TY  - JOUR
AB  - BACKGROUND: Steatotic liver disease is a major public health issue, with hepatic iron overload exacerbating fibrotic conditions. This study aimed to identify metabolites associated with hepatic fat and/or iron overload using targeted metabolomics in a population-based cohort. METHODS: We used the cross-sectional KORA-MRI study (N = 376 individuals). Hepatic fat and iron content were derived by magnetic resonance imaging, and serum metabolite concentrations were quantified through targeted metabolomics. Associations between 146 metabolites and 40 indicators with hepatic phenotypes were analyzed, adjusted for confounders, and corrected for multiple testing. Formal pathway analyses and mediation analyses including genetic data were conducted. Performance of metabolomics to diagnose steatosis or hepatic iron overload was evaluated using ROC curves, and compared to the fatty liver index (FLI). RESULTS: Overall, 50.8% of participants (mean age 56.4 years) had hepatic steatosis, and 43.6% iron overload. Twelve unique metabolites/indicators (amino acids, lysophosphatidylcholine, acyl-alkyl-phosphatidylcholine), and sums of branched chain and aromatic amino acids, and five lipids, and ratio of acyl-alkyl-phosphatidylcholines to diacyl-phosphatidylcholines were associated with hepatic fat content. 27 metabolites/indicators, including 25 lipids, were associated with hepatic iron content. Addition of these metabolites to the FLI improved diagnosis of steatosis and iron overload nominally. Glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and glycerophospholipid metabolism were shared pathway between steatosis and iron overload. Alanine, isoleucine, glutamine and pimeloylcarnitine (C7-DC) mediated effects between genetic variants and hepatic phenotypes. CONCLUSION: Metabolites were associated with hepatic fat and iron content, shared common pathways, and improved diagnosis of steatosis and iron overload, highlighting the role of iron in hepatic disorders.
AU  - Maushagen, J.
AU  - Nattenmüller, J.*
AU  - von Krüchten, R.*
AU  - Thorand, B.
AU  - Peters, A.
AU  - Rathmann, W.*
AU  - Adamski, J.
AU  - Schlett, C.L.*
AU  - Bamberg, F.*
AU  - Wang-Sattler, R.
AU  - Rospleszcz, S.
C1  - 75196
C2  - 57851
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Serum metabolites characterize hepatic phenotypes and reveal shared pathways: results from population-based imaging.
JO  - Mol. Med.
VL  - 31
IS  - 1
PB  - Springer
PY  - 2025
SN  - 1076-1551
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD), the primary hepatic consequence of obesity, is affecting about 25% of the global adult population. The aim of this study was to examine the in vivo role of STE20-type protein kinase TAOK3, which has been previously reported to regulate hepatocellular lipotoxicity in vitro, in the development of NAFLD and systemic insulin resistance in the context of obesity. METHODS: Taok3 knockout mice and wild-type littermates were challenged with a high-fat diet. Various in vivo tests were performed to characterize the whole-body metabolism. NAFLD progression in the liver, and lipotoxic damage in adipose tissue, kidney, and skeletal muscle were compared between the genotypes by histological assessment, immunofluorescence microscopy, protein and gene expression profiling, and biochemical assays. Intracellular lipid accumulation and oxidative/ER stress were analyzed in cultured human and mouse hepatocytes where TAOK3 was knocked down by small interfering RNA. The expression of TAOK3-related STE20-type kinases was quantified in different organs from high-fat diet-fed Taok3-/- and wild-type mice. RESULTS: TAOK3 deficiency had no impact on body weight or composition, food consumption, locomotor activity, or systemic glucose or insulin homeostasis in obese mice. Consistently, Taok3-/- mice and wild-type littermates developed a similar degree of high-fat diet-induced liver steatosis, inflammation, and fibrosis, and we detected no difference in lipotoxic damage of adipose tissue, kidney, or skeletal muscle when comparing the two genotypes. In contrast, the silencing of TAOK3 in vitro markedly suppressed ectopic lipid accumulation and metabolic stress in mouse and human hepatocytes. Interestingly, the hepatic mRNA abundance of several TAOK3-related kinases, which have been previously implicated to increase the risk of NAFLD susceptibility, was significantly elevated in Taok3-/- vs. wild-type mice. CONCLUSIONS: In contrast to the in vitro observations, genetic deficiency of TAOK3 in mice failed to mitigate the detrimental metabolic consequences of chronic exposure to dietary lipids, which may be partly attributable to the activation of liver-specific compensation response for the genetic loss of TAOK3 by related STE20-type kinases.
AU  - Xia, Y.*
AU  - Andersson, E.*
AU  - Caputo, M.*
AU  - Cansby, E.*
AU  - Sedda, F.*
AU  - Font-Gironès, F.*
AU  - Ruud, J.*
AU  - Kurhe, Y.*
AU  - Hallberg, B.*
AU  - Marschall, H.U.*
AU  - Asterholm, I.W.*
AU  - Romeo, S.*
AU  - Blüher, M.
AU  - Mahlapuu, M.*
C1  - 68712
C2  - 54921
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice.
JO  - Mol. Med.
VL  - 29
IS  - 1
PB  - Springer
PY  - 2023
SN  - 1076-1551
ER  - 

TY  - JOUR
AB  - Parkinson's disease (PD) commences several years before the onset of motor features. Pathophysiological understanding of the pre-clinical or early prodromal stages of PD are essential for the development of new therapeutic strategies. Two categories of patients are ideal to study the early disease stages. Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents a well-known prodromal stage of PD in which pathology is presumed to have reached the lower brainstem. The majority of patients with iRBD will develop manifest PD within years to decades. Another category encompasses non-manifest mutation carriers, i.e. subjects without symptoms, but with a known mutation or genetic variant which gives an increased risk of developing PD. The speed of progression from preclinical or prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level. Clinical trials will require inclusion of patients with a predictable conversion within a limited time window. Biomarkers are necessary that can confirm pre-motor PD status and can provide information regarding lead time and speed of progression. Neuroimaging changes occur early in the disease process and may provide such a biomarker. Studies have focused on radiotracer imaging of the dopaminergic nigrostriatal system, which can be assessed with dopamine transporter (DAT) single photon emission computed tomography (SPECT). Loss of DAT binding represents an effect of irreversible structural damage to the nigrostriatal system. This marker can be used to monitor disease progression and identify individuals at specific risk for phenoconversion. However, it is known that changes in neuronal activity precede structural changes. Functional neuro-imaging techniques, such as 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (18F-FDG PET) and functional magnetic resonance imaging (fMRI), can be used to model the effects of disease on brain networks when combined with advanced analytical methods. Because these changes occur early in the disease process, functional imaging studies are of particular interest in prodromal PD diagnosis. In addition, fMRI and 18F-FDG PET may be able to predict a specific future phenotype in prodromal cohorts, which is not possible with DAT SPECT. The goal of the current review is to discuss the network-level brain changes in pre-motor PD.
AU  - Meles, S.K.*
AU  - Oertel, W.H.
AU  - Leenders, K.L.*
C1  - 63047
C2  - 51242
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Circuit imaging biomarkers in preclinical and prodromal Parkinson's disease.
JO  - Mol. Med.
VL  - 27
IS  - 1
PB  - Springer
PY  - 2021
SN  - 1076-1551
ER  - 

TY  - JOUR
AB  - Introduction: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes.Methods: To explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls.Results: Our data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls.Conclusion: We conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes.
AU  - Mirea, A.-M.*
AU  - Toonen, E.J.M.*
AU  - van den Munckhof, I.*
AU  - Munsterman, I.D.*
AU  - Tjwa, E.T.T.L.*
AU  - Jaeger, M.*
AU  - Oosting, M.*
AU  - Schraa, K.*
AU  - Rutten, J.H.W.*
AU  - van der Graaf, M.*
AU  - Riksen, N.P.*
AU  - de Graaf, J.*
AU  - Netea, M.G.*
AU  - Tack, C.J.*
AU  - Chavakis, T.
AU  - Joosten, L.A.B.*
C1  - 55975
C2  - 46729
CY  - 233 Spring St, New York, Ny 10013 Usa
TI  - Increased proteinase 3 and neutrophil elastase plasma concentrations are associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.
JO  - Mol. Med.
VL  - 25
IS  - 1
PB  - Springer
PY  - 2019
SN  - 1076-1551
ER  - 

TY  - JOUR
AB  - Trifunctional bispecific antibodies (trAbs) used in tumor immunotherapy have the unique ability to recruit T cells toward antigens on the tumor cell surface and, moreover, to activate accessory cells through their immunoglobulin Fc region interacting with activating Fcγ receptors. This scenario gives rise to additional costimulatory signals required for T cell–mediated tumor cell destruction and induction of an immunologic memory. Here we show in an in vitro system that most effective trAb-dependent T-cell activation and tumor cell elimination are achieved in the presence of dendritic cells (DCs). On the basis of these findings, we devise a novel approach of cancer immunotherapy that combines the specific advantages of trAbs with those of DC-based vaccination. Simultaneous delivery of trAbs and in vitro differentiated DCs resulted in a markedly improved tumor rejection in a murine melanoma model compared with monotherapy.
AU  - Eissler, N.
AU  - Mysliwietz, J.
AU  - Deppisch, N.
AU  - Ruf, P.*
AU  - Lindhofer, H.*
AU  - Mocikat, R.
C1  - 24274
C2  - 31494
SP  - 54-61
TI  - Potential of the trifunctional bispecific antibody Surek depends on dendritic cells: Rationale for a new approach of tumor immunotherapy.
JO  - Mol. Med.
VL  - 19
IS  - 1
PB  - Feinstein Inst. Med. Res.
PY  - 2013
SN  - 1076-1551
ER  - 

TY  - JOUR
AB  - Our previously reported phase I clinical trial with the allogeneic gene-modified tumor cell line RCC-26/CD80/IL-2 showed that vaccination was well tolerated and feasible in metastatic renal cell carcinoma (RCC) patients. Substantial disease stabilization was observed in most patients despite a high tumor burden at study entry. To investigate alterations in immune responses that might contribute to this effect, we performed an extended immune monitoring that included analysis of reactivity against multiple antigens, cytokine/chemokine changes in serum and determination of the frequencies of immune suppressor cell populations, including natural regulatory T cells (nTregs) and myeloid-derived suppressor cell subsets (MDSCs). An overall immune response capacity to virus-derived control peptides was present in 100% of patients before vaccination Vaccine-induced immune responses to tumor-associated antigens occurred in 75% of patients, demonstrating the potent immune stimulatory capacity of this generic vaccine. Furthermore, some patients reacted to peptide epitopes of antigens not expressed by the vaccine, showing that epitope-spreading occurred in vivo. Frequencies of nTregs and MDSCs were comparable to healthy donors at the beginning of study. A significant decrease of nTregs was detected after vaccination (p = 0.012). High immune response rates, decreased frequencies of nTregs and a mixed T helper 1/T helper 2 (T(H)1/T(H)2)-like cytokine pattern support the applicability of this RCC generic vaccine for use in combination therapies.
AU  - Pohla, H.
AU  - Buchner, A.*
AU  - Stadlbauer, B.*
AU  - Frankenberger, B.
AU  - Stevanovic, S.*
AU  - Walter, S.*
AU  - Frank, R.
AU  - Schwachula, T.*
AU  - Olek, S.*
AU  - Kopp, J.*
AU  - Willimsky, G.*
AU  - Stief, C.G.*
AU  - Hofstetter, A.*
AU  - Pezzutto, A.*
AU  - Blankenstein, T.*
AU  - Oberneder, R.*
AU  - Schendel, D.J.
C1  - 23622
C2  - 31238
SP  - 1499-1508
TI  - High immune response rates and decreased frequencies of regulatory T cells in metastatic renal cell carcinoma patients after tumor cell vaccination.
JO  - Mol. Med.
VL  - 18
IS  - 12
PB  - Feinstein Inst. Med. Res.
PY  - 2013
SN  - 1076-1551
ER  - 

TY  - JOUR
AB  - Small sputum macrophages represent highly active cells that increase in the airways of patients with inflammatory diseases such as chronic obstructive pulmonary disease (COPD). It has been reported often that levels of cytokines, chemokines and pro-teases are increased in sputum supernatants of these patients. In COPD, the small sputum macrophages may contribute to these supernatant proteins and recruit additional cells via specific chemokine expression patterns. We therefore investigated the expression profile of chemokines in sputum macrophages obtained from COPD patients in comparison to cells from healthy donors and cells isolated after inhalation of lipopolysaccharide (LPS). We used the minimally invasive procedure of sputum induction and have purified macrophages with the RosetteSep technology. Using macrophage purification and flow cytometry we show that in COPD small sputum macrophages account for 85.9% ± 8.3% compared with 12.9% ± 7.1% of total macrophages in control donors. When looking at chemokine expression we found, for the small macrophages in COPD, increased transcript and protein levels for CCL2, CCL7, CCL13 and CCL22 with a more than 100-fold increase for CCL13 mRNA (P < 0.001). Looking at active smokers without COPD, there is a substantial increase of small macrophages to 60% ± 15% and, here, chemokine expression is increased as well. In a model of airway inflammation healthy volunteers inhaled 20 μg of lipopolysaccharide (LPS), which resulted in an increase of small sputum macrophages from 18% ± 19% to 64% ± 25%. The pattern of chemokine expression was, however, different with an upregulation for CCL2 and CCL7, while CCL13 was downregulated three-fold in the LPS-induced small macrophages. These data demonstrate that sputum macrophages in COPD show induction of a specific set of CCL chemokines, which is distinct from what can be induced by LPS.
AU  - Frankenberger, M.
AU  - Eder, C.
AU  - Hofer, T.P.
AU  - Heimbeck, I.
AU  - Skokann, K.
AU  - Kaßner, G.
AU  - Weber, N.*
AU  - Möller, W.
AU  - Ziegler-Heitbrock, L.
C1  - 6645
C2  - 29025
SP  - 762-770
TI  - Chemokine expression by small sputum macrophages in COPD.
JO  - Mol. Med.
VL  - 17
IS  - 7-8
PB  - Blackwell Scientific Publications
PY  - 2011
SN  - 1076-1551
ER  -