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  • 1.
    Andersson, Eva-Lotta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bläckberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Fält, Helen
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bile salt-stimulated lipase and pancreatic lipase-related protein 2: key enzymes for lipid digestion in the newborn examined using the Caco-2 cell line2011Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, nr 11, s. 1949-1956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In rodents, bile salt-stimulated lipase (BSSL) and pancreatic lipase-related protein 2 (PLRP2) are the dominant lipases expressed in the exocrine pancreas in early life, when milk is the main food. The aim of the present study was to evaluate if BSSL and PLRP2 are also key enzymes in neonatal intestinal fat digestion. Using Caco-2 cells as a model for the small intestinal epithelium, purified human enzymes were incubated in the apical chamber with substrates and bile salt concentrations resembling the milieu of the small intestine of newborn infants. BSSL and PLRP2 hydrolyzed triglycerides (TG) to free fatty acids (FA) and glycerol. The cells took up the FA, which were reesterfied to TG. Together, BSSL and PLRP2 have a synergistic effect, increasing cellular uptake 4-fold compared to the sum of each lipase alone. A synergistic effect was also observed with retinyl ester as a substrate. PLRP2 hydrolyzed cholesteryl ester but not as efficiently as BSSL, and the two had an additive rather than synergistic effect. We conclude the key enzymes in intestinal fat digestion are different in newborns than later in life. Further studies are needed to fully understand this difference and its implication for designing optimal neonatal nutrition.

  • 2.
    Andersson, Yvonne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bergström, S
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Three variants of parathyroid hormone-related protein messenger RNA are expressed in human mammary gland.1997Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 41, nr 3, s. 380-3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PTH-related protein (PTHrP) is found in a variety of tissues; particularly high levels are present in human milk. The structure of the human PTHrP gene is complex, and alternative splicing allows expression of three different variants PTHrP139, PTHrP173, and PTHrP141, respectively. To determine which of the variants are expressed in human mammary gland a reverse transcriptase polymerase chain reaction (RT-PCR) method was elaborated, distinguishing the three variants. mRNA isolated from human milk cells, human mammary epithelial cells (HMEC) and human nonlactating mammary gland cells were analyzed. The RT-PCR experiments resulted in amplification of DNA fragments corresponding to all three variants for all three cell sources tested. The nucleotide sequences of the PCR fragments were determined and verified to be identical to the reported sequences. Hence, it is concluded that human mammary gland epithelial cells express three variants of PTHrP. Whether these have different physiologic effects in the mammary gland or in the breast fed infant remain to be explored.

  • 3.
    Andersson, Yvonne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lagerqvist, Carina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lactoferrin is responsible for the fungistatic effect of human milk.2000Inngår i: Early Human Development, ISSN 0378-3782, E-ISSN 1872-6232, Vol. 59, nr 2, s. 95-105Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human milk has recognized anti-microbial effects and it has been repeatedly shown that breast-fed infants have fewer and less severe infections than formula-fed infants. While most studies have focused on anti-bacterial and anti-viral activities few have focused on the anti-fungal effect of human milk. Dermal and other infections caused by fungi are common in very low birth weight (VLBW) infants. Using a liquid culturing method and Candida albicans and Rhodotorula rubra as representative fungi, we studied the anti-fungal effect of human milk and certain human milk proteins. In vitro, human milk showed potent inhibitory effect on fungal growth. Most, if not all of this effect was caused by lactoferrin via its iron-binding capacity; increasing the iron content of the incubation medium abolished the inhibitory effect. In contrast, other human milk proteins with known or suggested anti-microbial effects rather increased fungal growth. Viability test and electron microscopy revealed that the growth inhibitory effect of human milk, i.e. mediated by lactoferrin, is fungistatic rather than fungicidal.

  • 4. Johansson, Bente B
    et al.
    Torsvik, Janniche
    Gundersen, Lise
    Vesterhus, Mette
    Ragvin, Anja
    Tjora, Erling
    Fjeld, Karianne
    Hoem, Dag
    Johansson, Stefan
    Rader, Helge
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Cnop, Miriam
    Saraste, Jaakko
    Flatmark, Torgeir
    Molven, Anders
    Njolstad, Pal R
    Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase gene (CEL-MODY): a protein misfolding disease2011Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, nr 40, s. 34593-34605Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CEL-MODY, diabetes with pancreatic lipomatosis and exocrine dysfunction, is due to dominant frame-shift mutations in the acinar cell carboxyl-ester lipase gene (CEL). As Cel knock-out mice do not express the phenotype and the mutant protein has an altered, intrinsically disordered tandem repeat domain, we hypothesized that the disease mechanism might involve a negative effect of the mutant protein. In silico analysis showed that the pI of the tandem repeat was markedly increased from pH 3.3 in wild-type (WT) to 11.8 in mutant (MUT) human CEL. By stably over-expressing CEL-WT and CEL-MUT in HEK293 cells, we found similar glycosylation, ubiquitination, constitutive secretion and quality control of the two proteins. The CEL-MUT protein demonstrated, however, a high propensity to form aggregates found intracellularly and extracellularly. Different physico-chemical properties of the intrinsically disordered tandem repeat domains of WT and MUT proteins may contribute to different short-range and long-range interactions with the globular core domain and other macromolecules, including cell membranes. Thus, we propose that CEL-MODY is a protein misfolding disease caused by a negative gain-of-function effect of the mutant proteins in pancreatic tissues.

  • 5.
    Li, X
    et al.
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Chen, R
    Lindquist, S
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Hernell, O
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Expression of cellular inhibitor of apoptosis protein-2 in human subcutaneous and omental adipose tissue2004Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 28, nr 3, s. 352-356Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: In the current study, we addressed the question if there is depot-specific expression of cellular inhibitor of apoptosis protein-2 (cIAP2) already in childhood and if the relative expression changes with age in parallel with increasing risk of developing visceral adiposity. SUBJECTS: Paired samples of human omental (OM) and subcutaneous (SC) adipose tissue were obtained from 23 patients (12 children and 11 adults). METHOD: mRNA level of cIAP2 was determined using reverse transcription-polymerase chain reaction (RT-PCR) and protein expression confirmed by Western blotting. Apoptosis indices were determined by terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end labelling (TUNEL). RESULTS: cIAP2 mRNA was 1.51-fold higher in OM compared with SC adipose tissue (OM>SC in 20 of 23 subjects; P<0.001). Western blots were in agreement with mRNA expression (OM>SC in nine of 10 subjects, P<0.01). Subgroup analyses showed depot difference in both children (P<0.01) and adults (P<0.05). Contrary to the hypothesis, depot-specific difference in mRNA expression of cIAP2 was significantly higher in children compared with adults (P<0.05). We were unable to demonstrate any difference in the basal apoptosis rate between adipocytes from the two depots. There was no significant association between cIAP2 mRNA expression and BMI or sex. CONCLUSIONS: The results demonstrated for the first time that depot-specific difference in cIAP2 expression is consistent in children and adults. This suggests that the higher expression of cIAP2 in OM than in SC adipose tissue may be due to inherent properties of cells from the two depots. The more pronounced depot-specific difference in children than in adults may reflect a net gain in visceral adipose tissue during growth.

  • 6.
    Li, X.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Chen, R.
    Children's Research Institute of Nanjing Medical University, Nanjing, China.
    Myrnäs, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Angsten, G.
    Department of Pediatric Surgery, University Children's Hospital, Uppsala, Sweden.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Depot-specific messenger RNA expression of 11 beta-hydroxysteroid dehydrogenase type 1 and leptin in adipose tissue of children and adults2007Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 31, nr 5, s. 820-828Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To compare expression of messenger RNA (mRNA) coding for the cortisol regenerating enzyme 11-hydroxysteroid dehydrogenase type 1 (11-HSD1), and the adipocytokines leptin and resistin in paired biopsies of subcutaneous adipose tissue (SC) and omental adipose tissue (OM) from children.

    Design: Paired biopsies (SC and OM) were obtained from 54 children (age 0.17–16 years, body mass index (BMI) 12.5–28.3 kg/m2, BMI standard deviation score (SDS) -2.5–4.5) and 16 adults (age 27–79 years, BMI 19–46 kg/m2) undergoing open abdominal surgery. mRNA levels of 11-HSD1, leptin and resistin were measured using quantitative real-time polymerase chain reaction (PCR).

    Results: 11-HSD1 mRNA level was higher in OM than in SC (P<0.05), whereas leptin mRNA was higher in SC than in OM (P<0.001). There was no difference in the resistin mRNA level between SC and OM. These results were consistent in children and adults. In children, 11-HSD1 mRNA in SC was positively associated with BMI SDS (P<0.05), whereas in OM it was positively associated with age (P<0.05). The association between 11-HSD1 expression and age remained significant after adjustment for BMI SDS and gender. Leptin mRNA was positively associated with BMI SDS (SC:P<0.001, OM: P<0.001) but not with age in children. In multiple regression analyses, including anthropometric variables and age, BMI SDS was independently associated with mRNA levels of 11-HSD1 (P<0.05) and leptin (P<0.001) in SC. When normal weight and overweight children were analyzed separately, 11-HSD1 mRNA levels were positively associated with leptin in OM in the overweight group (P<0.05).

    Conclusion: There are depot-specific differences in mRNA levels of 11-HSD1 and leptin in children and adults. The positive association of 11-HSD1 mRNA in OM with age may reflect a causal role in visceral fat accumulation during growth. Increasing 11-HSD1 and leptin mRNA in SC with increasing BMI SDS could suggest that the risk of metabolic consequences of obesity may be established early in life.

  • 7.
    Li, Xiaonan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Angsten, Gertrud
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Yi, Jun
    Olsson, Tommy
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Adiponectin and peroxisome proliferator-activated receptor gamma expression in subcutaneous and omental adipose tissue in children.2008Inngår i: Acta Paediatr, ISSN 0803-5253, Vol. 97, nr 5, s. 630-5Artikkel i tidsskrift (Annet vitenskapelig)
  • 8.
    Li, Xiaonan
    et al.
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Lowe, Mark
    Noppa, Laila
    Hernell, Olle
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Bile Salt-Stimulated Lipase and Pancreatic Lipase-Related Protein 2 Are the Dominating Lipases in Neonatal Fat Digestion in Mice and Rats.2007Inngår i: Pediatr Res, ISSN 0031-3998Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During infancy, the basic conditions for digestion of dietary fat differ from later in life. The bile salt-stimulated lipase (BSSL) is an enzyme expressed in the exocrine pancreas and in some species (including human) also in the lactating mammary gland and secreted with the milk. The aim of this study was to compare the ontogeny of four pancreatic lipases [BSSL, pancreatic triglyceride lipase (PL), pancreatic lipase-related protein 2 (PLRP2), and phospholipase A2 (PLA2)] in one species that supplies BSSL with milk (the mouse) and one that does not (the rat). We followed expression of the four pancreatic lipases from postnatal d 1 until after weaning in both species. We found that BSSL and PLRP2, two lipases with broad substrate specificity, dominated. It was not until weaning that significant expression of PL and PLA2 were induced. Thus, BSSL and PLRP2 seem to be responsible for fat digestion as long as milk is the main food. Moreover, the early temporal pattern of BSSL expression differed between species. We speculate that the milk-borne BSSL is able to compensate for a slower ontogeny of pancreatic BSSL expression in the mouse.

    PMID: 17805199 [PubMed - as supplied by publisher]

  • 9.
    Lindquist, Susanne
    et al.
    Umeå universitet. Lipum AB, Umeå, Sweden.
    Alenius, Gerd-Marie
    Umeå universitet.
    Berntson, Lillemor
    Umeå universitet.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet.
    Lundberg, Lennart
    Wang, Yuhang
    Umeå universitet.
    Hernell, Olle
    Umeå universitet. Lipum AB, Umeå, Sweden.
    A novel target for treatment of inflammatory joint diseases2019Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, s. 1525-1526Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: The bile salt-stimulated lipase (BSSL) is a hitherto unrecognized player in inflammation. Animals devoid of BSSL (knockout mice) are protected from developing collagen induced arthritis (CIA) and collagen antibody induced arthritis (CAIA), and antibodies directed towards BSSL has been proven to prevent or mitigate arthritis in mouse and rat arthritis models1. In humans, BSSL is present in blood2 and accumulate at sites of inflammation. Patients with acute pancreatitis have significantly increased plasma BSSL levels compared to healthy controls. Whether BSSL in blood originates from pancreas, inflammatory cells, or both remains to be elucidated.

    Objectives: To determine BSSL concentration in blood samples from patients with inflammatory joint disorders and to evaluate possible relationships between circulating BSSL levels and disease-activity variables.

    Methods: BSSL concentrations in plasma or serum were determined in patients with rheumatoid arthritis (RA), psoriasis arthritis (PsA), and juvenile idiopathic arthritis (JIA) by a sandwich enzyme-linked immunosorbent assay (ELISA). Correlations between BSSL concentrations and disease activity score, erythrocyte sedimentation rate (ESR), blood levels of C-reactive protein (CRP), S100A8/9, leukocyte- and neutrophil counts, proinflammatory cytokines and chemokines were analyzed using Spearman rank-order correlation.

    Results: Significant correlations between BSSL concentration in plasma and disease activity score (DAS28, rS=0.31, p=0.007), ESR (rS=0.58, p<0.000), CRP (rS=0.42, p=0.012), leukocytes (rS=0.66, p<0.000), and neutrophils (rS=0.71, p<0.000) were found in RA. The BSSL plasma concentration decreased with duration of treatment with the TNFα inhibitor infliximab, in parallel with decreasing DAS28 score.

    BSSL concentration was significantly higher in sera from PsA patients with both oligo- and polyarthritis compared with healthy controls. Moreover, BSSL concentration in serum correlated significantly with S100A8/A9 and CRP concentrations (rS=0.54, p<0.001 and rS=0.49, p<0.001, respectively). No correlation between levels of BSSL and cytokines or chemokines were found in RA or PsA plasma or serum, respectively.

    In JIA, levels of BSSL in serum correlated significantly with JIA disease activity score (JADAS27) (rS=0.26, p=0.007), ESR (rS=0.47, p<0.000), and leukocytes (rS=0.32, p<0.000).

    Conclusion: BSSL concentration in serum and plasma correlated with disease activity in patients with inflammatory joint disorders, i.e. RA, PsA and JIA. These data in humans support the relevance of our previous studies in rodents and therefore also our hypothesis 1 that BSSL is a novel target for treatment of inflammatory diseases.

  • 10.
    Lindquist, Susanne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Andersson, Eva-Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lundberg, Lennart
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bile salt-stimulated lipase plays an unexpected role in arthritis development in rodents2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 10, s. e47006-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The present study aimed to explore the hypothesis that bile salt-stimulated lipase (BSSL), in addition to being a key enzyme in dietary fat digestion during early infancy, plays an important role in inflammation, notably arthritis. Methods: Collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rodents are commonly used experimental models that reproduce many of the pathogenic mechanisms of human rheumatoid arthritis, i.e. increased cellular infiltration, synovial hyperplasia, pannus formation, and erosion of cartilage and bone in the distal joints. We used the CIA model to compare the response in BSSL wild type (BSSL-WT) mice with BSSL-deficient 'knock-out' (BSSL-KO) and BSSL-heterozygous (BSSL-HET) littermates. We also investigated if intraperitoneal injection of BSSL-neutralizing antibodies affected the development or severity of CIA and PIA in mice and rats, respectively. Results: In two consecutive studies, we found that BSSL-KO male mice, in contrast to BSSL-WT littermates, were significantly protected from developing arthritis. We also found that BSSL-HET mice were less prone to develop disease compared to BSSL-WT mice, but not as resistant as BSSL-KO mice, suggesting a gene-dose effect. Moreover, we found that BSSL-neutralizing antibody injection reduced both the incidence and severity of CIA and PIA in rodents. Conclusion: Our data strongly support BSSL as a key player in the inflammatory process, at least in rodents. It also suggests the possibility that BSSL-neutralizing agents could serve as a therapeutic model to reduce the inflammatory response in humans.

  • 11.
    Lindquist, Susanne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lipid digestion and absorption in early life: an update.2010Inngår i: Current opinion in clinical nutrition and metabolic care, ISSN 1363-1950, E-ISSN 1473-6519, Vol. 13, nr 3, s. 314-20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE OF REVIEW: To highlight our understanding of digestion and absorption of dietary lipids in newborn infants, and specifically how these processes differ from those in children and adults. RECENT FINDINGS: The intestinal concentration of pancreatic triglyceride lipase (PTL) and bile salts is lower in newborns compared to later in life. Instead the PTL-related protein 2 and bile salt-stimulated lipase (BSSL) are the key enzymes secreted from pancreas, which in concerted action with gastric lipase operate to achieve efficient fat absorption during infancy. BSSL is also present in human milk which affects fat absorption and growth in breast-fed preterm infants. Under conditions of low luminal bile salt concentrations fat absorption is likely to occur from liquid crystalline product phases, which may result in absorption from an extended part of the small intestinal mucosal surfaces compared to adults. Chylomicron assembly and secretion also seem to adapt to the specific situation of the newborn. SUMMARY: Both fat digestion and product absorption are different in newborn infants compared to adults; other lipases are used for digestion and different physical-chemical phases may be used for product absorption. Why these differences occur is still an unsolved question of considerable importance to neonatal nutrition.

  • 12.
    Lindquist, Susanne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Isehed, Catrine
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Folktandvården Gävleborg AV, Region Gävleborg.
    Lie, Anita
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Enamel matrix derivative does not affect osteoclast formation or bone resorption in mouse bone marrow macrophage culturesManuskript (preprint) (Annet vitenskapelig)
  • 13. Naarding, Marloes A
    et al.
    Dirac, Annette M
    Ludwig, Irene S
    Speijer, Dave
    Lindquist, Susanne
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Vestman, Eva-Lotta
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Stax, Martijn J
    Geijtenbeek, Teunis B H
    Pollakis, Georgios
    Hernell, Olle
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Pediatrik.
    Paxton, William A
    Bile salt-stimulated lipase from human milk binds DC-SIGN and inhibits human immunodeficiency virus type 1 transfer to CD4+ T cells.2006Inngår i: Antimicrob Agents Chemother, ISSN 0066-4804, Vol. 50, nr 10, s. 3367-74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A wide range of pathogens, including human immunodeficiency virus type 1 (HIV-1), hepatitis C virus, Ebola virus, cytomegalovirus, dengue virus, Mycobacterium, Leishmania, and Helicobacter pylori, can interact with dendritic cell (DC)-specific ICAM3-grabbing nonintegrin (DC-SIGN), expressed on DCs and a subset of B cells. More specifically, the interaction of the gp120 envelope protein of HIV-1 with DC-SIGN can facilitate the transfer of virus to CD4+ T lymphocytes in trans and enhance infection. We have previously demonstrated that a multimeric LeX component in human milk binds to DC-SIGN, preventing HIV-1 from interacting with this receptor. Biochemical analysis reveals that the compound is heat resistant, trypsin sensitive, and larger than 100 kDa, indicating a specific glycoprotein as the inhibitory compound. By testing human milk from three different mothers, we found the levels of DC-SIGN binding and viral inhibition to vary between samples. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blotting, and matrix-assisted laser desorption ionization analysis, we identified bile salt-stimulated lipase (BSSL), a Lewis X (LeX)-containing glycoprotein found in human milk, to be the major variant protein between the samples. BSSL isolated from human milk bound to DC-SIGN and inhibited the transfer of HIV-1 to CD4+ T lymphocytes. Two BSSL isoforms isolated from the same human milk sample showed differences in DC-SIGN binding, illustrating that alterations in the BSSL forms explain the differences observed. These results indicate that variations in BSSL lead to alterations in LeX expression by the protein, which subsequently alters the DC-SIGN binding capacity and the inhibitory effect on HIV-1 transfer. Identifying the specific molecular interaction between the different forms may aid in the future design of antimicrobial agents.

  • 14. Stax, Martijn J
    et al.
    Naarding, Marloes A
    Tanck, Michael W T
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lyle, Robert
    Brandtzaeg, Per
    Eggesbø, Merete
    Pollakis, Georgios
    Paxton, William A
    Binding of human milk to pathogen receptor DC-SIGN varies with bile salt-stimulated lipase (BSSL) gene polymorphism2011Inngår i: PloS one, ISSN 1932-6203, Vol. 6, nr 2, s. e17316-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The observed variation in DC-SIGN binding properties among milk samples may have implications for the risk of mucosal transmission of pathogens during breastfeeding.

  • 15.
    Vahid, Harandi M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Susanne, Lindquist
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Shrikant, Shantilal Kolan
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Thomas, Brännström
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jing-Xia, Liu
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of Mouse Model of Amyotrophic Lateral Sclerosis2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 10, artikkel-id e109833Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is currently an incurable fatal motor neuron syndrome characterized by progressive weakness, muscle wasting and death ensuing 3–5 years after diagnosis. Neurotrophic factors (NTFs) are known to be important in both nervous system development and maintenance. However, the attempt to translate the potential of NTFs into the therapeutic options remains limited despite substantial number of approaches, which have been tested clinically. Using quantitative RT-PCR (qRT-PCR) technique, the present study investigated mRNA expression of four different NTFs: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) in limb muscles and extraocular muscles (EOMs) from SOD1G93A transgenic mice at early and terminal stages of ALS. General morphological examination revealed that muscle fibres were well preserved in both limb muscles and EOMs in early stage ALS mice. However, in terminal ALS mice, most muscle fibres were either atrophied or hypertrophied in limb muscles but unaffected in EOMs. qRT-PCR analysis showed that in early stage ALS mice, NT-4 was significantly down-regulated in limb muscles whereas NT-3 and GDNF were markedly up-regulated in EOMs. In terminal ALS mice, only GDNF was significantly up-regulated in limb muscles. We concluded that the early down-regulation of NT-4 in limb muscles is closely associated with muscle dystrophy and dysfunction at late stage, whereas the early up-regulations of GDNF and NT-3 in EOMs are closely associated with the relatively well-preserved muscle morphology at late stage. Collectively, the data suggested that comparing NTFs expression between limb muscles and EOMs from different stages of ALS animal models is a useful method in revealing the patho-physiology and progression of ALS, and eventually rescuing motor neuron in ALS patients.

  • 16. Wang, Yuhang
    et al.
    Ding, Fangrong
    Wang, Tao
    Liu, Wenjie
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Wang, Jianwu
    Li, Jing
    Li, Ling
    Zhao, Yaofeng
    Dai, Yunping
    Li, Ning
    Purification and characterization of recombinant human bile salt-stimulated lipase expressed in milk of transgenic cloned cows2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 5, artikkel-id e0176864Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bile salt-stimulated lipase (BSSL) is a lipolytic digestive enzyme with broad substrate specificity secreted from exocrine pancreas into the intestinal lumen in all species and from the lactating mammary gland into the milk of some species, notably humans but not cows. BSSL in breast milk facilitates digestion and absorption of milk fat and promotes growth of small for gestational age preterm infants. Thus, purified recombinant human BSSL (rhBSSL) can be used for treatment of patients with fat malabsorption and expressing rhBSSL in the milk of transgenic cloned cows would therefore be a mean to meet a medical need. In the present study, a vector pBAC-hLF-hBSSL was constructed, which efficiently expressed active rhBSSL in milk of transgenic cloned cows to a concentration of 9.8 mg/ml. The rhBSSL purified from cow milk had the same enzymatic activity, N-terminal amino acid sequence, amino acid composition and isoelectric point and similar physicochemical characteristics as human native BSSL. Our study supports the use of transgenic cattle for the cost-competitive, large-scale production of therapeutic rhBSSL.

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