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PubMed1987

Kinetics of drug action in disease states. XX. Effects of acute starvation on the pharmacodynamics of phenobarbital, ethanol and pentylenetetrazol in rats and effects of refeeding and diet composition.

Severely ill patients often do not eat or cannot retain ingested food. Malnutrition occurs frequently in hospitalized individuals and is known to be associated with substantial changes in the pharmacokinetics of certain drugs. On the other hand, little is known about the effect of acute starvation or malnutrition on the pharmacodynamics (concentration-effect relationship) of drugs. To explore the effects of acute starvation on the pharmacodynamics of drugs that depress or stimulate the central nervous system, adult male Sprague-Dawley rats were deprived of food (but not water) for 3 days, whereas control animals had free access to food and water. Slow i.v. infusion of phenobarbital to onset of loss of righting reflex showed that the starved animals required a larger body weight normalized dose and that they had higher phenobarbital concentrations in serum, serum water, brain and cerebrospinal fluid at the pharmacologic endpoint. Refeeding of the rats for 2 or 7 days did not normalize the decreased body weight and serum total protein concentration. The starvation-associated decrease in the sensitivity of the central nervous system to the hypnotic effect of phenobarbital was only reversed slightly by refeeding for 2 days and persisted even after 7 days of refeeding. Acute starvation had no apparent effect on the dose of i.v. infused ethanol required to cause loss of righting reflex and on ethanol concentrations in serum, brain and cerebrospinal fluid at that time. The infused dose and the concentrations of pentylenetetrazol in serum, brain and cerebrospinal fluid at onset of maximal seizures did not differ significantly between starved and control (fed) rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of starvation on guanidino compound metabolism in mice.

Arginine levels diminished markedly in the plasma during starvation, suggesting that plasma arginine level principally depends on food intake. Organ arginine levels were relatively stable except for an extraordinary increase in the pancreas at 96 h. Guanidinoacetic acid decreased dramatically in all organs within 24 h and low level were maintained thereafter, except for the brain (and plasma). Creatinine output increased after 24h of starvation. The increased creatinine output recovered to the control level after 48 h. A small but significant amount of guanidinosuccinic acid was detected in the normal liver and decreased transitorily after 24 h and increased after 48 h starvation, corresponded with an increased output in the 24 h urine excretion. Otherwise this decrease may be related to the transitory decrease in arginine level in the liver over the same time course. Methylguanidine in the muscle and gamma-guanidinobutyric acid in the liver decreased gradually during starvation. These results suggest that guanidino compounds levels in mouse organs are principally dependent on exogenous nitrogen.

Animals↗
PubMed1974

Effects of cyclic starvation-feeding and of splenectomy on the development of hemosiderosis in rat livers.

The development of siderosis of liver and spleen was investigated in rats subjected alternately to periods of starvation and periods of feeding of diets rich in iron (0.71% or 1.23% Fe) or of control diets, during periods ranging up to 245 days. With 0.71% iron in the diet, cyclic starvation-feeding markedly enhanced the accumulation of iron in rat livers by comparison to feeding ad libitum even though rats fed ad libitum ingested far greater total amounts of iron than cyclically fed rats. With 1.23% iron in the diet, the concentration of iron in livers reached more or less the same plateau in cyclically starved-fed rats and in rats fed ad libitum (betwen 4 and 5 mg Fe/g wet weight); but the mean rate of accumulation of iron in the livers of cyclically starved and fed rats was more than twice that in rats fed ad libitum, whereas mean ingestion of iron per feeding day was only 16% higher in the former group. Surgical removal of the spleen enhanced the accumulation of iron in the liver in cyclically starved-fed rats and in rats fed ad libitum. Histologically, siderosis of the liver was moderate in rats fed the diet with 0.71% iron but was severe in rats fed the diet with 1.23% iron and most severe in those without spleens. Stainable iron was deposited in hepatocytes and in Kupffer cells. None of the rats developed cirrhosis of the liver. The data suggest that in rats a barrier to the absorption of iron from the gut, or to its later utilization, is surmounted if the concentration of iron in the food exceeds a certain limit value, somewhere between 0.71 and 1.23%. With iron in the food below this value, cyclic starvation-feeding markedly potentiates accumulation of iron in the liver in the course of several months, but siderosis is moderate. With iron in the food above the limit value, cyclic starvation-feeding and feeding ad libitum can equally lead to massive siderosis of the liver.

Animals↗
PubMed1984

Changes in the sensitivity of lipogenesis in rat hepatocytes to hormones and precursors over the diurnal cycle and during longer-term starvation of donor animals.

In rat hepatocytes freshly isolated from donor rats at different times of the day, the rates of lipogenesis (de novo fatty acid synthesis) varied with a diurnal periodicity. The maximal rate occurred approximately 5 hr after the end of the normal 8-hr feeding period and at this time was four- to fivefold higher than the minimum rate which occurred midway through the feeding period. A similar diurnal pattern of change persisted even when the supply of lipogenic substrate, present in the medium as pyruvate, was not limiting. Although insulin stimulated the basal rates of lipogenesis to different relative extents in hepatocytes isolated at different times of the day, in absolute terms the hormone had little effect on the overall pattern of change during the diurnal cycle. The presence of pyruvate protected lipogenesis against inhibition by glucagon. The degree of protection varied over the diurnal cycle. During the early stages of starvation (up to 24 hr) there was a continuous decline in the rate of hepatocyte lipogenesis, irrespective of whether insulin and/or lipogenic substrate (pyruvate) were available or not. After this time the decline in the rate of lipogenesis was much less rapid. Seventeen hr after removal of food from donor rats, a point was reached beyond which pyruvate was incapable of supporting the maximum basal rate of lipogenesis which occurred during the normal diurnal cycle of fed rats. After this time lipogenesis in the presence of pyruvate was inhibited by glucagon to a much greater relative extent than that observed during feeding. The results suggest that variations in the rate of lipogenesis over the diurnal cycle and during the first 24 hr of starvation could not be accounted for entirely by fluctuations in substrate availability. In contrast, changes which occurred subsequent to this (up to 43 hr of starvation) could be eliminated when lipogenic substrate was made more abundant. Longer periods of starvation were marked by a relative increase in the ability of glucagon to prevent the substrate-induced stimulation of lipogenesis.

Animals↗
PubMed1978

Renal sodium conservation during starvation in the rat.

The phenomenon of natriuresis during the early phase of total starvation has been described in man and rabbit. We have examined the pattern of electrolyte excretion initiated by starvation for 4 days in the male Wistar rat. Within 24 hr sodium excretion is significantly diminished when compared to prestarvation values (control 2.55 +/- 0.76 [S.D.] mEq/day; 1-day fast 0.42 +/- 0.27) and by day 2 is less than one tenth of the control value. Chloride retention parallels this sodium conservation. Concomitant changes in urinary pH and ammonia excretion (UNH4V) reflect the mild acidosis of starvation (control pH 7.46 +/- 0.18 [S.D.], UNH4V 0.21 +/- 0.08 [S.D.] mEq/day; day 2 pH 6.10 +/- 0.31, UNH4V 0.71 +/- 0.21). However, the excretion of organic acids is not elevated but is actually decreased by day 2 (control 1.02 +/- 0.21 [S.D.] mEq/day; day 2 0.66 +/- 0.26). The majority of the organic acids are excreted as salts (day-2 0.51 +/- 0.21). This level of excretion does not obligate excessive sodium loss and can be adequately matched by renal ammonia production. Normal plasma glucose levels are maintained, consistent with the well-documented increase in renal gluconeogenesis in the starved rat. Plasma levels of glucagon, a known natriuretic and ketogenic agent, do not rise, and this together with a normal plasma glucose concentration may account for the failure of the rat to exhibit the natriuresis of starvation that is observed in man and rabbit.

Ammonia↗
PubMed1980

[Changes in the pulmonary surfactant system during and after prolonged starvation].

In experiments on 76 white rats, a complex of physical and morphological techniques was used to study the state of the lung surfactant system in varying time after complete starvation and a possibility of its recovery with large doses of vitamin A. 4--5 day starvation without water restriction induced a significant decrease in surfactant secretion and diminution of its content in the alveolar lining. The intracellular reserves of the surfactant got recovered 4 weeks after the starvation was discontinued but the surface activity of the alveolar lining did not yet return to the initial level. Supplementary administration of large doses of vitamin A to rats by mouth after discontinuance of starvation led in two weeks to normalization of all the parameters characterizing the state of the lung surfactant system.

Animals↗
PubMedDate not supplied

[Oxidative phosphorylation and the activity of the polyenzyme systems of rat liver mitochondrial membranes in starvation].

The rate of mitochondrial phosphorylation, evaluation by coefficient of respiratory control and the ratio ADP/O, was decreased as a result of lowering in the rate of phosphorylation and DNP-stimulated oxidation, occurred in rat liver tissue under conditions of long-term starvation (5 days) as compared with control animals. In starvation rat liver mitochondria were most distinctly impaired by high temperature, phospholipase A2 and trypsin. Latent destructions, formed in mitochondrial membranes, were responsible for high lability of the organelles in starvation. In long-term starvation incorporation of exogenous cytochrome c into mitochondrial membrane was impaired also due to deterioration in structural relationship between phospholipids and protein of the membrane.

Animals↗
PubMed1980

[Effect of selection on the criterion of resistance to starvation in adults of Ceratitis capitata Wied (Diptera, Trypetidae)].

The mecanisms of resistance to starvation of adult Ceratitis capitata are analysed. This study is based on comparison of two laboratory strains: one which was previously selected for "resistance to starvation" the other which has never been selected. Resistance to starvation appears to be determined, on the one hand by reserves in the insect and their hourly rate of utilisation on the other hand by the efficiency of the antidiuretic system. The selection, which increased adult resistance to starvation acted upon these three factors. It modified the strategy of energy utilisation by inducing a more economic energy budget.

Animals↗
PubMed1998

Starvation induced hypothyroidism involves perturbations in thyroid superoxide-SOD system in pigeons.

This study investigated the influence of starvation over seven days on avian thyroidal superoxide radical levels and superoxide dismutase activity profiles in the Indian rock pigeon Columba livia intermeida, in relation with iodine metabolism. The serum thyroid hormone profile was assayed to correlate the thyroidal redox status with the circulating thyroid hormone levels. The spin-trapping results suggest a role for thyroidal superoxide anion (O2.-) in causing a hypothyroid state in pigeons during long term energy withdrawal. Pigeons starved for 1 day generated superoxide and iodide free radicals in their thyroids, with a significant decrease in SOD activity. Regain of SOD activity in 2nd- and 3rd-day starved birds is marked by complete scavenging of radicals in the thyroid, suggesting the significance of SOD in thyroid glands as a potential antioxidant sink against reactive oxygen species, O2.- Resurgence of O2.- radicals with a parallel decrease in SOD activity in the thyroid gland on 5th- and 7th-day of starvation provides evidence of disruption of homeostasis between pro-oxidant and antioxidant states, leading to oxidative stress in avian thyroid during long-term calorie crisis. Following starvation both thyroid hormones thyroxine (T4) and triiodothyronine (T3) decreased, putting pigeons in a hypothyroid state. We argue that oxidative inactivation of thyroid peroxidase and other thyroid proteins by radical attack during starvation invoked oxidative stress, which could be one of the factors responsible for the hypothyroid state in pigeons.

Animals↗
PubMed2000

Identification and transcription control of fission yeast genes repressed by an ammonium starvation growth arrest.

In fission yeast Schizosaccharomyces pombe, ammonium starvation induces a growth arrest, a cell cycle exit in G(1) and a further switch to meiosis. This process is regulated by the cAMP-dependent protein kinase and the Wis1-dependent MAP kinase cascade, and downstream transcription factors. In order to understand how cells adapt their genetic programme to the switch from mitotic cycling to starvation, a differential transcript analysis comparing mRNA from exponentially growing and ammonium-starved cells was performed. Genes repressed by this stimulus mainly concern cell growth, i.e. protein synthesis and global metabolism. Comparison of the expression of two of them, the ribosomal proteins Rps6 and TCTP, in many different growing conditions, evidenced a strong correlation, suggesting that their transcriptions are coordinately regulated. Nevertheless, by repeating the ammonium starvation on strains constitutively activated for the PKA pathway (Deltacgs1), or unable to activate the Wis1-dependent MAP kinase pathway (Deltawis1), or with both characteristics (Deltacgs1+Deltawis1), the transcriptional inhibition was found to be governed either by the PKA pathway, or by the Wis1 pathway, or by both. These results suggest that during the switch from exponential growth to ammonium starvation, cell homeostasis is maintained by downregulating the transcription of the most expressed genes by a PKA and a Wis1-dependent process. Accession Nos for the S30 and L14 ribosomal protein cDNA sequences are AJ2731 and AJ2732, respectively.

Biomarkers, Tumor↗
PubMed1999

Effect of serum starvation on expression and phosphorylation of PKC-alpha and p53 in V79 cells: implications for cell death.

The effect of serum starvation on the expression and phosphorylation of PKC-alpha and p53 in Chinese hamster V79 cells was investigated. Serum starvation led to growth arrest, rounding up of cells and the appearance of new PKC-alpha and p53 bands on Western blots. Prolonged incubation (> or = 48 hr) in serum-deprived medium led to cell detachment and death. Moving cells to fresh medium containing 10% serum before, but not after, cell detachment reversed the changes observed in PKC-alpha and p53, and also prevented later cell detachment. Radiolabelling studies showed that the higher-molecular-weight PKC-alpha and p53 bands result from increased phosphorylation, while a lower-molecular-weight PKC-alpha band reflects newly synthesized protein. Immunocomplex kinase assays have shown that the increased phosphorylation of PKC-alpha is associated with its increased activity. To study the relationship between PKC-alpha, p53 and cell death, cells were treated either with TPA, to down-regulate PKC or with staurosporine, to inhibit PKC activity. Staurosporine, a potent PKC inhibitor and inducer of programmed cell death, caused the appearance of new PKC-alpha and p53 bands similar to those induced by serum starvation. If serum starvation was preceded by prolonged (48 hr) TPA treatment to down-regulate PKC-alpha, cell detachment and death did not take place within the same time frame. Intracellular fractionation of cells demonstrated that increased expression of PKC-alpha and the appearance of the associated higher and lower molecular-weight bands occurred in the nucleus. These data highlight the association of PKC-alpha and p53 with cellular events leading to cell death.

Animals↗
PubMed2001

Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation.

The sensitive-to-apoptosis gene (SAG) was initially identified as a redox-inducible, apoptosis-protective protein and subsequently found to be the second family member of regulator of cullins (ROC)/RING box protein (Rbx)/Hrt, which acts as a component of E3 ubiquitin ligase. We report here that SAG promoted cell growth under serum starvation. Microinjection of SAG mRNA into quiescent NIH/3T3 cells induced S-phase entry as determined by [(3)H]-thymidine incorporation. Likewise, overexpression of SAG by either adenovirus infection of immortalized human epidermal keratinocytes (Rhek-1) or DNA transfection of SY5Y human neuroblastoma cells induced cell proliferation under serum starvation. Because cyclin-dependent kinase inhibitors (CKIs), including p21, p27, and p57, are degraded through the ubiquitin pathway, we tested whether SAG-induced cell growth is associated with CKI degradation. Although there was no significant difference in the levels of p21 and p57 between the vector controls and SAG-overexpressing cells, serum starvation induced 10- to 18-fold accumulation of p27 in control Rhek-1 cells. Accumulation of p27 was remarkably inhibited (only 2 to 5-fold) in SAG-infected cells. Inhibition of p27 accumulation was also observed in stably SAG-overexpressing SY5Y cells. Significantly, SAG-associated inhibition of p27 accumulation was largely abolished by the treatment with a proteasome inhibitor. In vivo binding of SAG and Skp2, an F-box protein that promotes p27 ubiquitination, was detected, and the binding was enhanced in SAG-overexpressing cells grown under serum starvation. Thus, SAG-induced growth with serum withdrawal appears to be associated with SAG-mediated p27 degradation. Mol. Carcinog. 30:37-46, 2001.

Animals↗
PubMed1978

Effect of extreme amino acid starvation on the protein synthetic machinery of CHO cells.

When CHO cells are incubated under conditions of extreme amino acid starvation, effected by withdrawal of an amino acid from the medium together with genetic or chemical interference with the activity of the corresponding aminoacyl-tRNA synthetase, there is a rapid and profound decline in the functional capacity of the protein synthetic machinery. The effect was observed for all amino acids tested including leucine, asparagine, histidine, methionine and glutamine. This decline in protein synthetic potential appears to be due to a progressive permanent inactivation of the specific aminoacyl-tRNA synthetase concerned, as shown by a decline in the amount of cellular, specific aminoacyl-tRNA and a decline in the cell-free enzyme activity, measured after reversal of the starvation conditions. When cells are left for more than several hours under these starvation conditions, they shrink in size, lose viability and eventually disintegrate, with anomalous rapidity. We suggest that the progressive loss of protein synthetic capacity of the cells is the prime cause of these subsequent events. If the starvation conditions are reversed before cell death, regeneration of the protein synthetic potential occurs rapidly but requires protein synthesis itself, implying the existence of strong control mechanisms for cellular aminoacyl-tRNA synthetase activities.

Amino Acids↗
PubMed1991

Yeast mutant affected for viability upon nutrient starvation: characterization and cloning of the RVS161 gene.

In yeast, nutrient starvation leads to entry into stationary phase. Mutants that do not respond properly to starvation conditions have been isolated in Saccharomyces cerevisiae. Among them the rvs161 mutant (RVS for Reduced Viability upon Starvation) is sensitive to carbon, nitrogen and sulphur starvation. When these nutrients are depleted in the medium, mutant cells show cellular viability loss with morphological changes. The mutation rvs161-1 is very pleiotropic, and besides the defects in stationary phase entry, the mutant strain presents other alterations: sensitivity to high salt concentrations, hypersensitivity to amino acid analogs, no growth on lactate or acetate medium. The addition of salts or amino acid analogs leads to the same morphological defects observed in starved cells, suggesting that the gene could be implicated mainly in the control of cellular viability. The gene RVS161 was cloned; it codes for a 30,252 daltons protein. No homology was detected with the proteins contained in the databases. Moreover, Southern analysis revealed the presence of other sequences homologous to the RVS161 gene in the yeast genome.

Amino Acid Sequence↗
PubMed1998

The signals for starvation response are transduced through elevated [Ca2+]i in Dictyostelium cells.

The mechanism by which cells recognize starvation to allow subsequent cellular development was analyzed using Dictyostelium discoideum, with special emphasis on Ca2+ as a crucial signal transducer in intra- and intercellular communications. As was expected, the cytosolic Ca2+ concentration ([Ca2+]i) in aequorin-expressing cells (RHI76 derived from D. discoideum Ax-3) was temporarily increased, when 3-5 microM thapsigargin (Tg), a specific inhibitor of the Ca(2+)-ATPase, was added into the cells incubated in semistarvation medium (SS-medium: 1 vol of growth medium plus 7 vol either of 20 mM Na2/K-phosphate buffer (pH 6.2) or of Bonner's salt solution (BSS)). Essentially the same result was obtained by the application of 5 microM nigericin (Ng), an acid ionophore to cells under the semistarved condition. Here it is of interest to note that in the SS-medium Tg and Ng are capable of enhancing cell differentiation as exemplified well by the earlier acquisition of chemotactic response to cAMP, possibly inducing the starvation response through the [Ca2+]i increase. From Western blot analysis of phosphotyrosine (pTyr)-containing proteins using anti-pTyr antibody, it was found that the pTyr-phosphorylation levels of 97-, 80-, and 45-kDa proteins increase specifically in response to starvation. Interestingly, Tg and Ng induced such a change of the 80-kDa protein in the cells incubated in the SS-medium. Taken together these results strongly suggest that the temporal increase of [Ca2+]i may be a matter of importance for signal transduction coupled with starvation response.

Animals↗
PubMed1993

Effect of glucose starvation on germ-tube production by Candida albicans.

By incubating starved and unstarved yeast cells in synthetic media with a pH of 4.5 or 6.7 at 37 degrees C the effect of a 3 hours' glucose starvation on germ-tube production by Candida albicans was evaluated. In addition the endocellular content of total carbohydrates, glycogen, trehalose and proteins after and before the starvation were dosed. The most interesting result was the overcoming of the pH-regulated dimorphism, thanks to the starvation treatment. In fact the starved cultures produced germ-tubes indifferently in neutral or acid media, whereas the filamentation of the unstarved cultures was more copious in pH 6.7 medium. The endocellular content of trehalose and protein was unchanged, whereas total carbohydrates and glycogen showed a shortage after the 3 hours' glucose starvation. The possible involvements of these metabolic changes in the regulation of dimorphic transition are discussed.

Candida albicans↗
PubMed2001

Starvation survivability of Thermococcus strains isolated from Japanese oil reservoirs.

The starvation survivability of seven Thermococcus strains isolated from four Japanese oil reservoirs was compared with that of Thermococcus strains from marine hydrothermal fields. 16S rDNA analyses showed the isolates to be closely related to Thermococcus litoralis. Growth of the isolates was dependent on amino acids, which were present at low concentrations in the oil reservoirs. At 80 degrees C in the formation water, strain CKU-1 from the oil reservoir showed a higher starvation survivability than strain KS-1 from the marine hydrothermal field. Crude oil did not affect the starvation survivability of strain CKU-1, but it reduced that of strain KS-1. These results indicate that strain CKU-1 could survive longer than stain KS-1 under the conditions of an oil reservoir. At 90 degrees C in artificial seawater without organic nutrients, the half-lives of the isolates were between 7.7 and 25.1 days. However, those of the strains from marine hydrothermal fields, except Thermococcus litoralis and Thermococcus chitonophagus, were less than 1.0 day. The higher starvation survivability is probably important for the hyperthermophiles to continue to exist in a hot subterranean oil reservoir where the supply of nutrients seems to be limited.

Adaptation, Physiological↗
PubMed1999

Changes in DNA Content and Cellular Death during a Starvation-Survival Process of Escherichia coli in River Water.

Abstract Four nucleoid staining procedures were compared during the starvation-survival process of Escherichia coli in river water. Only the method performed as a modification of the standard acridine orange direct procedure allowed us to visualize nucleoids during the 95 days of experimentation. Moreover, with this method the total number of cells and nucleoid-containing cells can be simultaneously enumerated. The decrease of the chromosomal DNA content of population and of the nucleoid-containing cells indicates that ghosts form and cellular death occurs throughout the starvation-survival process. A long time (<30 days) is needed for non-nucleoid-containing cells to appear in river water; plasmid DNA is also negatively affected by environmental stress. After 4 days of storage in river water, the need to increase the volume of lysed cells used for the plasmid band visualization as well as the decrease in the plasmid band intensity would indicate a decrease in the plasmid DNA content during the starvation-survival process. According to our results, both chromosomal and plasmid DNA content decrease during the starvation-survival process of E. coli in river water.

Journal Article↗