Refine
Has Fulltext
- no (102) (remove)
Year of publication
Document Type
- Article (102) (remove)
Language
- English (102)
Is part of the Bibliography
- yes (102)
Keywords
- acid sphingomyelinase (9)
- ceramide (9)
- Sphingolipids (7)
- sphingolipids (7)
- Dexamethasone (5)
- Sphingosine 1-phosphate (5)
- acid ceramidase (4)
- Drug delivery systems (3)
- Insulin resistance (3)
- Sphingosine-1-phosphate (3)
- sphingosine (3)
- sphingosine-1-phosphate (3)
- Acid sphingomyelinase (2)
- Biomarker (2)
- Ceramide (2)
- Clinical (2)
- DNA methylation (2)
- Dendritic cells (2)
- Dermal delivery (2)
- Drug delivery (2)
- FTY720 (2)
- Farber disease (2)
- Fluorescence lifetime imaging microscopy (2)
- Gestational diabetes (2)
- Global DNA methylation (2)
- Hepatocytes (2)
- LC-MS/MS (2)
- Metabolomics (2)
- Nanoparticle (2)
- Nanoparticle uptake (2)
- Nanotoxicology (2)
- Palmitate (2)
- Placenta (2)
- Pseudomonas aeruginosa (2)
- Skin nanocarrier (2)
- Skin penetration (2)
- Tandem mass spectrometry (2)
- Ulcerative colitis (2)
- amitriptyline (2)
- cystic fibrosis (2)
- liver metabolism (2)
- lysosomal storage disorders (2)
- measles virus (2)
- platelets (2)
- sphingomyelin (2)
- survival (2)
- (2E)-Hexadecenal (1)
- (2E)-hexadecenal (1)
- (2E)-hexadecenoic acid (1)
- 1-aminodecylidene bis-phosphonic acid (1)
- 1-phosphate (1)
- 3D tissue model (1)
- APOM protein (1)
- Acinetobacter baumannii (1)
- Adipocytes (1)
- Adipose tissue (1)
- Aging (1)
- Akt (1)
- Akt signaling (1)
- Alcohol dependence (1)
- Anxiety (1)
- Apoptosis (1)
- Arsenic speciation (1)
- Arsenic-containing hydrocarbons (1)
- Arsenolipids (1)
- Aryl-hydrocarbon receptor (1)
- Atherosclerosis (1)
- Atopic dermatitis (1)
- Autotaxin (1)
- B cells (1)
- Biocompatibility (1)
- Biocompatibility testing (1)
- Blood platelets (1)
- Broad-spectrum antibiotic therapy (1)
- Brown adipose tissue (1)
- CMS (1)
- CXCR2 (1)
- Caenorhabditis elegans (1)
- Cardiovascular (1)
- Case-control study (1)
- Cellular uptake (1)
- Cellulose acetate phthalate (1)
- Ceramidase inhibitors (1)
- Ceramides (1)
- Chemotherapy resistance (1)
- Citrobacter rodentium (1)
- Coating (1)
- Colitis (1)
- Colon cancer (1)
- Core-multishell nanocarriers (1)
- Cyp2b1 (1)
- DAIH (1)
- DNMT inhibitor (1)
- Delta F508 mutation (1)
- Dendritic core-multishell nanocarriers (1)
- Dengue (1)
- Depression (1)
- Derivatisation (1)
- Derivatization (1)
- Dermal drug delivery (1)
- Diagnostic (1)
- Dichlorofluorescein assay (1)
- Disease (1)
- Dolichol lipids (1)
- Dopamine (1)
- EBI3 (1)
- EDC (1)
- Electron paramagnetic resonance spectroscopy (1)
- Endocrine disruption (1)
- Endothelial cells (1)
- Endothelial nitric oxide synthase (1)
- Energy expenditure (1)
- Enteric polymer (1)
- Epigenetic (1)
- Epigenetics (1)
- Erosion kinetics (1)
- Ethyl cellulose (1)
- Eudragit (R) (1)
- Eudragit (R) RS (1)
- Eudragit L 100 (1)
- FGF21 (1)
- Factor-Xa (1)
- Fetal programming (1)
- Fingolimod (1)
- Fluorescence (1)
- Forster resonance energy transfer (FRET) (1)
- Free radicals (1)
- Gastrointestinal tract (1)
- Gene expression (1)
- Global (1)
- Glp1r(-/-) mice (1)
- Glutathione (1)
- Glycerophospholipids (1)
- HNRNPA1 (1)
- HPLC-ESI-QTOF (1)
- HPMCP (1)
- HaCaT cells (1)
- Hepatic insulin resistance (1)
- Hepatic stellate cells (1)
- High resolution microscopy (1)
- Histone deacetylase inhibitor (1)
- Human (1)
- Hyperglycaemia (1)
- Hypermethylation (1)
- IDH1 (1)
- Imiquimod (1)
- Inflammatory skin disease (1)
- Inhibitory cytokines (1)
- Insulin signaling (1)
- Insulin signalling (1)
- Interleukin-35 (1)
- Ischemia/reperfusion (1)
- Isotope-dilution (1)
- Isotope-dilution analysis (1)
- Jurkat cells (1)
- Keratinocytes (1)
- LPA(3) receptor subtype (1)
- Langerhans cells (1)
- Lipogenesis (1)
- Liquid chromatography-tandem mass spectrometry (1)
- Liver (1)
- Liver fibrosis (1)
- Liver injury (1)
- Lysophosphatidic acid (1)
- Lysophosphatidylcholines (1)
- Mass spectrometry (1)
- Metabolism (1)
- Methylation (1)
- Microbiota (1)
- Microdialysis (1)
- Multi-domain nanoparticles (1)
- Multiple sclerosis (1)
- NZO (1)
- Nanogel (1)
- Nanomaterials (1)
- Nanoparticles (1)
- Neisseria gonorrhoeae (1)
- Nitric oxide (1)
- Obesity (1)
- Ocular delivery (1)
- Oxazolone (1)
- Oxidative stress (1)
- PCaaC38:6 (1)
- PTEN (1)
- Penetration enhancement (1)
- Permeability (1)
- Phosphatidylcholine acyl-alkyl C 32:1 (1)
- Phosphatidylcholines (1)
- Phosphatidylinositols (1)
- Plasma (1)
- Plasmalogens (1)
- Plastic surfaces (1)
- Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] (1)
- Polymeric nanoparticle (1)
- Polymeric nanoparticles (1)
- Polymers (1)
- Pregnancy (1)
- Preterm birth (1)
- Proliferation (1)
- Proline (1)
- Protein restriction (1)
- Psoriasis (1)
- Retinoblastoma (1)
- S1P receptors (1)
- S1P-receptors (1)
- SAHA (1)
- SCID mice (1)
- ST-1071 (1)
- ST-1893 (1)
- ST-1894 (1)
- ST-968 (1)
- Selenium (1)
- Serotonin (1)
- Skeletal muscle cells (1)
- Skin (1)
- Skin absorption (1)
- Skin barrier disruption (1)
- Skin model (1)
- Smooth muscle cells (1)
- Smpd1 (1)
- Sphingomyelin (1)
- Sphingosine (1)
- Sphingosine 1phosphate (1)
- Sphingosine kinase (1)
- Sphingosine kinase-1 (1)
- Sphingosine-1-phosphate lyase (1)
- Srebf1 (1)
- Staphylococcus aureus (1)
- Structure-activity-relationship (1)
- T cell receptor (1)
- T(h)1 (1)
- T(h)17 (1)
- TET (1)
- TGF-beta 1 (1)
- TNF alpha (1)
- TRPC6 (1)
- Thyroid hormone (1)
- Topical treatment (1)
- Transplantation (1)
- Type 2 diabetes (1)
- UDP-glucuronosyltransferase (1)
- Ventilation (1)
- Ventilator-induced lung injury (1)
- Vitamin C (1)
- Xenobesity (1)
- YB-1 (1)
- acid ceramidase inhibitor ceranib-2 (1)
- acute lung injury (1)
- alpha-SMA (1)
- annexins (1)
- anti-inflammatory therapy (1)
- anticancer (1)
- antidepressants (1)
- anxiety-like behavior (1)
- appetite (1)
- autoimmunity (1)
- bacterial toxins (1)
- binding (1)
- birth weight (1)
- bisphosphonates (1)
- blebbing (1)
- blood banking (1)
- brain insulin signaling (1)
- burn injury (1)
- c. elegans (1)
- calcium (1)
- cancer cells (1)
- cell migration (1)
- cells (1)
- cerami-des (1)
- ceramides (1)
- cholesteryl ester (1)
- chronic kidney disease (1)
- chronic psychosocial stress (1)
- chronic subordinate colony housing (CSC) (1)
- circulation (1)
- click chemistry (1)
- colitis (1)
- collagen I (1)
- decitabine (1)
- dendritic cell (1)
- depressive-like behavior (1)
- diacylglycerol (1)
- disease (1)
- distress (1)
- drug delivery (1)
- drug design (1)
- drug metabolism (1)
- dysfunction (1)
- enzyme assays (1)
- enzymology (1)
- epigenetics (1)
- etanercept (1)
- experimental antigen-induced encephalomyelitis (1)
- extinction (1)
- fatty acid metabolism (1)
- fetal origins hypothesis (1)
- fibrosis (1)
- fingolimod (1)
- force-field (1)
- forebrain (1)
- functional inhibitors of acid sphin-gomyelinase (1)
- genes (1)
- glucocorticoid receptor (1)
- growth restriction (1)
- high density (1)
- hippocampus (1)
- human excised skin (1)
- hyperforin (1)
- immune (1)
- immunology (1)
- immunomodulator (1)
- immunonutrition (1)
- infection (1)
- inhibitory cytokines (1)
- integrins (1)
- interleukin-35 (1)
- intestine (1)
- invasion (1)
- keratinocytes (1)
- later health (1)
- life-span (1)
- linagliptin (1)
- lipid metabolism (1)
- lipid rafts (1)
- lipoproteins (1)
- liposomes (1)
- long chain base (1)
- lung cancer (1)
- lung infection (1)
- lung inflammation (1)
- lymphopenia (1)
- lyso-phospholipids (1)
- lysosomal hydrolases (1)
- lysosome (1)
- mass spectrometry (1)
- membrane fusion (1)
- membrane lipids (1)
- membrane repair (1)
- membrane-lipid therapy (1)
- menadione (1)
- microparticle (1)
- migration (1)
- mitochondria (1)
- molecular dynamics (1)
- molecular modeling (1)
- morpholino analogues of fingolimod (1)
- mortality (1)
- multiple sclerosis (1)
- n-acetyl-cysteine (1)
- nanogels (1)
- nanoparticles (1)
- nanotoxicology (1)
- neutral sphingomyelinase-2 (1)
- neutrophil chemotaxis (1)
- nutrient transport (1)
- operant behavior (1)
- oxidative stress (1)
- pH-sensitive nanoparticle (1)
- pH-sensitive nanoparticles (1)
- particle characterization (1)
- patterns (1)
- phagocytosis (1)
- plasma membrane (1)
- pneumococcal pneumonia (1)
- pregnancy (1)
- primary immunodeficiencies (1)
- proliferation (1)
- protein (1)
- proteomic analysis (1)
- refinement (1)
- repetitive elements (1)
- s-glutathionylation (1)
- serine palmitoyltransferase (1)
- skin equivalents (1)
- skin penetration (1)
- sphingolipid de novo synthesis (1)
- sphingolipid metabolism (1)
- sphingosine kinase (1)
- sphingosine kinase 1 (1)
- sphingosine kinase inhibitor SKI-II (1)
- sphingosine kinases (1)
- sphingosine-1-phosphate receptor 2 (1)
- stable-isotope labeling (1)
- storage (1)
- sulfotransferase (1)
- tacrolimus formulation (1)
- thermoresponsive-nanogel (1)
- thymosin beta 4 (1)
- topical (1)
- transfusion-related acute lung injury (1)
- transport proteins (1)
- tumor-metastasis (1)
- type 2 diabetes mellitus (1)
Institute
Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P(3). Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P(3)-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time-and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
Infection is a common and often deadly complication after burn injury. A major underlying factor is burn-induced immune dysfunction, particularly with respect to neutrophils as the primary responders to infection. Temporally after murine scald injury, we demonstrate impaired bone marrow neutrophil chemotaxis toward CXCL1 ex vivo. Additionally, we observed a reduced recruitment of neutrophils to the peritoneal after elicitation 7 days after injury. We demonstrate that neutrophil ceramide levels increase after burn injury, and this is associated with decreased expression of CXCR2 and blunted chemotaxis. A major signaling event upon CXCR2 activation is Akt phosphorylation and this was reduced when ceramide was elevated. In contrast, PTEN levels were elevated and PTEN-inhibition elevated phospho-Akt levels and mitigated the burn-induced neutrophil chemotaxis defect. Altogether, this study identifies a newly described pathway of ceramide-mediated suppression of neutrophil chemotaxis after burn injury and introduces potential targets to mitigate this defect and reduce infection-related morbidity and mortality after burn.
Breaking the Barrier
(2018)
Topical administration permits targeted, sustained delivery of therapeutics to human skin. Delivery to the skin, however, is typically limited to lipophilic molecules with molecular weight of < 500 Da, capable of crossing the stratum corneum. Nevertheless, there are indications protein delivery may be possible in barrier deficient skin, a condition found in several inflammatory skin diseases such as psoriasis, using novel nanocarrier systems. Methods: Water in water thermo-nanoprecipitation; dynamic light scattering; zeta potential measurement; nanoparticle tracking analysis; atomic force microscopy; cryogenic transmission electron microscopy; UV absorption; centrifugal separation membranes; bicinchoninic acid assay; circular dichroism; TNF alpha binding ELISA; inflammatory skin equivalent construction; human skin biopsies; immunohistochemistry; fluorescence microscopy; western blot; monocyte derived Langerhans cells; ELISA Results: Here, we report the novel synthesis of thermoresponsive nanogels (tNG) and the stable encapsulation of the anti-TNFa fusion protein etanercept (ETR) (similar to 150 kDa) without alteration to its structure, as well as temperature triggered release from the tNGs. Novel tNG synthesis without the use of organic solvents was conducted, permitting in situ encapsulation of protein during assembly, something that holds great promise for easy manufacture and storage. Topical application of ETR loaded tNGs to inflammatory skin equivalents or tape striped human skin resulted in efficient ETR delivery throughout the SC and into the viable epidermis that correlated with clear anti-inflammatory effects. Notably, effective ETR delivery depended on temperature triggered release following topical application. Conclusion: Together these results indicate tNGs hold promise as a biocompatible and easy to manufacture vehicle for stable protein encapsulation and topical delivery into barrier-deficient skin.
Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.
Being born large for gestational age is associated with increased global placental DNA methylation
(2020)
Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
Here were report the combination of biocompatible click chemistry of omega-azidosphinganine with fluorescence microscopy and mass spectrometry as a powerful tool to elaborate the sphingolipid metabolism. The azide probe was efficiently synthesized over 13 steps starting from l-serine in an overall yield of 20% and was used for live-cell fluorescence imaging of the endoplasmic reticulum in living cells by bioorthogonal click reaction with a DBCO-labeled fluorophore revealing that the incorporated analogue is mainly localized in the endoplasmic membrane like the endogenous species. A LC-MS(/MS)-based microsomal in vitro assay confirmed that omega-azidosphinganine mimics the natural species enabling the identification and analysis of metabolic breakdown products of sphinganine as a key starting intermediate in the complex sphingolipid biosynthetic pathways. Furthermore, the sphinganine-fluorophore conjugate after click reaction was enzymatically tolerated to form its dihydroceramide and ceramide metabolites. Thus, omega-azidosphinganine represents a useful biofunctional tool for metabolic investigations both by in vivo fluorescence imaging of the sphingolipid subcellular localization in the ER and by in vitro high-resolution mass spectrometry analysis. This should reveal novel insights of the molecular mechanisms sphingolipids and their processing enzymes have e.g. in infection.
Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents. After treatment with AsHC 360, flap structure-specific endonuclease 1 (FEN1) as well as xeroderma pigmentosum group A complementing protein (XPA) and (cytosine-5)-methyltransferase 3A (DNMT3A) showed time- and concentration-dependent alterations in gene expression, thereby indicating an impact on genomic stability. In the subsequent analysis of epigenetic markers, within 72 h, neither AsHC 332 nor AsHC 360 showed an impact on the global DNA methylation level, whereas incubation with AsHC 360 increased the global DNA hydroxymethylation level. Analysis of cell extracts and cell media by HPLC-mass spectrometry revealed that both AsHCs were considerably biotransformed. The identified metabolites include not only the respective thioxo-analogs of the two AsHCs, but also several arsenic-containing fatty acids and fatty alcohols, contributing to our knowledge of biotransformation mechanisms of arsenolipids.