TY - JOUR AB - BACKGROUND: Iron overload is a common phenomenon in patients undergoing transfusions or organ transplantation. Clinical studies indicate that iron overload interferes with immune function. Baseless supplementation of iron leads to higher morbidity and mortality. In iron overload T-cell differentiation is skewed towards a Th2 response, with lower levels of interferon (IFN)-γ. Zinc is known for its immune balancing abilities, e.g. by induction of regulatory T cells. This study aims to investigate the interaction of iron and zinc in mixed lymphocyte cultures (MLC). METHODS: MLC, peripheral blood mononuclear cells (PBMC) stimulation with phytohemagglutinin, ELISA, PCR, ICP-MS RESULTS: Zn2+ supplementation leads to a significantly lower IFN-γ production in MLC compared with control (p<0.03). Fe2+ supplementation lowers the IFN-γ production in MLC (P<0.0017), too. However, Fe3+ has a slightly increasing effect on IFN-γ release which differs significantly from Fe2+ (p<0.03). In 2,2-Bipyridyl-induced iron deficiency IFN-γ production is lowered (p<0.0003), whereas zinc deficiency does not significantly affect IFN-γ production. Examinations of Interleukin (IL)-2 and IL-6 show comparable tendencies. The Fe2+ effect can be imitated by sodium sulfite. Fe3+ treatment increases intracellular free iron in PBMC significantly compared to Fe2+ treatment (p<0.02). CONCLUSION: Iron (II) and zinc both suppress cytokine production in MLC. Fe3+ shows a significantly different effect on IFN-γ production. The underlying mechanism is likely a donation of electrons by Fe2+ or oxidative stress. These findings provide mechanistic insights on how the oxidation state of iron differentially modulates human immune cell function and highlights the importance of iron speciation in nutritional immunology. AU - Fast, E.* AU - Jakobs, J.* AU - Bertram, J.* AU - Wessels, I. AU - Sailer, J.* AU - Michalke, B.* AU - Rink, L.* C1 - 76150 C2 - 58436 TI - Zinc, Fe2+ and Fe3+ differentially influence IFN-γ production in human peripheral blood mononuclear cells. JO - J. Nutr. Biochem. PY - 2025 SN - 0955-2863 ER - TY - JOUR AB - The prevalence of chronic kidney disease (CKD) continues to rise, highlighting the urgent need for effective therapeutic interventions to address its various complications including sarcopenia. Lactoferrin, a multifunctional iron-binding glycoprotein found in mammalian breast milk, exhibits various biological activities and holds potential for treating CKD and its complications. This study investigated the effects of lactoferrin on CKD progression, its complications, and underlying mechanisms. A mouse model of adenine-induced renal failure was used as a CKD model. Lactoferrin was administered during the same period as adenine administration to assess its preventative effect on the progression of CKD. In another experiment, lactoferrin was administered after the adenine administration period to examine its effect on already advanced CKD. Effects of lactoferrin on renal function, renal pathology, and muscle atrophy were evaluated. Additionally, mechanistic insights were explored through mRNA and protein expression profiling, gut microbiota characterization, and metabolomic analysis. Lactoferrin administration improved reduction of renal function, and mitigated renal atrophy, and tubulointerstitial damage, and ameliorated skeletal muscle atrophy in CKD mice. In the skeletal muscle, CKD induced aberrant activation of mTOR1, impaired autophagy, and disrupted branched-chain amino acid metabolism. These abnormal activation of the proteolysis pathways was ameliorated by lactoferrin. Furthermore, lactoferrin attenuated dysbiosis-induced production of microbiota-derived uremic toxins, thereby reducing the indoxyl sulfate accumulation in blood and muscle. These effects contributed to decreased renal damage and delayed sarcopenia progression. Collectively, these findings suggest that lactoferrin may serve as a promising preventive and therapeutic agent for CKD-associated sarcopenia via the gut-kidney-skeletal muscle axis. AU - Iwamoto, Y.* AU - Yamakoshi, S.* AU - Sekimoto, A.* AU - Hosomi, K.* AU - Toyama, T.* AU - Saito, Y.* AU - Kunisawa, J.* AU - Takahashi, N.* AU - Mishima, E. AU - Sato, E.* C1 - 75245 C2 - 57875 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Lactoferrin attenuates renal fibrosis and uremic sarcopenia in a mouse model of adenine-induced chronic kidney disease. JO - J. Nutr. Biochem. VL - 146 PB - Elsevier Science Inc PY - 2025 SN - 0955-2863 ER - TY - JOUR AB - Acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) are both hematological malignancies characterized by genetic alterations leading to the formation of oncofusion proteins. The classical chromosomal aberrations in APL and CML result in the PML-RARα and BCR-ABL1 oncofusion proteins, respectively. Interestingly, our flow cytometric analyses revealed elevated free intracellular zinc levels in various leukemia cells, which may play a role in stabilizing oncofusion proteins in leukemia and thus support cell proliferation and malignancy. Long-term zinc deficiency resulted in the degradation of PML-RARα in NB4 cells (APL cell line) and of BCR-ABL1 in K562 cells (CML cell line). This degradation may be explained by increased caspase 3 activity observed in zinc deficient cells, whereas zinc reconstitution normalized the caspase 3 activity and abolished zinc deficiency-induced oncofusion protein degradation. In NB4 cells, fluorescence microscopic images further indicated enlarged and enriched lysosomes during zinc deficiency, suggesting increased rates of autophagy. Moreover, NB4 cells exhibited increased expression of the zinc transporters ZIP2, ZIP10 and ZnT3 during zinc deficiency and revealed excessive accumulation of zinc in contrast to healthy peripheral blood mononuclear cells (PBMCs), when zinc was abundantly available extracellularly. Our results highlight the importance of altered zinc homeostasis for some characteristics in leukemia cells, uncover potential pathways underlying the effects of zinc deficiency in leukemia cells, and provide potential alternative strategies by which oncofusion proteins can be degraded. AU - Görg, R.* AU - Büttgenbach, A.* AU - Jakobs, J.* AU - Kurtoğlu Babayev, F.H.* AU - Rolles, B.* AU - Rink, L.* AU - Wessels, I. C1 - 68818 C2 - 55003 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Leukemia cells accumulate zinc for oncofusion protein stabilization. JO - J. Nutr. Biochem. VL - 123 PB - Elsevier Science Inc PY - 2024 SN - 0955-2863 ER - TY - JOUR AB - Alcohol consumption and high caloric diet are leading causes of progressive fatty liver disease. Genetic variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for alcoholic liver cirrhosis (ALC) and hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype-phenotype relationships in mice upon chow and alcohol-high fat/high sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after one year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic inflammation or fibrosis, but induced a striking lipid remodelling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-polyunsaturated fatty acids (LC-PUFA)-containing TGs, docosapentaenoic acid (C22:5 n3) and omega-3-derived eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated enzymes for fatty acid and TG transport and metabolism. These findings suggest (dietary) lipids as an important and independent driver of hepatic tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modelling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans. AU - Patsenker, E.* AU - Thangapandi, V.R.* AU - Knittelfelder, O.* AU - Palladini, A. AU - Hefti, M.* AU - Beil-Wagner, J.* AU - Rogler, G.* AU - Buch, T.* AU - Shevchenko, A.* AU - Hampe, J.* AU - Stickel, F.* C1 - 65439 C2 - 52682 TI - The PNPLA3 variant I148M reveals protective effects toward hepatocellular carcinoma in mice via restoration of omega-3 polyunsaturated fats. JO - J. Nutr. Biochem. VL - 108 PY - 2022 SN - 0955-2863 ER - TY - JOUR AB - Dietary obesity compromises brain function, but the effects of high-fat food on synaptic transmission in hypothalamic networks, as well as their potential reversibility, are yet to be fully characterized. We investigated the impact of high-fat feeding on a hallmark of synaptic plasticity, i.e., the expression of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) that contain the subunits GluA1 and GluA2, in hypothalamic and cortical synaptoneurosomes of male rats. In the main experiment (experiment 1), three days, but not one day of high-fat diet (HFD) decreased the levels of AMPAR GluA1 and GluA2 subunits, as well as GluA1 phosphorylation at Ser845, in hypothalamus but not cortex. In experiment 2, we compared the effects of the three-day HFD with those a three-day HFD followed by four recovery days of normal chow. This experiment corroborated the suppressive effect of high-fat feeding on hypothalamic but not cortical AMPAR GluA1, GluA2, and GluA1 phosphorylation at Ser845, and indicated that the effects are reversed by normal-chow feeding. High-fat feeding generally increased energy intake, body weight, and serum concentrations of insulin, leptin, free fatty acids, and corticosterone; only the three-day HFD increased wakefulness assessed via video analysis. Results indicate a reversible down-regulation of hypothalamic glutamatergic synaptic strength in response to short-term high-fat feeding. Preceding the manifestation of obesity, this rapid change in glutamatergic neurotransmission may underlie counter-regulatory efforts to prevent excess body weight gain, and therefore, represent a new target of interventions to improve metabolic control. AU - Liu, J.* AU - Dimitrov, S. AU - Sawangjit, A.* AU - Born, J. AU - Ehrlich, I.* AU - Hallschmid, M. C1 - 60426 C2 - 49451 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Short-term high-fat feeding induces a reversible net decrease in synaptic AMPA receptors in the hypothalamus. JO - J. Nutr. Biochem. VL - 87 PB - Elsevier Science Inc PY - 2021 SN - 0955-2863 ER - TY - JOUR AB - The authors regret that data was incorrectly assigned between study groups “CD Cd36-/-” and “PD Cd36+/+” in Figure 4C. The correct assignment is shown below. The authors would like to apologise for any inconvenience caused. [Formula presented] AU - Maida, A. AU - Zota, A. AU - Vegiopoulos, A.* AU - Appak-Baskoy, S.* AU - Augustin, H.G.* AU - Heikenwalder, M.* AU - Herzig, S. AU - Rose, A.J.* C1 - 62511 C2 - 50828 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Corrigendum to "Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance" [The Journal of Nutritional Biochemistry 57 (2018) 189-196]. JO - J. Nutr. Biochem. VL - 97 PB - Elsevier Science Inc PY - 2021 SN - 0955-2863 ER - TY - JOUR AB - Recent studies have demonstrated that dietary protein dilution (PD) can promote metabolic inefficiency and improve glucose metabolism. However, whether PD can promote other aspects of metabolic health, such as improve systemic lipid metabolism, and mechanisms therein remains unknown. Mouse models of obesity, such as high-fat-diet-fed C57B1/6 N mice, and New Zealand Obese mice were fed normal (i.e., 20%P) and protein-dilute (i.e., 5%EP) diets. FGF21 -/-and Cd36-/-and corresponding littermate +/+ controls were also studied to examine gene-diet interactions. Here, we show that chronic PD retards the development of hypertrigylceridemia and fatty liver in obesity and that this relies on the induction of the hepatokine fibroblast growth factor 21 (FGF21). Furthermore, PD greatly enhances systemic lipid homeostasis, the mechanisms by which include FGF21-stimulated, and cluster of differentiation 36 (CD36) mediated, fatty acid clearance by oxidative tissues, such as heart and brown adipose tissue. Taken together, our preclinical studies demonstrate a novel nutritional strategy, as well as highlight a role for FGF21-stimulated systemic lipid metabolism, in combating obesity-related dyslipidemia. AU - Maida, A. AU - Zota, A. AU - Vegiopoulos, A.* AU - Appak-Baskoy, S.* AU - Augustin, H.G.* AU - Heikenwalder, M.* AU - Herzig, S. AU - Rose, A.J.* C1 - 53505 C2 - 44880 CY - 360 Park Ave South, New York, Ny 10010-1710 Usa SP - 189-196 TI - Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance. JO - J. Nutr. Biochem. VL - 57 PB - Elsevier Science Inc PY - 2018 SN - 0955-2863 ER - TY - JOUR AB - DJ-1 constitutes a ubiquitously expressed, oxidative stress-responsive protein with multiple functions. DJ-1 emerged as a candidate from our previous proteome analysis investigating alterations in the hypothalamus in three mouse strains differing in their susceptibility to diet-induced obesity (DIO). Validation studies demonstrated a high-fat diet (HFD)-induced shift in the DJ-1 isoform pattern in the hypothalamus and several other tissues of mice. Others found HFD-induced alterations in DJ-1 protein abundance in adipose tissue and pancreatic islets in wild-type rodents. Here, we investigated the gene-diet interaction by challenging Dj-1(-/-) mice with a HFD. We demonstrate that the development of diet-induced obesity (DIO) Dj-1(-/-) mice is according to wild-type mice with the exception of transient higher gains in fat mass at the expense of lean mass after 14 weeks of feeding. AU - Seyfarth, K.* AU - Poschmann, G.* AU - Rozman, J. AU - Fromme, T.* AU - Rink, N.* AU - Hofmann, A. AU - Wurst, W. AU - Stühler, K.* AU - Klingenspor, M. C1 - 42896 C2 - 35729 SP - 75-81 TI - The development of diet-induced obesity and associated metabolic impairments in Dj-1 deficient mice. JO - J. Nutr. Biochem. VL - 26 IS - 1 PY - 2015 SN - 0955-2863 ER - TY - JOUR AB - The regulation of cell growth and protein biosynthesis is triggered by the mammalian target of rapamycin complex 1 (mTORC1) responding to amino acids, especially leucine. The molecular mechanisms linking leucine to mTORC1 activation are not well understood. We analyzed whether the free intracellular leucine availability, a metabolite of leucine catabolism or the process of leucine oxidation activates mTORC1 signaling. We further investigated whether mTORC1 signaling is subject to altered regulation in disturbed leucine metabolism. Human fibroblasts with deficiencies in leucine catabolic steps and those from healthy control subjects were utilized. In all cells, leucine-induced mTORC1 signaling was significantly related to leucine pool size and leucine repletion capacity. The leucine/glutamine antiporter SLC7A5/SLC3A2 and the amino acid sensor MAP4K3 were identified as crucial determinants of signaling leucine availability to downstream targets. In cells with defective leucine catabolism, mTORC1 signaling towards phosphorylation of ribosomal protein S6 kinase 1 (S6K1) was significantly increased, whereas transcriptional down-regulation of MAP4K3 upon reduced amino acid supply was abrogated. Remarkably, these effects were observed irrespective of the localization of the enzymatic blockage. Our data provide evidence that mechanisms determining intracellular leucine availability and the amino acid sensor MAP4K3 are key upstream modulators of nutrient-sensitive mTORC1 signaling, whereas specific leucine metabolites or leucine oxidation rates do not play a role. In human fibroblasts deficient in leucine catabolic steps, we observed regulation consistent with sustaining a more efficient MAP4K3 and mTOR-S6K1 signaling. Such regulatory circuit might serve to protect cells against detrimental consequences of reduced nutrient utilization in human conditions associated with disturbed leucine metabolism. AU - Schriever, S.C.* AU - Deutsch, M.J.* AU - Adamski, J. AU - Roscher, A.A.* AU - Ensenauer, R.* C1 - 10424 C2 - 30250 SP - 824-831 TI - Cellular signaling of amino acids towards mTORC1 activation in impaired human leucine catabolism. JO - J. Nutr. Biochem. VL - 24 IS - 5 PB - Elsevier PY - 2013 SN - 0955-2863 ER -