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PubMed2004

Production of the kringle fragments of human apolipoprotein(a) by continuous lactose induction strategy.

A novel lactose induction strategy for the production of rhLK68, the kringle fragments of human apolipoprotein(a) (apo(a)) as a novel anti-angiogenic protein, was investigated. A scale-up of the production was accompanied by a decrease in expression level, and severe aggregation occurred during the solubilization of rhLK68 from the inclusion body during a conventional single introduction of lactose. To overcome this problem, a continuous induction strategy was applied where lactose was mixed with glycerol and fed continuously in a dissolved oxygen (DO)-stat manner. With the sub-optimal feed medium consisted of 1:50 of lactose/glycerol (w/w), the expression level reached 16% of the total cellular protein, which was 1.6-fold higher than that obtained from the conventional lactose induction. Moreover, the solubilization yield of rhLK68 from the inclusion body increased from 30 +/- 5 to 85 +/- 3% compared to the conventional single introduction of lactose. This result suggests that the continuous lactose induction strategy beneficially influenced the expression level of rhLK68 and the quality of its inclusion body.

Apolipoproteins↗
PubMed2005

Measurement of lactose crystallinity using Raman spectroscopy.

Raman spectroscopy (RS) was used to determine the crystallinity of lactose (a commonly used carrier in dry powder inhaler (DPI) formulations). Samples of alpha-lactose monohydrate and amorphous lactose were prepared using ethanol precipitation and lyophilisation respectively. The anomeric forms were confirmed using DSC at a rate of 10 degrees C/min and heated to 250 degrees C. The Raman spectra of both alpha-lactose monohydrate and amorphous lactose were obtained. Distinguishable differences were seen between the two spectra including peak areas and intensities. Depolarisation ratios (rho) of each form were then determined to identify the crystallinity of the lactose carrier samples. At the prominent Raman bands 865 and 1082 cm-1, significant differences in rho values were observed for crystalline (0.80+/-0.07, 0.89+/-0.06 respectively) and amorphous samples (0.44+/-0.07, 0.51+/-0.10).

Calorimetry, Differential Scanning↗
PubMed1980

Lactose malabsorption by premature infants: magnitude and clinical significance.

Sequential studies of breath hydrogen excretion in response to lactose feeding were carried out in 22 premature infants during the first seven weeks of life. Seventy-five percent of infants excreted H2 in breath during the first two weeks, 100% by the end of the third week. The peak H2 concentration and the five-hour mean breath H2 excretions were significantly related to lactose intake per day, lactose intake per feeding and postnatal age, though only lactose intake per day remained significant when all three variables were included in multiple regression analysis. Preprandial breath H2 concentration was inversely related to the frequency of feeding. Using the five-hour mean H2 excretion, it was estimated that 66% or more of ingested lactose entered the colon and was fermented. Throughout the studies stool patterns and rates of weight gain of the infants were normal. Premature infants normally malabsorb substantial amounts of lactose. The elevation of breath H2 in these infants apparently represents a successful adaptation of the colonic microflora to this physiologic malabsorption and should not be cause to modify the diet of an infant who is clinically well.

Humans↗
PubMed2003

Gentamicin release from modified acrylic bone cements with lactose and hydroxypropylmethylcellulose.

Modified polymethylmethacrylate (PMMA) bone cements formulations were prepared by including different proportions of gentamicin and release modulators such as lactose or hydroxypropylmethylcellulose (HPMC). Surface aspect, gentamicin release and porosity of these modified formulations were studied by means of scanning electron microscopy (SEM), a specially designed system for the dissolution studies of the bone cements, and mercury intrusion porosimetry. Lactose modified cements presented an irregular surface with numerous hollows and voids due to the lactose dissolution. HPMC cements presented a characteristic laminated and flaky surface. The drug release of lactose formulations was up to four-fold greater (13%) than the commercial bone cement CMW1 Gentamicin one (3%). The amount of gentamicin eluted at the first withdrawn sample ranged from 30% to 60% of total gentamicin released over the assay. Gentamicin release from lactose formulations increased as lactose percentage was increased which agree with the porosity results. Nevertheless, the use of release modulator HPMC increased porosity, but did not produce an increase in the gentamicin release. HPMC dissolution creates a surrounding sticky and viscous medium similar to a gel that makes the gentamicin release from the cement matrix difficult.

Anti-Bacterial Agents↗
PubMed1998

Effects of acute bovine trypanosomosis (Trypanosoma vivax) on plasma kinetics of intravenously administered lactose.

Four calves infected with Trypanosoma vivax and four uninfected control calves were each injected intravenously with repeated doses of 0.5 g lactose kg-1 body weight, thrice daily at intervals of 4 h. Plasma samples were collected at specified time intervals and analysed for lactose. Pharmacokinetic parameters were calculated from the data. T. vivax infection delayed excretion of lactose from the body, thus leading to significantly (P < 0.001) increased biological half life (t1/2) and a significantly (P < 0.001) reduced elimination rate constant for lactose in the body. The apparent volume of distribution and total clearance of lactose were not affected by the infection. T. vivax infection also appeared to cause accumulation of lactose in the plasma after repeated intravenous administration.

Acute Disease↗
PubMed2001

Quantifying amorphous content of lactose using parallel beam X-ray powder diffraction and whole pattern fitting.

The objective of this study was to demonstrate the applicability of parallel beam X-ray powder diffraction (XRPD) and a new method for whole pattern fitting to the quantification of the residual amount of amorphous content in a pharmaceutical solid using lactose as a model system. Lactose monohydrate, prepared by slurry conversion of anhydrous lactose, was mixed with different amounts of amorphous lactose produced by lyophilization. X-ray powder diffractograms of each mixture were recorded and analyzed by whole pattern fitting using Percentage Crystallinity Determination Software from Kratos Analytical Inc. The polycapillary X-ray optic, which provides a parallel beam of X-radiation, has advantages over Bragg-Brentano Optics with respect to sample height artifacts. Significant shifts in peak position with changes in sample height of lactose monohydrate were observed using Bragg-Brentano Optics while no change was detected for the polycapillary X-ray optic. A technique to normalize all diffractograms to have the same total integrated intensity was necessary to eliminate tube fluctuation effects. After normalization, the amorphous content of lactose in the range of 1-10% was reproducibly predicted (small standard deviation between samplings) using whole pattern fitting. The limit of detection was calculated to be 0.37% amorphous content. The results indicated that parallel beam XRPD and whole pattern fitting can provide accurate analysis of relatively small amounts of amorphous content in pharmaceuticals compared to typical XRPD analysis.

Lactose↗
PubMed2003

Evaluation of beta-lactose, PVP K12 and PVP K90 as excipients to prepare piroxicam granules using two wet granulation techniques.

The present investigation aimed at evaluating the use of different excipients, beta-lactose and polyvinylpyrrolidone of two molecular weights (PVP K12 and PVP K90), in the production of improved release piroxicam granules, by wet granulation using both water and steam as granulation liquid. The formulations examined were: piroxicam (Px)/beta-lactose; Px/PVP K12 and Px/PVP K90, each one at a 1:9 weight ratio. The most significant difference between beta-lactose and PVP is that, using the first excipient, both steam and water granules were produced while, when PVP were employed, only steam granules were obtained. Image analysis revealed that beta-lactose steam granules had a larger surface area with respect to water granules, whereas lower values of this parameter were observed in PVP-s granules, confirming the Scanning Electron Microscopy micrographs and the fractal analysis results. As regards the enhancement of the dissolution profiles, the best result was obtained using beta-lactose steam granules followed by PVP K12 ones, even if the reactive dimension values indicated that during the dissolution process PVP K12 granules modified the surface more than beta-lactose granules. As regards PVP K90, this excipient was the one less influencing the granule morphology and the dissolution behaviour. Differential Scanning Calorimetry analysis suggested the partial amorphisation of the drug in the granules containing the three excipients. This result was then confirmed by X-ray powder diffraction analysis. Therefore, beta-lactose and PVP K12 could be proposed as useful excipients to enhance the dissolution rate of Px from granules prepared using the steam granulation technique.

Drug Evaluation, Preclinical↗
PubMed1995

Role of glycine residues in the structure and function of lactose permease, an Escherichia coli membrane transport protein.

By using oligonucleotide-directed, site-specific mutagenesis, the role of 34 Gly residues in the lactose permease of Escherichia coli has been studied systematically. Each of 34 out of a total of 36 Gly residues was replaced with Cys in a functional permease mutant devoid of Cys residues (C-less permease), as previous experiments demonstrate that Gly-402 and Gly-404 can be deleted by truncation of the C-terminus with no loss of activity [Roepe, P. D., et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 3992; McKenna, E., et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 2969]. Out of the 34 Cys-replacement mutants described, 15 transport lactose with high activity, 16 exhibit decreased but significant ability to catalyze lactose accumulation, and 3 (Gly-64-->Cys, Gly-115-->Cys and Gly-147-->Cys) exhibit no activity whatsoever. The inactive mutants were studied in more detail by replacement of Gly with Ala, Val, or Pro. C-less permease with Gly-115-->Ala or Gly-147-->Ala transports lactose almost as well as the control, while mutants with Val or Pro in place of Gly have little or no capacity to accumulate the disaccharide. In contrast, mutants with Ala, Val, or Pro in place of Gly-64 are inactive. Strikingly, however, when the mutations are placed in the wild-type background, Gly-64-->Ala permease transports lactose, beta,D-galactopyranosyl 1-thio-beta,D-galactopyranoside, and methyl 1-thio-beta,D-galactopyranoside 40-60% as well as wild-type permease, while Gly-64-->Val or Gly-64-->Pro permease is inactive toward all of these substrates. The results indicate that although none of the Gly residues in lactose permease is mandatory for activity, the bulk of the side chain at positions 64, 115, and 147, rather than conformational flexibility at these positions, is particularly important.

Amino Acid Sequence↗
PubMed2001

A face on transmembrane segment 8 of the lactose permease is important for transport activity.

Previous work on the lactose permease of Escherichia coli has shown that mutations along a face of predicted transmembrane segment 2 (TMS-2) play a critical role in conformational changes associated with lactose transport [Green, A. L., Anderson, E. J., and Brooker, R. J. (2000) J. Biol. Chem. 275, 23240-23246]. In the current study, mutagenesis was conducted along the side of predicted TMS-8 that contains the first amino acid in the conserved loop 8/9 motif. Several substitutions at positions 261, 265, 272, and 276 were markedly defective for downhill lactose transport although these mutants were well expressed. Substitutions along the entire side of TMS-8 containing the first amino acid in the loop 8/9 motif displayed defects in uphill lactose transport. Again, substitutions at positions 261, 265, 268, 272, and 276 were the most defective, with several of these mutants showing no lactose accumulation against a gradient. According to helical wheel plots, Phe-261, Thr-265, Gly-268, Asn-272, and Met-276 form a continuous stripe along one face of TMS-8. These results are discussed according to our hypothetical model, in which the two halves of the protein form a rotationally symmetrical dimer. In support of this model, alignment of predicted TMS-2 and TMS-8 shows an agreement between the amino acid residues in these transmembrane segments that are critical for lactose transport activities.

Amino Acid Sequence↗
PubMed2005

The activity of the lactose transporter from Streptococcus thermophilus is increased by phosphorylated IIA and the action of beta-galactosidase.

The metabolism of lactose by Streptococcus thermophilus is highly regulated, allowing the bacterium to prefer lactose over glucose as main source of carbon and energy. In vitro analysis of the enzymes involved in transport and hydrolysis of lactose showed that the transport reaction benefits from the hydrolysis of lactose at the trans side of the membrane. Furthermore, the activity of LacS is modulated by PEP-dependent phosphorylation of the IIA domain via the general energy coupling proteins of the PTS, Enzyme I and HPr. To determine whether unphosphorylated LacS-IIA inhibited, or the phosphorylated form stimulated lactose counterflow, a LacS-IIA truncation mutant of LacS was constructed. Detailed analyses of transport in whole cells and in proteoliposomes indicated that unphosphorylated LacS-IIA does not functionally interact with the carrier domain. Instead, interaction of the phosphorylated form of LacS-IIA with the carrier stimulates lactose counterflow transport. The proposed mode of regulation thus proceeds via a mechanism opposite to the inducer exclusion type of regulation in gram-negative bacteria, where transporters are inhibited by binding of the unphosphorylated form of IIA(Glc).

Amino Acid Sequence↗
PubMed1997

Fructose and sorbitol malabsorption in ambulatory patients with functional dyspepsia: comparison with lactose maldigestion/malabsorption.

The aim of this study was to study sugar maldigestion/malabsorption in patients with functional dyspepsia using H2 breath testing. End-expiratory breath H2 after separate challenges with lactose (25 g), fructose (25 g), and sorbitol (5 g) were used to determine malabsorption, as well as small bowel transit time (SBTT). Five hundred twenty patients with functional dyspepsia received all three challenges. Smaller groups were also tested after lactulose (10 g, N = 36) and glucose (50 g, N = 90) challenges. Fructose and sorbitol were closely linked with respect to absorption and malabsorption status. Only in the case of lactose maldigestion/malabsorption was there a greater than random prevalence of malabsorption (P < 0.001) for fructose and sorbitol. In contrast to lactose, ethnic origin did not influence fructose or sorbitol malabsorption, and females predominated among fructose and sorbitol malabsorbers. In Jews, the prevalence of lactose maldigestion/malabsorption decreased in the age group of 25-55 and subsequently rose after 55, while fructose and sorbitol malabsorption decreased progressively with advancing age. With respect to small bowel transit time (SBTT), in the case of sorbitol and lactulose, it was significantly greater (P < 0.05) than those for fructose and lactose. Multiple sugar malabsorptions are common when lactose maldigestion/malabsorption is present.

Breath Tests↗
PubMed1973

Progesterone and the metabolic control of the lactose biosynthetic pathway during lactogenesis in the rat.

1. Lactogenesis was initiated in pregnant rats by ovariectomy, thereby causing progesterone withdrawal, after which the mammary tissue was analysed for contents of enzymes and metabolites concerned with the biosynthesis of lactose. 2. Lactose synthesis increased about 126-fold with little or no accompanying change in the contents of most metabolic intermediates or in the adenine nucleotide energy charge. 3. Comparison of mass-action ratios with equilibrium constants showed that phosphoglucomutase (EC 2.7.5.1), UDP-glucose pyrophosphorylase (EC 2.7.7.9) and UDP-glucose epimerase (EC 5.1.3.2.) catalysed reactions close to equilibrium. Nucleoside diphosphokinase (EC 2.7.4.6.) activity was very high and probably equilibrates the UTP-UDP and ATP-ADP couples. Lactose synthetase and hexokinase (EC 2.7.1.1) appeared to catalyse rate-limiting reactions. 4. Large increases were seen of UDP-glucose pyrophosphorylase (5-fold), lactose synthetase A protein (3.8-fold) and alpha-lactalbumin (28-fold), but not of hexokinase, phosphoglucomutase, UDP-glucose epimerase, nucleoside diphosphokinase or glucose 6-phosphate dehydrogenase (EC 1.1.1.49) activities. 5. It appeared that the increased lactose synthesis was largely accounted for by the increased lactose synthetase A protein activity and alpha-lactalbumin.

Adenine Nucleotides↗
PubMed2004

The galactokinase of Hypocrea jecorina is essential for cellulase induction by lactose but dispensable for growth on d-galactose.

Lactose is the only soluble carbon source which can be used economically for the production of cellulases or heterologous proteins under cellulase expression signals by Hypocrea jecorina (=Trichoderma reesei). Towards an understanding of lactose metabolism and its role in cellulase formation, we have cloned and characterized the gal1 (galactokinase) gene of H. jecorina, which catalyses the first step in d-galactose catabolism. It exhibits a calculated Mr of 57 kDa, and shows moderate identity (about 40%) to its putative homologues of Saccharomyces cerevisiae and Kluyveromyces lactis. Gal1 is a member of the GHMP family, shows conservation of a Gly/Ser rich region involved in ATP binding and of amino acids (Arg 51, Glu 57, Asp 60, Asp 214, Tyr 270) responsible for galactose binding. A single transcript was formed constitutively during the rapid growth phase on all carbon sources investigated and accumulated to about twice this level during growth on d-galactose, l-arabinose and their corresponding polyols. Deletion of gal1 reduces growth on d-galactose but does only slightly affect growth on lactose. This is the result of the operation of a second pathway for d-galactose catabolism, which involves galactitol as an intermediate, and whose transient concentration is strongly enhanced in the delta-gal1 strain. In this pathway, galactitol is catabolised by the lad1-encoded l-arabinitol-4-dehydrogenase, because a gal1/lad1 double delta-mutant failed to grow on d-galactose. In the delta-gal1 strain, induction of the Leloir pathway gene gal7 (encoding galactose-1-phosphate uridylyltransferase) by d-galactose, but not by l-arabinose, is impaired. Induction of cellulase gene expression by lactose is also impaired in a gal1 deleted strain, whereas their induction by sophorose (the putative cellulose-derived inducer) was shown to be normal, thus demonstrating that galactokinase is a key enzyme for cellulase induction during growth on lactose, and that induction by lactose and sophorose involves different mechanisms.

Amino Acid Sequence↗
PubMed1985

Isolation and nucleotide sequencing of lactose carrier mutants that transport maltose.

The wild-type lactose carrier of Escherichia coli has a poor ability to transport the disaccharide maltose. However, it is possible to select lactose carrier mutants that have an enhanced ability to transport maltose by growing E. coli cells on maltose minimal plates in the presence of isopropyl thiogalactoside (an inducer of the lac operon). We have utilized this approach to isolate 18 independent lactose permease mutants that transport maltose. The relevant DNA sequences have been determined, and all of the mutations were found to be single base pair changes either at triplet 177 or at triplet 236. The nucleotide changes replace alanine-177 with valine or threonine, or tyrosine-236 with phenylalanine, asparagine, serine, or histidine. Transport experiments indicate that all of the mutants have faster maltose transport compared with the wild-type strain. Position 177 mutants retain the ability to transport galactosides, such as lactose and melibiose, at rates similar to the rate of the wild-type strain. In contrast, the position 236 mutants are markedly defective in the ability to transport galactosides. With regard to secondary structure, alanine-177 and tyrosine-236 are located on adjacent hydrophobic segments of the lactose carrier that are predicted to span the membrane. Thus, the results of this study indicate that the substrate recognition site of the lactose carrier is located within the plane of the lipid bilayer. In addition, a tertiary structure model is proposed that suggests how certain transmembrane segments might be localized relative to one another.

Base Sequence↗
PubMed1995

Phosphatidylethanolamine is required for in vivo function of the membrane-associated lactose permease of Escherichia coli.

Experiments with mutant Escherichia coli cells lacking phosphatidylethanolamine (PE) as a membrane component (DeChavigny, A., Heacock, P. N., and Dowhan, W. (1991) J. Biol. Chem. 266, 5323-5332) were carried out to establish whether or not PE is necessary for full function of the lac permease in vivo. The Vmax for active transport of both lactose (in cells lacking beta-galactosidase, lacZ) and the unhydrolyzable lactose analog, methyl-beta-D-galactopyranoside (TMG), by mutant cells lacking PE was reduced 5-10-fold relative to cells containing PE, while the Km for the uptake of both substrates was the same in both types of cells. The low rate of TMG and lactose uptake by PE-deficient cells was unaffected by the presence of a protonophore (uncoupler) and for TMG uptake was on the order of the greatly reduced rate of uptake in uncoupler-treated cells containing PE. The rate of entry of lactose into lacZ+ derivatives of both types of cells, as a measure of facilitated diffusion, was nearly the same. The Km for lactose (lacZ cells) and TMG transport in PE-deficient cells was unaffected by the presence of an uncoupler which had a small effect on Vmax. In PE-containing cells these kinetic parameters for TMG transport were reduced by an uncoupler to the level found with PE-deficient cells while an uncoupler reduced lactose uptake by PE-containing (lacZ) cells to below measureable levels. Inverted membrane vesicles made from both types of cells could be loaded with TMG, but energizing TMG-loaded vesicles by ATP only induced rapid, uphill, permease-dependent efflux of TMG from PE-containing vesicles. The decrease in apparent active transport activity of cells with no PE was not due to a change in membrane permeability, to a reduced delta microH+ (proton electrochemical gradient) across the cell membrane, or to a reduced level of membrane-associated lac permease protein. These results suggest that in the absence of PE the lac permease cannot couple substrate uptake to delta microH+ in order to effect accumulation of substrate and as a result only carries out facilitated diffusion.

Biological Transport, Active↗
PubMed1992

Enhancement of intestinal hydrolysis of lactose by microbial beta-galactosidase (EC 3.2.1.23) of kefir.

The effect of microbial beta-galactosidase (EC 3.2.1.23) activity on intestinal lactose digestion was estimated directly by following post-prandial venous plasma galactose concentrations. To avoid superimposing effects of free galactose, as with yogurt, fresh or heat-treated suspensions of mechanically disintegrated kefir grains in kefir, containing lactose but no free galactose, were fed to ten Göttingen minipigs. Each meal contained 101.1 (SEM 0.1) mmol lactose in kefir supplemented by either native or heat-treated kefir grains corresponding to a mean beta-galactosidase activity of either 72 (SEM 8) U or zero. Feeding kefir with beta-galactosidase activity resulted in a 30% enhancement of the mean post-prandial plasma galactose peak concentration from 33 (SEM 7) to 43 (SEM 12) mumol/l (n 10), as well as in 23% greater mean areas under the galactose-response curves (8.1 (SEM 1.5) v. 6.6 (SEM 1.2) mmol/min per l) if compared with kefir with heat-treated grains. Both differences were significant (P less than 0.05; paired Wilcoxon test by ranks). There was no induction of intestinal beta-galactosidase (EC 3.2.1.108) activity or intestinal lactose-hydrolysing bacteria by lactose feeding. These results give direct evidence of an enhanced lactose digestion and absorption in native fermented milk products due to the microbial beta-galactosidase activity.

Animals↗
PubMed2006

Excretion of lactose in urine as a measure of increased permeability of the lactating breast during inflammation.

HYPOTHESIS: The increased excretion of lactose in urine will be an accurate predictor of increased breast permeability during inflammation of the breast and therefore could predict whether there is a relationship between the severity and type of symptoms suffered during mastitis and changes in breast permeability. METHODS: Twenty-six mothers were followed prospectively from Day 5 postpartum to the end of their lactation. Milk from each breast, blood, 24-hour urine samples, and data on breast and systemic pathologies were collected at reference intervals during the first three months postpartum, daily during the occurrence of any breast inflammation and 7 days after resolution of symptoms. RESULTS: The 24-h excretion of lactose in urine was higher during mastitis (p < 0.001), peaking at the commencement of the mastitis and decreasing over time until there was no significant difference at the time of follow-up when compared to mothers without mastitis (p < 0.25). The changes in lactose in urine were consistent with the changes in sodium, chloride, and lactose in milk, confirming milk expressed for sample analysis was representative of milk from the site of inflammation. Increased severity of breast symptoms experienced during mastitis was a significant predictor for an increased excretion of lactose in urine (p < 0.022). CONCLUSIONS: The use of 24-h excretion of lactose in urine provided a reliable marker of changes occurring in breast permeability and subsequently has shown that an increasing area of inflammation of the breast was predictive of an increase in breast permeability and associated changes in milk composition.

Adult↗
PubMed1982

Influence of dietary lactose on the gut flora of chicks.

1. The gut microflora of chicks fed on a purified diet containing 300 g lactose plus 300 g starch/kg was compared with that of control birds receiving a diet containing 600 g starch/kg. 2. In 14-d-old conventional chicks, lactose in the diet decreased the incidence of lactobacilli and clostridia in the caecal contents, although when presenting lactose-fed chicks the counts of lactobacilli exceeded those of control chicks. 3. High counts of Proteus sp. were present in the caeca of control birds but they were completely suppressed in conventional birds fed on the lactose diet. In vitro tests showed that this inhibition was partially due to Escherichia coli and Streptococcus faecalis. 4. The growth of Lactobacillus acidophilus was inhibited by lactose when gnotobiotic chicks were monoassociated but not when polyassociated. The protective effect was shown in vitro to be due to L. salivarius. 5. The pH was markedly lowered in the caecum of conventional and polyassociated chicks receiving dietary lactose. Of the strains used in gnotobiotic experiments E. coli, S. faecalis and L. salivarius produced the lowest pH values in the caeca.

Animals↗