuloendothelial system, are significantly compromised by raising the water temperature or by starvation.

Animals↗

PubMed1993

Impaired response of polycythemic mice to erythropoietin induced by protein starvation imposed after hormone administration.

The present study was performed to determine the stage of the erythropoietic pathway which is affected by starvation or protein deprivation and whose manifestation is a depressed response to exogenous erythropoietin (EPO). The response to recombinant human EPO was measured in post-hypoxic polycythemic mice by determination of 59Fe uptake into red cells, spleen and femur and/or erythroid colony forming units (CFU-E) and erythroid precursor cell concentrations in femoral marrow. Experimental mice were either starved or fed one of seven different diets whose protein (casein) content ranged from 0 to 20%. All diets were isocaloric. The response of mice maintained on the standard diet (Purina Lab chow) was taken as the normal one. Starvation during the 48-hour period immediately before EPO injection had no effect on the response to the hormone. Starvation, and protein deprivation to a lesser extent, during the 48-hour period following EPO, on the other hand, significantly reduced the response. There was a progressive increase in the response as the casein content of the diet was increased. A normal response was observed when dietary casein concentration was 10%. These findings indicate that nutritional deprivation or dietary protein alterations during the period immediately following EPO injection in polycythemic mice can have detrimental effects on the erythroid response in a model in which nutritional deprivation was relatively short and acute. They also indicate that the subnormal response is not due to a decreased size of the erythroid progenitor pool available for differentiation but to deficient rates of differentiation of erythropoietic units.

Animals↗

PubMed1994

Identification of chicken liver mitochondrial alanine:2-oxoglutarate aminotransferase and its response to starvation.

In chicken liver, alanine:2-oxoglutarate aminotransferase was located only in the mitochondria. In 40-day-old chickens, starvation resulted in a dramatic increase of liver mitochondrial alanine:2-oxoglutarate aminotransferase activity, reaching about a 100-fold increase in the activity (units/g of liver) on Day 7 of starvation. The mitochondrial alanine:2-oxoglutarate aminotransferase was purified to homogeneity and characterized from the mitochondrial extract of 7-day-starved chicken liver. The enzyme possessed alanine:glyoxylate aminotransferase activity and was also present in control chicken liver. The enzyme was found in the present study for the first time and named alanine:2-oxoglutarate (glyoxylate) aminotransferase. Alanine:2-oxoglutarate aminotransferase specific for alanine and 2-oxoglutarate as substrates was not detected in both control and starved chicken livers. In contrast, liver mitochondrial alanine:2-oxoglutarate aminotransferase from mammals did not possess alanine:glyoxylate aminotransferase activity. The increase in mitochondrial alanine:2-oxoglutarate aminotransferase activity during starvation was found to be attributed to an increase in enzyme protein.

4-Aminobutyrate Transaminase↗

PubMed1993

Effect of activation of the serotoninergic system during prolonged starvation on subsequent caloric intake and macronutrient selection in the Zucker rat.

Starvation or dietary restriction are known to modify post-fasting dietary self-selection. We have examined the effects of activation of the serotoninergic system and food deprivation on macronutrient self-selection following a period of starvation. Rats were starved for 4 days and either treated or not with dl-fenfluramine or fluoxetine. Starved untreated animals showed a post-fasting anorexia and an increased preference for carbohydrate intake, even though lipids remained the preferred source of calories. Treatment with fenfluramine or fluoxetine increased post-fasting anorexia, abolished the preference for carbohydrates and decreased lipid intake. Fluoxetine, but not fenfluramine, resulted in decreased protein intake as well. Following a 2-day refeeding period ad libitum, during which the animals were not treated with drugs, the anorectic effect of fenfluramine disappeared but that of fluoxetine remained unchanged. In addition, we noted that at an equimolar dose to dl-fenfluramine (100 mumol/kg/day) fluoxetine treatment resulted in the death of all the animals in the group by the second day of refeeding; no deaths were observed in any of the other groups. In conclusion, we confirm a post-starvation anorexia and increased carbohydrate intake following long-term fasting. In addition we show that activation of the serotoninergic system abolishes the increase in carbohydrate intake and potentiates post-starving anorexia.

Animals↗

PubMed1996

Sequestration of centrally administered insulin by the brain: effects of starvation, aluminum, and TNF-alpha.

Insulin found in the CNS may be a key regulator in the balance of energy in the body. Since the peripheral circulation is the principal source of insulin in the CNS, insulin must cross the blood-brain barrier. We examined the retention of radioactively labeled insulin in the brain and its transport from the brain after injection icv in mice. The results were compared with those found in mice after fasting, starvation, refeeding, and the addition of aluminum (previously shown to affect the transport of peptides from the CNS) as well as tumor necrosis factor-alpha (TNF-alpha) (known to interact with peripheral insulin). There was no obvious saturable transport system for insulin from the brain, but the retention of insulin was regulated by both aluminum and starvation. Although TNF-alpha was neither required nor involved chronically in the retention of insulin in the brain, acute ip administration of TNF-alpha produced an early increase in the retention of insulin similar to that found after starvation.

Aluminum↗

PubMed1977

[The ketone bodies in the hemolymph of Biomphalaria glabrata under starvation and infection with Schistosoma mansoni (author's transl)].

The metabolism of the snail Biomphalaria glabrata stressed by five days' starvation as well as by infection with Schistosoma mansoni was examined with regard to the metabolism of ketone bodies. Previous studies in the metabolism of this host--parasite relationship always resulted in changes in the same direction with starvation as well as with infection. Contrary to that the concentration of acetoacetate and beta-hydroxybutyrate measured in the hemolymph decreased significantly with starvation but increased significantly with infection. The following problems concerning the ketone body metabolism are discussed: on the one hand the differences between infected and starved snails, and on the other hand the differences between the snails and the mammals as well as in the invertebrates so far investigated.

Acetoacetates↗

PubMed1976

Histochemical findings in the rat gastric mucosa during starvation.

The influence of starving on the activity of enzymes of the rat gastric mucosa was investigated by selected histochemical methods. Beside the conventional methods of enzymatic histochemistry the technique of semipermeable membranes was used in the proof of lysosomal enzymes. Dehydrogenases were proved in aqueous and also in gel media with PMS. During the starvation in the parietal cells a marked increase took place in the activity of acid phosphatase, E-600 resistant esterase, less in beta-glucuronidase. High activity of the lysosomal enzymes in macrophages did not change during starvation. Nor did any changes took place in the activity of alkaline phosphatase in the endothelium of the capillaries. The chief cells in the control and starving animals, in contrast to the human gastric mucosa, did not contain any non-specific esterase. Concerning dehydrogenases, parietal cells with a different activity of these enzymes were observed both in starved and control animals. In the rat gastric mucosa starving induced changes in the activity of the enzymes which mark important organelles of the cells. Thus it is possible to consider the observed histochemical changes as a functional manifestation of morphological damage of cellular structures which are affected during starvation.

Acetylglucosaminidase↗

PubMed1991

Effects of brief starvation on brain protease activity.

Changes in the activity of proteases (cathepsin D and calpains) caused by 48-h food withdrawal were studied in the brain, liver, kidney, spleen, and heart of 3-, 12-, and 24-month-old Fischer rats. Cathepsin D activity was similar in brain, liver, and heart of control animals; in kidney it was 5-fold higher and in spleen about 10-fold higher. With age, activity increased in all organs tested except spleen. Brief starvation caused no change of cathepsin D activity in brain, but caused an increase in liver and a decrease in spleen. Neutral proteolytic activity in control was highest in the pons-medulla-cerebellum fraction of brain, and activity in liver and heart was below that in brain. Activity increased with age in brain and decreased in other organs. Brief starvation in young animals caused an increase in activity in brain, and a decrease in liver and spleen. Isolated calpain II activity was high in control brain. It increased with age in the cerebrum. Brief starvation resulted in a decrease in the brain. The results indicate that the protease content of the brain is altered with age and in malnutrition, with changes not being the same for all proteases, and changes in brain being different from those in other organs.

Aging↗

PubMedDate not supplied

Starvation reduces pyruvate dehydrogenase phosphate phosphatase activity in rat kidney.

Pyruvate dehydrogenase complex (PDC) from rat kidney or pig heart previously inactivated by phosphorylation (PDHP) was activated in vitro by PDHP phosphatase from kidneys of starved or fed rats. Starvation for 48 h of the rats from which the PDC was prepared led to a decrease in the rate of activation of PDC at early time periods (< 2 min), particularly at submaximal concentrations of Mg2+. Using intact permeable kidney mitochondria incubated for 15 sec, it was found that starvation of rats more than doubled the Mg2+ concentration at which the half maximal increment of PDC activity (PDCa) was observed. Reduction of PDHP phosphatase activity due to starvation was also apparent when phosphatase was separated from PDC and recombined with PDC from the same or different animals. Intraperitoneal injection of insulin and glucose 1 h before sacrifice of starved rats prevented the reduction of PDHP phosphatase activity whether or not protein synthesis was inhibited. The effect of insulin in restoration of PDHP phosphatase activity of starved rats was not mimicked by 5-methylpyrazole 3-carboxylic acid, an inhibitor of lipolysis. When renal PDHP phosphatase was incubated with pig heart PDC in the presence of 10 mM Mg2+ and 0.1 mM Ca2+ the increment in PDCa, in 1 min was 30% of fully activated PDC activity (PDCt) observed after 15 min. Removal of divalent cations did not affect the increment in 1 min but prevented further increments. Conversely okadaic acid diminished 1 min increment but did not disturb PDCt. It is suggested that the different behaviour of renal PDC from fed and starved animals may partly be due to different divalent cation independent PDHP phosphatase activity.

Animals↗

PubMed1995

Predominant periportal expression of the fructose 1,6-bisphosphatase gene in rat liver: dynamics during the daily feeding rhythm and starvation-refeeding cycle.

Expression of the gene of the key gluconeogenic enzyme fructose 1,6-bisphosphatase (FBPase) was studied in rat liver during the daily feeding cycle and during refeeding after starvation. Total abundance of FBPase mRNA could be quantified by Northern blotting analysis with a digoxigenin-labelled 40-mer oligonucleotide probe. The zonal localization could not be demonstrated by in situ hybridization under several varied conditions with the 32P-end-labelled oligonucleotide probably due to insufficient sensitivity but was demonstrated with a 35S-labelled cRNA probe; the latter was synthesized from a polymerase chain reaction (PCR)-amplified 751 bp cDNA fragment inserted into a pBluescript. During a normal 12:12 h day/night rhythm (darkness with feeding from 1900 to 0700 hours), the total amount of FBPase mRNA stayed almost the same throughout the whole day. After 60 h of starvation the FBPase mRNA level decreased from a maximum at 1800 hours by approximately one-third at the end of refeeding at 0700 hours. Both during the normal feeding rhythm, after 60 h of starvation and during refeeding, i.e. under all conditions, FBPase mRNA was predominantly distributed in the periportal zone. The results clearly show that the preferentially periportal distribution of the FBPase enzyme activity is controlled mainly at a pretranslational level.

Animals↗

PubMed1981

[Influence of starvation and kinesitherapy on blood lipids and their fractions (author's transl)].

In 24 obese patients triglycerides, cholesterol, HDL- and LDL-cholesterol were determined repeatedly during a period of starvation up to 21 days, combined with kinesitherapy. The average loss of body weight was after 10 days 6.4 kg and after 21 days 10.5 kg. While the triglycerides decreased only in the first week significantly, cholesterol decreased highly significant in 21 days from an average of 224 mg/dl to an average of 160 mg/dl. LDL-cholesterol was reduced from the 4th to the 21st day of starvation highly significant to an average of 100 mg/dl. On the other hand HDL-cholesterol decreased only in the first days and showed later a tendency to increase. Therefore the quotient LDL/HDL-cholesterol changed from 3.0 to 2.0. It is discussed that starvation diminishes the atherogenic fractions of cholesterol much more than the fractions which may have a protective effect against coronary heart disease.

Adult↗