We investigated the mechanism by which cationic antimicrobial peptides block the activation of macrophages by LPS. The initial step in LPS signaling is the transfer of LPS to CD14 by LPS binding protein (LBP). Because many cationic antimicrobial peptides bind LPS, we asked whether these peptides block the binding of LPS to LBP. Using an assay that measures the binding of LPS to immobilized LBP, we show for the first time that a variety of structurally diverse cationic antimicrobial peptides block the interaction of LPS with LBP. The relative ability of different cationic peptides to block the binding of LPS to LBP correlated with their ability to block LPS-induced TNF-α production by the RAW 264.7 macrophage cell line.

Summary Background Measures during the COVID‐19 pandemic, including the closure of schools and sports facilities, may have lasting impact on the physical activity (PA) of children that persists for a long time. Objective To investigate the effect of COVID‐19 measures on screen time and PA in Dutch children pre‐, during‐ and post‐school closures. Methods In cohort A (n = 102, 10.5 ± 3.6 years, 42.4% boys), data on PA and screen time during the lockdown were collected using a questionnaire. In cohort B (n = 131, 10.2 ± 0.9 years, 43.5% boys), data on PA and screen time were collected using a questionnaire and accelerometry 1 year before and after school closure. Results In cohort A, 62% reported less total PA. Self‐reported screen time on week days increased 34 ± 105 min/d during the lockdown. In cohort B, sedentary time as measured by accelerometry, increased by 45 ± 67 min/d and only 20% reached PA levels of 60 min/d compared to 64% in May 2019. Self‐reported screen time increased by 59 ± 112 min/d and 62 ± 130 min/d during week and weekend days, respectively. Conclusions Children were less physically active, and screen time was higher during and after the school closures due to the COVID‐19 lockdown. This is alarming as an active lifestyle in children is crucial in preventing chronic diseases such as obesity.

Chylomicrons have been shown to protect against endotoxin-induced lethality. LPS-binding protein (LBP) is involved in the inactivation of bacterial toxin by lipoproteins. The current study examined the interaction among LBP, chylomicrons, and bacterial toxin. LBP was demonstrated to associate with chylomicrons and enhance the amount of LPS binding to chylomicrons in a dose-dependent fashion. In addition, LBP accelerated LPS binding to chylomicrons. This LBP-induced interaction of LPS with chylomicrons prevented endotoxin toxicity, as demonstrated by reduced cytokine secretion by PBMC. When postprandial circulating concentrations of chylomicrons were compared with circulating levels of low density lipoprotein, very low density lipoprotein, and high density lipoprotein, chylomicrons exceeded the other lipoproteins in LPS-inactivating capacity. Furthermore, highly purified lipoteichoic acid, an immunostimulatory component of Gram-positive bacteria, was detoxified by incubation with LBP and chylomicrons. In conclusion, our results indicate that LBP associates with chylomicrons and enables chylomicrons to rapidly bind bacterial toxin, thereby preventing cell activation. Besides a role in the detoxification of bacterial toxin present in the circulation, we believe that LBP-chylomicron complexes may be part of a local defense mechanism of the intestine against translocated bacterial toxin.

SUMMARY BackgroundEnterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I-FABP) is a sensitive marker to study enterocyte damage.

IntroductionLPS is a constituent of the outer membrane of gramnegative bacteria and evokes an inflammatory response by activation of monocytes and endothelial cells. LPSinduced cellular responses are the net result of the interaction of LPS with various plasma components such as soluble CD14, LPS-binding protein (LBP) and membrane receptors such as membrane-bound CD14 and Toll-like receptors. This initiation of cellular responses is essential for the host defense against bacterial infections. However, if large amounts of endotoxin are present in the circulation, an excessive cellular response can be deleterious for the host, and, therefore, endotoxin-inactivating processes are of extreme importance.LPS is detoxified in the circulation by incorporation into lipoproteins (reviewed in ref. 1). Physiological levels of lipoproteins protect against endotoxicity in vitro and in vivo (2, 3). Early studies have demonstrated an interaction of LPS with HDL (4); albeit later, also VLDL and LDL were found to bind and inactivate LPS (5-7). Consistent with this, LDL, VLDL, chylomicrons, and HDL all have been observed to reduce the lethal effect of endotoxin in mice (8-10).Evidence for a physiological role for LBP in inflammation is supported by studies that demonstrate enhanced mortality and uncontrolled multiplication and spread of bacteria in LBP knockout mice compared with wild-type mice after intraperitoneal administration of bacteria (11). The results of these studies indicate that LBP is required to induce a rapid inflammatory response, which is essential for the resistance to bacteria. However, LBP has the paradoxical dual function of sensitizing the immune system to endotoxin and, on the other hand, enhancing detoxification of endotoxin. LBP catalyzes the transfer of LPS into lipoproteins, thereby enhancing LPS detoxification (12). Likewise, LBP catalyzes the lipoprotein neutralization of lipoteichoic acid, a component of the cell membrane of gram-positive bacteria (13). Lamping et al. demonstrated in a murine model that high levels of LBP in the circulation, as seen during an acute-phase response, inhibit LPS effects and prevent mortality induced by endotoxemia (14). The latter observation strongly supports a physiological role for LBP-dependent detoxification of LPS in the host defense.Endotoxemia induces an acute-phase response characterized by multiple physiological adaptations. This response appears to play a role in host defense mechanisms, although its physiological relevance needs further elucidation. One aspect of the acute-phase response is a dramatic rise in circulating levels of LBP LPS-binding protein (LBP) and serum lipoproteins cooperate in reducing the toxic properties of LPS.In the present study, we demonstrate that LBP circulates in association with LDL and VLDL in healthy persons. ApoB was found to account at least in part for the interaction of LBP with LDL and VLDL. Although LBP interacted with purified apoA-I in vitro, no association of LBP with apoA-I or HDL was found in serum. Consistent with th...

No abstract

This study demonstrates for the first time that respiratory epithelial cells are able to produce the acute phase protein lipopolysaccharide (LPS)-binding protein (LBP), which is known to play a central role in the defense to bacterial endotoxins (or LPS). Indications for local presence of LBP in human lung was obtained via reverse transcriptase/polymerase chain reaction that showed LBP messenger RNA (mRNA) expression. Therefore, LBP production by the human lung epithelial cell line A549, a human adenocarcinoma with features of type II pneumocytes, was studied. These cells produced LBP in response to interleukin (IL)-1beta, IL-6, and tumor necrosis factor- alpha, a response that was strongly enhanced by dexamethasone. In addition, LBP mRNA was detected in A549 cells, in increasing amounts as a result of stimulation. The pattern of cytokine-induced LBP production in A549 cells was similar to the pattern in the human liver epithelial cell line HuH-7. Moreover, the molecular weight of A549-derived LBP was approximately 60 kD, which is similar to HuH-7-derived LBP. Biologic activity of LBP produced by A549 cells was evaluated on the basis of its ability to interact with LPS. Further indications that type II alveolar epithelial cells are able to produce LBP were obtained from the observations that the murine lung type II epithelial cell line C10 produced murine LBP, and that isolated human primary type II pneumocytes expressed LBP mRNA, which was enhanced after stimulation of cells. The local production of this endotoxin binding protein by lung epithelial cells might contribute to a highly specific response at the site of exposure to bacteria and bacterial endotoxins.

Children with overweight, obesity, and morbid obesity benefit equally from an ongoing, outpatient, tailored lifestyle intervention, and demonstrate significant weight loss and improvement of cardiovascular risk parameters.