@article{HenkelOberlaenderKlauderStatzetal.2021, author = {Henkel-Oberl{\"a}nder, Janin and Klauder, Julia and Statz, Meike and Wohlenberg, Anne-Sophie and Kuipers, Sonja and Vahrenbrink, Madita and P{\"u}schel, Gerhard}, title = {Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E₂}, series = {Biomedicines : open access journal}, volume = {9}, journal = {Biomedicines : open access journal}, number = {5}, publisher = {MDPI}, address = {Basel}, issn = {2227-9059}, doi = {10.3390/biomedicines9050449}, pages = {10}, year = {2021}, abstract = {Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E₂ (PGE₂) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE₂ to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE₂ synthesis. PGE₂ in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE₂ in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.}, language = {en} } @article{HenkelKlauderStatzetal.2021, author = {Henkel, Janin and Klauder, Julia and Statz, Meike and Wohlenberg, Anne-Sophie and Kuipers, Sonja and Vahrenbrink, Madita and P{\"u}schel, Gerhard Paul}, title = {Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E-2}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {5}, publisher = {MDPI}, address = {Basel}, issn = {2227-9059}, doi = {10.3390/biomedicines9050449}, pages = {10}, year = {2021}, abstract = {Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E-2 (PGE(2)) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE(2) to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE(2) synthesis. PGE(2) in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE(2) in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.}, language = {en} } @article{SchellWardelmannKleinridders2021, author = {Schell, Mareike and Wardelmann, Kristina and Kleinridders, Andre}, title = {Untangling the effect of insulin action on brain mitochondria and metabolism}, series = {Journal of neuroendocrinology}, volume = {33}, journal = {Journal of neuroendocrinology}, number = {4}, publisher = {Wiley}, address = {Hoboken}, issn = {0953-8194}, doi = {10.1111/jne.12932}, pages = {14}, year = {2021}, abstract = {The regulation of energy homeostasis is controlled by the brain and, besides requiring high amounts of energy, it relies on functional insulin/insulin-like growth factor (IGF)-1 signalling in the central nervous system. This energy is mainly provided by mitochondria in form of ATP. Thus, there is an intricate interplay between mitochondrial function and insulin/IGF-1 action to enable functional brain signalling and, accordingly, propagate a healthy metabolism. To adapt to different nutritional conditions, the brain is able to sense the current energy status via mitochondrial and insulin signalling-dependent pathways and exerts an appropriate metabolic response. However, regional, cell type and receptor-specific consequences of this interaction occur and are linked to diverse outcomes such as altered nutrient sensing, body weight regulation or even cognitive function. Impairments of this cross-talk can lead to obesity and glucose intolerance and are linked to neurodegenerative diseases, yet they also induce a self-sustainable, dysfunctional 'metabolic triangle' characterised by insulin resistance, mitochondrial dysfunction and inflammation in the brain. The identification of causal factors deteriorating insulin action, mitochondrial function and concomitantly a signature of metabolic stress in the brain is of utter importance to offer novel mechanistic insights into development of the continuously rising prevalence of non-communicable diseases such as type 2 diabetes and neurodegeneration. This review aims to determine the effect of insulin action on brain mitochondrial function and energy metabolism. It precisely outlines the interaction and differences between insulin action, insulin-like growth factor (IGF)-1 signalling and mitochondrial function; distinguishes between causality and association; and reveals its consequences for metabolism and cognition. We hypothesise that an improvement of at least one signalling pathway can overcome the vicious cycle of a self-perpetuating metabolic dysfunction in the brain present in metabolic and neurodegenerative diseases.}, language = {en} } @article{EngelSchraplauWochatzetal.2021, author = {Engel, Tilman and Schraplau, Anne and Wochatz, Monique and Kopinski, Stephan and Sonnenburg, Dominik and Schom{\"o}ller, Anne and Risch, Lucie and Kaplick, Hannes and Mayer, Frank}, title = {Feasability of An Eccentric Isokinetic Protocol to Induce Trunk Muscle Damage: A Pilot Study}, series = {Sports Medicine International Open}, volume = {6}, journal = {Sports Medicine International Open}, edition = {1}, publisher = {Thieme}, address = {Stuttgart}, issn = {2367-1890}, doi = {10.1055/a-1757-6724}, pages = {E9 -- E17}, year = {2021}, abstract = {Eccentric exercise is discussed as a treatment option for clinical populations, but specific responses in terms of muscle damage and systemic inflammation after repeated loading of large muscle groups have not been conclusively characterized. Therefore, this study tested the feasibility of an isokinetic protocol for repeated maximum eccentric loading of the trunk muscles. Nine asymptomatic participants (5 f/4 m; 34±6 yrs; 175±13 cm; 76±17 kg) performed three isokinetic 2-minute all-out trunk strength tests (1x concentric (CON), 2x eccentric (ECC1, ECC2), 2 weeks apart; flexion/extension, 60°/s, ROM 55°). Outcomes were peak torque, torque decline, total work, and indicators of muscle damage and inflammation (over 168 h). Statistics were done using the Friedman test (Dunn's post-test). For ECC1 and ECC2, peak torque and total work were increased and torque decline reduced compared to CON. Repeated ECC bouts yielded unaltered torque and work outcomes. Muscle damage markers were highest after ECC1 (soreness 48 h, creatine kinase 72 h; p<0.05). Their overall responses (area under the curve) were abolished post-ECC2 compared to post-ECC1 (p<0.05). Interleukin-6 was higher post-ECC1 than CON, and attenuated post-ECC2 (p>0.05). Interleukin-10 and tumor necrosis factor-α were not detectable. All markers showed high inter-individual variability. The protocol was feasible to induce muscle damage indicators after exercising a large muscle group, but the pilot results indicated only weak systemic inflammatory responses in asymptomatic adults.}, language = {en} } @article{SchellChudobaLeboucheretal.2020, author = {Schell, Mareike and Chudoba, Chantal and Leboucher, Antoine and Alfine, Eugenia and Flore, Tanina and Ritter, Katrin and Weiper, Katharina and Wernitz, Andreas and Henkel, Janin and Kleinridders, Andr{\´e}}, title = {Interplay of Dietary Fatty Acids and Cholesterol Impacts Brain Mitochondria and Insulin Action}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {5}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu12051518}, pages = {22}, year = {2020}, abstract = {Overconsumption of high-fat and cholesterol-containing diets is detrimental for metabolism and mitochondrial function, causes inflammatory responses and impairs insulin action in peripheral tissues. Dietary fatty acids can enter the brain to mediate the nutritional status, but also to influence neuronal homeostasis. Yet, it is unclear whether cholesterol-containing high-fat diets (HFDs) with different combinations of fatty acids exert metabolic stress and impact mitochondrial function in the brain. To investigate whether cholesterol in combination with different fatty acids impacts neuronal metabolism and mitochondrial function, C57BL/6J mice received different cholesterol-containing diets with either high concentrations of long-chain saturated fatty acids or soybean oil-derived poly-unsaturated fatty acids. In addition, CLU183 neurons were stimulated with combinations of palmitate, linoleic acid and cholesterol to assess their effects on metabolic stress, mitochondrial function and insulin action. The dietary interventions resulted in a molecular signature of metabolic stress in the hypothalamus with decreased expression of occludin and subunits of mitochondrial electron chain complexes, elevated protein carbonylation, as well as c-Jun N-terminal kinase (JNK) activation. Palmitate caused mitochondrial dysfunction, oxidative stress, insulin and insulin-like growth factor-1 (IGF-1) resistance, while cholesterol and linoleic acid did not cause functional alterations. Finally, we defined insulin receptor as a novel negative regulator of metabolically stress-induced JNK activation.}, language = {en} } @article{ZwaagHorstBlaženovićetal.2020, author = {Zwaag, Jelle and Horst, Rob ter and Blaženović, Ivana and St{\"o}ßel, Daniel and Ratter, Jacqueline and Worseck, Josephine M. and Schauer, Nicolas and Stienstra, Rinke and Netea, Mihai G. and Jahn, Dieter and Pickkers, Peter and Kox, Matthijs}, title = {Involvement of lactate and pyruvate in the anti-inflammatory effects exerted by voluntary activation of the sympathetic nervous system}, series = {Metabolites}, volume = {10}, journal = {Metabolites}, number = {4}, publisher = {MDPI}, address = {Basel}, issn = {2218-1989}, doi = {10.3390/metabo10040148}, pages = {1 -- 18}, year = {2020}, abstract = {We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints, of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration, and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1 beta and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore, this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects.}, language = {en} } @article{LoepfeDussZafeiropoulouetal.2019, author = {L{\"o}pfe, Moira and Duss, Anja and Zafeiropoulou, Katerina-Alexandra and Bjoergvinsdottir, Oddny and Eglin, David and Fortunato, Giuseppino and Klasen, J{\"u}rgen and Ferguson, Stephen J. and W{\"u}rtz-Kozak, Karin and Krupkova, Olga}, title = {Electrospray-Based Microencapsulation of Epigallocatechin 3-Gallate for Local Delivery into the Intervertebral Disc}, series = {Pharmaceutics}, volume = {11}, journal = {Pharmaceutics}, number = {9}, publisher = {MDPI}, address = {Basel}, issn = {1999-4923}, doi = {10.3390/pharmaceutics11090435}, pages = {15}, year = {2019}, abstract = {Locally delivered anti-inflammatory compounds can restore the homeostasis of the degenerated intervertebral disc (IVD). With beneficial effects on IVD cells, epigallocatechin 3-gallate (EGCG) is a promising therapeutic candidate. However, EGCG is prone to rapid degradation and/or depletion. Therefore, the purpose of this study was to develop a method for controlled EGCG delivery in the degenerated IVD. Primary IVD cells were isolated from human donors undergoing IVD surgeries. EGCG was encapsulated into microparticles by electrospraying of glutaraldehyde-crosslinked gelatin. The resulting particles were characterized in terms of cytocompatibility and anti-inflammatory activity, and combined with a thermoresponsive carrier to produce an injectable EGCG delivery system. Subsequently, electrospraying was scaled up using the industrial NANOSPIDER (TM) technology. The produced EGCG microparticles reduced the expression of inflammatory (IL-6, IL-8, COX-2) and catabolic (MMP1, MMP3, MMP13) mediators in pro-inflammatory 3D cell cultures. Combining the EGCG microparticles with the carrier showed a trend towards modulating EGCG activity/release. Electrospray upscaling was achieved, leading to particles with homogenous spherical morphologies. In conclusion, electrospray-based encapsulation of EGCG resulted in cytocompatible microparticles that preserved the activity of EGCG and showed the potential to control EGCG release, thus favoring IVD health by downregulating local inflammation. Future studies will focus on further exploring the biological activity of the developed delivery system for potential clinical use.}, language = {en} } @article{MouserArkesteijnvanDijketal.2019, author = {Mouser, Vivian H. M. and Arkesteijn, Irene T. M. and van Dijk, Bart G. M. and W{\"u}rtz-Kozak, Karin and Ito, Keita}, title = {Hypotonicity differentially affects inflammatory marker production by nucleus pulposus tissue in simulated disc degeneration versus herniation}, series = {Journal of orthopaedic research}, volume = {37}, journal = {Journal of orthopaedic research}, number = {5}, publisher = {Wiley}, address = {Hoboken}, issn = {0736-0266}, doi = {10.1002/jor.24268}, pages = {1110 -- 1116}, year = {2019}, abstract = {Inflammatory cytokines play an important role in intervertebral disc degeneration. Although largely produced by immune cells, nucleus pulposus (NP) cells can also secrete them under various conditions, for example, under free swelling. Thus, tissue hypotonicity may be an inflammatory trigger for NP cells. The aim of this study was to investigate whether decreased tonicity under restricted swelling conditions (as occurring in early disc degeneration) could initiate an inflammatory cascade that mediates further degeneration. Healthy bovine NP tissue was balanced against different PEG concentrations (0-30\%) to obtain various tissue tonicities. Samples were then placed in an artificial annulus (fixed volume) and were cultured for 3, 7, or 21 days, with free swelling NP as control. Tissue content (water, glycosaminoglycan, collagen) was analyzed, and both the tissue and medium were screened for tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin-E-2 (PGE(2)), and nitric oxide (NO). A range of tonicities (isotonic to hypotonic) was present at day 3 in the PEG-treated samples. However, during culture, the tonicity range narrowed as GAGs leached from the tissue. TNF-alpha and IL-1 beta were below detection limits in all conditions, while mid- and downstream inflammatory cytokines were detected. This may suggest that the extracellular environment directly affects NP cells instead of inducing a classical inflammatory cascade. Furthermore, IL-8 increased in swelling restricted samples, while IL-6 and PGE(2) were elevated in free swelling controls. These findings may suggest the involvement of different mechanisms in disc degeneration with intact AF compared to herniation, and encourage further investigation. (c) 2019 The Authors. Journal of Orthopaedic Research (R) Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res}, language = {en} } @article{HassHerpichNorman2019, author = {Haß, Ulrike and Herpich, Catrin and Norman, Kristina}, title = {Anti-Inflammatory Diets and Fatigue}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {10}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu11102315}, pages = {24}, year = {2019}, abstract = {Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals' use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue.}, language = {en} } @article{HarmsScalbertZamoraRosetal.2019, author = {Harms, Laura M. and Scalbert, Augustin and Zamora-Ros, Raul and Rinaldi, Sabina and Jenab, Mazda and Murphy, Neil and Achaintre, David and Tj{\o}nneland, Anne and Olsen, Anja and Overvad, Kim and Aleksandrova, Krasimira}, title = {Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations}, series = {British Journal of Nutrition}, volume = {123}, journal = {British Journal of Nutrition}, number = {2}, publisher = {Cambridge University Press}, address = {Cambridge}, issn = {0007-1145}, doi = {10.1017/S0007114519002538}, pages = {198 -- 208}, year = {2019}, abstract = {Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 \% CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 \% CI 50, 1) \% lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 \% CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 \% CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 \% CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 \% CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 \% CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 \% CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.}, language = {en} }