| 1. |
- Bachar-Wikstrom, Etty, et al.
(författare)
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Darier disease is associated with heart failure : a cross-sectional case-control and population based study
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in heart disease is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum Ca2+ ATPase isoform 2 (SERCA2), which causes calcium dyshomeostasis and ER stress. We hypothesized that DD patients would have an increased risk for common heart disease. We performed a cross-sectional case-control clinical study on 25 DD patients and 25 matched controls; and a population-based cohort study on 935 subjects with DD and matched comparison subjects. Main outcomes and measures were N-terminal pro-brain natriuretic peptide, ECG and heart diagnosis (myocardial infarction, heart failure and arrythmia). DD subjects showed normal clinical heart phenotype including heart failure markers and ECG. The risk for heart failure was 1.59 (1,16-2,19) times elevated in DD subjects, while no major differences were found in myocardial infarcation or arrhythmias. Risk for heart failure when corrected for cardivascular risk factors or alcohol misuse was 1.53 (1.11-2.11) and 1.58 (1,15-2,18) respectively. Notably, heart failure occurred several years earlier in DD patients as compared to controls. We conclude that DD patients show a disease specific increased risk of heart failure which should be taken into account in patient management. The observation also strenghtens the clinical evidence on the important role of SERCA2 in heart failure pathophysiology.
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| 2. |
- Bachar-Wikstrom, Etty, et al.
(författare)
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Identification of Novel Glycans in the Mucus Layer of Shark and Skate Skin
- 2023
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Ingår i: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 24:18
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Tidskriftsartikel (refereegranskat)abstract
- The mucus layer covering the skin of fish has several roles, including protection against pathogens and mechanical damage. While the mucus layers of various bony fish species have been investigated, the composition and glycan profiles of shark skin mucus remain relatively unexplored. In this pilot study, we aimed to explore the structure and composition of shark skin mucus through histological analysis and glycan profiling. Histological examination of skin samples from Atlantic spiny dogfish (Squalus acanthias) sharks and chain catsharks (Scyliorhinus retifer) revealed distinct mucin-producing cells and a mucus layer, indicating the presence of a functional mucus layer similar to bony fish mucus albeit thinner. Glycan profiling using liquid chromatography-electrospray ionization tandem mass spectrometry unveiled a diverse repertoire of mostly O-glycans in the mucus of the two sharks as well as little skate (Leucoraja erinacea). Elasmobranch glycans differ significantly from bony fish, especially in being more sulfated, and some bear resemblance to human glycans, such as gastric mucin O-glycans and H blood group-type glycans. This study contributes to the concept of shark skin having unique properties and provides a foundation for further research into the functional roles and potential biomedical implications of shark skin mucus glycans.
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| 3. |
- Bachar-Wikstrom, Etty, et al.
(författare)
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Mass Spectrometry Analysis of Shark Skin Proteins
- 2023
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Ingår i: International Journal of Molecular Sciences. - 1661-6596 .- 1422-0067. ; 24:23
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Tidskriftsartikel (refereegranskat)abstract
- The mucus layer covering the skin of fish has several roles, including protection against pathogens and mechanical damage in which proteins play a key role. While proteins in the skin mucus layer of various common bony fish species have been explored, the proteins of shark skin mucus remain unexplored. In this pilot study, we examine the protein composition of the skin mucus in spiny dogfish sharks and chain catsharks through mass spectrometry (NanoLC-MS/MS). Overall, we identified 206 and 72 proteins in spiny dogfish (Squalus acanthias) and chain catsharks (Scyliorhinus retifer), respectively. Categorization showed that the proteins belonged to diverse biological processes and that most proteins were cellular albeit a significant minority were secreted, indicative of mucosal immune roles. The secreted proteins are reviewed in detail with emphasis on their immune potentials. Moreover, STRING protein–protein association network analysis showed that proteins of closely related shark species were more similar as compared to a more distantly related shark and a bony fish, although there were also significant overlaps. This study contributes to the growing field of molecular shark studies and provides a foundation for further research into the functional roles and potential human biomedical implications of shark skin mucus proteins.
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| 4. |
- Curman, Philip, et al.
(författare)
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Darier disease is associated with neurodegenerative disorders and epilepsy
- 2024
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments.
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| 5. |
- Curman, Philip, et al.
(författare)
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Hailey-Hailey Disease is Associated with Diabetes : A Population-based Cohort Study, Clinical Cohort Study, and Pedigree Analysis
- 2023
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden. - 0001-5555 .- 1651-2057. ; 103
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Tidskriftsartikel (refereegranskat)abstract
- Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey disease was performed to assess the risks of type 1 diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology.
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| 6. |
- Herter, Eva K., et al.
(författare)
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WAKMAR2, a Long Noncoding RNA Downregulated in Human Chronic Wounds, Modulates Keratinocyte Motility and Production of Inflammatory Chemokines
- 2019
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Ingår i: Journal of Investigative Dermatology. - : ELSEVIER SCIENCE INC. - 0022-202X .- 1523-1747. ; 139:6, s. 1373-1384
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Tidskriftsartikel (refereegranskat)abstract
- Chronic wounds represent a major and growing health and economic burden worldwide. A better understanding of molecular mechanisms of normal as well as impaired wound healing is needed to develop effective treatment. Herein we studied the potential role of long noncoding RNA LOC100130476 in skin wound repair. LOC100130476 is an RNA polymerase IIeencoded polyadenylated transcript present in both cytoplasm and nucleus. We found that its expression was lower in wound-edge keratinocytes of human chronic wounds compared to normal wounds of healthy donors and intact skin. In cultured keratinocytes, LOC100130476 expression was induced by TGF-beta signaling. By reducing LOC100130476 expression with antisense oligos or activating its transcription with CRISPR/Cas9 Synergistic Activation Mediator system, we showed that LOC100130476 restricted the production of inflammatory chemokines by keratinocytes, while enhancing cell migration. In line with this, knockdown of LOC100130476 impaired re-epithelization of human ex vivo wounds. Based on these results, we named LOC100130476 wound and keratinocyte migration-associated long noncoding RNA 2 (WAKMAR2). Moreover, we identified a molecular network that may mediate the biological function of WAKMAR2 in keratinocytes using microarray. In summary, our data suggest that WAKMAR2 is an important regulator of skin wound healing and its deficiency may contribute to the pathogenesis of chronic wounds.
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| 7. |
- Leong, Ivone U. S., et al.
(författare)
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Novel mutations in Darier disease and association to self-reported disease severity
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Darier disease is a rare and severe autosomal dominant skin disease characterised by malodorous keratotic papules in seborrheic areas of the skin. Darier disease affects up to 1 in 30 000 people and is caused by mutations in the ATP2A2 gene, which encodes to the sarco/endoplasmic reticulum calcium-ATPase isoform 2 that pumps calcium into the endoplasmic reticulum. Although many ATP2A2 variants have been described, it is not known if genotype correlates with phenotype, which could be important for prognosis and treatment. This is the first study to use whole exome sequencing to screen the ATP2A2 gene in a cohort of 28 clinically diagnosed Darier disease patients. Twenty-one different disease causing variants were identified and 15 of these were novel. Sixteen of the 21 variants were predicted to be pathogenic using in silico prediction programs. There were seven missense, four intronic/splice-sites, three frameshifts, two in-frame deletions, four nonsense and one synonymous mutations. This study also found ten patients who harbour more than one ATP2A2 variant. The phenotype of the patient cohort was assessed by photography and by patient questionnaires. The genotype-phenotype association was examined for all variants in relation to the patient's disease severity score, and no correlation could be established.
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| 8. |
- Li, Dongqing, et al.
(författare)
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Human skin long noncoding RNA WAKMAR1 regulates wound healing by enhancing keratinocyte migration
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:19, s. 9443-9452
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-beta signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed "wound and keratinocyte migration-associated lncRNA 1" (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds.
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| 9. |
- Wikstrom, Jakob D, 1978-
(författare)
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Brown adipocyte activation is characterized by a wave of mitochondrial fission and depolarization that is dependent on β3 receptor stimulation and Drp1, and is characterized by complete, but reversible, arrest of fusion
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Mitochondria are dynamic organelles that frequently undergo fusion and fission. Mitochondrial dynamics has been shown to be essential for a variety of cellular functions and its abrogation has been associated with several diseases. However, the role fusion, fission and architecture play in mitochondrial bioenergetics is still not well understood. Brown adipose tissue (BAT) is a mitochondria dense organ that converts cellular fuels into heat by mitochondrial uncoupling. When activated adrenergically, BAT shows a unique increase in mitochondrial respiratory activity. Therefore, BAT may be a good model to study the interdependence between mitochondrial morphology, dynamics and function. To date, mitochondrial dynamics was not studied in BAT. In this study we set out to examine mitochondrial morphology in BAT and test the hypothesis that mitochondrial morphology is of importance for BAT function. Materials and methods: BAT was harvested from 3 to 4-week-old wild-type male C57BL6/J mice and from 5-8 day old pups (Mitofusin2 knockout). Brown adipocytes were differentiated in vitro. A LSM 710 laser scanning confocal microscopy (Zeiss) was used for imaging of mitochondrial morphology using several fluorescent dyes and proteins. Oxygen consumption was measured using the XF24 platform (Seahorse Bioscience). The pro fusion protein Mfn2 was knocked out under the AP2 promoter and the pro fission protein Drp1 was inhibited with adenoviral expression of its dominant negative form. Results: Mitochondria were found to be highly networked and dependent on mitochondrial dynamics proteins. When stimulating cells with a combination of norepinephrine and free fatty acids we found a synergistic response that included a marked increase in oxygen consumption rates and mitochondrial membrane potential (Δψm) depolarization. Somewhat unexpectedly it was also found that mitochondria in parallel underwent a distinct fragmentation. The fragmented mitochondria appeared sphere-like and had dampened fusion; however cells regained normal function as well as mitochondrial morphology and Δψm within 24h. Interestingly, Δψm depolarized and mitochondria fragmented in a wave-like fashion where depolarization preceded fragmentation. Inhibition of the pro-fission protein Drp1 was found to inhibit the synergistic response, while knock-out of the pro-fusion protein Mfn2 did not. Thus, mitochondrial fission appeared essential for proper BAT function. Finally, we found the synergistic response to go through the β-adrenergic pathway and be dependent on reactive oxygen species but not on Ca++, permeability transition pore or uncoupling protein 1 expression levels. Conclusion: Taken together, these findings suggest that mitochondrial morphology in general and mitochondrial fission in particular may play an important physiological role in BA. Future studies will reveal if this may represent a therapeutic target for manipulating BAT activity.
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| 10. |
- Wikstrom, Jakob D, 1978-
(författare)
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Islet bioenergetic efficiency is regulated by nutrients
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims Excessive or unbalanced nutrient intake may cause diabetes. A growing body of evidence points to that mitochondrial dysfunction plays an important role in Materials and methods To enable the study we developed a high-throughput islet respirometry approach based on the XF24 platform, originally designed to study monolayers of cells. By applying drugs that act on the respiratory chain we can estimate the level of fuel-stimulated, uncoupled (reflecting proton leak), maximal as well as non-mitochondrial respiration under various conditions. Islets were derived from wildtype and high fat diet fed C57Bl6/J mice as well as from human donors. β-cell dysfunction. The reason for this is likely that mitochondria stand in the center of nutrient metabolism. In this study we tested the hypothesis that islets from diabetic animals have defect mitochondrial respiratory function. Results We found that due to increased proton leak, islets from diabetic high fat diet fed animals exhibit lower respiratory efficiency as compared to animals fed control chow. Examining the regulation of the leak we found that fuels that stimulate insulin secretion also increase uncoupled respiration, and that this may be mediated by reactive oxygen species. Moreover, dissecting the molecular mechanism, we show that the adenine nucleotide transporter contributes to one-third of the leak while uncoupling protein 2 and permeability transition pore appear not to contribute. Finally, we examined a cohort of human islets and found lower levels of uncoupled respiration as compared to mouse islets. However, as in the mouse islets glucose challenge induced increase in uncoupled respiration. Interestingly, there was a trend towards lower oxygen consumption rates in islets from obese donors. Conclusion: Islets have relative high levels of proton leak, which is regulated by cellular fuels and reactive oxygen species. Adenine nucleotide transporter but not uncoupling protein 2 or permeability transition pore appears to contribute to the observed uncoupled respiration. Interestingly, levels of uncoupled respiration increase in a diabetes animal model. In theory, tuning islet mitochondrial efficiency may represent a therapeutic target.
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