514 research outputs found
Diagnostic Accuracy of Protein Glycation Sites in Long-Term Controlled Patients with Type 2 Diabetes Mellitus and Their Prognostic Potential for Early Diagnosis
Current screening tests for type 2 diabetes mellitus (T2DM) identify less than 50% of
undiagnosed T2DM patients and provide no information about how the disease will develop in
prediabetic patients. Here, twenty-nine protein glycation sites were quantified after tryptic digestion of
plasma samples at the peptide level using tandem mass spectrometry and isotope-labelled peptides
as internal standard. The glycation degrees were determined in three groups, i.e., 48 patients with a
duration of T2DM exceeding ten years, 48 non-diabetic individuals matched for gender, BMI, and age,
and 20 prediabetic men. In long-term controlled diabetic patients, 27 glycated peptides were detected at
significantly higher levels, providing moderate diagnostic accuracies (ACCs) from 61 to 79%, allowing
a subgrouping of patients in three distinct clusters. Moreover, a feature set of one glycated peptides
and six established clinical parameters provided an ACC of 95%. The same number of clusters was
identified in prediabetic males (ACC of 95%) using a set of eight glycation sites (mostly from serum
albumin). All patients present in one cluster showed progression of prediabetic state or advanced
towards diabetes in the following five years. Overall, the studied glycation sites appear to be promising
biomarkers for subgrouping prediabetic patients to estimate their risk for the development of T2DM
Electronic properties of curved few-layers graphene: a geometrical approach
We show the presence of non-relativistic L\'evy-Leblond fermions in flat
three- and four-layers graphene with AB stacking, extending the results
obtained in [Curvatronics2017] for bilayer graphene. When the layer is curved
we obtain a set of equations for Galilean fermions that are a variation of
those of L\'evy-Leblond with a well defined combination of pseudospin, and that
admit L\'evy-Leblond spinors as solutions in an approriate limit. The local
energy of such Galilean fermions is sensitive to the intrinsic curvature of the
surface. We discuss the relationship between two-dimensional pseudospin,
labelling layer degrees of freedom, and the different energy bands. For
L\'evy-Leblond fermions an interpretation is given in terms of massless
fermions in an effective 4D spacetime, and in this case the pseudospin is
related to four dimensional chirality. A non-zero energy band gap between
conduction and valence electronic bands is obtained for surfaces with positive
curvature.Comment: 16 pages, 4 figures. Matches the published version. Refined theory
that describes the unique combination of isospin states ocurring in curved
bilayer graphene sheet
The Emerging Plasticizer Alternative DINCH and Its Metabolite MINCH Induce Oxidative Stress and Enhance Inflammatory Responses in Human THP-1 Macrophages
The use of the plasticizer bis(2-ethylhexyl)phthalate (DEHP) and other plasticizers in the manufacture of plastic products has been restricted due to adverse health outcomes such as obesity, metabolic syndrome, and asthma, for which inflammation has been described to be a driving factor. The emerging alternative plasticizer 1,2-cyclohexanedioic acid diisononyl ester (DINCH) still lacks information regarding its potential effects on the immune system. Here, we investigated the effects of DINCH and its naturally occurring metabolite monoisononylcyclohexane-1,2-dicarboxylic acid ester (MINCH) on the innate immune response. Human THP-1 macrophages were exposed to 10 nM–10 μM DINCH or MINCH for 4 h, 16 h, and 24 h. To decipher the underlying mechanism of action, we applied an untargeted proteomic approach that revealed xenobiotic-induced activation of immune-related pathways such as the nuclear factor κB (NF-κB) signaling pathway. Key drivers were associated with oxidative stress, mitochondrial dysfunction, DNA damage repair, apoptosis, and autophagy. We verified increased reactive oxygen species (ROS) leading to cellular damage, NF-κB activation, and subsequent TNF and IL-1β release, even at low nM concentrations. Taken together, DINCH and MINCH induced cellular stress and pro-inflammatory effects in macrophages, which may lead to adverse health effects
Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling
Objective
Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state.
Methods
Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modelled in vitro by exposing mature adipocytes to isoproterenol subsequent to stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively.
Results
Inguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. In line with mouse data, OSM gene expression in human WAT positively correlated with BMI (r=0.284, p=0.021, n=66) and negatively with UCP1 expression (r=-0.413, p<0.001, n=66).
Conclusions
Our data support the notion that OSM negatively regulates thermogenesis in WAT and, thus, may be an attractive target to treat obesity
Comorbidities as an Indication for Metabolic Surgery
Metabolic diseases, comprising type 2 diabetes mellitus
(T2DM), dyslipidemia, and non-alcoholic steatohepatitis
(NASH), are rapidly increasing worldwide. Conservative
medical therapy, including the newly available drugs,
has only limited effects and does neither influence survival or the development of micro- or macrovascular
complications, nor the progression of NASH to liver cirrhosis, nor the development of hepatocellular carcinomas in the NASH liver. In contrast, metabolic surgery is
very effective independent of the preoperative body
mass index (BMI) in reducing overall and cardiovascular
mortality in patients with T2DM. Furthermore, metabolic
surgery significantly reduces the development of microand macrovascular complications while being the most
effective therapy in order to achieve remission of T2DM
and to reach the targeted glycemic control. Importantly,
even existing diabetic complications such as nephropathy as well as the features of NASH can be reversed by
metabolic surgery. Here, we propose indications for metabolic surgery due to T2DM and NASH based on a simple but objective, disease-specific staging system. We
outline the use of the Edmonton Obesity Staging System
(EOSS) as a clinical staging system independent of the
BMI that will identify patients who will benefit the most
from metabolic surgery
Palmitate Induced IL-6 and MCP-1 Expression in Human Bladder Smooth Muscle Cells Provides a Link between Diabetes and Urinary Tract Infections
Therefore we studied the effects of the free fatty acid palmitate and bacterial lipopolysaccharide (LPS) on interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) expression and secretion in cultured human bladder smooth muscle cells (hBSMC).Biopsies were taken from patients undergoing cystectomy due to bladder cancer. Palmitate or LPS stimulated hBSMC were analysed for the production and secretion of the IL-6, gp80, gp80soluble, gp130, MCP-1, pSTAT3, SOCS3, NF-κB and SHP2 by quantitative PCR, ELISA, Western blotting, and confocal immunofluorescence. In signal transduction inhibition experiments we evaluated the involvement of NF-κB and MEK1 in IL-6 and MCP-1 regulation. Palmitate upregulates IL-6 mRNA expression and secretion via NF-κB dependent pathways in a concentration- and time-dependent manner. MCP-1 was moderately upregulated by palmitate but was strongly upregulated by LPS involving NF-κB and MEK1 dependent pathways. Soluble IL-6 receptor (gp80soluble) was downregulated by palmitate and LPS, while membrane-bound gp80 was moderately upregulated. LPS increased SOCS3 and SHP2, whereas palmitate only induced SOCS3. Secondary finding: most of the IL-6 is secreted.Bacterial infection (LPS) or metabolic alterations (palmitate) have distinct effects on IL-6 expression in hBSMC, (i) short term LPS induced autocrine JAK/STAT signaling and (ii) long-term endocrine regulation of IL-6 by palmitate. Induction of IL-6 in human bladder smooth muscle cells by fatty acids may represent a pathogenetic factor underlying the higher frequency and persistence of urinary tract infections in patients with metabolic diseases
Lack of Association between the Tagging SNP A+930→G of SOCS3 and Type 2 Diabetes Mellitus: Meta-Analysis of Four Independent Study Populations
BACKGROUND: The suppressor of cytokine signalling 3 (SOCS3) provides a link between cytokine action and their negative consequences on insulin signalling. Thus SOCS3 is a potential candidate gene for type 2 diabetes (T2DM). METHODOLOGY/PRINCIPAL FINDINGS: Based on HapMap we identified the polymorphism A+930-->G (rs4969168) as a haplotype tagging SNP (htSNP) sufficiently covering the genetic variation of the whole gene. We therefore examined the association between rs4969168 within SOCS3 and T2DM in three independent study populations; one prospective case-cohort study and two cross-sectional study populations. Due to the low frequency of individuals being homozygous for the polymorphism a dominant model of inheritance was assumed. The case-cohort study with 2,957 individuals (764 of them with incident T2DM) showed no effect of the polymorphism on diabetes risk (hazard ratio (95%CI): 0.86 (0.66-1.13); p = 0.3). Within the MeSyBePo-study population 325 subjects had T2DM from a total of 1,897 individuals, while the second cross-sectional cohort included 851 cases of T2DM within a total of 1653 subjects. According to the results in the prospective study, no association with T2DM was found (odds ratio (95%CI): 0.78 (0.54-1.12) for MesyBepo and 1.13 (0.90-1.42) for the Leipzig study population). There was also no association with metabolic subtraits such as insulin sensitivity (p = 0.7), insulin secretion (p = 0.8) or the hyperbolic relation of both, the disposition index (p = 0.7). In addition, no evidence for interaction with BMI or sex was found. We subsequently performed a meta-analysis, additionally including the publicly available data from the T2DM-subcohort of the WTCCC (n = 4,855). The overall odds ratio within that meta-analysis was 0.96 (0.88-1.06). CONCLUSIONS/SIGNIFICANCE: There is no strong effect of the common genetic variation within the SOCS3 gene on the development of T2DM
Reduced Serum Levels of Bone Formation Marker P1NP in Psoriasis
Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data
emphasize an association with dysregulated glucose and fatty acid metabolism, obesity,
elevated blood pressure and cardiac disease, summarized as metabolic syndrome.
TNF-a and IL-17, central players in the pathogenesis of psoriasis, are known to
impair bone formation. Therefore, the relation between psoriasis and bone metabolism
parameters was investigated. Two serum markers of either bone formation—N-terminal
propeptide of type I procollagen (P1NP) or bone resorption—C-terminal telopeptide
of type I collagen (CTX-I)—were analyzed in a cohort of patients with psoriasis
vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to
gender-, age-, and body mass index-matched healthy controls. CTX-I levels were
indistinguishable between patients with psoriasis and controls. Consistently, induction
of psoriasis-like skin inflammation in mice decreases bone volume and activity of
osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but
did not reverse decreased P1NP level suggesting that independent of efficient skin
treatment psoriasis did affect bone metabolism and might favor the development of
osteoporosis. Taken together, evidence is provided that bone metabolism might be
affected by psoriatic inflammation, which may have consequences for future patient
counseling and disease monitoring
Developmentally Driven Changes in Adipogenesis in Different Fat Depots Are Related to Obesity
Subcutaneous (sc) and visceral (vis) adipose tissue (AT) contribute to the variability
in pathophysiological consequences of obesity and adverse fat distribution. To gain
insights into the molecular mechanisms distinguishing vis and sc fat, we compared the
transcriptome during differentiation of immortalized adipocytes from murine epididymal
(epi) and inguinal (ing) AT. RNA was extracted on different days of adipogenesis (−2, 0, 2,
4, 6, 8) and analyzed using ClariomTM D mouse assays (Affymetrix) covering >214,900
transcripts in >66,100 genes. Transcript Time Course Analysis revealed 137 differentially
expressed genes. The top genes with most divergent expression dynamics included
developmental genes like Alx1, Lhx8, Irx1/2, Hoxc10, Hoxa5/10, and Tbx5/15. According
to pathway analysis the majority of the genes were enriched in pathways related to AT
development. Finally, in paired samples of human vis and sc AT (N = 63), several of
these genes exhibited depot-specific variability in expression which correlated closely
with body mass index and/or waist-to-hip ratio. In conclusion, intrinsically programmed
differences in gene expression patterns during adipogenesis suggest that fat depot
specific regulation of adipogenesis contributes to individual risk of obesity
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