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Biomedical subjects

H S Paul

Publications and source records attributed to H S Paul.

At least 19 recordsLinked to original sources
PubMed2001

Acute erythroleukemia--M6B.

Acute Erythroleukemia is a rare disorder of hematopoietic system, accounts for 1-3% of all acute leukemia and 15% of myeloid leukemia. Recently, the World Health Organisation & Society of Haematopathology proposed a change in the categorization, with M6a and M6b subgroups of the original FAB classification. Hereby we report a case of acute erythroleukemia--M6b subtype, presented with pain abdomen and vomiting. The patient died within two days. The case is being reported for its rarity and uncommon presentation.

Fever↗
PubMed1999

Inverse alterations of BCKA dehydrogenase activity in cardiac and skeletal muscles of diabetic rats.

Rat cardiac and skeletal muscles, which have been used as model tissues for studies of regulation of branched-chain alpha-keto acid (BCKA) oxidation, vary greatly in the activity state of their BCKA dehydrogenase. In the present experiment, we have investigated whether they also vary in response of their BCKA dehydrogenase to a metabolic alteration such as diabetes and, if so, to investigate the mechanism that underlies the difference. Diabetes was produced by depriving streptozotocin-treated rats of insulin administration for 96 h. The investigation of BCKA dehydrogenase in the skeletal muscle (gastrocnemius) showed that diabetes 1) increased its activity, 2) increased the protein and gene expressions of all of its subunits (E(1)alpha, E(1)beta, E(2)), 3) increased its activity state, 4) decreased the rate of its inactivation, and 5) decreased the protein expression of its associated kinase (BCKAD kinase) without affecting its gene expression. In sharp contrast, the investigation of BCKA dehydrogenase in the cardiac muscle showed that diabetes 1) decreased its activity, 2) had no effect on either protein or gene expression of any of its subunits, 3) decreased its activity state, 4) increased its rate of inactivation, and 5) increased both the protein and gene expressions of its associated kinase. In conclusion, our data suggest that, in diabetes, the protein expression of BCKAD kinase is downregulated posttranscriptionally in the skeletal muscle, whereas it is upregulated pretranslationally in the cardiac muscle, causing inverse alterations of BCKA dehydrogenase activity in these muscles.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1996

Alteration in gene expression of branched-chain keto acid dehydrogenase kinase but not in gene expression of its substrate in the liver of clofibrate-treated rats.

We previously showed that the oxidation of branched-chain amino acids is increased in rats treated with clofibrate [Paul and Adibi (1980) J. Clin. Invest. 65, 1285-1293]. Two subsequent studies have reported contradictory results regarding the effect of clofibrate treatment on gene expression of branched-chain keto acid dehydrogenase (BCKDH) in rat liver. Furthermore, there has been no previous study of the effect of clofibrate treatment on gene expression of BCKDH kinase, which regulates the activity of BCKDH by phosphorylation. The purpose of the present study was to investigate the above issues. Clofibrate treatment for 2 weeks resulted in (a) a 3-fold increase in the flux through BCKDH in mitochondria isolated from rat liver, and (b) a modest but significant increase in the activity of BCKDH. However, clofibrate treatment had no significant effect on the mass of E1 alpha, E1 beta, and E2 subunits of BCKDH or the abundance of mRNAs encoding these subunits. On the other hand, clofibrate treatment significantly reduced the activity, the protein mass and the mRNA levels of BCKDH kinase in the liver. In contrast to the results obtained in liver, clofibrate treatment had no significant effect on any of these parameters of BCKDH kinase in the skeletal muscle. In conclusion, our results show that clofibrate treatment increases the activity of BCKDH in the liver and the mechanism of this effect is the inhibition of gene expression of the BCKDH kinase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1995

Pyruvate inhibits clofibrate-induced hepatic peroxisomal proliferation and free radical production in rats.

In an effort to identify the effects of the 3-carbon compound pyruvate on free radical production, we measured hepatic total peroxisomal beta-oxidation and catalase activity and the production of lipofuscin-like products in male Sprague-Dawley rats consuming an adequate diet supplemented with pyruvate, vitamin E, or the peroxisome proliferator and free radical enhancer clofibrate for 22 days (n = 5 in each group). Clofibrate feeding induced hepatomegaly, a fivefold increase in total peroxisomal beta-oxidation activity, and a threefold increase in hepatic lipofuscin-like products (P < .05). Pyruvate but not vitamin E inhibited the increase in liver size by 70% (P < .05). Both pyruvate and vitamin E completely inhibited clofibrate-induced increases in lipofuscin-like products (P < .05). Pyruvate but not clofibrate or vitamin E increased plasma concentrations of the nitric oxide metabolites nitrite and nitrate (P < .05). We conclude that with clofibrate-induced peroxisomal proliferation and free radical production, pyruvate will inhibit peroxisomal proliferation and free radical production, inhibit free radical-induced lipid peroxidation, and enhance metabolism of nitric oxide.

Animals↗
PubMed1995

Complementation of defective leucine decarboxylation in fibroblasts from a maple syrup urine disease patient by retrovirus-mediated gene transfer.

Maple syrup urine disease (MSUD) is a genetic disease caused by a deficiency of branched-chain keto acid dehydrogenase, a mitochondrial multienzyme complex responsible for the decarboxylation of leucine, isoleucine and valine. The complex consists of three subunits (E1, E2, and E3) and mutations in any subunit result in MSUD. No satisfactory treatment for MSUD is currently available. Here we report the successful use of retroviral gene transfer to restore leucine decarboxylation activity in fibroblasts derived from a MSUD patient containing a mutation in the E2 subunit. A full-length human E2 cDNA was inserted into a retroviral vector (MFG) and a stable CRIP producer line was generated. The amphotropic virus was then used to transduce mutant human fibroblasts. In untransduced mutant cells, 1-14C leucine decarboxylation activity was less than 2% that of the wild-type cells. Decarboxylation of 1-14C leucine in transduced mutant cells was restored to 93% of the wild-type level. Correct targeting of the expressed wild-type E2 protein to mitochondria was demonstrated by comparing the immunofluorescent pattern of E2 and a mitochondrial marker protein. Stable expression of enzyme activity has been obtained for at least 7 weeks. In contrast to most previous gene therapy attempts, which replace a single enzyme defect, the present results demonstrate complementation of a phenotype resulting from a gene defect whose product is a part of a multienzyme complex. Based on these results, studies can now be undertaken to investigate the feasibility of gene therapy to correct MSUD.

Amino Acid Oxidoreductases↗
PubMed1994

Regulation of gene expression of branched-chain keto acid dehydrogenase complex in primary cultured hepatocytes by dexamethasone and a cAMP analog.

The present study demonstrates that dexamethasone and 8-(4-chlorophenylthio)adenosine 3',5'-monophosphate (CPT-cAMP), a cAMP analog, increase the substrate flux through branched-chain keto acid dehydrogenase (BCKDH) in primary rat hepatocytes cultured in defined medium. Maximum response (2.7-fold increase in flux) was observed when hepatocytes were cultured with 1 microM dexamethasone plus 50 microM CPT-cAMP for 24 h. This increase in the flux rate was accompanied by significant increases in both the basal and total activities of BCKDH (2.2- and 2.0-fold, respectively), without any significant change in the activity state of this enzyme. The increase in BCKDH activity was the result of increased protein mass of E1 alpha (3.2-fold), E1 beta (2.9-fold), and E2 (1.6-fold) subunits of BCKDH, indicating that E2 is the limiting subunit for the expression of BCKDH. The relative abundance of mRNAs encoding the E1 alpha, E1 beta, and E2 subunits of BCKDH increased by 7.4-, 21.7-, and 4.8-fold, respectively. We conclude that increased flux through BCKDH in hepatocytes cultured with dexamethasone and CPT-cAMP is due to increased expression of BCKDH subunit genes. However, nonstoichiometric expression of individual subunits and the corresponding mRNAs suggests regulation of BCKDH also at translational and post-translational steps.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1994

Role of testosterone in the induction of hepatic peroxisome proliferation by clofibrate.

Hepatic peroxisome proliferation is induced by a number of agents, including clofibrate. Sustained proliferation of peroxisomes is associated with the development of hepatocellular carcinoma. In the present study, we have investigated the role of testosterone in peroxisome proliferation induced by clofibrate. Three groups of male rats (intact, castrated, and castrated replaced with testosterone) were studied. Proliferation of peroxisomes was induced by feeding clofibrate (0.25%, 0.50%, and 1.0% of diet) for 2 weeks. Peroxisome proliferation was monitored by measuring total peroxisomal beta-oxidation activity. In intact rats, the peroxisomal beta-oxidation activity (nmol/min/mg protein) increased in a dose-dependent manner and was 7.2 +/- 0.4, 52.6 +/- 7.5, 63.2 +/- 3.7, and 92.4 +/- 4.0 at clofibrate doses of 0%, 0.25%, 0.50%, and 1.0%, respectively. In contrast, in castrated rats, the total peroxisomal beta-oxidation activity was significantly (P < .01) lower at clofibrate levels of 0.25% and 0.50% (25.8 +/- 2.7 and 42.5 +/- 2.2, respectively), but not at the clofibrate level of 1.0% (85.0 +/- 6.3). Testosterone replacement of castrated rats restored the peroxisomal beta-oxidation activity. To determine whether the above results were related to the metabolism of clofibrate in the absence or presence of testosterone, we measured serum clofibrate levels. These levels were 50% lower in castrated rats than in intact rats or in testosterone-treated castrated rats. The activity of hepatic uridine diphosphate (UDP)-glucuronyltransferase, the enzyme catalyzing the glucuronidation of clofibrate, was measured using either bilirubin or 4-methylumbelliferone as substrates and was found to be unaffected by castration or testosterone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Mechanism of increased conversion of branched chain keto acid dehydrogenase from inactive to active form by a medium chain fatty acid (octanoate) in skeletal muscle.

We and others have previously shown that octanoate increases the oxidation of branched chain amino acids (BCAA) in skeletal muscle. The present study was designed to investigate the mechanism of this increased oxidation. Studies were performed with rat hind limbs perfused with 0.50 mM L-[1-14C]leucine with or without octanoate. The flux through branched chain keto acid (BCKA) dehydrogenase was measured, and the basal and total activity of BCKA dehydrogenase in skeletal muscle was determined. The rate of flux through BCKA dehydrogenase increased by 37, 119, and 297% with 0.5, 1.0, and 2.0 mM octanoate, respectively. This increase in flux was not due to a change in BCAA aminotransferase activity but was due to an increase in the basal activity of BCKA dehydrogenase. There was a strong correlation (r = 0.96) between increases in flux through BCKA dehydrogenase and increases in the basal activities of BCKA dehydrogenase. Preincubation of BCKA dehydrogenase with Mg2+ caused full activation of this enzyme, but preincubation with octanoate did not activate this enzyme. On the other hand, octanoate completely prevented the ATP-dependent inactivation of fully activated BCKA dehydrogenase. We conclude that octanoate increases the oxidation of leucine in skeletal muscle by increasing the activation of BCKA dehydrogenase. The mechanism of this activation is the inhibition of BCKA dehydrogenase kinase rather than the stimulation of a specific or nonspecific protein phosphatase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1992

Inhibition of carnitine acyltransferase activities by bile acids in rat liver peroxisomes.

We recently reported that purified carnitine acetyltransferase is competitively inhibited by bile acids (Sekas, G. and Paul, H.S. (1989) Anal. Biochem. 179, 262-267). In the present study, we initially investigated the effect of bile acids on carnitine acyltransferases in rat hepatic peroxisomes. Activities of carnitine acetyltransferase, carnitine octanoyltransferase, and carnitine palmitoyltransferase were progressively inhibited by increasing concentrations of chenodeoxycholic acid. Kinetic studies revealed that the inhibition by chenodeoxycholic acid was competitive with respect to carnitine with an apparent Ki of 890 microM for carnitine acetyltransferase, 650 microM for carnitine octanoyltransferase and 600 microM for carnitine palmitoyltransferase. We then investigated whether bile acids inhibit the activities of these enzymes ex vivo. The hepatic concentration of bile acids was increased by inducing cholestasis by bile duct ligation. Cholestasis reduced the activity of carnitine acetyltransferase, carnitine octanoyltransferase, and carnitine palmitoyltransferase to 66 +/- 2%, 64 +/- 3%, and 40 +/- 2%, of the control, respectively. The inhibition for each of these enzymes was proportional to the degree of cholestasis. The effect of cholestasis appeared specific for carnitine acyltransferases since the activity of catalase, another peroxisomal enzyme, was not affected by cholestasis. We conclude that bile acids inhibit the activities of carnitine acyltransferases in hepatic peroxisomes. This inhibition by bile acids may be of significance in cholestatic liver disease.

Animals↗
PubMed1992

Carnitine biosynthesis in hepatic peroxisomes. Demonstration of gamma-butyrobetaine hydroxylase activity.

We have investigated whether hepatic peroxisomes are capable of synthesizing carnitine. When purified peroxisomes were incubated with gamma-butyrobetaine, a precursor of carnitine, formation of carnitine was observed. These results indicate that peroxisomes contain gamma-butyrobetaine hydroxylase, the enzyme which catalyzes the final step in the biosynthesis of carnitine. This enzyme was previously believed to be present only in the cytosol. gamma-Butyrobetaine hydroxylase activity in peroxisomes was not due to cytosolic contamination as evaluated by marker enzyme analysis. When proliferation of peroxisomes was induced by clofibrate treatment, gamma-butyrobetaine hydroxylase/mass liver increased by 7.6-fold and the specific activity by 2.5-fold. We conclude that hepatic peroxisomes synthesize carnitine and this synthesis becomes substantial under conditions of peroxisomal proliferation.

Animals↗
PubMed1992

Investigation of the presence of branched-chain alpha-keto acid dehydrogenase in mammalian hepatic peroxisomes.

1. Rat liver was fractionated into peroxisomes and mitochondria and branched-chain keto acid (BCKA) dehydrogenase activity was measured. 2. All BCKA dehydrogenase activity was associated with the mitochondrial fraction and none with the peroxisomal fraction. 3. BCKA dehydrogenase was also not detected in hepatic peroxisomes of rats treated with clofibrate which induces several peroxisomal enzymes. 4. Hepatic peroxisomes from rabbit, hamster and dog also did not show any BCKA dehydrogenase activity. 5. We conclude that mammalian hepatic peroxisomes do not contain BCKA dehydrogenase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1992

Hepatic release of carnitine: effect of increased concentration by clofibrate treatment.

The release of carnitine is an important metabolic function of the liver. In the present study, we have investigated the effect of increased carnitine concentration on the hepatic release of carnitine. Hepatic carnitine concentration was increased in rats by clofibrate treatment. Release of carnitine was investigated as its efflux from perfused liver and its secretion into bile. A significantly smaller proportion of the hepatic pool of carnitine was released into the perfusion medium when carnitine concentration was increased by clofibrate treatment. However, the amount of carnitine released (nmol/g liver) was comparable to that of control rats. Increased carnitine concentration by clofibrate treatment also did not affect the rate of biliary secretion of carnitine. In control rats, nearly 50% of the released carnitine, in both the perfusion medium and bile, was acylcarnitine whereas in clofibrate-treated rats 35% of the released carnitine was acylcarnitine. Release into the perfusion medium was the major route for the hepatic export of carnitine. We conclude that when hepatic carnitine concentration is increased by clofibrate treatment, a smaller proportion of the hepatic carnitine pool is released, but the amount of carnitine released (nmol/g liver) is not greatly different than that from control animals.

Animals↗
PubMed1991

Wave propagation in a piezoelectric human bone of arbitrary cross section with a circular cylindrical cavity.

A theoretical study of wave propagation in a piezoelectric cylinder of infinite length of arbitrary cross section with a circular cylindrical cavity of class 6 is investigated. The frequency equations are obtained by using the Fourier expansion collocation method and are analyzed numerically. The frequencies are evaluated for circular, elliptic, and cardioidal sections of bone and are tabulated. A plot of frequency spectrum is also presented for the cardioidal cross-section bar.

Biomechanical Phenomena↗
PubMed1989

Inhibition of carnitine acetyltransferase by bile acids: implications for carnitine analysis.

Carnitine acetyltransferase is used in a radioenzymatic assay to measure the concentration of carnitine. While determining the concentration of carnitine in rat bile, we found that the apparent concentration increased as bile was diluted (6.7 +/- 1.0 and 66.6 +/- 9.4 nmol/ml in undiluted and 20-fold diluted bile, respectively). The present study was designed to investigate whether a component of bile inhibited carnitine acetyltransferase. Inhibition was evaluated by measuring carnitine concentration in bile or by determining the recovery of a known amount of carnitine in the presence of bile. Inhibitory activity was extractable in organic solvents, stable to heat and base treatments, resistant to trypsin and lipase digestions, and removable by cholestyramine, a bile acid-binding resin. These results suggested that the inhibitory activity was associated with bile acids. Direct evidence was obtained by showing a reduced detectability of carnitine in the presence of individual bile acids. Chenodeoxycholic acid was the most potent inhibitor. Inhibition was unrelated to the detergent properties of bile acids. Kinetic studies revealed that carnitine acetyltransferase was inhibited competitively by chenodeoxycholic acid with a Ki of 520 microM. Bile acids also interfered in the quantitation of carnitine in cholestatic plasma. Carnitine concentration in such plasma was underestimated (17.5 +/- 2.1 mmol/ml). Reduction of bile acid concentration by a 20-fold dilution of cholestatic plasma resulted in a 3-fold higher carnitine concentration (54.6 +/- 9.0 nmol/ml). Results demonstrate that, because of the inhibition of carnitine acetyltransferase by bile acids, the radioenzymatic assay will underestimate carnitine concentration in bile or in cholestatic plasma. Accurate measurement requires either the removal of bile acids or a marked reduction in their concentration.

Acetyltransferases↗
PubMed1988

Zinc status of children with sickle cell disease: relationship to poor growth.

We examined the zinc status of 80 children with sickle cell disease (SCD) and 44 disease-free sibling controls aged 3 to 18 years. For both patients and controls, variations in serum zinc by age, type of hemoglobinopathy, and growth status were measured. The mean serum zinc concentration of patients was significantly lower than for controls (77.8 +/- 9.9 vs. 82.2 +/- 9.8 micrograms/dl, mean +/- 1SD, P less than .05). Serum levels of alkaline phosphatase (AP) and retinol-binding protein (RBP), two zinc-dependent proteins, were also lower among patients (AP: 171 +/- 66 vs. 243 +/- 97 IU/L, P less than .001; RBP: 1.92 +/- .9 vs. 2.77 +/- .9 mg/dl, P less than .001). Patients greater than or equal to 12 years of age (n = 34) had significantly lower zinc levels than those less than 12 years (74.5 +/- 8.4 vs. 80.3 +/- 10.3 micrograms/dl, P less than .01), and children with homozygous SCD (Hb SS, n = 55) had a more pronounced deficiency than those with a variant hemoglobinopathy (76.3 +/- 8.9 vs. 81.5 +/- 11.5, micrograms/dl, P less than .05). Patients classified as having "poor" growth (height-for-age less than 5th percentile, n = 24) had a lower serum zinc level than those with "normal" growth (72.8 +/- 8.0 vs. 79.8 +/- 10.0 micrograms/dl, P less than .01). Dietary intake data, body mass index, and serum total protein and albumin levels were similar for patients and controls, suggesting that zinc deficiency in SCD does not relate to inadequate dietary intake. The origin of low serum zinc levels in children with SCD is more likely to relate to factors such as increased urinary zinc excretion, chronic intravascular hemolysis, and/or zinc malabsorption.

Adolescent↗
PubMed1988

Intravenously infused carnitine: influence on protein and branched-chain amino acid metabolism in starved and parenterally fed rats.

We studied the effect of intravenously infused carnitine (34 mumol.100 g-1.d-1) on protein and branched-chain amino acid (BCAA) metabolism in rats either starved for 3 d or parenterally fed for 7 d. Carnitine infusion did not significantly affect nitrogen balance, protein content of liver and muscle, plasma concentrations of BCAA and branched-chain keto acid, or leucine oxidation and incorporation into liver and muscle proteins of either starved or fed rats. Despite a two- to threefold increase in plasma carnitine level, tissue concentrations of carnitine and its acyl-derivatives were not significantly affected by carnitine infusion. Of the amount of carnitine infused, 91% was lost in the urine of starved rats and 87% in the urine of fed rats. We conclude that intravenous carnitine infusion does not affect protein and BCAA metabolism and that this lack of effect may be related to the failure of carnitine infusion to enrich tissue pools of carnitine.

3-Hydroxybutyric Acid↗
PubMed1988

Regulation of leucine catabolism by caloric sources. Role of glucose and lipid in nitrogen sparing during nitrogen deprivation.

Previously we showed that hypocaloric amounts of glucose reduce leucine catabolism while an isocaloric amount of fat does not (1985. J. Clin. Invest. 76:737.). This study was designed to investigate whether the same difference exists when the entire caloric need is provided either as glucose or lipid. Rats were maintained for 3 d on total parenteral nutrition (350 cal/kg per d), after which the infusion of amino acids was discontinued and rats received the same amount of calories entirely as glucose or lipid for three more days. A third group of rats was infused with saline for 3 d. In comparison to glucose, lipid infusion resulted in higher urinary nitrogen excretion (55 +/- 3 vs. 37 +/- 2 mg N/24 h, P less than 0.05), muscle concentrations of tyrosine (95 +/- 8 vs. 42 +/- 8 microM, P less than 0.01), and leucine (168 +/- 19 vs. 84 +/- 16 microM, P less than 0.01), activity of BCKA dehydrogenase in muscle (2.2 +/- 0.2 vs. 1.4 +/- 0.04 nmol/mg protein per 30 min, P less than 0.05), and whole body rate of leucine oxidation (3.3 +/- 0.5 vs. 1.4 +/- 0.2 mumol/100 g per h, P less than 0.05). However, all these parameters were significantly lower in lipid-infused than starved rats. There was no significant difference between leucine incorporation into liver and muscle proteins of lipid and glucose-infused rats. On the other hand, starved rats showed a lower leucine incorporation into liver proteins. The data show that under conditions of adequate caloric intake lipid has an inhibitory effect on leucine catabolism but not as great as that of glucose. The mechanism of this difference may be related to a lesser inhibition of muscle protein degradation by lipid than glucose, thereby increasing the leucine pool, which in turn stimulates leucine oxidation.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗