| 1. |
- Dawed, Adem Y., et al.
(author)
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Pharmacogenomics of GLP-1 receptor agonists : a genome- wide analysis of observational data and large randomised controlled trials
- 2023
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In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 11:1, s. 33-41
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Journal article (peer-reviewed)abstract
- Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods:In this genome-wide analysis we included adults (aged & GE;18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings:4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G & RARR;A (Gly168Ser) in the GLP1R (0.08% [95% CI 0.04-0.12] or 0.9 mmol/mol lower reduction in HbA1c per serine, p=6.0 x 10-5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10-8), largely driven by rs140226575G & RARR;A (Thr370Met; 0.25% [SE 0.06] or 2.7 mmol/mol [SE 0.7] greater HbA1c reduction per methionine, p=5.2 x 10-6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation:This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.
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| 2. |
- Elksnis, Andris, et al.
(author)
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Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK
- 2021
-
In: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 135:19, s. 2243-2263
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Journal article (peer-reviewed)abstract
- The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against islet amyloid polypeptide (IAPP)-aggregation, thioredoxin interacting protein (TXNIP) up-regulation and beta-cell death. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme enoyl coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1). In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and acyl-CoA carboxylase (ACC) phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP down-regulation, which in turn protects against beta-cell death.
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| 3. |
- Wang, Xuan, 1984-, et al.
(author)
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ZBED6 counteracts high-fat diet-induced glucose intolerance by maintaining beta cell area and reducing excess mitochondrial activation
- 2021
-
In: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 64:10, s. 2292-2305
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Journal article (peer-reviewed)abstract
- Aims/hypothesisZBED6 (zinc finger, BED-type containing 6) is known to regulate muscle mass by suppression of Igf2 gene transcription. In insulin-producing cell lines, ZBED6 maintains proliferative capacity at the expense of differentiation and beta cell function. The aim was to study the impact of Zbed6 knockout on beta cell function and glucose tolerance in C57BL/6 mice.MethodsBeta cell area and proliferation were determined in Zbed6 knockout mice using immunohistochemical analysis. Muscle and fat distribution were assessed using micro-computed tomography. Islet gene expression was assessed by RNA sequencing. Effects of a high-fat diet were analysed by glucose tolerance and insulin tolerance tests. ZBED6 was overexpressed in EndoC-βH1 cells and human islet cells using an adenoviral vector. Beta cell cell-cycle analysis, insulin release and mitochondrial function were studied in vitro using propidium iodide staining and flow cytometry, ELISA, the Seahorse technique, and the fluorescent probes JC-1 and MitoSox.ResultsIslets from Zbed6 knockout mice showed lowered expression of the cell cycle gene Pttg1, decreased beta cell proliferation and decreased beta cell area, which occurred independently from ZBED6 effects on Igf2 gene expression. Zbed6 knockout mice, but not wild-type mice, developed glucose intolerance when given a high-fat diet. The high-fat diet Zbed6 knockout islets displayed upregulated expression of oxidative phosphorylation genes and genes associated with beta cell differentiation. In vitro, ZBED6 overexpression resulted in increased EndoC-βH1 cell proliferation and a reduced glucose-stimulated insulin release in human islets. ZBED6 also reduced mitochondrial JC-1 J-aggregate formation, mitochondrial oxygen consumption rates (OCR) and mitochondrial reactive oxygen species (ROS) production, both at basal and palmitate + high glucose-stimulated conditions. ZBED6-induced inhibition of OCR was not rescued by IGF2 addition. ZBED6 reduced levels of the mitochondrial regulator PPAR-γ related coactivator 1 protein (PRC) and bound its promoter/enhancer region. Knockdown of PRC resulted in a lowered OCR.Conclusions/interpretationIt is concluded that ZBED6 is required for normal beta cell replication and also limits excessive beta cell mitochondrial activation in response to an increased functional demand. ZBED6 may act, at least in part, by restricting PRC-mediated mitochondrial activation/ROS production, which may lead to protection against beta cell dysfunction and glucose intolerance in vivo.
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| 4. |
- Krizhanovskii, Camilla, et al.
(author)
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EndoC-beta H1 cells display increased sensitivity to sodium palmitate when cultured in DMEM/F12 medium
- 2017
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In: Islets. - : Informa UK Limited. - 1938-2014 .- 1938-2022. ; 9:3, s. 43-48
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Journal article (peer-reviewed)abstract
- 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.
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| 5. |
- Li, Yonghong, et al.
(author)
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Novel strains with superior degrading efficiency for lincomycin manufacturing biowaste
- 2021
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In: Ecotoxicology and Environmental Safety. - : Elsevier BV. - 1090-2414 .- 0147-6513. ; 209
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Journal article (peer-reviewed)abstract
- As the antibiotic pollution source in the environment, a large amount of biowastes generated from antibiotic fermentation manufacture needs proper disposal. Recycling the biowaste as resources and nutrients is of great interest. Besides, degradation or removal of antibiotics is indispensable for the reclamation of antibiotic manufacturing biowaste. To establish environmentally friendly disposal strategies for lincomycin manufacturing biowaste (LMB), we screened the microbial strains that could efficiently degrade lincomycin from the antibiotic wastewater treatment plant. Among them, three novel strains were identified as Bacillus subtilis (strain LMB-A), Rhodotorula mucilaginosa (strain LMB-D) and Penicillium oxalicum (strain LMB-E), respectively. LMB-A and LMB-D could degrade 92.69% and 74.05% of lincomycin with an initial concentration of 1117.55 mg/L in 144 h, respectively. The lincomycin degradation products were formed by the breakage of amide bond or losing N-demethyl/thiomethyl group from the pyrrolidine/pyranose ringcata cata catalyzed by the strains. Moreover, LMB-A could decontaminate LMB, and the decontaminated LMB could be used as a nitrogen source to culture salt-resistant bacteria and other useful microorganisms. LMB-A and LMB-D have the potential to be used for the bioremediation of water and soil polluted by lincomycin and its analogs. LMB-E could degrade 88.20% LMB after 144-h cultivation. In summary, this study gives an insight into the green disposal of LMB, and the established strategy has potential application for biotreatment of other antibiotic fermentation manufacturing biowastes.
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| 6. |
- Nazemosadat Arsanjani, Seyedeh Bentolhoda, 1984, et al.
(author)
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Hot-Cavity Spectroscopy of Dark Pulse Kerr Combs in Microresonators
- 2019
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In: 2019 Conference on Lasers and Electro-Optics Europe and European Quantum Electronics Conference, CLEO/Europe-EQEC 2019. ; June 2019
-
Conference paper (peer-reviewed)abstract
- Kerr frequency combs are generated through cascaded four-wave mixing in high-Q microresonators [1]. These devices are pumped with a continuous-wave laser and modulational instability (MI) is responsible for the growth of the initial comb lines. Since it is easier to satisfy the MI phase matching condition in the anomalous dispersion regime, most studies on Kerr combs have focused on anomalous dispersion microresonators. However, coherent microresonator combs can also take place in the normal dispersion regime. In these combs, phase matching is attained with the aid of the mode coupling between transverse modes of the microresonator [2]. One particularly interesting comb state that operates in the normal dispersion regime is the dark pulse Kerr comb [3]. The time domain pulses of these combs arise as interlocking switching waves that connect the upper and lower homogenous steady state solutions of the bi-stability curve in the continuous-wave-driven Kerr cavity [see Fig. (a)] [3]. These combs are of high interest as most nonlinear materials suitable for fabricating microresonators display normal dispersion in the visible and near infrared ranges. Moreover, these combs provide a much higher power conversion efficiency compared to bright-soliton combs, which makes them particularly useful for telecommunications [4].
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| 7. |
- Nazemosadat Arsanjani, Seyedeh Bentolhoda, 1984, et al.
(author)
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Switching dynamics of dark-pulse Kerr frequency comb states in optical microresonators
- 2021
-
In: Physical Review A. - 2469-9934 .- 2469-9926. ; 103:1
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Journal article (peer-reviewed)abstract
- Dissipative Kerr solitons are localized structures that exist in nonlinear optical cavities. They lead to the formation of microcombs - chip-scale frequency combs that could facilitate precision frequency synthesis and metrology by capitalizing on advances in silicon photonics. Previous demonstrations have mainly focused on anomalous dispersion cavities. Notwithstanding, localized structures also exist in the normal dispersion regime in the form of circulating dark pulses, but their physical dynamics is far from being understood. Here, we explore dark-pulse Kerr combs generated in normal dispersion optical microresonators and report the discovery of reversible switching between coherent dark-pulse combs, whereby distinct states can be accessed deterministically. Furthermore, we reveal that the formation of dark-pulse Kerr combs is associated with the appearance of another resonance, a feature that has never been observed for dark pulses and is ascribed to soliton behavior. These results contribute to understanding the nonlinear physics in normal dispersion nonlinear cavities and provide insight into the generation of microcombs with high conversion efficiency.
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| 8. |
- Nazemosadat Arsanjani, Seyedeh Bentolhoda, 1984, et al.
(author)
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Switching Dynamics of Dark Solitons in Kerr Microresonators
- 2019
-
In: Optics InfoBase Conference Papers. - 2162-2701. ; paper ef_8_4
-
Conference paper (peer-reviewed)abstract
- Dissipative Kerr solitons (DKS) are localized structures in optical resonators that arise from a double balance between dispersion and Kerr effect, and linear loss and parametric gain [1]. The periodic nature of DKS corresponds to frequency combs. DKS can be generated in high-Q microresonators for diverse applications, from coherent communications to precision frequency synthesis [1]. Most studies of DKS have focused on microresonator cavities operating in the anomalous dispersion regime, where the waveforms correspond to bright soliton pulses. Coherent microresonator combs can also be formed in the normal dispersion regime [2]. The time-domain waveform corresponds to a localized dark-pulse structure, interpreted as two interlocked switching waves connecting the two branches of the bi-stability curve in continuous-wave-pumped Kerr resonators [2, 3]. Each switching wave connects the two branches following an oscillating behavior. These type of Kerr combs are relevant for practical applications because they display unusually high power-conversion efficiency [4, 5], but their physical dynamics remain largely unexplored. Here, we report the discovery of deterministic switching of dark pulse Kerr combs, where the number of oscillations that appear between the switching waves can be either increased or decreased one at a time. The switching dynamics observed here have intriguing similarities to the switching behavior of bright temporal solitons in anomalous dispersion microresonators [6], and they indicate that dark pulse Kerr combs arise as a complex interplay of dark solitons circulating in the cavity.
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| 9. |
- Ngamjariyawat, Anongnad, 1976-, et al.
(author)
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GDF15 Protects Insulin-Producing Beta Cells against Pro-Inflammatory Cytokines and Metabolic Stress via Increased Deamination of Intracellular Adenosine
- 2024
-
In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:2
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Journal article (peer-reviewed)abstract
- It has been proposed that antidiabetic drugs, such as metformin and imatinib, at least in part, promote improved glucose tolerance in type 2 diabetic patients via increased production of the inflammatory cytokine GDF15. This is supported by studies, performed in rodent cell lines and mouse models, in which the addition or production of GDF15 improved beta-cell function and survival. The aim of the present study was to determine whether human beta cells produce GDF15 in response to antidiabetic drugs and, if so, to further elucidate the mechanisms by which GDF15 modulates the function and survival of such cells. The effects and expression of GDF15 were analyzed in human insulin-producing EndoC-betaH1 cells and human islets. We observed that alpha and beta cells exhibit considerable heterogeneity in GDF15 immuno-positivity. The predominant form of GDF15 present in islet and EndoC-betaH1 cells was pro-GDF15. Imatinib, but not metformin, increased pro-GDF15 levels in EndoC-betaH1 cells. Under basal conditions, exogenous GDF15 increased human islet oxygen consumption rates. In EndoC-betaH1 cells and human islets, exogenous GDF15 partially ameliorated cytokine- or palmitate + high-glucose-induced loss of function and viability. GDF15-induced cell survival was paralleled by increased inosine levels, suggesting a more efficient disposal of intracellular adenosine. Knockdown of adenosine deaminase, the enzyme that converts adenosine to inosine, resulted in lowered inosine levels and loss of protection against cytokine- or palmitate + high-glucose-induced cell death. It is concluded that imatinib-induced GDF15 production may protect human beta cells partially against inflammatory and metabolic stress. Furthermore, it is possible that the GDF15-mediated activation of adenosine deaminase and the increased disposal of intracellular adenosine participate in protection against beta-cell death.
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| 10. |
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| 11. |
- Tang, Jinfeng, 1984, et al.
(author)
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Optimizing critical metals recovery and correlative decontamination from MSWI fly ash: Evaluation of an integrating two-step leaching hydrometallurgical process
- 2022
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In: Journal of Cleaner Production. - : Elsevier BV. - 0959-6526. ; 368
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Journal article (peer-reviewed)abstract
- While municipal solid waste incineration (MSWI) fly ash is classified as hazardous waste, it can also serve as an urban mining source for numerous precious metals. Of particular interest are antimony (Sb) and zinc (Zn); the former of which is a strategic and critical metal that is being rapidly depleted, putting society at high risk for supply shortages. In this work, a two-step leaching method for recovering Sb and Zn from MSWI fly ash is proposed. Furthermore, the leaching behavior and adsorption mechanism of Sb in the MSWI fly ash waste stream were also investigated. Results from the first constant pH leaching tests (CPLT) showed that under diluted acidic condition, the maximum amount of Sb released from fly ash was ∼20%. In addition, at pH 4.0, 67% of the fly ash was dissolved, while 79.3% and 12.1% of the Zn and Sb, respectively, were recovered. After optimizing and executing a second Sb leaching procedure (6 M HCl solution at 60 °C), >80% of the Sb was recovered. Thus, the proposed two-step leaching process, consisting of extraction followed by decontamination using a magnetic HAP@CoFe2O4 adsorbent, can eliminate the Sb in fly ash effluent with a removal efficiency >95%. Moreover, this process produces less toxic products and lowers the effluent residue concentration. As such, the two-step process described herein is suggested for Sb and Zn recovery from fly ash; as it not only enables precious metal recovery, but also aids in treating secondary waste streams produced from urban mining.
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| 12. |
- Turpaev, Kyril, et al.
(author)
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The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice : role of translation factor eIF5A hypusination
- 2019
-
In: The FASEB Journal. - : FEDERATION AMER SOC EXP BIOL. - 0892-6638 .- 1530-6860. ; 33:3, s. 3510-3522
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Journal article (peer-reviewed)abstract
- 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
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| 13. |
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| 14. |
- Wang, Xuan, 1984-, et al.
(author)
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Knock-down of ZBED6 in insulin-producing cells promotes N-cadherin junctions between beta-cells and neural crest stem cells in vitro
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- The role of the novel transcription factor ZBED6 for the adhesion/clustering of insulin-producing mouse MIN6 and βTC6 cells was investigated. Zbed6-silencing in the insulin producing cells resulted in increased three-dimensional cell-cell clustering and decreased adhesion to mouse laminin and human laminin 511. This was paralleled by a weaker focal adhesion kinase phosphorylation at laminin binding sites. Zbed6-silenced cells expressed less E-cadherin and more N-cadherin at cell-to-cell junctions. A strong ZBED6-binding site close to the N-cadherin gene transcription start site was observed. Three-dimensional clustering in Zbed6-silenced cells was prevented by an N-cadherin neutralizing antibody and by N-cadherin knockdown. Co-culture of neural crest stem cells (NCSCs) with Zbed6-silenced cells, but not with control cells, stimulated the outgrowth of NCSC processes. The cell-to-cell junctions between NCSCs and βTC6 cells stained more intensely for N-cadherin when Zbed6-silenced cells were co-cultured with NCSCs. We conclude that ZBED6 decreases the ratio between N- and E-cadherin. A lower N- to E-cadherin ratio may hamper the formation of three-dimensional beta-cell clusters and cell-to-cell junctions with NCSC, and instead promote efficient attachment to a laminin support and monolayer growth. Thus, by controlling beta-cell adhesion and cell-to-cell junctions, ZBED6 might play an important role in beta-cell differentiation, proliferation and survival.
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| 15. |
- Wang, Xuan, 1984-
(author)
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Study of the Proliferation, Function and Death of Insulin-Producing Beta-Cells in vitro: Role of the Transcription Factor ZBED6
- 2014
-
Doctoral thesis (other academic/artistic)abstract
- A thorough understanding of beta-cell proliferation, function, death and regeneration under normal condition as well as in the progression of diabetes is crucial to the conquest of this disease. The work presented in this thesis aimed to investigate the expression and role of a novel transcription factor, Zinc finger BED domain-containing protein 6 (ZBED6), in beta-cells.ZBED6 was present in mouse βTC-6 cells and human islets as a double nuclear band at 115/120 kDa and as a single cytoplasmic band at 95-100 kDa, which lacked N-terminal nuclear localization signals. Lentiviral shRNA-mediated stable silencing of ZBED6 in βTC-6 cells resulted in altered morphology, decreased proliferation, a partial S/G2 cell cycle arrest, increased expression of beta-cell specific genes, and higher rates of apoptosis. ChIP sequencing of human islets showed that ZBED6 binding was preferentially to genes that control transcription, macromolecule biosynthesis and apoptosis. We proposed that ZBED6 supported proliferation and survival of beta-cells, possibly at the expense of specialized beta-cell function, i.e. insulin production.To further investigate the role of ZBED6 in beta-cells, ChIP sequencing and whole transcriptome analysis were performed using MIN6 cells. More than 4000 putative target genes of ZBED6 were identified, including Pdx1, MafA and Nkx6.1. ZBED6-silencing resulted in differential expression of more than 700 genes, which was paralleled by an increase in the content and release of insulin in response to a high glucose concentration. Altered morphology/growth patterns as indicated by increased cell clustering were observed in ZBED6 silenced cells. We found also that ZBED6 decreased the ratio between N- and E-cadherin. A lower N- to E-cadherin ratio may hamper the formation of three-dimensional beta-cell clusters and cell-to-cell junctions with neural crest stem cells, and instead promote efficient attachment to a laminin support and monolayer growth. Thus, by controlling beta-cell adhesion and cell-to-cell junctions, ZBED6 might play an important role in beta-cell differentiation, proliferation and survival.
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| 16. |
- Wang, Xuan, 1984-, et al.
(author)
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The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro
- 2018
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In: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 13:9
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Journal article (peer-reviewed)abstract
- 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.
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| 17. |
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| 18. |
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| 19. |
- Wang, Xuan, 1984-, et al.
(author)
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ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells
- 2019
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In: The FASEB Journal. - : FEDERATION AMER SOC EXP BIOL. - 0892-6638 .- 1530-6860. ; 33:1, s. 88-100
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Journal article (peer-reviewed)abstract
- 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.
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| 20. |
- Wu, Yuan, et al.
(author)
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A Comparison of Functional Features in Chinese and US Mobile Apps for Diabetes Self-Management : A Systematic Search in App Stores and Content Analysis
- 2019
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In: JMIR mhealth and uhealth. - : JMIR PUBLICATIONS, INC. - 2291-5222. ; 7:8
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Journal article (peer-reviewed)abstract
- Background: Mobile health interventions are widely used for self-management of diabetes, which is one of the most burdensome noncommunicable chronic diseases worldwide. However, little is known about the distribution of characteristics and functions of in-store mobile apps for diabetes. Objective: This study aimed to investigate the distribution of characteristics and functions of the in-store mobile apps for self-management of diabetes in the United States and China using a predefined functional taxonomy, which was developed and published in our previous study. Methods: We identified apps by searching diabetes in English or Chinese in the Apple iTunes Store and Android Markets (both in the United States and China) and included apps for diabetes self-management. We examined the validity and reliability of the predefined functional taxonomy with 3 dimensions: clinical module, functional module, and potential risk. We then classified all functions in the included apps according to the predefined taxonomy and compared the differences in the features of these apps between the United States and China. Results: We included 171 mobile diabetes apps, with 133 from the United States and 38 from China. Apps from both countries faced the challenges of evidence-based information, proper risk assessment, and declaration, especially Chinese apps. More Chinese apps provide app-based communication functions (general communication: Chinese vs US apps, 39%, 15/38 vs 18.0%, 24/133; P=.006 and patient-clinician communication: Chinese vs US apps, 68%, 26/38 vs 6.0%, 8/133; P<.001), whereas more US apps provide the decision-making module (Chinese vs US apps, 0%, 0/38 vs 23.3%, 31/133; P=.001), which is a high-risk module. Both complication prevention (Chinese vs US apps, 8%, 3/38 vs 3.8%, 5/133; P=.50) and psychological care (Chinese vs US apps, 0%, 0/38 vs 0.8%, 1/133; P>.99) are neglected by the 2 countries. Conclusions: The distribution of characteristics and functions of in-store mobile apps for diabetes self-management in the United States was different from China. The design of in-store diabetes apps needs to be monitored closely.
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| 21. |
- Younis, Shady, et al.
(author)
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The importance of the ZBED6-IGF2 axis for metabolic regulation in mouse myoblast cells
- 2020
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In: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 34:8, s. 10250-10266
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Journal article (peer-reviewed)abstract
- The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5'-GGCTCG-3' in intron 1 of Igf2. Deletion of this motif (Igf2ΔGGCT ) or complete ablation of Zbed6 leads to ~20-fold upregulation of the IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2ΔGGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2ΔGGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 upregulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with an enrichment of upregulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities, and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2ΔGGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study adds new insights how the ZBED6-Igf2 axis affects muscle metabolism.
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| 22. |
- Zhang, Chenghui, et al.
(author)
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Circulating Tissue Factor-Positive Procoagulant Microparticles in Patients with Type 1 Diabetes
- 2019
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In: Diabetes, Metabolic Syndrome and Obesity. - : DOVE MEDICAL PRESS LTD. - 1178-7007. ; 12, s. 2819-2828
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Journal article (peer-reviewed)abstract
- Aim: To investigate the count of circulating tissue factor-positive (TF+) procoagulant microparticles (MPs) in patients with type 1 diabetes mellitus (T1DM).Methods: This case-control study included patients with T1DM and age and sex-matched healthy volunteers. The counts of phosphatidylserine-positive (PS+) MPs and TF(+)PS(+)MPs and the subgroups derived from different cell types were measured in the peripheral blood sample of the two groups using multicolor flow cytometric assay. We compared the counts of each MP between groups as well as the ratio of the TF(+)PS(+)MPs and PS(+)MPs (TF(+)PS(+)MPs/PS(+)MPs).Results: We recruited 36 patients with T1DM and 36 matched healthy controls. Compared with healthy volunteers, PS(+)MPs, TF(+)PS(+)MPs and TF(+)PS(+)MPs/PS(+)MPs were elevated in patients with T1DM (PS(+)MPs: 1078.5 +/- 158.08 vs 686.84 +/- 122.04/mu L, P <0.001; TF(+)PS(+)MPs: 202.10 +/- 47.47 vs 108.33 +/- 29.42/mu L, P <0.001; and TF(+)PS(+)MPs/PS(+)MPs: 0.16 +/- 0.04 vs 0.19 +/- 0.05, P = 0.004), mostly derived from platelet, lymphocytes and endothelial cells. In the subgroup analysis, the counts of total and platelet TF(+)PS(+)MPs were increased in patients with diabetic retinopathy (DR) and with higher HbA1c, respectively.Conclusion: Circulating TF(+)PS(+)MPs and those derived from platelet, lymphocytes and endothelial cells were elevated in patients with T1DM.
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