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R J Feuers

Publications and source records attributed to R J Feuers.

At least 37 records · Page 2Linked to original sources
PubMed1996

The effect of aging and dietary restriction on the retinoylation of nuclear matrix proteins in rats.

The labeling in vivo of young ad libitum (Y/AL) and old diet restricted (O/DR) rats with [3H]retinoic acid (RA) for 6 hours, and the exposure of electrophoretically separated nuclear matrix proteins from bone marrow tissue on film for 48 days revealed the presence of eleven retinoylated proteins. Dosing with RA (100 mg/kg body weight) for 96 hours and exposure to [3H]RA enhanced the levels of radioactive incorporation of several nuclear matrix proteins, including p51, and p55, similarly in Y/AL and O/DR rats. Dosing of old ad libitum (O/AL) rats with [3H]RA for 6 hours showed the incorporation of six proteins following 48 days of exposure on film. Long-term dosing of RA (96 hours) did not increase [3H]RA incorporation in these proteins, including p51 and p55, in O/AL rats. Increasing the level of RA by two-fold (200 mg/kg body weight) in Y/AL and O/DR rats elicited an increase in the incorporation levels of [3H]RA in five proteins. This dose response following increased levels of RA was not seen in the retinoylated proteins of O/AL animals. Analysis by the Western blotting technique showed p51 and p55 from rat bone marrow cells to have the same immunochemical determinates with proteins of identical molecular masses in HL60 cells. The levels of retinoylation of nuclear matrix proteins in O/DR animals, altered by age- and diet-dependent factors, suggests a condition that is more reminiscent of Y/AL than of O/AL animals.

Aging↗
PubMed1996

P48: a novel nuclear protein possibly associated with aging and mortality.

The synthesis ([35S]-incorporation) of stress proteins (sps, i.e., 24, 25, 70, 90 Mr) and of nuclear protein 48 (p48) was investigated in the heart and bone marrow cells of three groups of male Fischer 344 rats following administration of isoproterenol (IPR). Two groups of rats, young ad libitum (Y/AL-3 1/2 months) and old/AL (O/AL-28 months), had full access to rat chow; a third group of old diet restricted (O/DR-28 months) rats was maintained on a diet restricted intake of 40% of the Y/AL animals. Sp synthesis in the bone marrow (25, 70, 90 Mr) and heart (24, 70, 90 Mr) nuclei of O/AL was significantly reduced, as compared with Y/AL and O/DR rats, following their induction with IPR. A unique sp24 was expressed in heart following IPR dosing. A 1 mg/kg dose of IPR was lethal for O/AL, but not for Y/AL or O/DR animals. This lethal dose induced synthesis of p48 in heart and bone marrow nuclei of O/AL rats only. P48 existed in isoform states in bone marrow, and when a lethal dose of IPR was administered in this tissue, it was expressed in O/AL rats in a cell-cycle regulated pattern. Stress proteins and other non-sps were seen as cell cycle regulated following IPR administration. P48 in bone marrow and heart nuclei from O/AL rats showed an antigenic response identical to that of p48 in HL60 nuclei. The presence of p48 is correlated with mortality and with an ad libitum diet in old rats, since it is absent in old diet restricted animals; therefore, DR may impede the expression of p48 through a mechanism(s) that is undisclosed at this time.

Aging↗
PubMed1996

Comparison of the cell cycle regulated synthesis and phosphorylation of stress proteins, actin isoforms and a novel actin-like protein following drug administration in cultured rat lymphocytes.

Administration of phytohemagglutinin initiated cycling of rat lymphocytes in vitro, and following treatment with this drug and other drugs in combination, lymphocytes were pulse labeled with [3H] leucine of [32P] phosphate. The nuclei were isolated from lymphocytes and collected from partitions of the cell cycle, and the proteins analyzed from fluorographs following gel electrophoresis for protein biomarkers after drug exposure. Stress proteins (sps) were dependent on a specific drug or drugs in combination (i.e., interleukin-2, bleomycin) for their synthesis that occurred only during the G1-phase of the cell cycle. An "actin-like" protein (A4) with electrophoretic mobilities similar to the actin complex, was synthesized in S and G2 phases and phosphorylated in all phases of the cell cycle only following the administration of drugs in combination. A4 exhibited a binding affinity for sp 24 that was cell cycle regulated (i.e., A4 from S phase did not bind with sp 24, but A4 from G2 phase did bind with the sp. Protein A4 appeared similar in some structural aspects to the nonmuscular actin isoform family but differed in epitope, suggesting a unique relationship and represented a stable protein, perhaps a product from the mutation of an actin gene. The dependence of certain sps and protein A4 for their induction by drugs in combination may serve as biomarkers of chemical interaction and toxicity.

Actins↗
PubMed1996

Effects of ischemia-hypoxia induced by interruption of uterine blood flow on fetal rat liver and brain enzyme activities and offspring behavior.

The effects of acute perinatal ischemia-hypoxia on fetal liver and brain energy metabolism, fetal brain total free fatty acid concentration and subsequent offspring behavior were investigated in rats. Ischemia-hypoxia was induced at term either by ligation of the uterine blood vessels or submersion of the entire uterine horn in warmed saline. Fetuses of the adjacent horn served as within-dam controls for all assessments and fetuses of dams which had not undergone the surgical stress served as independent controls for enzyme assays. Ischemia-hypoxia was associated with reduced activity of fatty acid synthase in the liver and brain. Total free fatty acid concentration significantly increased in the fetal hypoxic brain. Pups not used for enzyme analyses were cross-fostered for behavioral assessments. Relative to the enzymatic alterations, there were few behavioral alterations associated with ischemia-hypoxia. At postnatal day 30, rats made hypoxic by ligation of the uterine blood vessels had decreased caudate nucleus and brain stem weights relative to within-dam controls. At postnatal day 85, rats made hypoxic by submersion of the uterine horn had decreased olfactory bulb weight. The results of this study indicate an initial acute response to a brief period of ischemia-hypoxia at term pregnancy in the fetal rat brain and liver.

Age Factors↗
PubMed1995

Genotoxicity of tacrine in primary hepatocytes isolated from B6C3F1 mice and aged ad libitum and calorie restricted Fischer 344 rats.

Tacrine (1,2,3,4-tetrahydro-9-aminoacridine; THA), a reversible centrally acting anticholinesterase, has been shown to be potentially useful for treatment of patients with Alzheimer's disease. However, currently available forms of THA may be therapeutically limited by the fact that high doses have resulted in liver and kidney damage. To determine if THA is hepatotoxic via a genotoxic mechanism, we evaluated its ability to induce unscheduled DNA synthesis (UDS) in primary cultures of rodent hepatocytes. Positive dose-dependent increases in UDS were observed in hepatocytes derived from male B6C3F1 mice and from young, middle-aged, old, and old Aroclor-induced (ARO) male F344 rats maintained on either an ad libitum (AL) or a caloric restricted (CR) diet (60% of AL) and exposed to 0.05-1000.0 micrograms/ml of THA. Hepatocytes from old AL rats, treated with THA, exhibited significant age-related decreases in DNA repair compared to young and middle-aged AL rats. By contrast, cultures from CR rats exhibited age- and diet-related decreases in UDS from the AL and young CR animals, respectively. Moreover, ARO-induced old AL- and CR-derived hepatocytes exhibited significant increases in UDS compared to uninduced old AL and CR animals. No cytotoxicity was observed in the uninduced old AL- or any CR-derived hepatocytes. These data indicate that the aged and CR fed animal is less susceptible to the cytotoxic and genotoxic effects of THA; while the younger AL fed and enzyme induced old AL or CR fed animals were more susceptible. The data suggest that THA may be a genotoxic rodent carcinogen. At present, the relationship of these findings to the clinical use of THA are unclear and further study is required.

Aging↗
PubMed1994

Temporal and substrate-dependent patterns of stress protein expression in the hypothalamus of caloric restricted rats.

Stress proteins (sps) 27, 34, 70 and 90 (Mr x 10(3)) were induced in the hypothalamus of caloric restricted (CR) rats by feeding stress. A definite time pattern for sps synthesis was observed when their induction was examined at several time points after the rats were fed, and the level of sps expression was found to vary significantly at different times of the day. The same group of proteins was induced in ad libitum fed rats when they were subjected to food deprivation for 48 h. Stress protein 34 expression in the hypothalamus of old caloric restricted rats was found to be dependent on blood glucose levels, and was substantially reduced when insulin was added to the glucose infusion. The expression of sps 27, 70 and 90, however, was little changed with glucose and/or insulin infusion.

Aging↗
PubMed1994

Chronic caloric restriction induces stress proteins in the hypothalamus of rats.

The induction of stress proteins (sps) in the hypothalamus of female Fischer 344 rats in response to caloric restriction (CR) and to heat stress was investigated. Caloric restriction was found to elicit sps 27, 34, 70, and 90 in the hypothalamus of both young and old rats while none was found in the hypothalamus of ad libitum (AL) fed controls. Heat stress initiated heat shock proteins (hsps/sps) 27, 70, and 90 in the hypothalamus of the young (AL) fed animals, the same proteins evoked by feeding stress. The same sps were induced in the old (AL) rats although the expression showed substantial decline with age. This reduction was less marked, however, with the old CR rats. Stress protein 34, an infrequently reported protein, was related to feeding and was not induced by heat shock. Recent reports point to the important role sps play in the cellular reaction to stress, as well as their involvement in the higher functions. The findings reported here suggest that sps are involved in the regulatory mechanisms allowing CR animals to tolerate stress related to metabolic substrate deprivation.

Aging↗
PubMed1994

The homology of a novel polypeptide with stress protein characteristics in embryonic mice brain and in the hypothalamus of caloric restricted rats as determined by ultramicro western blotting.

A novel protein (p34) was observed in polyacrylamide gel fluorographs of gestation day 13 embryonic mouse brain following retinoic acid dosing of dams. Another p34 polypeptide with identical gel migratory characteristics was seen in the hypothalamus of old caloric restricted rats after "food deprivation stress". Western blotting, employing an ultramicro trans-blot cell developed in our laboratory, detected identical immunochemical determinants between these proteins, verifying their homology. Peptide mapping and Western blotting further validated the uniqueness of p34 compared with other stress proteins including heme oxygenase.

Animals↗
PubMed1994

The temporal relationships of synthesis and phosphorylation in stress proteins 70 and 90 in aged caloric restricted rats exposed to bleomycin.

A single intraperitoneal injection of the human therapeutic drug bleomycin (BL) was administered to three groups of male Fischer 344 rats at time 0, and the incorporation of [35S]methionine ("synthesis") and phosphorylation patterns of stress proteins (sps/hsps) from bone marrow cells were analyzed over time by two-dimensional electrophoresis and fluorography. Two groups of rats, young ad libitum (Y/AL--3 months) and old ad libitum (O/AL--28 months), had free access to rat chow, and a third group of old rats (O/CR--28 months) were maintained on a caloric restricted intake (60% of the AL diet). The administration of BL in Y/AL, O/AL and O/CR animals activated the 35S-labeling of sp 90 which reached a peak at 4 hours. Labeling of sp 90 was significantly greater in Y/AL compared to O/AL, and the incorporation pattern of O/CR was intermediate to Y/AL and O/AL animals. All labeling of sp 90 in each group had disappeared by 10 hours after BL administration. Stress protein 70x (inducible form) in these three animal groups displayed a similar pattern of 35S-incorporation, but the amount of labeling was less than that of sp 90. No labeling of sp 70x remained by 13 hours after BL administration. Phosphorylation ([32P] phosphate incorporation) of sp 90 reached a maximum level at 2 hours in all animals, and 32P-labeling in Y/AL was significantly increased over O/AL and O/CR with an intermediate level found in O/CR animals. The turnover rate (phosphorylation/dephosphorylation) of sp 90 induced by BL was significantly suppressed and temporarily extended in O/AL as compared with O/CR, which implied that CR not only increased incorporation of sp 90, but also enhanced a utilization of the phosphate pool very similar to that seen in Y/AL animals.

Aging↗
PubMed1994

Acute toxicity of ganciclovir: effect of dietary restriction and chronobiology.

The effect of diet, age and time of dose delivery on the mortality of female B6C3F1 mice from ganciclovir sodium (DHPG) was determined for both single (SD; 400 mg DHPG/kg, ip) and multiple doses (MD; same dose ip for 10 additional days) of the drug. Young (7-10 months) and middle-aged (MA; 19-22 months) mice (B6C3F1), both fed ad lib. (AL) and calorie restricted (CR), were dosed at 0, 6, 12 and 18 hr after lights on (HALO; SD study) and at 12.00 hr (MD study). The SD study mortality rate was 38% (AL) and 1.7% (CR) (P < 0.00001). Mortality was 53% (AL, young; P < 0.00001), over 20% (AL, MA), over 1.8% (CR, MA; P = 0.00004) or more than 1.7% (CR, young; P = 0.00002). Effects were independent of lean body mass differences between AL and CR mice. In the SD study, comparing AL mice only, the greatest mortality was seen in young mice at 6 HALO, (73%; P = 0.0034) and lowest mortality in MA mice at 12 HALO (8%; P = 0.026), whereas in the MD study mortality was 63% AL and 33% CR (P = 0.015). By age, MD mortality was 80% (AL, young; P = 0.0035), 50% (CR, MA), 47% (AL, MA), and 15% (CR, young; P = 0.0013). CR protected both young and MA mice in SD and young mice in MD. Lowest mortality for AL was at 12 HALO. It is suggested that dosing at 12 HALO may protect by decreasing DHPG uptake during a period of minimal DNA synthesis in the affected organ(s). CR and timing of DHPG dose may obviate the necessity to discontinue DHPG because of toxicity in humans. The most significant finding of this study is the impact of diet on mortality.

Aging↗
PubMed1994

Dietary restriction attenuates age-related increases in rat skeletal muscle antioxidant enzyme activities.

Dietary restriction (DR) retards aging in rodents, but its mechanism of action remains unclear. Free radicals have been hypothesized to be involved in aging and in DR's actions. We investigated the influences of age and DR on the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD) in skeletal muscle from 11-, 26- and 34-mo-old (BN x Fischer 344) F1 rats fed either ad libitum (AL) or subjected to a 30% DR from 14 weeks of age. The mass of the upper hindlimb muscles recoverable in 34-mo-old AL rats was only 52% that of 11-mo-old AL rats, whereas rats on DR showed a stable, intermediate value at both ages. CAT and GPX activities increased progressively and markedly in muscle of AL animals with aging. The increase in CAT activity was partially attenuated by DR, while that of GPX was entirely prevented. These effects of aging and DR were more profound in 12,000 x g pellets than in cytosolic fractions. SOD activities were more variable and not clearly influenced by age or DR. These data agree with prior reports of an age-related increase in skeletal muscle antioxidant enzyme activities. Further, DR attenuates this alteration and does so most profoundly in the 12,000 x g pellet, the fraction which is enriched in mitochondria.

Aging↗
PubMed1993

Chronobiology as it relates to toxicology, pharmacology, and chemotherapy.

Examples of circadian (daily) rhythms in man are presented and discussed. This is followed by presentation of experimental data indicating how the temporal organization affects the response of the host to potentially toxic agents, namely amphetamine and sodium pentobarbital. Data also are presented indicating that one unequivocally can improve therapeutic efficacy using the L1210 mouse leukemia model. This was accomplished by taking into consideration the circadian host toxicity response to anticancer agents, namely cytosine arabinoside, adriamycin, and cyclophosphamide. The subject monitored was the "cure rate" subsequent to treatment of different tumor loads.

Animals↗
PubMed1993

Evidence that DNA repair may not be modified by age or chronic caloric restriction.

Pretreatment of animals with mixed-function oxidase inducers has been shown to increase the metabolic activation capacity of isolated hepatocytes resulting in an apparent increase in DNA repair. We recently reported decreases in chemically-induced DNA repair, measured as unscheduled DNA synthesis (UDS), in hepatocyte cultures isolated from aging ad libitum (AL) and caloric restricted (CR) diet-fed animals. In the present study, we evaluated the effects of pretreatment with Aroclor 1254 (ARO) on the genotoxicity of 4 carcinogens, from different chemical classes, in primary hepatocytes isolated from male Fischer 344 rats. ARO-induced old AL- and CR-derived cultures, treated with 2-acetylaminofluorene (2-AAF), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMBA), and dimethylnitrosamine (DMN), exhibited significant induction-related increases in DNA repair in comparison to uninduced old AL and CR animals. These data indicate that the constitutive levels of specific cytochrome P450 decline with age and chronic caloric restriction, while the ability to respond to exogenous inducers is retained, and suggest that DNA repair may not be modified with age or diet restriction.

2-Acetylaminofluorene↗
PubMed1993

Comparative studies of synthesis, phosphorylation, DNA binding and proteolytic characteristics of a novel protein during phases of the mouse spleen cell cycle.

1. Cultured mouse spleen cells were exposed to the mitogen Concanavalin A followed by isoproterenol, and nuclei were electronically sorted from seven partitions of the cell cycle. 2. Several nuclear proteins, including stress proteins, which were cell-cycle-stage specific, were elicited by isoproterenol as determined by micro-electrophoresis and fluorography. 3. Two novel S-phase proteins (X0 and X') demonstrated differing synthesis and phosphorylation patterns during the cell-cycle phases. 4. X' showed DNA binding characteristics and proteolytic properties (hydrolyzing X0 or beta-galactosidase); both proteins were cell-cycle regulated.

Animals↗
PubMed1993

Application of an integrated rate equation to the inactivation of catalase.

A feature of catalase that has received scant attention in recent years and that may have physiological significance is the peroxide-dependent inactivation of the enzyme. In this article we show how to obtain the second-order rate constant for the inactivation reaction by fitting the reaction progress curve to an integrated rate equation. This method will simplify quantitation of the inactivation and reactivation of catalase. These measurements in tissues with altered metabolic states may reveal new information about the role of catalase in nutrition, aging, and pathology.

Animals↗
PubMed1993

Effects of aging and caloric restriction on the genotoxicity of four carcinogens in the in vitro rat hepatocyte/DNA repair assay.

The effects of aging and chronic caloric restriction (CR) on the genotoxicity of four carcinogens, representing four different classes of chemicals, in the in vitro rat hepatocyte/DNA repair assay were investigated. Hepatocyte cultures were isolated from young, middle-aged, and old male Fischer (F344) rats which were maintained on either an ad libitum (AL) or a CR diet (60% of AL). Hepatocyte cultures from old AL rats, treated with 2-acetylaminofluorene (2-AAF), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMBA) and dimethylnitrosamine (DMN), exhibited age-related decreases in DNA repair as compared to young AL rats. By contrast, cultures from young CR rats exhibited significant diet-related decreases in DNA repair with 2-AAF, AFB1, DMBA and DMN, when compared to results from young AL diet-fed rats. Old CR F344 rat derived cultures exhibited no significant age-related dose-dependent decrease in the DNA repair response with any of the chemicals tested. However, in cultures from old CR rats 10.0 microM AFB1 produced an age-related decrease in DNA repair from the response observed in young CR rats. When hepatocytes were isolated from Aroclor 1254-induced rats, increases in DNA repair were observed. These data indicate an age- and diet-related decrease in DNA repair and/or DNA damage and suggest that this decrease is due to a decrease in metabolic activation of these carcinogens to genotoxic species.

2-Acetylaminofluorene↗