| 1. |
- Adam, Julie, et al.
(författare)
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Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:13, s. 3135-3148
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Tidskriftsartikel (refereegranskat)abstract
- We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic β cells (Fh1βKO mice) appear normal for 6–8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1α or Nrf2. Progressive hyperglycemia in Fh1βKO mice led to dysregulated metabolism in β cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+]i elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1βKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D. Adam et al. have shown that progressive diabetes develops if fumarate hydratase is deleted in mouse pancreatic β cells. Such β cells exhibit elevated fumarate and protein succination and show progressively reduced ATP production and insulin secretion. The depleted insulin response to glucose recovers when diabetic islets are cultured in reduced glucose.
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| 2. |
- Ahmed Khandker, Meftun, et al.
(författare)
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Mitochondrial proteome analysis reveals altered expression of voltage dependent anion channels in pancreatic beta-cells exposed to high glucose
- 2010
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Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 2:5, s. 283-292
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Tidskriftsartikel (refereegranskat)abstract
- Chronic hyperglycemia leads to deterioration of insulin release from pancreatic beta-cells as well as insulin action on peripheral tissues. However, the mechanism underlying beta-cell dysfunction resulting from glucose toxicity has not been fully elucidated. The aim of the present study was to define a set of alterations in mitochondrial protein profiles of pancreatic beta-cell line in response to glucotoxic condition using 2-DE and tandem mass spectrometry. INS1E cells were incubated in the presence of 5.5 and 20 mM glucose for 72 hrs and mitochondria were isolated. Approximately 75 protein spots displayed significant changes (p < 0.05) in relative abundance in the presence of 20 mM glucose compared to controls. Mitochondrial proteins downregulated under glucotoxic conditions includes ATP synthase a chain and delta chain, malate dehydrogenase, aconitase, trifunctional enzyme beta subunit, NADH-cytochrome b5 reductase and voltage-dependent anion-selective channel protein (VDAC) 2. VDAC 1, 75 kDa glucose-regulated protein, heat shock protein (HSP) 60 and HSP10 were found to be upregulated. The orchestrated changes in expression of VDACs and multiple other proteins involved in nutrient metabolism, ATP synthesis, cellular defense, glycoprotein folding and mitochondrial DNA stability may explain cellular dysfunction in glucotoxicity resulting in altered insulin secretion.
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| 3. |
- Brænne, Ingrid, et al.
(författare)
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A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.
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| 4. |
- Dwane, Lisa, et al.
(författare)
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A Functional Genomic Screen Identifies the Deubiquitinase USP11 as a Novel Transcriptional Regulator of ERα in Breast Cancer
- 2020
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Ingår i: Cancer Research. - 1538-7445. ; 80:22, s. 5076-5088
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 70% of breast cancers express estrogen receptor α (ERα) and depend on this key transcriptional regulator for proliferation and differentiation. While patients with this disease can be treated with targeted antiendocrine agents, drug resistance remains a significant issue, with almost half of patients ultimately relapsing. Elucidating the mechanisms that control ERα function may further our understanding of breast carcinogenesis and reveal new therapeutic opportunities. Here, we investigated the role of deubiquitinases (DUB) in regulating ERα in breast cancer. An RNAi loss-of-function screen in breast cancer cells targeting all DUBs identified USP11 as a regulator of ERα transcriptional activity, which was further validated by assessment of direct transcriptional targets of ERα. USP11 expression was induced by estradiol, an effect that was blocked by tamoxifen and not observed in ERα-negative cells. Mass spectrometry revealed a significant change to the proteome and ubiquitinome in USP11-knockdown (KD) cells in the presence of estradiol. RNA sequencing in LCC1 USP11-KD cells revealed significant suppression of cell-cycle-associated and ERα target genes, phenotypes that were not observed in LCC9 USP11-KD, antiendocrine-resistant cells. In a breast cancer patient cohort coupled with in silico analysis of publicly available cohorts, high expression of USP11 was significantly associated with poor survival in ERα-positive (ERα+) patients. Overall, this study highlights a novel role for USP11 in the regulation of ERα activity, where USP11 may represent a prognostic marker in ERα+ breast cancer. SIGNIFICANCE: A newly identified role for USP11 in ERα transcriptional activity represents a novel mechanism of ERα regulation and a pathway to be exploited for the management of ER-positive breast cancer.
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| 5. |
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| 6. |
- Iglesias-Gato, Diego, et al.
(författare)
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OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo
- 2015
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Ingår i: Molecular Cancer. - : BioMed Central (BMC). - 1476-4598. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background:Ubiquitination is a highly dynamic and reversible process with a central role in cell homeostasis. Deregulation of several deubiquitinating enzymes has been linked to tumor development but their specific role in prostate cancer progression remains unexplored.Methods:RNAi screening was used to investigate the role of the ovarian tumor proteases (OTU) family of deubiquitinating enzymes on the proliferation and invasion capacity of prostate cancer cells. RhoA activity was measured in relation with OTUB1 effects on prostate cancer cell invasion. Tumor xenograft mouse model with stable OTUB1 knockdown was used to investigate OTUB1 influence in tumor growth.Results:Our RNAi screening identified OTUB1 as an important regulator of prostate cancer cell invasion through the modulation of RhoA activation. The effect of OTUB1 on RhoA activation is important for androgen-induced repression of p53 expression in prostate cancer cells. In localized prostate cancer tumors OTUB1 was found overexpressed as compared to normal prostatic epithelial cells. Prostate cancer xenografts expressing reduced levels of OTUB1 exhibit reduced tumor growth and reduced metastatic dissemination in vivo.Conclusions:OTUB1 mediates prostate cancer cell invasion through RhoA activation and promotes tumorigenesis in vivo. Our results suggest that drugs targeting the catalytic activity of OTUB1 could potentially be used as therapeutics for metastatic prostate cancer.
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| 7. |
- Moussa, Ehab, et al.
(författare)
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Proteomic profiling of the brain of mice with experimental cerebral malaria
- 2018
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 180, s. 61-69
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral malaria (CM) is a severe neurological complication of malaria infection in both adults and children. In pursuit of effective treatment of CM, clinical studies, postmortem analysis and animal models have been employed to understand the pathology and identify effective interventions. In this study, a shotgun proteomics analysis was conducted to profile the proteomic signature of the brain tissue of mice with experimental cerebral malaria (ECM) in order to further understand the underlying pathology. To identify CM-associated response, proteomic signatures of the brains of C57/Bl6N mice infected with P. berghei ANKA that developed neurological syndrome were compared to those of mice infected with P. berghei NK65 that developed equally high parasite burdens without neurological signs, and to those of non-infected mice. The results show that the CM-associated response in mice that developed neurological signs comprise mainly acute-phase reaction and coagulation cascade activation, and indicate the leakage of plasma proteins into the brain parenchyma. SIGNIFICANCE: Cerebral malaria (CM) remains a major cause of death in children. The majority of these deaths occur in sub-Saharan Africa. Even with adequate access to treatment, mortality remains high and neurological sequelae can be found in up to 20% of survivors. No adjuvant treatment to date has been shown to reduce mortality and the pathophysiology of CM is largely unknown. Experimental cerebral malaria (ECM) is a well-established model that may contribute to identify and test druggable targets. In this study we have identified the disruption of the blood-brain barrier following inflammatory and vascular injury as a mechanism of disease. In this study we report a number of proteins that could be validated as potential biomarkers of ECM. Further studies, will be required to validate the clinical relevance of these biomarkers in human CM.
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| 8. |
- Seisenbaeva, Gulaim, et al.
(författare)
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Structural characterization, solution stability, and potential health and environmental effects of the Nano-TiO2 bioencapsulation matrix and the model product of its biodegradation TiBALDH
- 2012
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 2, s. 4228-4235
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Tidskriftsartikel (refereegranskat)abstract
- Dispersions of small TiO2 nanoparticles in alcohol, stabilized by surface complexation with protonated triethanolamine ligands, are proposed as bio-encapsulation matrices. They were characterized by TEM and EXAFS spectroscopy, and DLS was used to investigate the nanoparticles stability over time in their pure form and after insertion into aqueous medium. This study reveals unusual structural features that explain the recently demonstrated facile formation of dense encapsulates on the surface of biological objects. In the view of the potentially broad application of this already industrially available material in agriculture as an encapsulation matrix for biocontrol organisms, its potential health and environmental effects were characterized by employing a number of model systems. The potential health effects of the produced stable aqueous dispersions were studied in vitro using A549 and U1810 lung carcinoma cell lines. The nanotitania in the environment is partly bio-digested with the formation of citrate and lactate complexes. The effects on the growth of tobacco pollen grains by the nanotitania and of the ammonium lactato-oxo-titanate (TiBALDH, a product already broadly used in biomineralization studies) were investigated to gain insight into the impact of these materials on the environment and specifically on plant reproduction. TiBALDH was used as a model product of the bio-digestion and its structure has been probed in this work by X-ray powder diffraction and EXAFS spectroscopy. No acute negative bio-effects could be observed for the studied materials at significantly high concentrations, such as 50 mu g ml(-1) for the viability of human lung cancer cells and up to about 120 mu g ml(-1) for the growth of pollen grains, corresponding to the conditions of proposed field applications. This observation was contrasted by the apparently high toxicity of the LaAlO3 based nanophosphor which was applied as a positive control.
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| 9. |
- Zhang, Ming, et al.
(författare)
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Identification of the target self-antigens in reperfusion injury.
- 2006
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 203:1, s. 141-52
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Tidskriftsartikel (refereegranskat)abstract
- Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction.
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