A5081220303- Pancreatic function and diabetes
- Histone Deacetylase Inhibitors Research
- Genetics and Neurodevelopmental Disorders
- Adipose Tissue and Metabolism
- Adenosine and Purinergic Signaling
- Inflammasome and immune disorders
- Parkinson's Disease Mechanisms and Treatments
- Diabetes and associated disorders
- Calpain Protease Function and Regulation
- Phagocytosis and Immune Regulation
- Receptor Mechanisms and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Connexins and lens biology
- Endoplasmic Reticulum Stress and Disease
- Drug Transport and Resistance Mechanisms
- Autophagy in Disease and Therapy
- Protein Degradation and Inhibitors
- Pancreatitis Pathology and Treatment
- Ion Transport and Channel Regulation
- Dietary Effects on Health
- Cellular transport and secretion
- Ophthalmology and Visual Impairment Studies
- Lysosomal Storage Disorders Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Adipokines, Inflammation, and Metabolic Diseases
University of Copenhagen
2011-2024
Novo Nordisk Foundation
2022-2024
University of Utah
2023
McLean Hospital
2019
Harvard University
2019
Endocrinology Research Center
2012-2014
Faculty of Public Health
2014
Objective Dietary fibres are essential for maintaining microbial diversity and the gut microbiota can modulate host physiology by metabolising fibres. Here, we investigated whether soluble dietary fibre oligofructose improves metabolism modulating bacterial transformation of secondary bile acids in mice fed western-style diet. Design To assess impact supplementation on acid bacteria, conventional wild-type TGR5 knockout diet enriched or not with cellulose oligofructose. In addition, used...
The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity type 2 diabetes1. Yet current pharmacological approaches require conjugation multiple receptor agonists to achieve both effects2–4, so far, no safe energy-expending option has reached the clinic. Here we show that activation neurokinin (NK2R) is sufficient suppress appetite centrally increase peripherally. We focused on NK2R...
Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it difficult to dissect the role individual HDACs due lack selective small-molecule inhibitors. Here, we report synthesis series highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes clinically experienced inhibitor CI-994. We used this toolkit isochemogenic or chemically matched...
Abstract This study utilized human fibroblasts as a preclinical discovery and diagnostic platform for identification of cell biological signatures specific the LRRK2 G2019S mutation producing Parkinson’s disease (PD). Using live imaging with pH-sensitive Rosella biosensor probe reflecting lysosomal breakdown mitochondria, mitophagy rates were found to be decreased in carrying compared cells isolated from healthy subject (HS) controls. The mutant increased kinase activity was reduced by...
Significance Type 1 diabetes is due to immune-mediated pancreatic β-cell destruction. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. The orally active clinically well-tolerated KDACi vorinostat givinostat reverted a mouse model of type counteracted target cell damage. Importantly, these effects were achieved with doses that safe effective human diseases. Of note, the mechanism action was compatible...
Aim: An insufficient functional β-cell mass is a prerequisite to develop diabetes. Thus, means protect or restore are important goals in diabetes research. Inflammation and proinflammatory cytokines play roles dysfunction death, recent data show that 2 miRNAs, miR-21 miR-34a, may be involved mediating cytokine-induced dysfunction. Therefore, manipulation of miR-34a levels potentially beneficial β cells. To study the effect long-term alterations upon net number, we stably overexpressed...
The pathogenesis of colorectal neoplasia is still unresolved but has been associated with alterations in epithelial clearance xenobiotics and metabolic waste products. aim this study was to functionally characterize the transport cyclic nucleotides colonic biopsies from patients without neoplasia. Cyclic were used as model substrates shared by some OATP- ABC-transporters, which part are responsible for metabolites epithelium. On neoplasia, molecular electrophysiologically registered...
Pancreatic β-cell dysfunction is central to type 2 diabetes pathogenesis. Prolonged elevated levels of circulating free-fatty acids and hyperglycemia, also termed glucolipotoxicity, mediate apoptosis associated with increased c-Jun N-terminal Kinase (JNK) activity. Endoplasmic reticulum (ER) oxidative stress are elicited by palmitate high glucose concentrations further potentiating JNK Our aim was determine the role subtypes JNK1, JNK2 JNK3 in glucose-induced apoptosis. We established...
Here, we report that activation of different types tissue macrophages, including microglia, by lipopolysaccharide (LPS) or GM-CSF stimulation correlates with the quantitative redistribution NADPH oxidase (cyt b(558)) from plasma membrane to an intracellular stimulus-responsive storage compartment. Cryo-immunogold labeling gp91(phox) and CeCl(3) cytochemistry showed presence oxidant production in numerous small (<100 nm) vesicles. Cell homogenization sucrose gradient centrifugation...
Mechanisms explaining exercise-induced β-cell health are unknown.This study aimed to define the role of muscle contraction and acute exercise-derived soluble humoral mediators on health.In vitro models were used.University.Healthy subjects.Conditioned media (CM) collected from human skeletal (HSkM) cells treated with or without electrical pulse stimulation (EPS). Antecubital femoral venous blood serum before after an exercise bout. CM sera IL-6 neutralization used incubate insulin-producing...
The proinflammatory cytokines interleukin-1 beta (IL-1β) and interferon gamma (IFN-γ) play important roles in the progressive loss of beta-cell mass function during development both type 1 2 diabetes. We have recently showed that bone morphogenetic protein (BMP)-2 -4 are expressed pancreatic islets inhibit growth function. In this study, we describe IL-1β IFN-γ induce expression BMP-2 suggesting a possible role for mediating effects on apoptosis dysfunction. increased mRNA levels 6- 3-fold...
Abstract Background Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect a novel peptide antagonist IL-1 signaling, Ilantide. Methods investigated binding Ilantide to receptor type I (IL-1RI) using surface plasmon resonance, inhibition Il-1β-induced activation nuclear factor κB (NF-κB) HEK-Blue cells that contained IL-1β-sensitive reporter, secretion TNF-α macrophages, protection against...
Secretion of proteopathic α-synuclein (α-SNC) species from neurons is a suspected driving force in the propagation Parkinson's disease (PD). We have previously implicated exophagy, exocytosis autophagosomes, as dominant mechanism α-SNC secretion differentiated PC12 or SH-SY5Y nerve cells. Here we examined regulation exophagy associated with different forms cell stress relevant to PD. identify cJUN-N-terminal kinase (JNK) activity pivotal secretory fate autophagosomes containing α-SNC....
Purpose: To compare visual outcomes after LASIK using the VISX STAR S4 CustomVue, with and without Iris Registration technology. Methods: In this retrospective study, was performed on 239 myopic eyes, or astigmatism, of 142 patients. registration 121 eyes non-iris 118 eyes. Primary outcome measures were uncorrected acuity (UCVA), best spectacle-corrected (BSCVA), manifest refraction. Results: At 6 months, mean values for UCVA (logMAR) 0.00±0.09 in iris group −0.01±0.11 ( P =.587)....
Histone deacetylase (HDAC) inhibition protects pancreatic beta-cells against apoptosis induced by the combination of proinflammatory cytokines interleukin (IL)-1β and interferon (IFN)-γ. Decreased expression cell damage-related genes is observed on transcriptional level upon HDAC using either IL-1β or IFN-γ alone. Whereas has been shown to regulate NFκB-activity, related primarily signaling, it unknown whether HDACs affect signaling in beta-cells. Further, non-beta-cells, there a dispute...
Pro-inflammatory cytokines and chemokines, in particular IL-1β, IFNγ, CXCL10, contribute to β-cell failure loss DM via IL-1R, IFNγR, TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1β secretion, hyperglycemia animal models of diabetes. Further, IL-1R antagonism improves normoglycemia function type 2 diabetic patients. Inhibition lysine deacetylases (KDACi) counteracts toxicity induced by the combination IFNγ incidence non-obese (NOD) mice. We hypothesized that...
The Na+;HCO3- co-transporter NBCn1 (SLC4A7) is a major regulator of intracellular pH yet its trafficking and turnover are essentially unstudied. Here, we used MDCK-II MCF-7 cells to investigate these processes in epithelial cells. GFP-NBCn1 membrane localization was abolished by truncation the full C-terminal tail (C-tail) did not require PDZ-binding motif (ETSL). Glutathione-S-Transferase-pulldown C-tail followed mass spectrometry analysis revealed putative interactions with multiple...
Biological activity of the neural cell adhesion molecule (NCAM) depends on both and activation intra-cellular signaling. Based in vitro experiments with truncated extra-cellular domains, several models describing homophilic NCAM trans- cis-interactions have been proposed. However, cis-dimerization living cells has not shown directly role cytoplasmic part dimerization is poorly understood. Here, we used bioluminescence resonance energy transfer (BRET(2)) technique to demonstrate that...