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Welsh, Nils
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Publications (10 of 53) Show all publications
Turpaev, K., Krizhanovskii, C., Wang, X., Sargsyan, E., Bergsten, P. & Welsh, N. (2019). The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination. The FASEB Journal, 33(3), 3510-3522
Open this publication in new window or tab >>The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 3, p. 3510-3522Article in journal (Refereed) Published
Abstract [en]

The naturally occurring quassinoid compound brusatol improves the survival of insulin-producing cells when exposed to the proinflammatory cytokines IL-1b and IFN-g in vitro. The aim of the present study was to investigatewhetherbrusatol also promotes beneficial effects inmice fed a high-fat diet (HFD), and if so, to study the mechanisms by which brusatol acts. In vivo, we observed that the impaired glucose tolerance of HFD-fed male C57BL/ 6micewas counteracted by a 2wk treatmentwith brusatol. Brusatol treatment improvedbothb-cell function and peripheral insulin sensitivity of HFD-fed mice. In vitro, brusatol inhibited b-cell total protein and proinsulin biosynthesis, withanED50 of 40nM. In linewith this, brusatol blocked cytokine-inducediNOSprotein expression via inhibition of iNOS mRNA translation. Brusatol may have affected protein synthesis, at least in part, via inhibition of eukaryotic initiation factor 5A (eIF5A) hypusination, as eIF5A spermidine association and hypusinationin RIN-5AHcellswas reducedinadose-andtime-dependentmanner. The eIF5AhypusinationinhibitorGC7 promoted a similar effect. Both brusatol and GC7 protected rat RIN-5AH cells against cytokine-induced cell death. Brusatol reduced eIF5A hypusination and cytokine-induced cell death in EndoC-bH1 cells as well. Finally, hypusinated eIF5A was reduced in vivo by brusatol in islet endocrine and endothelial islet cells of mice fed anHFD. The results of the present study suggest that brusatol improves glucose intolerance in mice fed an HFD, possibly by inhibiting protein biosynthesis and eIF5A hypusination.-Turpaev, K., Krizhanovskii, C., Wang, X., Sargsyan, E., Bergsten, P., Welsh, N. The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/ 6 mice: role of translation factor eIF5A hypusination. FASEB J. 33, 3510-3522 (2019). www.fasebj.org

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2019
Keywords
iNOS, insulin release, -cell death
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-379572 (URN)10.1096/fj.201801698R (DOI)000459794800034 ()30462531 (PubMedID)
Funder
Swedish Child Diabetes Foundation
Available from: 2019-04-12 Created: 2019-04-12 Last updated: 2019-04-12Bibliographically approved
Wang, X., Jiang, L., Wallerman, O., Younis, S., Yu, Q., Klaesson, A., . . . Andersson, L. (2019). ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells. The FASEB Journal, 33(1), 88-100
Open this publication in new window or tab >>ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 1, p. 88-100Article in journal (Refereed) Published
Abstract [en]

Zinc finger BED domain containing protein 6 (Zbed6) has evolved from a domesticated DNA transposon and encodes a transcription factor unique to placental mammals. The aim of the present study was to investigate further the role of ZBED6 in insulin-producing cells, using mouse MIN6 cells, and to evaluate the effects of Zbed6 knockdown on basal -cell functions, such as morphology, transcriptional regulation, insulin content, and release. Zbed6-silenced cells and controls were characterized with a range of methods, including RNA sequencing, chromatin immunoprecipitation sequencing, insulin content and release, subplasma membrane Ca2+ measurements, cAMP determination, and morphologic studies. More than 700 genes showed differential expression in response to Zbed6 knockdown, which was paralleled by increased capacity to generate cAMP, as well as by augmented subplasmalemmal calcium concentration and insulin secretion in response to glucose stimulation. We identified >4000 putative ZBED6-binding sites in the MIN6 genome, with an enrichment of ZBED6 sites at upregulated genes, such as the -cell transcription factors v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and Nk6 homeobox 1. We also observed altered morphology/growth patterns, as indicated by increased cell clustering, and in the appearance of axon-like Neurofilament, medium polypeptide and tubulin 3, class III-positive protrusions. We conclude that ZBED6 acts as a transcriptional regulator in MIN6 cells and that its activity suppresses insulin production, cell aggregation, and neuronal-like differentiation.Wang, X., Jiang, L., Wallerman, O., Younis, S., Yu, Q., Klaesson, A., Tengholm, A., Welsh, N., Andersson, L. ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2019
Keywords
-cells, cell adhesion, transcriptome analysis, ChIP-seq
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-377365 (URN)10.1096/fj.201600835R (DOI)000457401500007 ()29957057 (PubMedID)
Funder
Swedish Research Council, 80576801Swedish Research Council, 70374401Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Child Diabetes FoundationNovo NordiskErnfors FoundationSwedish Diabetes Association
Available from: 2019-02-19 Created: 2019-02-19 Last updated: 2019-02-19Bibliographically approved
Oskarsson, M. E., Hermansson, E., Wang, Y., Welsh, N., Presto, J., Johansson, J. & Westermark, G. (2018). The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proceedings of the National Academy of Sciences of the United States of America, 115(12), E2752-E2761
Open this publication in new window or tab >>The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 12, p. E2752-E2761Article in journal (Refereed) Published
Abstract [en]

Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Aβ42, an amyloid-forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-βH1. Bri2 colocalizes with IAPP intracellularly and is present in amyloid deposits in patients with type 2 diabetes. The BRICHOS domain of Bri2 effectively inhibits fibril formation in vitro and instead redirects IAPP into formation of amorphous aggregates. Reduction of endogenous Bri2 in EndoC-βH1 cells with siRNA increases sensitivity to metabolic stress leading to cell death while a concomitant overexpression of Bri2 BRICHOS is protective. Also, coexpression of IAPP and Bri2 BRICHOS in lateral ventral neurons of Drosophila melanogaster results in an increased cell survival. IAPP is considered to be the most amyloidogenic peptide known, and described findings identify Bri2, or in particular its BRICHOS domain, as an important potential endogenous inhibitor of IAPP aggregation and toxicity, with the potential to be a possible target for the treatment of type 2 diabetes.

Keywords
Bri2, BRICHOS, chaperone, IAPP, amyloid, islet amyloid, beta cells, type 2 diabetes
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-265483 (URN)10.1073/pnas.1715951115 (DOI)000427829500014 ()
Funder
Swedish Research CouncilSwedish Diabetes AssociationNovo NordiskErnfors Foundation
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-06-01Bibliographically approved
Wang, X., Elksnis, A., Wikström, P., Walum, E., Welsh, N. & Carlsson, P.-O. (2018). The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro. PLoS ONE, 13(9), Article ID e0204271.
Open this publication in new window or tab >>The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 9, article id e0204271Article in journal (Refereed) Published
Abstract [en]

It has been proposed that pancreatic beta-cell dysfunction in type 2 diabetes is promoted by oxidative stress caused by NADPH oxidase (Nox) over-activity. The aim of the present study was to evaluate the efficacy of novel Nox inhibitors as protective agents against cytokine- or high glucose + palmitate-induced human beta-cell death. The Nox2 protein was present mainly in the cytoplasm and was induced by cytokines. Nox4 protein immunoreactivity, with some nuclear accumulation, was observed in human islet cells, and was not affected by islet culture in the presence of cytokines or high glucose + palmitate. Nox inhibitors with partial or no isoform selectivity (DPI, dapsone, GLX351322, and GLX481372) all reduced ROS production of human islet cells exposed to high glucose + palmitate. This was paralleled by improved viability and reduced caspase 3 activation. The Nox1 selective inhibitor ML171 failed to reduce human islet cell death in response to both cytokines and high glucose + palmitate. The selective Nox2 inhibitor Phox-12 also failed to protect against cytokines, but protected partially against high glucose + palmitate-induced cellular death. The highly selective Nox4 inhibitor GLX7013114 protected islet cells against both cytokines and high glucose + palmitate. However, as no osmotic control for high glucose was used, we cannot exclude the possibility that the high glucose effect was due to osmosis. It is concluded that Nox4 may participate in stress-induced islet cell death in human islets in vitro. We propose that Nox4 mediates pro-apoptotic effects in intact islets under stressful conditions and that selective Nox4-inhibition may be a therapeutic strategy in type 2 diabetes.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368106 (URN)10.1371/journal.pone.0204271 (DOI)000446005500024 ()30265686 (PubMedID)
Funder
Swedish Research Council, 2017-01343Stiftelsen Olle Engkvist ByggmästareSwedish Diabetes AssociationNovo NordiskErnfors FoundationSwedish Child Diabetes Foundation
Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2018-12-03Bibliographically approved
Krizhanovskii, C., Fred, R. G., Oskarsson, M. E., Westermark, G. T. & Welsh, N. (2017). Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells. Upsala Journal of Medical Sciences, 122(3), 149-159
Open this publication in new window or tab >>Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 149-159Article in journal (Refereed) Published
Abstract [en]

Background: Enhanced IAPP production may contribute to islet amyloid formation in type 2 diabetes. The objective of this study was to determine the effects of the saturated fatty acid palmitate on IAPP levels in human beta-cells. Methods: EndoC-beta H1 cells and human islets were cultured in the presence of sodium palmitate. Effects on IAPP/insulin mRNA expression and secretion were determined using real-time qPCR/ELISA. Pharmacological activators and/or inhibitors and RNAi were used to determine the underlying mechanisms. Results: We observed that EndoC-beta H1 cells exposed to palmitate for 72 h displayed decreased expression of Pdx-1 and MafA and increased expression of thioredoxin-interacting protein (TXNIP), reduced insulin mRNA expression and glucose-induced insulin secretion, as well as increased IAPP mRNA expression and secretion. Further, these effects were independent of fatty acid oxidation, but abolished in response to GPR40 inhibition/downregulation. In human islets both a high glucose concentration and palmitate promoted increased IAPP mRNA levels, resulting in an augmented IAPP/insulin mRNA ratio. This was paralleled by elevated IAPP/insulin protein secretion and content ratios. Conclusions: Addition of exogenous palmitate to human beta-cells increased the IAPP/insulin expression ratio, an effect contributed to by activation of GPR40. These findings may be pertinent to our understanding of the islet amyloid formation process.

Keywords
Amyloid, fatty acids, insulin, islet amyloid polypeptide (IAPP), palmitate
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-340975 (URN)10.1080/03009734.2017.1368745 (DOI)000414107800001 ()28980863 (PubMedID)
Available from: 2018-02-06 Created: 2018-02-06 Last updated: 2018-02-06Bibliographically approved
Welsh, N. (Ed.). (2017). Department of Medical Cell Biology: Annual Report 2016. Uppsala: Uppsala University
Open this publication in new window or tab >>Department of Medical Cell Biology: Annual Report 2016
2017 (English)Collection (editor) (Other academic)
Place, publisher, year, edition, pages
Uppsala: Uppsala University, 2017. p. 91
Series
Annual Reports - Department of Medical Cell Biology
Keywords
Annual report
National Category
Cell and Molecular Biology Physiology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-326291 (URN)
Available from: 2017-07-05 Created: 2017-07-05 Last updated: 2018-01-13Bibliographically approved
Krizhanovskii, C., Kristinsson, H., Elksnis, A., Wang, X., Gavali, H., Bergsten, P., . . . Welsh, N. (2017). EndoC-beta H1 cells display increased sensitivity to sodium palmitate when cultured in DMEM/F12 medium. Islets, 9(3), 43-48
Open this publication in new window or tab >>EndoC-beta H1 cells display increased sensitivity to sodium palmitate when cultured in DMEM/F12 medium
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2017 (English)In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 9, no 3, p. 43-48Article in journal (Refereed) Published
Abstract [en]

Aims - Human pancreatic islets are known to die in response to the free fatty acid of sodium palmitate when cultured in vitro. This is in contrast to EndoC-beta H1 cells, which in our hands are not sensitive to the cell death-inducing effects sodium palmitate, making these cells seemingly unsuitable for lipotoxicity studies. However, the EndoC-beta H1 cells are routinely cultured in a nutrient mixture based on Dulbecco's Modified Eagle Medium (DMEM), which may not be the optimal choice for studies dealing with lipotoxicity. The aim of the present investigation was to define culture conditions that render EndoC-beta H1 cells sensitive to toxic effects of sodium palmitate. Methods - EndoC-beta H1 cells were cultured at standard conditions in either DMEM or DMEM/F12 culture medium. Cell death was analyzed using propidium iodide staining and flow cytometry. Insulin release and content was quantified using a human insulin ELISA. Results - We presently observe that substitution of DMEM for a DMEM/Ham's F12 mixture (50%/50% vol/vol) renders the cells sensitive to the apoptotic effects of sodium palmitate and sodium palmitate + high glucose leading to an increased cell death. Supplementation of the DMEM culture medium with linoleic acid partially mimicked the effect of DMEM/F12. Culture of EndoC-beta H1 cells in DMEM/F12 resulted also in increased proliferation, ROS production and insulin contents, but markers for metabolic stress, autophagy or amyloid deposits were unaffected. Conclusions - The culture conditions for EndoC-beta H1 cells can be modified so these cells display signs of lipotoxicity in response to sodium palmitate.

Keywords
cell death, EndoC-beta H1 cells, insulin, ROS production, sodium palmitate
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-331910 (URN)10.1080/19382014.2017.1296995 (DOI)000405586500001 ()
Funder
EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes AssociationSwedish Child Diabetes Foundation
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2017-10-23Bibliographically approved
Turpaev, K. & Welsh, N. (2016). Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines. European Journal of Pharmacology, 784, 69-80
Open this publication in new window or tab >>Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines
2016 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 784, p. 69-80Article in journal (Refereed) Published
Abstract [en]

We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin producing beta TC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in beta TC6 and counteract to impairments of glucose stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells. Nrf2 up-regulation and HO-1 induction by AG-126 are attenuated at the presence of siRNA against Nrf2 and brusatol, an inhibitor of the Nrf2 signaling pathway. Our present results indicate that in respect of inhibition of IL-1 beta-dependent iNOS induction, beta TC6 cells are more sensitive to EMK 1071 (2-((5-methylthiophen-2-yl) methylene)malononitrile) and EMK 31 (2-(4-hydroxy-3-methoxybenzylidene)malononitrile) as compared to other analyzed AMN compounds. We suggest that the ability of AMN compounds to inhibit iNOS induction and other cytokine-induced transcriptional events might be a tool to achieve improved beta-cell survival and functionality.

Keywords
beta-cells, Oxidative stress, Aromatic malononitriles, Heme oxygenase 1, iNOS, Nrf2
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-300432 (URN)10.1016/j.ejphar.2016.05.010 (DOI)000379653600008 ()27178899 (PubMedID)
Funder
Swedish Diabetes Association, DIA 2014050
Available from: 2016-08-09 Created: 2016-08-09 Last updated: 2018-01-10Bibliographically approved
Welsh, N. (Ed.). (2016). Department of Medical Cell Biology: Annual Report 2015. Uppsala: Uppsala University
Open this publication in new window or tab >>Department of Medical Cell Biology: Annual Report 2015
2016 (English)Collection (editor) (Other (popular science, discussion, etc.))
Place, publisher, year, edition, pages
Uppsala: Uppsala University, 2016. p. 88
Series
Annual Reports - Department of Medical Cell Biology
National Category
Cell and Molecular Biology Physiology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-315739 (URN)
Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2018-01-13Bibliographically approved
King, A. J. F., Griffiths, L. A., Persaud, S. J., Jones, P. M., Howell, S. L. & Welsh, N. (2016). Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome. Upsala Journal of Medical Sciences, 121(2), 140-145
Open this publication in new window or tab >>Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome
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2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 140-145Article in journal (Refereed) Published
Abstract [en]

Introduction Improving islet transplantation outcome could not only bring benefits to individual patients but also widen the patient pool to which this life-changing treatment is available. Imatinib has previously been shown to protect beta cells from apoptosis in a variety of in vitro and in vivo models. The aim of this study was to investigate whether imatinib could be used to improve islet transplantation outcome. Methods Islets were isolated from C57BI/6 mice and pre-cultured with imatinib prior to exposure to streptozotocin and cytokines in vitro. Cell viability and glucose-induced insulin secretion were measured. For transplantation experiments, islets were pre-cultured with imatinib for either 72 h or 24 h prior to transplantation into streptozotocin-diabetic C57BI/6 mice. In one experimental series mice were also administered imatinib after islet transplantation. Results Imatinib partially protected islets from beta cell death in vitro. However, pre-culturing islets in imatinib or administering the drug to the mice in the days following islet transplantation did not improve blood glucose concentrations more than control-cultured islets. Conclusion Although imatinib protected against beta cell death from cytokines and streptozotocin in vitro, it did not significantly improve syngeneic islet transplantation outcome.

Keywords
Imatinib, islet, transplantation
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-298912 (URN)10.3109/03009734.2016.1151090 (DOI)000376695600009 ()26953716 (PubMedID)
Available from: 2016-07-12 Created: 2016-07-12 Last updated: 2018-01-10Bibliographically approved
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