Liliana Håversen - Academia.edu (original) (raw)

Papers by Liliana Håversen

Research paper thumbnail of Sulfone-based human liver pyruvate kinase inhibitors – Design, synthesis and in vitro bioactivity

European journal of medicinal chemistry, Apr 1, 2024

Research paper thumbnail of Cover Feature: Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase (ChemBioChem 1/2023)

ChemBioChem, Dec 14, 2022

Research paper thumbnail of 128 ARAP2-INDUCED Changes in Sphingolipid Biosynthesis Promote Lipid Droplet Formation by Increasing GLUT1 Levels in the Plasma Membrane

Atherosclerosis Supplements, Jun 1, 2011

Research paper thumbnail of Statement of Retraction. The SNARE Protein SNAP23 and the SNARE-Interacting Protein Munc18c in Human Skeletal Muscle Are Implicated in Insulin Resistance/Type 2 Diabetes. Diabetes 2010;59:1870–1878. DOI: 10.2337/db09-1503. PMID: 20460426

Research paper thumbnail of CD38 as a therapeutic target in pediatric Burkitt’s Lymphoma: insights from a comparative approach (Running title: Targeting CD38 in pediatric Burkitt's Lymphoma)

Background: Pediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin's B-cell ... more Background: Pediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin's B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse and resistance to current therapies remains challenging. CD38, a transmembrane protein highly expressed in pBL, is a promising therapeutic target. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab (DARA) and isatuximab (ISA), in impairing crucial cellular processes and survival pathways in pBL malignant cells. Methods: In silico analyses of pBL cell line and patient sample datasets, combined with in 51 vitro experiments using the Ramos cell line model, were conducted to assess the impact of 52 DARA and ISA on cellular proliferation, apoptosis, and the phosphoinositide 3-kinase (PI3K) 53 pathway. Comparative approaches were utilized to evaluate the therapeutic potential of these 54 mAbs, focusing on B-cell receptor signaling, calcium flux, metabolic shifts, and interaction of 55 key proteins on the cell surface. 56 Results: ISA was found to be more effective than DARA in disrupting B-cell receptor 57 signaling, reducing cellular proliferation, and inducing apoptosis. Additionally, ISA caused a significant impairment of the PI3K pathway and induced metabolic shifts in pBL cells, indicating its role in metabolic reprogramming. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38's involvement in key oncogenic processes. Conclusions: The study emphasizes the therapeutic potential of CD38-targeting mAbs, particularly ISA, in pBL. These findings suggest that targeting CD38 with mAbs may offer a novel approach for treating pBL, particularly in cases where patients show resistance or relapse after conventional therapies.

Research paper thumbnail of ARAP2 promotes GLUT1-mediated basal glucose uptake through regulation of sphingolipid metabolism

Biochimica Et Biophysica Acta - Molecular And Cell Biology Of Lipids, Nov 1, 2016

Lipid droplet formation, which is driven by triglyceride synthesis, requires several dropletassoc... more Lipid droplet formation, which is driven by triglyceride synthesis, requires several dropletassociated proteins. We identified ARAP2 (an ADP-ribosylation factor 6 GTPase-activating protein) in the lipid droplet proteome of NIH-3T3 cells and showed that knockdown of ARAP2 resulted in decreased lipid droplet formation and triglyceride synthesis. We also showed that ARAP2 knockdown did not affect fatty acid uptake but reduced basal glucose uptake, total levels of the glucose transporter GLUT1, and GLUT1 levels in the plasma membrane and the lipid micro-domain fraction (a specialized plasma membrane domain enriched in sphingolipids). Microarray analysis showed that ARAP2 knockdown altered expression of genes involved in sphingolipid metabolism. Because sphingolipids are known to play a key role in cell signaling, we performed lipidomics to further investigate the relationship between ARAP2 and sphingolipids and potentially identify a link with glucose uptake. We found that ARAP2 knockdown increased glucosylceramide and lactosylceramide levels without affecting ceramide levels, and thus speculated that the rate-limiting enzyme in glycosphingolipid synthesis, namely glucosylceramide synthase (GCS), could be modified by ARAP2. In agreement with our hypothesis, we showed that the activity of GCS was increased by ARAP2 knockdown and reduced by ARAP2 overexpression. Furthermore, pharmacological inhibition of GCS resulted in increases in basal glucose uptake, total GLUT1 levels, triglyceride biosynthesis from glucose, and lipid droplet formation, indicating that the effects of GCS inhibition are the opposite to those resulting from ARAP2 knockdown. Taken together, our data suggest that ARAP2 promotes lipid droplet formation by modifying sphingolipid metabolism through GCS.

Research paper thumbnail of The formation of lipid droplets: possible role in the development of insulin resistance/type 2 diabetes

Prostaglandins Leukotrienes and Essential Fatty Acids, Nov 1, 2011

Neutral lipids are stored in so-called lipid droplets, which are formed as small primordial dropl... more Neutral lipids are stored in so-called lipid droplets, which are formed as small primordial droplets at microsomal membranes and increase in size by a fusion process. The fusion is catalyzed by the SNARE proteins SNAP23, syntaxin-5 and VAMP4. SNAP23 is involved in the insulin dependent translocation of GLUT4 to the plasma membrane, and has an important role in the development of insulin resistance. Thus fatty acids relocalize SNAP23 from the plasma membrane (and the translocation of GLUT 4) to the interior of the cell giving rise to insulin resistance. Moreover this relocalization is seen in skeletal muscles biopsies from patients with type 2 diabetes compared to matched control. Thus a missorting of SNAP23 is essential for the development of insulin resistance.

Research paper thumbnail of Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators

European journal of medicinal chemistry, Mar 1, 2023

Research paper thumbnail of Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages

Atherosclerosis, Feb 1, 2009

Increased circulating free fatty acids in subjects with type 2 diabetes may contribute to activat... more Increased circulating free fatty acids in subjects with type 2 diabetes may contribute to activation of macrophages, and thus the development of atherosclerosis. In this study, we investigated the effect of the saturated fatty acids (SFA) palmitate, stearate, myristate and laurate, and the unsaturated fatty acid linoleate, on the production of proinflammatory cytokines in phorbol ester-differentiated THP-1 cells, a model of human macrophages. Palmitate induced secretion and mRNA expression of TNF-␣, IL-8 and IL-1␤, and enhanced lipopolysaccharide (LPS)-induced IL-1␤ secretion. Proinflammatory cytokine secretion was also induced by stearate, but not by the shorter chain SFA, myristate and laurate, or linoleate. Triacsin C abolished the palmitate-induced cytokine secretion, suggesting that palmitate activation to palmitoyl-CoA is required for its effect. Palmitate-induced cytokine secretion was decreased by knockdown of serine palmitoyltransferase and mimicked by C 2-ceramide, indicating that ceramide is involved in palmitate-induced cytokine secretion. Palmitate phosphorylated p38 and JNK kinases, and blocking of these kinases with specific inhibitors diminished the palmitate-induced cytokine secretion. Palmitate also activated the AP-1 (c-Jun) transcription factor. Knockdown of MyD88 reduced the palmitate-induced IL-8, but not TNF-␣ or IL-1␤ secretion. In conclusion, our data suggest that the long-chain SFA induce proinflammatory cytokines in human macrophages via pathways involving de novo ceramide synthesis. This might contribute to the activation of macrophages in atherosclerotic plaques, especially in type 2 diabetes.

Research paper thumbnail of Tu-P7:188 Palmitate induces proinflammatory cytokine secretion in macrophages

Atherosclerosis Supplements, 2006

Research paper thumbnail of Design and development of a photoswitchable DFG-out kinase inhibitor

Chemical Communications, 2021

We report the synthesis and characterisation of a photoswitchable DFG-out kinase inhibitor. Photo... more We report the synthesis and characterisation of a photoswitchable DFG-out kinase inhibitor. Photocontrol of the target kinase in both enzymatic and living cell assays is demonstrated.

Research paper thumbnail of Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Scientific Reports, Sep 11, 2018

Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS), which drives the ... more Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS), which drives the production of proinflammatory cytokines. Earlier studies have indicated that cholesterol-and glycosphingolipidrich subregions of the plasma membrane (lipid domains) are important for TLR4-mediated signaling. We report that inhibition of glucosylceramide (GluCer) synthase, which resulted in decreased concentrations of the glycosphingolipid GluCer in lipid domains, reduced the LPS-induced inflammatory response in both mouse and human macrophages. Atomistic molecular dynamics simulations of the TLR4 dimer complex (with and without LPS in its MD-2 binding pockets) in membranes (in the presence and absence of GluCer) showed that: (1) LPS induced a tilted orientation of TLR4 and increased dimer integrity; (2) GluCer did not affect the integrity of the LPS/TLR4 dimer but reduced the LPS-induced tilt; and (3) GluCer increased electrostatic interactions between the membrane and the TLR4 extracellular domain, which could potentially modulate the tilt. We also showed that GCS inhibition reduced the interaction between TLR4 and the intracellular adaptor protein Mal. We conclude that the GluCerinduced effects on LPS/TLR4 orientation may influence the signaling capabilities of the LPS/TLR4 complex by affecting its interaction with downstream signaling proteins.

Research paper thumbnail of 432 the Importance of De Novo Lipogenesis of Lipid Loading in Human Macrophages

Atherosclerosis Supplements, Jun 1, 2011

Atherosclerosis Supplements 12, no. 1 (2011) 13-184 Poster presentations Interleukin-6,-8 and C-r... more Atherosclerosis Supplements 12, no. 1 (2011) 13-184 Poster presentations Interleukin-6,-8 and C-reactive protein levels were significantly lower after periodontal treatment. Treatment had no effect on plasma levels total cholesterol, HDL and LDL. The value of non-linear index of refraction of low density lipoprotein and the IgG antibodies against oxidized low-density lipoprotein were significantly higher and lower, respectively 12 months after periodontal treatment. Leukocyte and neutrophils counts were lower after 3 months of periodontal treatment. Conclusion: In conclusion, this study indicates that standard treatment for periodontal disease induces systemic changes in several biochemical markers that reflect the risk for atherosclerosis.

Research paper thumbnail of PO9-217 Palmitate Induces Proinflammatory Cytokine Secretion in Human Macrophages via Activation of P38 and JNK Kinases

Atherosclerosis Supplements, Jun 1, 2007

Research paper thumbnail of Anti-infectious and anti-inflammatory activities of lactoferrin and fragments thereof

Det här verket är upphovrättskyddat enligt Lagen (1960:729) om upphovsrätt till litterära och kon... more Det här verket är upphovrättskyddat enligt Lagen (1960:729) om upphovsrätt till litterära och konstnärliga verk. Det har digitaliserats med stöd av Kap. 1, 16 § första stycket p 1, för forskningsändamål, och får inte spridas vidare till allmänheten utan upphovsrättsinehavarens medgivande. Alla tryckta texter är OCR-tolkade till maskinläsbar text. Det betyder att du kan söka och kopiera texten från dokumentet. Vissa äldre dokument med dåligt tryck kan vara svåra att OCR-tolka korrekt vilket medför att den OCR-tolkade texten kan innehålla fel och därför bör man visuellt jämföra med verkets bilder för att avgöra vad som är riktigt. Th is work is protected by Swedish Copyright Law (Lagen (1960:729) om upphovsrätt till litterära och konstnärliga verk). It has been digitized with support of Kap. 1, 16 § första stycket p 1, for scientifi c purpose, and may no be dissiminated to the public without consent of the copyright holder. All printed texts have been OCR-processed and converted to machine readable text. Th is means that you can search and copy text from the document. Some early printed books are hard to OCR-process correctly and the text may contain errors, so one should always visually compare it with the images to determine what is correct.

Research paper thumbnail of Design and development of photoswitchable DFG-Out RET kinase inhibitors

European journal of medicinal chemistry, Apr 1, 2022

REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required... more REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required for development of multiple human tissues, but which is also an important contributor to human cancers. RET activation through rearrangement or point mutations occurs in thyroid and lung cancers. Furthermore, activation of wild type RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET is therefore an attractive therapeutic target for small-molecule kinase inhibitors. Non-invasive control of RET signaling with light offers the promise of unveiling its complex spatiotemporal dynamics in vivo. In this work, photoswitchable DFG-out RET kinase inhibitors based on heterocycle-derived azobenzenes were developed, enabling photonic control of RET activity. Based on the binding mode of DFG-out kinase inhibitors and using RET kinase as the test model, we developed a photoswitchable inhibitor with a quinoline "head" constituting the azoheteroarene. This azo compound was further modified by three different strategies to increase the difference in biological activity between the E-isomer and the light enriched Z-isomer. Stilbene-based derivatives were used as model compounds to guide in the selection of substituents that could eventually be introduced to the corresponding azo compounds. The most promising quinoline-based compound showed more than a 15-fold difference in bioactivity between the two isomers in a biochemical assay. However, the same compound showed a decreased Z/E (IC50) ratio in the cellular assay, tentatively assigned to stability issues. The corresponding stilbene compound gave a Z/E (IC50) ratio well above 100, consistent with that measured in the biochemical assay. Ultimately, a 7-azaindole based photoswitchable DFG-out kinase inhibitor was shown to display more than a 10-fold difference in bioactivity between the two isomers, in both a biochemical and a cell-based assay, as well as excellent stability even under reducing conditions.

Research paper thumbnail of P283 the Role of Snare Proteins in Human Insulin Resistance

Atherosclerosis Supplements, 2010

Research paper thumbnail of The Transfer of Immunity from Mother to Child

Annals of the New York Academy of Sciences, 2003

: The newborn's immune system grows fast from a small size at birth by exposure primarily to ... more : The newborn's immune system grows fast from a small size at birth by exposure primarily to the intestinal microflora normally obtained from the mother at and after birth. While building up its immune system, the infant is supported by the transplacental IgG antibodies, which also contain anti‐idiotypic antibodies, possibly also actively priming the offspring. The second mode of transfer of immunity occurs via the milk. Numerous major protective components, including secretory IgA (SIgA) antibodies and lactoferrin, are present.The breastfed infant is better protected against numerous common infections than the non‐breastfed. Breastfeeding also seems to actively stimulate the infant's immune system by anti‐idiotypes, uptake of milk lymphocytes, cytokines, etc. Therefore, the breastfed child continues to be better protected against various infections for some years. Vaccine responses are also often enhanced in breastfed infants. Long‐lasting protection against certain immunological diseases such as allergies and celiac disease is also noted.

Research paper thumbnail of How can we prevent cardiovascular disease in diabetes

Journal of Internal Medicine, Aug 1, 2007

Evidence based goals for the treatment and prevention of atherosclerosis in diabetes are given in... more Evidence based goals for the treatment and prevention of atherosclerosis in diabetes are given in international and national guidelines. The importance of optimal control of lipids and blood pressure has been shown in several studies. With available drugs and behavioural modifications the treatment goals can be reached in most cases. However, only a few patients with diabetes are treated optimally today. A major possibility to reduce cardiovascular disease in diabetes is to treat patients according to guidelines.New treatment targets may include specific treatment of the dyslipidaemia, manifested in high levels of small dense LDL and low HDL, active anti-inflammatory treatments, specific reduction of inflammatory activity in adipose tissue, reduced volume of adipose tissue, antioxidants and reduction of advanced glycosylation endproducts production. Possible strategies for these treatments are available, and should be evaluated in clinical trials.

Research paper thumbnail of ARF6 Regulates Neuron Differentiation through Glucosylceramide Synthase

PLOS ONE, Mar 28, 2013

The small GTPase ADP ribosylation factor 6 (ARF6) mediates endocytosis and has in addition been s... more The small GTPase ADP ribosylation factor 6 (ARF6) mediates endocytosis and has in addition been shown to regulate neuron differentiation. Here we investigated whether ARF6 promotes differentiation of Neuro-2a neuronal cells by modifying the cellular lipid composition. We showed that knockdown of ARF6 by siRNA in Neuro-2a cells increased neuronal outgrowth as expected. ARF6 knockdown also resulted in increased glucosylceramide levels and decreased sphingomyelin levels, but did not affect the levels of ceramide or phospholipids. We speculated that the ARF6 knockdown-induced increase in glucosylceramide was caused by an effect on glucosylceramide synthase and, in agreement, showed that ARF6 knockdown increased the mRNA levels and activity of glucosylceramide synthase. Finally, we showed that incubation of Neuro-2a cells with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) normalized the increased neuronal outgrowth induced by ARF6 knockdown. Our results thus show that ARF6 regulates neuronal differentiation through an effect on glucosylceramide synthase and glucosylceramide levels.

Research paper thumbnail of Sulfone-based human liver pyruvate kinase inhibitors – Design, synthesis and in vitro bioactivity

European journal of medicinal chemistry, Apr 1, 2024

Research paper thumbnail of Cover Feature: Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase (ChemBioChem 1/2023)

ChemBioChem, Dec 14, 2022

Research paper thumbnail of 128 ARAP2-INDUCED Changes in Sphingolipid Biosynthesis Promote Lipid Droplet Formation by Increasing GLUT1 Levels in the Plasma Membrane

Atherosclerosis Supplements, Jun 1, 2011

Research paper thumbnail of Statement of Retraction. The SNARE Protein SNAP23 and the SNARE-Interacting Protein Munc18c in Human Skeletal Muscle Are Implicated in Insulin Resistance/Type 2 Diabetes. Diabetes 2010;59:1870–1878. DOI: 10.2337/db09-1503. PMID: 20460426

Research paper thumbnail of CD38 as a therapeutic target in pediatric Burkitt’s Lymphoma: insights from a comparative approach (Running title: Targeting CD38 in pediatric Burkitt's Lymphoma)

Background: Pediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin's B-cell ... more Background: Pediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin's B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse and resistance to current therapies remains challenging. CD38, a transmembrane protein highly expressed in pBL, is a promising therapeutic target. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab (DARA) and isatuximab (ISA), in impairing crucial cellular processes and survival pathways in pBL malignant cells. Methods: In silico analyses of pBL cell line and patient sample datasets, combined with in 51 vitro experiments using the Ramos cell line model, were conducted to assess the impact of 52 DARA and ISA on cellular proliferation, apoptosis, and the phosphoinositide 3-kinase (PI3K) 53 pathway. Comparative approaches were utilized to evaluate the therapeutic potential of these 54 mAbs, focusing on B-cell receptor signaling, calcium flux, metabolic shifts, and interaction of 55 key proteins on the cell surface. 56 Results: ISA was found to be more effective than DARA in disrupting B-cell receptor 57 signaling, reducing cellular proliferation, and inducing apoptosis. Additionally, ISA caused a significant impairment of the PI3K pathway and induced metabolic shifts in pBL cells, indicating its role in metabolic reprogramming. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38's involvement in key oncogenic processes. Conclusions: The study emphasizes the therapeutic potential of CD38-targeting mAbs, particularly ISA, in pBL. These findings suggest that targeting CD38 with mAbs may offer a novel approach for treating pBL, particularly in cases where patients show resistance or relapse after conventional therapies.

Research paper thumbnail of ARAP2 promotes GLUT1-mediated basal glucose uptake through regulation of sphingolipid metabolism

Biochimica Et Biophysica Acta - Molecular And Cell Biology Of Lipids, Nov 1, 2016

Lipid droplet formation, which is driven by triglyceride synthesis, requires several dropletassoc... more Lipid droplet formation, which is driven by triglyceride synthesis, requires several dropletassociated proteins. We identified ARAP2 (an ADP-ribosylation factor 6 GTPase-activating protein) in the lipid droplet proteome of NIH-3T3 cells and showed that knockdown of ARAP2 resulted in decreased lipid droplet formation and triglyceride synthesis. We also showed that ARAP2 knockdown did not affect fatty acid uptake but reduced basal glucose uptake, total levels of the glucose transporter GLUT1, and GLUT1 levels in the plasma membrane and the lipid micro-domain fraction (a specialized plasma membrane domain enriched in sphingolipids). Microarray analysis showed that ARAP2 knockdown altered expression of genes involved in sphingolipid metabolism. Because sphingolipids are known to play a key role in cell signaling, we performed lipidomics to further investigate the relationship between ARAP2 and sphingolipids and potentially identify a link with glucose uptake. We found that ARAP2 knockdown increased glucosylceramide and lactosylceramide levels without affecting ceramide levels, and thus speculated that the rate-limiting enzyme in glycosphingolipid synthesis, namely glucosylceramide synthase (GCS), could be modified by ARAP2. In agreement with our hypothesis, we showed that the activity of GCS was increased by ARAP2 knockdown and reduced by ARAP2 overexpression. Furthermore, pharmacological inhibition of GCS resulted in increases in basal glucose uptake, total GLUT1 levels, triglyceride biosynthesis from glucose, and lipid droplet formation, indicating that the effects of GCS inhibition are the opposite to those resulting from ARAP2 knockdown. Taken together, our data suggest that ARAP2 promotes lipid droplet formation by modifying sphingolipid metabolism through GCS.

Research paper thumbnail of The formation of lipid droplets: possible role in the development of insulin resistance/type 2 diabetes

Prostaglandins Leukotrienes and Essential Fatty Acids, Nov 1, 2011

Neutral lipids are stored in so-called lipid droplets, which are formed as small primordial dropl... more Neutral lipids are stored in so-called lipid droplets, which are formed as small primordial droplets at microsomal membranes and increase in size by a fusion process. The fusion is catalyzed by the SNARE proteins SNAP23, syntaxin-5 and VAMP4. SNAP23 is involved in the insulin dependent translocation of GLUT4 to the plasma membrane, and has an important role in the development of insulin resistance. Thus fatty acids relocalize SNAP23 from the plasma membrane (and the translocation of GLUT 4) to the interior of the cell giving rise to insulin resistance. Moreover this relocalization is seen in skeletal muscles biopsies from patients with type 2 diabetes compared to matched control. Thus a missorting of SNAP23 is essential for the development of insulin resistance.

Research paper thumbnail of Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators

European journal of medicinal chemistry, Mar 1, 2023

Research paper thumbnail of Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages

Atherosclerosis, Feb 1, 2009

Increased circulating free fatty acids in subjects with type 2 diabetes may contribute to activat... more Increased circulating free fatty acids in subjects with type 2 diabetes may contribute to activation of macrophages, and thus the development of atherosclerosis. In this study, we investigated the effect of the saturated fatty acids (SFA) palmitate, stearate, myristate and laurate, and the unsaturated fatty acid linoleate, on the production of proinflammatory cytokines in phorbol ester-differentiated THP-1 cells, a model of human macrophages. Palmitate induced secretion and mRNA expression of TNF-␣, IL-8 and IL-1␤, and enhanced lipopolysaccharide (LPS)-induced IL-1␤ secretion. Proinflammatory cytokine secretion was also induced by stearate, but not by the shorter chain SFA, myristate and laurate, or linoleate. Triacsin C abolished the palmitate-induced cytokine secretion, suggesting that palmitate activation to palmitoyl-CoA is required for its effect. Palmitate-induced cytokine secretion was decreased by knockdown of serine palmitoyltransferase and mimicked by C 2-ceramide, indicating that ceramide is involved in palmitate-induced cytokine secretion. Palmitate phosphorylated p38 and JNK kinases, and blocking of these kinases with specific inhibitors diminished the palmitate-induced cytokine secretion. Palmitate also activated the AP-1 (c-Jun) transcription factor. Knockdown of MyD88 reduced the palmitate-induced IL-8, but not TNF-␣ or IL-1␤ secretion. In conclusion, our data suggest that the long-chain SFA induce proinflammatory cytokines in human macrophages via pathways involving de novo ceramide synthesis. This might contribute to the activation of macrophages in atherosclerotic plaques, especially in type 2 diabetes.

Research paper thumbnail of Tu-P7:188 Palmitate induces proinflammatory cytokine secretion in macrophages

Atherosclerosis Supplements, 2006

Research paper thumbnail of Design and development of a photoswitchable DFG-out kinase inhibitor

Chemical Communications, 2021

We report the synthesis and characterisation of a photoswitchable DFG-out kinase inhibitor. Photo... more We report the synthesis and characterisation of a photoswitchable DFG-out kinase inhibitor. Photocontrol of the target kinase in both enzymatic and living cell assays is demonstrated.

Research paper thumbnail of Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Scientific Reports, Sep 11, 2018

Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS), which drives the ... more Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS), which drives the production of proinflammatory cytokines. Earlier studies have indicated that cholesterol-and glycosphingolipidrich subregions of the plasma membrane (lipid domains) are important for TLR4-mediated signaling. We report that inhibition of glucosylceramide (GluCer) synthase, which resulted in decreased concentrations of the glycosphingolipid GluCer in lipid domains, reduced the LPS-induced inflammatory response in both mouse and human macrophages. Atomistic molecular dynamics simulations of the TLR4 dimer complex (with and without LPS in its MD-2 binding pockets) in membranes (in the presence and absence of GluCer) showed that: (1) LPS induced a tilted orientation of TLR4 and increased dimer integrity; (2) GluCer did not affect the integrity of the LPS/TLR4 dimer but reduced the LPS-induced tilt; and (3) GluCer increased electrostatic interactions between the membrane and the TLR4 extracellular domain, which could potentially modulate the tilt. We also showed that GCS inhibition reduced the interaction between TLR4 and the intracellular adaptor protein Mal. We conclude that the GluCerinduced effects on LPS/TLR4 orientation may influence the signaling capabilities of the LPS/TLR4 complex by affecting its interaction with downstream signaling proteins.

Research paper thumbnail of 432 the Importance of De Novo Lipogenesis of Lipid Loading in Human Macrophages

Atherosclerosis Supplements, Jun 1, 2011

Atherosclerosis Supplements 12, no. 1 (2011) 13-184 Poster presentations Interleukin-6,-8 and C-r... more Atherosclerosis Supplements 12, no. 1 (2011) 13-184 Poster presentations Interleukin-6,-8 and C-reactive protein levels were significantly lower after periodontal treatment. Treatment had no effect on plasma levels total cholesterol, HDL and LDL. The value of non-linear index of refraction of low density lipoprotein and the IgG antibodies against oxidized low-density lipoprotein were significantly higher and lower, respectively 12 months after periodontal treatment. Leukocyte and neutrophils counts were lower after 3 months of periodontal treatment. Conclusion: In conclusion, this study indicates that standard treatment for periodontal disease induces systemic changes in several biochemical markers that reflect the risk for atherosclerosis.

Research paper thumbnail of PO9-217 Palmitate Induces Proinflammatory Cytokine Secretion in Human Macrophages via Activation of P38 and JNK Kinases

Atherosclerosis Supplements, Jun 1, 2007

Research paper thumbnail of Anti-infectious and anti-inflammatory activities of lactoferrin and fragments thereof

Det här verket är upphovrättskyddat enligt Lagen (1960:729) om upphovsrätt till litterära och kon... more Det här verket är upphovrättskyddat enligt Lagen (1960:729) om upphovsrätt till litterära och konstnärliga verk. Det har digitaliserats med stöd av Kap. 1, 16 § första stycket p 1, för forskningsändamål, och får inte spridas vidare till allmänheten utan upphovsrättsinehavarens medgivande. Alla tryckta texter är OCR-tolkade till maskinläsbar text. Det betyder att du kan söka och kopiera texten från dokumentet. Vissa äldre dokument med dåligt tryck kan vara svåra att OCR-tolka korrekt vilket medför att den OCR-tolkade texten kan innehålla fel och därför bör man visuellt jämföra med verkets bilder för att avgöra vad som är riktigt. Th is work is protected by Swedish Copyright Law (Lagen (1960:729) om upphovsrätt till litterära och konstnärliga verk). It has been digitized with support of Kap. 1, 16 § första stycket p 1, for scientifi c purpose, and may no be dissiminated to the public without consent of the copyright holder. All printed texts have been OCR-processed and converted to machine readable text. Th is means that you can search and copy text from the document. Some early printed books are hard to OCR-process correctly and the text may contain errors, so one should always visually compare it with the images to determine what is correct.

Research paper thumbnail of Design and development of photoswitchable DFG-Out RET kinase inhibitors

European journal of medicinal chemistry, Apr 1, 2022

REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required... more REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required for development of multiple human tissues, but which is also an important contributor to human cancers. RET activation through rearrangement or point mutations occurs in thyroid and lung cancers. Furthermore, activation of wild type RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET is therefore an attractive therapeutic target for small-molecule kinase inhibitors. Non-invasive control of RET signaling with light offers the promise of unveiling its complex spatiotemporal dynamics in vivo. In this work, photoswitchable DFG-out RET kinase inhibitors based on heterocycle-derived azobenzenes were developed, enabling photonic control of RET activity. Based on the binding mode of DFG-out kinase inhibitors and using RET kinase as the test model, we developed a photoswitchable inhibitor with a quinoline "head" constituting the azoheteroarene. This azo compound was further modified by three different strategies to increase the difference in biological activity between the E-isomer and the light enriched Z-isomer. Stilbene-based derivatives were used as model compounds to guide in the selection of substituents that could eventually be introduced to the corresponding azo compounds. The most promising quinoline-based compound showed more than a 15-fold difference in bioactivity between the two isomers in a biochemical assay. However, the same compound showed a decreased Z/E (IC50) ratio in the cellular assay, tentatively assigned to stability issues. The corresponding stilbene compound gave a Z/E (IC50) ratio well above 100, consistent with that measured in the biochemical assay. Ultimately, a 7-azaindole based photoswitchable DFG-out kinase inhibitor was shown to display more than a 10-fold difference in bioactivity between the two isomers, in both a biochemical and a cell-based assay, as well as excellent stability even under reducing conditions.

Research paper thumbnail of P283 the Role of Snare Proteins in Human Insulin Resistance

Atherosclerosis Supplements, 2010

Research paper thumbnail of The Transfer of Immunity from Mother to Child

Annals of the New York Academy of Sciences, 2003

: The newborn's immune system grows fast from a small size at birth by exposure primarily to ... more : The newborn's immune system grows fast from a small size at birth by exposure primarily to the intestinal microflora normally obtained from the mother at and after birth. While building up its immune system, the infant is supported by the transplacental IgG antibodies, which also contain anti‐idiotypic antibodies, possibly also actively priming the offspring. The second mode of transfer of immunity occurs via the milk. Numerous major protective components, including secretory IgA (SIgA) antibodies and lactoferrin, are present.The breastfed infant is better protected against numerous common infections than the non‐breastfed. Breastfeeding also seems to actively stimulate the infant's immune system by anti‐idiotypes, uptake of milk lymphocytes, cytokines, etc. Therefore, the breastfed child continues to be better protected against various infections for some years. Vaccine responses are also often enhanced in breastfed infants. Long‐lasting protection against certain immunological diseases such as allergies and celiac disease is also noted.

Research paper thumbnail of How can we prevent cardiovascular disease in diabetes

Journal of Internal Medicine, Aug 1, 2007

Evidence based goals for the treatment and prevention of atherosclerosis in diabetes are given in... more Evidence based goals for the treatment and prevention of atherosclerosis in diabetes are given in international and national guidelines. The importance of optimal control of lipids and blood pressure has been shown in several studies. With available drugs and behavioural modifications the treatment goals can be reached in most cases. However, only a few patients with diabetes are treated optimally today. A major possibility to reduce cardiovascular disease in diabetes is to treat patients according to guidelines.New treatment targets may include specific treatment of the dyslipidaemia, manifested in high levels of small dense LDL and low HDL, active anti-inflammatory treatments, specific reduction of inflammatory activity in adipose tissue, reduced volume of adipose tissue, antioxidants and reduction of advanced glycosylation endproducts production. Possible strategies for these treatments are available, and should be evaluated in clinical trials.

Research paper thumbnail of ARF6 Regulates Neuron Differentiation through Glucosylceramide Synthase

PLOS ONE, Mar 28, 2013

The small GTPase ADP ribosylation factor 6 (ARF6) mediates endocytosis and has in addition been s... more The small GTPase ADP ribosylation factor 6 (ARF6) mediates endocytosis and has in addition been shown to regulate neuron differentiation. Here we investigated whether ARF6 promotes differentiation of Neuro-2a neuronal cells by modifying the cellular lipid composition. We showed that knockdown of ARF6 by siRNA in Neuro-2a cells increased neuronal outgrowth as expected. ARF6 knockdown also resulted in increased glucosylceramide levels and decreased sphingomyelin levels, but did not affect the levels of ceramide or phospholipids. We speculated that the ARF6 knockdown-induced increase in glucosylceramide was caused by an effect on glucosylceramide synthase and, in agreement, showed that ARF6 knockdown increased the mRNA levels and activity of glucosylceramide synthase. Finally, we showed that incubation of Neuro-2a cells with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) normalized the increased neuronal outgrowth induced by ARF6 knockdown. Our results thus show that ARF6 regulates neuronal differentiation through an effect on glucosylceramide synthase and glucosylceramide levels.