Supplementary drug treatment to reduce weight in adolescents with severe obesity. / Medikamentell tilleggsbehandling for vektreduksjon hos ungdom med alvorlig fedme.

In 2021, the Norwegian Medicines Agency approved the use of daily injection of liraglutide 3.0 mg (Saxenda) as a supplement to lifestyle treatment for weight control in children ≥ 12 years of age with obesity (isoBMI ≥ 30). We share the treatment experiences of six multidisciplinary obesity clinics in the specialist health service.

FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine release.

The aims of this study are to examine the effect of sphingosine 1-phosphate (S1P) on IL-2-activated natural killer (NK) cell lysis of K562 tumor cells and immature dendritic cells (iDCs), and to investigate the mechanisms involved in S1P activity. Our results show that S1P protected K562 cells or iDCs from NK cell lysis, which was reversed by FTY720 and SEW2871, the antagonists of S1P(1). S1P did not modulate the expression of NKG2D, NKp30, NKp44 or CD158 on the surface of NK cells, and neither affected the expression of CD80, CD83, or CD86 on the surface of DCs. In contrast, it increased the expression of HLA-I and HLA-E on DCs, an activity that was inhibited by FTY720 or SEW2871. Similarly, the inhibitory effect of S1P for NK cell lysis of K562 cells was directed toward S1P(1) expressed on the tumor cells but not on NK cells. Further analysis indicates that NK cells secreted various cytokines and chemokines with various intensities: (1) low (IL-4, IL-6, IL-12, TNF-alpha and MCP-1); (2) intermediate (IL-1beta, IL-10, TGF-beta1, and IL-17A); (3) high (IFN-gamma, and MIP-1alpha); and (4) very high (MIP-1beta). S1P significantly reduced the release of IL-17A and IFN-gamma from NK cells, but this inhibition was S1P(1)-independent. These results indicate that S1P is an anti-inflammatory molecule, and that S1P(1) is important for the interaction among NK cells and tumor cells or DCs leading to up-regulation of HLA-I and HLA-E on the surface of DCs, but not in S1P inhibition of the release of inflammatory cytokines from NK cells. Further, the results suggest that FTY720 and SEW2871 may potentially be used as prophylactic and/or therapeutic drugs to treat cancer patients.

Splenic natural killer cell activity in two models of experimental neurodegenerative diseases.

Natural killer (NK) cells are antitumour/anti-viral effectors and play important roles in shaping the immune system, but their role in neurodegenerative diseases is not clear. Here, we investigated the fate of these cells in two neurodegenerative diseases. In the first model, the activity of NK cells was examined in mice with experimental autoimmune encephalomyelitis (EAE) treated with glatiramer acetate (GA or Copaxone), a drug used to treat EAE in animals and multiple sclerosis in human. The second disease model is twitcher (Galc(twi)/Galc(twi)) mice, which represents an authentic model of human Krabbe's disease. Administration of GA ameliorated EAE in SJL mice corroborated with isolating NK cells that expressed higher killing than cells isolated from vehicle-dosed animals against immature or mature dendritic cells (DCs). However, this drug showed no effect on the numbers of NK cells or the expression of CD69 molecule. On the other hand, NK cells either disappeared from the spleens or were present in low numbers in the white pulp areas of Galc(twi)/Galc(twi) mice, which have increased D-galactosyl-beta1-1'-sphingosine (GalSph) levels. Analysis by confocal microscopy shows that NK cells found in the spleens of Galc(twi)/Galc(twi) mice were apoptotic. Incubating NK cells in vitro with GalSph induced the apoptosis in these cells, confirming the results of twitcher mice. Our results provide the first evidence showing that amelioration of EAE in mice is corroborated with NK cell lysis of antigen-presenting DCs, whereas NK cell distribution into the spleen is altered in a devastating lipid disorder corroborated with induction of their apoptosis.

Implications of chemokine receptors and inflammatory lipids in cancer.

Inflammatory lipids receive much attention due to their important biological activities. Knowledge of the chemokine system has also reached a level that makes it interesting in clinics, which prompted clinical trials into compounds manipulating chemokines or their receptors. However, little attention has been devoted to understand the relations between these two systems. Here, we will review the role of inflammatory lipids and chemokines in innate and adaptive immunity with an attempt to link the two systems and with emphasis on their importance in cancer development.

Implications of chemokines, chemokine receptors, and inflammatory lipids in atherosclerosis.

Chemokines are a diverse group of molecules with important implications for the development of solid tissues and normal function of the immune system. However, change of the conditions for such a complex system can have important and dangerous consequences leading to diseases. The specific implications of the various chemokines in diseases have been elucidated in the last few years, prompting hope of manipulating this system for therapy or prevention of diseases. On the other hand, inflammatory lipids are biologically active molecules with crucial impacts on the function of various cell types, including immune cells in health and disease. Here, we describe how these lipids affect the chemokine system and how they interact with chemokines to shape chronic inflammation in the case of atherosclerosis.

Oxidized lipids and lysophosphatidylcholine induce the chemotaxis, up-regulate the expression of CCR9 and CXCR4 and abrogate the release of IL-6 in human monocytes.

Lipids through regulation of chronic inflammation play key roles in the development of various diseases. Here, we report that a mixed population of human primary monocytes migrated towards LPC, as well as oxidized linoleic acid isoforms 9-S-HODE, 9-R-HODE and 13-R-HODE. Incubation with 9-R-HODE, 13-R-HODE and LPC resulted in increased expression of CXCR4, the receptor for SDF-1α/CXCL12, correlated with increased monocyte migration towards SDF-1α/CXCL12. Further, we report increased expression of CCR9, the receptor for TECK/CCL25, after stimulation with these lipids. Upon examining the migratory response towards TECK/CCL25, it was observed that an increase in CCR9 expression upon pre-treatment with 9-S-HODE, 9-R-HODE, 13-R-HODE and LPC resulted in increased migration of monocytes expressing CCR9. Only LPC but not any other lipid examined increased the influx of intracellular Ca2+ in monocytes. Finally, 9-S-HODE, 9-R-HODE, 13-R-HODE, or LPC inhibited the release of IL-6 from monocytes suggesting that these lipids may play important role in controlling inflammatory responses.

Oxidized lipids and lysophosphatidylcholine induce the chemotaxis and intracellular calcium influx in natural killer cells.

We previously reported that human NK cells express G2A and they respond to LPC. Here, we report that oxidized lipids such as 9-R-HODE, 9-S-HODE and 13-R-HODE, as well as LPC induced the in vitro chemotaxis of human NK cells, although with variable efficacies. The chemotactic effects of these lipids were inhibited by prior treatment of NK cells with pertussis toxin (PTX). 9-S-HODE, 9-R-HODE and LPC optimally induced the influx of intracellular Ca(2+) in NK cells. Addition of 9-S-HODE prior to the addition of LPC inhibited more than 50% of the effect of LPC, whereas addition of LPC prior to the addition of 9-S-HODE completely inhibited the effect of the latter lipid. Also, there was a complete reciprocal desensitization among 9-R-HODE and LPC on the influx of intracellular Ca(2+). Further analysis showed that the four lipids did not affect NK cell lysis of tumor target cells. 9-R-HODE but not any other lipid increased the percentages of NK cells producing IFN-γ and is the only lipid that enhanced the release of this cytokine by these cells. In conclusion, we provide novel evidence showing that oxidized lipids and LPC exert important functions for cells of innate immune system.

Effects of lysophospholipids on tumor microenvironment.

The effects of lysophospholipids (LPLs) on cancer microenvironment is a vast and growing field. These lipids are secreted physiologically by various cell types. They play highly important roles in the development, activation and regulation of the immune system. They are also secreted by cancerous cells and there is a strong association between LPLs and cancer. It is clear that these lipids and in particular sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) play major roles in regulating the growth of tumor cells, and in manipulating the immune system. These activities can be divided into two parts; the first involves the ability of S1P and LPA to either directly or through some of the enzymes that generate them such as sphingosine kinases or phospholipases, induce the motility and invasiveness of tumor cells. The second mechanism involves the recently discovered effects of these lipids on the anti-tumor effector natural killer (NK) cells. Whereas S1P and LPA induce the recruitment of these effector cells, they also inhibit their cytolysis of tumor cells. This may support the environment of cancer and the ability of cancer cells to grow, spread and metastasize. Consequently, LPLs or their receptors may be attractive targets for developing drugs in the treatment of cancer where LPLs or their receptors are up-regulated.