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Biomedical subjects

J W Bauman

Publications and source records attributed to J W Bauman.

At least 19 recordsLinked to original sources
PubMed1995

Inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on rat hepatocyte proliferation induced by 2/3 partial hepatectomy.

To better understand the mode of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced alterations in hepatic cell proliferation and the potential link to tumour-promoting activity, we investigated the effects of TCDD on the expression of certain key genes involved in liver cell growth and the effects of TCDD on induced hepatocyte cell proliferation. Gene expression analysis was conducted, by Northern blot hybridization, using RNA isolated from female Sprague-Dawley rat livers collected at various times during a 14-day dosing period with TCDD known to produce alterations in cell proliferation. No major changes were observed in the expression of the transforming growth factors TGF-alpha and TGF-beta or in oncogenes ras, src and myc. However, the expression of the transcription factors C/EBP, HNF-1 alpha and HNF-4 decreased after 14 days of TCDD treatment. To investigate how TCDD affects hepatic growth, cell proliferation analysis was conducted in rats stimulated to undergo hepatocyte proliferation following either 2/3 partial hepatectomy or lead nitrate treatment. Cell proliferation was quantified by means of immunocytochemical detection of Proliferating Cell Nuclear Antigen (PCNA). Fourteen days of pretreatment with TCDD caused an overall inhibition of hepatocytes in the growth fraction (G1, S, G2 and M) from 61 +/- 3% in the control-partial hepatectomy group to 41 +/- 3% in the TCDD-partial hepatectomy group. A periportal pattern of cell proliferation was observed in the TCDD-partial hepatectomy group as compared to the panlobular pattern of cell proliferation in the control-partial hepatectomy group. TCDD pretreatment also produced an inhibition of cell proliferation induced by the liver mitogen lead nitrate. TCDD-induced inhibition of hepatocyte proliferation could play a role in TCDD tumour promotion and hepatocarcinogenesis through the creation of a environment whereby preneoplastic cells continue to expand while normal hepatocyte proliferation is inhibited.

Animals↗
PubMed1993

Induction of metallothionein by arsenicals in mice.

Metallothionein (MT) is a sulfhydryl-rich, metal-binding protein that provides protection against metal toxicity. MT is induced by acute stress, hormones, metals, and various organic compounds. Recently, arsenicals have also been shown to induce MT. However, the mechanism and character of MT induction by arsenicals is unknown. Therefore, the effect of various arsenic forms on the tissue concentration of MT was determined. Mice were injected sc with various doses of arsenite [As(III)], arsenate [As(V)], monomethylarsenate (MMAA), and dimethylarsenate (DMAA), and MT content in the liver was measured 24 hr later by the Cd-hemoglobin radioassay. As(III) is a potent hepatic MT inducer in that a 30-fold increase in MT was observed at the dose of 85 mumol/kg. In comparison, it took 3-, 50-, and 120-fold higher molar amounts of As(V), MMAA, and DMAA, respectively to produce a similar effect. MMAA produces the largest increase in hepatic MT (80-fold), followed by As(III) (30-fold), As(V) (25-fold), and DMAA (10-fold). However, none of the arsenicals induced MT in mouse primary hepatocyte cultures. Both MT-I and MT-II were coordinately induced by As(III), As(V), and MMAA. MT induction by As(III) was further characterized following sc administration of arsenite (85 mumol/kg). Hepatic MT induction peaked at 24 hr, and in addition to the liver, As(III) also increased MT in kidney, spleen, stomach, intestine, heart, and lung. MT-I mRNA increased 24-, 52-, and 11-fold at 3, 6, and 15 hr after As(III) administration. This induction profile is similar to that observed after Zn or Cd exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Production of metallothionein and heat-shock proteins in response to metals.

Acute stress, such as heat, and some metals, such as arsenite, will induce a specific group of stress proteins referred to as heat-shock proteins. The heat-shock proteins contribute to the survival of cells following a variety of stresses. Similarly, metals such as cadmium and zinc, will increase the levels of metallothionein (MT). The metal-binding protein, MT, has also been found to have a protective role in the cellular response to acute stresses like heavy metals. The purpose of the present study was to examine the production of these proteins in response to metals. Rat hepatocytes were maintained in monolayer culture for 22 hr, and subsequently treated with various concentrations of metals for 4 hr, or incubated at 43.5 degrees C for 15-60 min. Following two washes with fresh media, the cells were labeled with [35S]-methionine (25 microCi/ml) in methionine-free media for 4 hr for determination of heat-shock protein production, or reincubated in fresh media for 20 hr for MT determination. Heat-shock protein production was determined by SDS-polyacrylamide gel electrophoresis followed by autoradiography. The autoradiograms were quantified by densitometric scanning. MT was determined by the Cd/hemoglobin affinity assay. Three metals (arsenite, cadmium, and zinc) strongly increased the heat-shock proteins. Whereas arsenite was a much less effective inducer of MT than was cadmium or zinc, arsenite was as effective as the other metals in inducing heat-shock proteins. Nickel was a good inducer of MT; however, it resulted in only a slight increase in the levels of heat-shock proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of galactose regimen on glomerular heparan sulfate synthesis and albumin excretion in diabetic rats.

Decreased glomerular heparan sulfate synthesis could account for the increased albuminuria observed in experimental diabetes. A similar albuminuria has been observed in galactose-fed animals. To test whether heparan sulfate synthesis is also decreased in galactosemic animals we measured the heparan sulfate synthesis in isolated renal glomeruli from streptozotocin diabetic and normal rats fed regular diets or 30% galactose diets for 11-12 weeks. Albumin excretion and glomerular heparan sulfate synthesis were determined at the time of sacrifice. As predicted by this hypothesis glomerular heparan sulfate synthesis was significantly lower in the diabetic group than in normals given regular diets (309 +/- 23 vs 487 +/- 56 dpm/mg glomerular wt.; P < 0.01), and albumin excretion greater in these diabetics than in the normals (20 +/- 4.3 vs 2.0 +/- 0.7 mg/24 hr; P < 0.002). Albumin excretion and glomerular heparan sulfate synthesis were also consistent with the hypothesis, but unpredictably reversed, in the galactose-fed diabetic group. Glomerular heparan sulfate synthesis was significantly increased in this group (713 +/- 67 dpm/mg glomerular wt.) and albumin excretion decreased (10.7 +/- 3.6 mg/24 hr) compared to the diabetic on regular diet. Some possible explanations are discussed, but the galactose effect described here remains phenomenological.

Albuminuria↗
PubMed1992

Induction of metallothionein by diethyl maleate.

Metallothionein (MT) is a sulfhydryl-rich protein whose levels are increased by administration of a variety of agents including metals, cytokines, and oxidative stress agents. Recent studies have suggested that MT is involved in protecting against various forms of oxidative stress, but little is known about the induction of MT by oxidative stress agents. Diethyl maleate (DEM) causes oxidative stress by depleting glutathione levels and is quite effective at increasing hepatic concentrations of MT. The purpose of the current study was to learn more about the relationship between induction of MT and oxidative stress by characterizing this increase in hepatic MT levels produced by DEM. Administration of DEM (3 to 9 mmol/kg, sc) increased hepatic MT concentration in mice as much as 37-fold to 213 micrograms MT/g liver, which is similar to the hepatic MT level seen after administration of other effective MT inducers, such as Cd. The maximal increase of hepatic MT took place 12 to 24 hr after administration of 5 mmol DEM/kg. This rise in MT was preceded by a 60% depletion of hepatic glutathione 3 hr after DEM and increases in both MT-I and MT-II mRNA, which reached a peak 6 to 9 hr after DEM. Administration of DEM (3-5 mmol/kg, sc) also increased MT levels in Sprague-Dawley rats. Pretreatment with DEM protected against Cd-induced hepatotoxicity in a fashion which suggested that a functional MT was being synthesized. In summary, DEM is a highly effective inducer of MT which increases MT at the mRNA level.

Animals↗
PubMed1992

Examination of potential mechanism(s) of metallothionein induction by diethyl maleate.

Diethyl maleate (DEM) is a glutathione-depleting agent that can increase the levels of the sulfhydryl-rich protein metallothionein (MT) in liver. The purpose of the present study was to examine the mechanism(s) by which DEM increases mouse hepatic MT levels. DEM appears to be an indirect MT inducer as suggested by the lack of increase in MT levels when cultured mouse hepatocytes were exposed to DEM. Four possible mechanisms by which indirect MT inducers may cause an elevation in MT concentrations in liver were examined. Zn levels did not increase prior to the increase in hepatic MT, thus, a Zn redistribution to the liver is not the cause of the liver MT induction by DEM. The adrenal gland products were not required for MT induction in liver, as adrenalectomy did not abolish the increase in hepatic MT caused by DEM. The elevation in liver MT does not appear to be due solely to the decrease in liver glutathione (60%) in the initial hour after DEM, because phorone, which decreases liver glutathione (80%), produced only a fourfold increase in hepatic MT. Activation of macrophages does not seem to account for the rise in liver MT levels, as there was no increase in abundance of cytokine mRNAs for TNF-alpha, IL-1 beta, or IL-6 in the liver. These data suggest that the induction of hepatic MT by DEM does not occur in response to (1) an increase in liver Zn that precedes the increase in liver MT, (2) release of adrenal gland products, (3) decrease in liver glutathione, or (4) increased cytokine gene expression.

Adrenalectomy↗
PubMed1992

Induction of hepatic metallothionein by paraquat.

Paraquat, a frequently used contact herbicide, produces oxidative stress by undergoing redox cycling and generating reactive oxygen species. Paraquat is also effective at increasing hepatic levels of metallothionein (MT). The mechanism(s) by which agents that induce oxidative stress produce increases in MT concentrations is not yet known. Therefore, the goal of the current study was to characterize the elevation in hepatic MT produced by paraquat administration to mice and to examine potential mechanism(s) of this increase. A dose-response study for increases in MT showed that administration of 0.1 to 0.5 mmol/kg of paraquat, sc, increased hepatic MT with a maximal increase of 36-fold. Subsequent studies were carried out with paraquat at a dose (0.3 mmol/kg, sc) that caused oxidative stress, as shown by a 35-fold increase in the biliary excretion of oxidized glutathione. There were coordinate elevations of both hepatic MT-I and MT-II mRNA of approximately 5-fold with peaks at both 6 and 24 hr after paraquat. The time course for the elevation in hepatic MT protein following paraquat treatment showed that MT levels had a maximal increase of 18-fold obtained at 36 hr. Paraquat appears to be an indirect MT inducer, in that there were no elevations in MT when cultured mouse hepatocytes were exposed to paraquat. No rise in liver Zn was observed prior to the increase in hepatic MT, thus, a Zn redistribution to the liver did not cause the increase in hepatic MT following paraquat administration. Adrenalectomy did not abolish the increase in MT produced by paraquat, suggesting that adrenal gland products are not required for the increase in MT produced by paraquat. In conclusion, the chemical mediator responsible for the increase in hepatic MT after paraquat was not determined, but the elevation in MT concentration appears to be due to increased transcription.

Animals↗
PubMed1991

Increase in metallothionein produced by chemicals that induce oxidative stress.

Metallothionein (MT) is a low-molecular-weight protein with a high cysteine content that has been proposed to play a role in protecting against oxidative stress. For example, MT has been shown to be a scavenger of hydroxyl radicals in vitro, and cells with high levels of MT are resistant to radiation. However, it is not known if compounds that cause oxidative stress affect MT levels. Therefore, mice were injected subcutaneously with 11 chemicals (t-butyl hydroperoxide, paraquat, diquat, menadione, metronidazole, adriamycin, 3-methylindole, cisplatin, diamide, diethyl maleate, and phorone) that produce oxidative stress by four main mechanisms. MT was quantitated in the cytosol of major organs (liver, pancreas, spleen, kidney, intestine, heart, and lung) by the Cd/hemoglobin radioassay 24 hr after administration of the chemicals. All agents significantly increased MT levels in at least one organ. Liver was the most responsive to these agents in that all 11 chemicals increased MT concentrations in liver, with diethyl maleate, paraquat, and diamide producing 20- to 30-fold increases. Pancreas and kidney were the next most responsive organs to these chemicals. The organ least responsive to these agents was the heart, as only 3 compounds caused significant increases in MT concentrations in heart. Diethyl maleate and diquat were the most general inducers of MT in that they increased MT in six of the seven organs examined. No treatment resulted in a significant decrease in MT concentration in any organ. In conclusion, chemicals that produce oxidative stress by one of four distinct mechanisms are very effective at increasing MT concentrations in a variety of organs. This suggests that MT might be involved in protecting against oxidative stress.

Animals↗
PubMed1983

Na+-K+-ATPase in rat vascular smooth muscle cell grown in vitro.

This study has focused on the characteristics of the Na+-K+-ATPase in in vitro preparations of vascular smooth muscle cells (VSMCs) derived from the rat carotid artery. The maximum velocity of enzyme reaction (Vmax) for the specific activity of the enzyme in the VSMCs' preparations was 2.36 +/- 0.04 (SE) mumol Pi X mg cell protein-1 X h-1 or 0.82 +/- 0.02 mumol Pi X 10(6) cells-1 X h-1. The activation of the enzyme by potassium, sodium and ATP has been investigated. The half-maximal values for potassium and sodium activation of the enzyme in the preparations were 1.18 and 10-20 meq/l, respectively. The respective Vmax values for potassium and sodium activation were reached at concentrations of 4-10 and 80-100 meq/l. The Michaelis constant for ATP was 0.83 mM. Calcium exerted a potent inhibition on the activity of the enzyme (I50 at 1 mM). It has been concluded that the Na+-K+-ATPase kinetic pattern in in vitro preparations of VSMCs is quite similar to that observed in homogenates or subcellular fractions of other tissues.

Animals↗
PubMed1983

Vanadium, Na-K-ATPase, and potassium adaptation in the rat.

Vanadate is a potent inhibitor of Na-K-ATPase in vitro. It has been suggested that vanadium may function as a cellular regulator of Na-K-ATPase in vivo. To examine this speculation, we studied in rats the effect of high vanadate intake on 1) the tissue levels and distribution of vanadium, 2) basal activity of Na-K-ATPase in various tissues, and 3) the activity of Na-K-ATPase in various organs under conditions of massive chronic potassium loading known to stimulate Na-K-ATPase in the kidney and colon. Despite extremely high tissue levels of vanadium there was no demonstrable effect of the element on the basal activity of Na-K-ATPase. When subjected to chronic potassium loading, rats with high tissue vanadium concentrations underwent potassium adaptation that was associated with a rise in Na-K-ATPase activity in the renal cortex, renal medulla, and colonic mucosa. Further studies are needed to support or refute the thesis that vanadium might be an intracellular regulator of Na-K-ATPase in vivo.

Animals↗
PubMed1982

Balance and tissue distribution of vanadium after short-term ingestion of vanadate.

Forty-six female Sprague-Dawley rats (170-200 g) were randomly assigned to one of six treatment groups receiving 0.1, 5.0, or 25.0 ppm dietary vanadium with either normal (0.13 mEq/g) or high (1.82 mEq/g) dietary potassium. Supplemental vanadium was administered as sodium metavanadate. These diets were fed for 2 weeks, and all feces and urine collected. At the end of the treatment period, brain, liver, renal cortex and medulla, whole blood, and plasma were obtained and analyzed for vanadium by atomic absorption spectrophotometry, as were the urine and feces samples. Tissue vanadium concentration increased significantly (P less than 0.00001) with increasing food vanadium content, but were not affected by dietary potassium in spite of the polyuria induced in animals on the high potassium diets. The highest vanadium concentrations were found in the renal cortex and the lowest, in the brain. Although urinary vanadium excretion was higher in animals fed the high potassium diets, a relatively small percentage of ingested vanadium was excreted in the urine. Rats fed diets containing no supplemental sodium metavanadate (0.1 ppm vanadium) were in negative vanadium balance, but their growth was not inhibited. Animals receiving 5.0 and 25.0 ppm vanadium diets retained 39.7 +/- 18.5% of ingested vanadium and excreted 59.1 +/- 18.8% of ingested vanadium in the feces. These values indicate greater absorption and retention of ingested vanadium than found In previously reported investigations.

Animals↗
PubMed1982

Chronic sodium deficit in the immature rat: its effect on adaptation to sodium excess.

The impact of chronic low-sodium intake during early development on body sodium homeostasis is not sufficiently known. To explore this effect, we have investigated the influence of chronic sodium deficit during the rapid growth period of rats (first phase, age 3-7 wk) and the short-term effect of sodium repletion (second phase, age 8-9 wk) on parameters such as growth rate, urinary aldosterone excretion, 22Na volume of distribution (space), and various renal functions. Three groups were studied: group I (control) and groups II and III. During the first phase the respective sodium intake values for these groups were 8.9, 3.1, and 1.5 meq.kg body wt-1.day-1. During the second phase, all groups had sodium intake of 8.7-8.8 meq.kg body wt-1.day-1. At the end of the first phase, group II showed weight gain and 22Na space values similar to those of group I. Group III demonstrated severe growth retardation and reduced 22Na space. During the second phase, both groups II and III demonstrated expansion of the 22Na space and persistently elevated urinary "acid-labile" aldosterone excretions. Despite the 2 wk of sodium repletion, group III failed to catch up with the body weight of groups I and II. It is concluded that chronic sodium deficit during early development transition is made to a higher sodium intake.

Aging↗
PubMed1981

On the mechanism of angiotensin-induced proteinuria. I. Studies in aminonucleoside nephrotic rats and in saralasin blockade.

To test whether angiotensin (AII) induces proteinuria via its effect on renal hemodynamics, or by another mechanism, two experimental approaches were used. In the first, it was found that AII was as effective in inducing proteinuria in nephrotic as in intact rats. In all AII augmented proteinurias, filtration fraction was increased. These effects plus electrophoretic profiles of AII proteinuria in intact rats suggested that hemodynamic changes underly the increased glomerular permeability to protein. In the second approach, the AII inhibitor, sar-ala-angiotensin, does not itself induce proteinuria or changes in GFR and RPF, but prevented the hemodynamic responses to AII and the proteinuric response as well.

Angiotensin II↗
PubMed1979

Corticoid effects on angiotensin- and norepinephrine-induced proteinuria in rats.

Adrenalectomy is known to prevent the proteinuria induced by renin or angiotensin, but it is not clear whether the loss of glucocorticoids or mineralocorticoids is responsible. The problem was reinvestigated using dexamethasone and aldosterone, essentially pure glucocorticoid and mineralocorticoid, respectively. Dexamethasone treatment for 2--5 days completely restored the protein-uric response to angiotensin II or norepinephrine, but aldosterone did not, even though the dose and treatment were sufficient to induce changes in electrolyte excretion. Fractional sodium excretion was also increased by angiotensin II and norepinephrine in the dexamethasone-treated rats, but not in the aldosterone-treated rats. Both dexamethasone and aldosterone treatments restored the increase in filtration fraction, but the increase was not associated with proteinuria in some groups, and it is concluded that there is no causal relationship between increased filtration fraction and proteinuria. Reasons for considering binding of norepinephrine and angiotensin to the glomerular basement membrane as causal for the proteinuria and the hormonal requirements for such binding are discussed.

Aldosterone↗