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N-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia

ABSTRACT: N-octanoyl dopamine (NOD), but not dopamine dose dependently induces the UPR. This was also found for other synthetic N-Acyl dopamine derivates (NADD). Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury. N-octanoyl dopamine (NOD) and other synthetic N-Acyl dopamine derivates (NADD), but not dopamine dose dependently induces the UPR. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56285 | GEO | 2014/03/28

SECONDARY ACCESSION(S): PRJNA242854

REPOSITORIES: GEO

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N-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia

Project description:N-octanoyl dopamine (NOD), but not dopamine dose dependently induces the UPR. This was also found for other synthetic N-Acyl dopamine derivates (NADD). Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury. N-octanoyl dopamine (NOD) and other synthetic N-Acyl dopamine derivates (NADD), but not dopamine dose dependently induces the UPR. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. Genome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by NOD

2014-03-28 | E-GEOD-56285 | biostudies-arrayexpress

The expression of inflammatory genes in endothelial cells is inhibited by N-octanoyl dopamine via modulation of the NFkB pathway

Project description:Background: Dopamine has intrinsic receptor-independent anti-inflammatory properties when used at high concentrations. Since cellular uptake of N-octanoyl dopamine (NOD) is far better than of dopamine, NOD might display anti-inflammatory effects already at relative low concentrations. The present study was conducted to assess the anti-inflammatory potential of NOD and to elucidate how this was mediated. Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-Î± in the presence of various NOD concentrations. Affymetrix gene expression profiling (GEP), Western blotting, adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells and NFÎºB activation was studied. Compounds that were structurally related to NOD were used to address the molecular entities within NOD that were required for its anti-inflammatory properties. Results: GEP revealed that NOD down-regulates a wide range of pro-inflammatory mediators. Down-regulation of adhesion molecules was confirmed at the protein level and resulted in a decreased adhesion of PBMC to endothelial cells under static and flow conditions. NOD inhibited NFÎºB independently of IÎºBÎ± degradation. Inhibition was associated with an overall decrease in p65 expression and a significant decrease in p65 phosphorylation at Ser276. De novo protein synthesis was not required for inhibition and was not mediated via HO-1. Redox activity and hydrophobicity of NOD seemed to be important entities for its anti-inflammatory properties. Conclusion: Our data demonstrate that NOD has potent anti-inflammatory effects through its action on NFÎºB. Unlike dopamine, NOD has no adverse effects on blood pressure, making it a promising candidate drug to reduce excessive inflammation occurring under various pathological conditions. A total of 6 different HUVEC lines were used, n=3 for each group (TNF or TNF+ NOD).

2012-08-30 | E-GEOD-34059 | biostudies-arrayexpress

The expression of inflammatory genes in endothelial cells is inhibited by N-octanoyl dopamine via modulation of the NFkB pathway

Project description:Background: Dopamine has intrinsic receptor-independent anti-inflammatory properties when used at high concentrations. Since cellular uptake of N-octanoyl dopamine (NOD) is far better than of dopamine, NOD might display anti-inflammatory effects already at relative low concentrations. The present study was conducted to assess the anti-inflammatory potential of NOD and to elucidate how this was mediated. Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α in the presence of various NOD concentrations. Affymetrix gene expression profiling (GEP), Western blotting, adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells and NFκB activation was studied. Compounds that were structurally related to NOD were used to address the molecular entities within NOD that were required for its anti-inflammatory properties. Results: GEP revealed that NOD down-regulates a wide range of pro-inflammatory mediators. Down-regulation of adhesion molecules was confirmed at the protein level and resulted in a decreased adhesion of PBMC to endothelial cells under static and flow conditions. NOD inhibited NFκB independently of IκBα degradation. Inhibition was associated with an overall decrease in p65 expression and a significant decrease in p65 phosphorylation at Ser276. De novo protein synthesis was not required for inhibition and was not mediated via HO-1. Redox activity and hydrophobicity of NOD seemed to be important entities for its anti-inflammatory properties. Conclusion: Our data demonstrate that NOD has potent anti-inflammatory effects through its action on NFκB. Unlike dopamine, NOD has no adverse effects on blood pressure, making it a promising candidate drug to reduce excessive inflammation occurring under various pathological conditions.

2012-08-30 | GSE34059 | GEO

Proteomics analysis for the study of beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE)

Project description:Appropriate tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with highly variable demand for insulin synthesis. An efficient UPR ensures a sufficient beta cell mass and secretory output but can also affect beta cell resilience to autoimmune aggression. However, the factors regulating protein homeostasis in the face of metabolic and immune challenges are insufficie tly understood. We examined beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE), a ubiquitous protease with high affinity for insulin, a putative ill-defined role in protein homeostasis, and genetic association with type 2 diabetes. IDE deficiency induces a low-level UPR in both standard and autoimmune non-obese diabetic (NOD) mice, associated with rapamycin-sensitive beta cell proliferation, as well as protection from diabetes in NOD mice. Moreover, in NOD islets, IDE deficiency specifically induces strong upregulation of regenerating islet-derived protein 2, a protein attenuating inflammation and protecting from autoimmunity. Our findings establish a role of IDE in islet cell protein homeostasis, corroborate the link between low-level UPR and proliferation, and identify an anti-inflammatory islet cell response uncovered in the absence of IDE of potential interest in autoimmune diabetes.

2024-06-16 | PXD034826 | Pride

CMMC Feb 01 2024 Carboxylic Acids Conjugated with Amino Acids - 1

Project description:Amidation reaction was used. Acyl chlorides and amines were used to create these compounds. The following reactants are: Palmitoyl, Tetradecanoyl, Decanoyl, Octanoyl, Hexanoyl, Butyryl, Acetyl chlorides with Arg, Phe, Tyr, Trp, Ser, Met, Gly, Homoserine, Leu, GABA, 5-aminobutanoic acid, His, Lys, Thr.

2024-03-01 | MSV000094220 | MassIVE

Stress-induced beta cell dedifferentiation prior to immune cell infiltration prevents type 1 diabetes [Single]

Project description:Immune-mediated destruction of insulin-producing β-cells causes type 1 diabetes (T1D). However, how β-cells themselves participate in the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in β-cells of non-obese diabetic (NOD) mice in early stages of disease results in preserved β-cell function, substantially reduced islet immune cell infiltration, and β-cell apoptosis leading to protection from T1D. NOD mice that lack the UPR sensor IRE1α in β-cells show greatly reduced expression of β-cell identity markers, islet autoantigens, and genes involved in antigen presentation. These mice exhibit upregulation of immune inhibitory markers in β-cells and significantly less cytotoxic CD8+ T cells in the pancreas. Our results indicate that triggering transient β-cell dedifferentiation via targeting a specific branch of the UPR in β-cells, prior to insulitis, allow β-cells to escape from immune destruction and may be used as a novel preventive strategy for high-risk individuals.

2020-01-30 | GSE144471 | GEO

Stress-induced beta cell dedifferentiation prior to immune cell infiltration prevents type 1 diabetes [Bulk]

2020-01-30 | GSE144461 | GEO

RNA-Seq to decipher breast cancer-adipocytes reciprocal reprogramming: evaluating the impact of glucose

Project description:The tumor microenvironment, including adipocytes, is a critical element for breast cancer (BC) progression, also responding to metabolic stimuli characterizing obesity and/or diabetes. The reciprocal reprogramming established between BC cells and adipocytes remains to be deciphered. We investigated (i) the effect of mammary adipocytes on BC cells and vice versa, (ii) the impact of glucose on BC cells, adipocytes and (iii) the impact of glucose on their cross-talk. We have identified adipocyte-modulated genes in BC cells and BC cell-modulated genes in adipocytes, dependently and independently of glucose levels. We identified the adipogenesis process as the most relevantly differentially regulated pathway both in cancer cells and in adipocytes upon exposure to high glucose concentration. Specifically, we observed that BC cells promote de-differentiation of adipocytes and re-shaping toward a fibroblast-like phenotype, particularly upon glucose lowering; the de-lipidation of adipocytes is paralleled by induction of adipogenesis genes in BC cells.

2024-09-19 | GSE243555 | GEO

A chemical probe unravels the reactive proteome of health-associated catechols

Project description:Catechol-containing natural products are common constituents of foods, drinks, and drugs. Natural products carrying this motif are often associated with beneficial biological effects such as anticancer activity and neuroprotection. However, the molecular mode of action behind these properties is poorly understood. Here, we apply a mass spectrometry-based competitive chemical proteomics approach to elucidate the target scope of catechol-containing bioactive molecules from diverse foods and drugs. Inspired by the protein reactivity of catecholamine neurotransmitters, we designed and synthesised a broadly reactive minimalist catechol chemical probe based on dopamine. Initial labelling experiments in live human cells demonstrated broad protein binding by the probe, which was largely outcompeted by its parent compound dopamine. Next, we investigated the competition profile of a selection of biologically relevant catechol-containing compounds. With this approach, we characterised the protein reactivity and the target scope of dopamine and ten catechols. Strikingly, proteins associated with the endoplasmic reticulum (ER) were among the main targets. ER stress assays in the presence of reactive catechols revealed an activation of the IRE1-branch of the unfolded protein response (UPR), whereas unreactive catechols had no effect. As the UPR is an intriguing oncology target, this provides a possible explanation of the health-promoting effects attributed to many catechol natural products.

2023-10-24 | PXD043348 | Pride

proteomic content of HUVEC-Exos in HP and NP conditions

Project description:HUVEC were treated with 3 mM (pH=7.4) as the high concentration of phosphorus (HP) and normal phosphorus (NP) for exosomes concentration. The HUVEC-Exos samples (HP: 3 samples, NP: 3 samples) were processed for label-free-based quantitative proteomic analysis using high-performance liquid chromatography tandem mass spectrometry (HPLC–MS/MS).

2022-09-21 | PXD036925 |

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