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Sökning: WFRF:(Törmä Hans)

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1.
  • Liu, Wei, et al. (författare)
  • Biosynthesis and function of all-trans- and 9-cis retinoic acid in parathyroid cells
  • 1996
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 229:3, s. 922-929
  • Tidskriftsartikel (refereegranskat)abstract
    • We demonstrate that cultured human and bovine parathyroid cells incubated with all-trans-[11,12-3H]-retinol convert this tracer into all-trans- and 9-cis-retinoic acid. By using RT-PCR, cellular retinol-binding protein type I (CRBP I), cellular retinoic acid binding protein I and II (CRABP I and II), retinoic acid receptors (RARs) alpha, beta and gamma, and 9-cis-retinoic acid receptor (RXR) alpha transcripts were detected in human parathyroid cDNA. CRBP I and CRABP I expression was confirmed by immunohistochemistry. Both 9-cis- and all-trans-RA were found to suppress parathyroid hormone (PTH) secretion from dispersed human adenomatous parathyroid cells, which was augmented by combined treatment with 1mM RA and 100 nM 1,25 (OH)2D3. The present data establish parathyroid gland as a target for retinoids and as a site of synthesis of the hormonal forms of vitamin A (retinol), all-trans- and 9-cis-retinoic acid.
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2.
  • Andersson, Eva, 1946-, et al. (författare)
  • Differential effects of UV irradiation on nuclear retinoid receptor levels in cultured keratinocytes and melanocytes
  • 2003
  • Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 12:5, s. 563-71
  • Tidskriftsartikel (refereegranskat)abstract
    • A major risk factor for skin cancer is UV irradiation, which not only damages DNA and other photosensitive compounds like vitamin A, but may also perturb cellular signaling, e.g. via the retinoid receptor system believed to be important for cancer protection. We used cultured normal human keratinocytes and melanocytes to examine the effects of UV irradiation on the expression of the predominant retinoid receptors in the human skin (RARalpha, RARgamma and RXRalpha) and the AP-1 protein c-Jun; mRNA levels were studied by real-time PCR and protein levels by Western blot. In keratinocytes, a single dose of UVB (50 mJ/cm2) caused a rapid drop in the expression of all three receptors (mRNA levels minus 35-50% after 4 h; protein levels minus 20-45% after 8 h), which was followed over the next 40 h by a variable response, leading to full normalization for RARalpha only. In contrast, the levels of c-Jun did not change significantly after UV exposure. In melanocytes, UVB caused a similar drop of the retinoid receptor levels as in keratinocytes but this was soon followed by an increased expression leading to a complete normalization of all receptor levels within 1-3 days. The c-Jun levels in melanocytes increased 1 day after UV exposure and remained high (plus 50%) thereafter. In both cell types, a approximately 3-fold increase in apoptosis (measured by DNA fragmentation) was observed 8-48 h after UVB irradiation. In conclusion, a depletion of vitamin A and retinoid receptors by UV irradiation, together with unchanged or even increased c-Jun levels, might seriously interfere with retinoid signaling and thus promote future tumor development, especially in keratinocytes.
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3.
  • Andersson, Eva, 1946-, et al. (författare)
  • Ultraviolet irradiation depletes cellular retinol and alters the metabolism of retinoic acid in cultured human keratinocytes and melanocytes
  • 1999
  • Ingår i: Melanoma research. - 0960-8931 .- 1473-5636. ; 9:4, s. 339-346
  • Tidskriftsartikel (refereegranskat)abstract
    • Vitamin A is an intrinsic modulator of proliferation and differentiation in human epidermis, and may be destroyed by ultraviolet radiation (UVR) impinging on the skin. To identify the deleterious effects of a perturbed cellular vitamin A status, we investigated the endogenous retinoid concentrations and the metabolism of [3H]retinol and all-trans [3H]retinoic acid in cultured human keratinocytes and melanocytes exposed to UVR, using high performance liquid chromatography. Before UVR the retinoid content was similar in keratinocytes and melanocytes, but the uptake of [3H]retinol was three-fold higher and the uptake of [3H]retinoic acid was 10-fold higher in the melanocytes. In both cell types, UVR (UVA 360 mJ/cm2 plus UVB 140 mJ/cm2) instantaneously reduced the concentration of retinol by about 50% and that of 3,4-didehydroretinol by about 20%. The retinoid concentrations returned to normal within 1-2 days post-irradiation, despite there being no overt increase in the uptake of [3H]retinol or the biosynthesis of 3,4-didehydroretinol. However, in both types of irradiated cells, the accumulation of the biologically most active metabolite, all-trans [3H]retinoic acid, was about 60% higher than in control cells. Furthermore, the metabolism of authentically supplied [3H]retinoic acid was reduced, especially in irradiated keratinocytes, which probably contributed to the restoration of retinoid levels after UV exposure.
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5.
  • Botling, Johan, et al. (författare)
  • Vitamin D3 and retinoic acid induced monocytic differentiation : Interactions between the endogenous vitamin D3, retinoic acid and retinoid X receptors in U-937 cells
  • 1996
  • Ingår i: Cell growth & differentiation. - 1044-9523. ; 7:9, s. 1239-49
  • Tidskriftsartikel (refereegranskat)abstract
    • Retinoic acid (RA) and 1,25 alpha-dihydroxycholecalciferol (VitD3) are potent regulators of hematopoletic differentiation. Yet, little is known as to how the RA and VitD3 receptor network operates in hematopoietic cells, and whether receptor interactions can explain the interplay between the RA- and VitD3-signaling pathways during differentiation. Therefore, we analyzed the expression, DNA binding, and transcriptional activity of the endogenous RA and VitD3 receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), and VitD3 receptor (VDR)] in the U-937 cell line, in which RA and VitD3 induce distinct monocytic differentiation pathways. VitD3 induction resulted in the formation of VDR/RXR DNA-binding complexes on both VitD3 response elements and RA response elements (RAREs). However, transcriptional activation was only observed from a VitD3 response element-driven reporter construct. Several DNA-binding complexes were detected on RAREs in undifferentiated cells. Stimulation by RA resulted in increased RAR beta/RXR DNA binding, activated RARE-dependent transcription, and increased expression of RAR-beta. Concomitant stimulation by VitD3 inhibited the RA-stimulated formation of RAR beta/RXR heterodimers, favoring VDR/RXR binding to the RARE. Also, VitD3 inhibited the expression of CD23 and CD49f, characteristic markers of retinoid-induced U-937 cell differentiation. In contrast, neither the RA-stimulated, RARE-mediated transcription nor the induced RAR-beta expression was suppressed by VitD3, suggesting that VitD3 selectively inhibited the retinoid-induced differentiation program but not the RARE-mediated signal. These results demonstrate a complex role for VitD3 in modifying the retinoid differentiation pathway and may have implications for differentiation-inducing therapy of hematopoietic tumors.
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6.
  • Buraczewska, Izabela, et al. (författare)
  • Changes in skin barrier function following long-term treatment with moisturizers, a randomized controlled trial
  • 2007
  • Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 156:3, s. 492-498
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Moisturizers are commonly used by patients with dry skin conditions as well as people with healthy skin. Previous studies on short-term treatment have shown that moisturizers can weaken or strengthen skin barrier function and also influence skin barrier recovery. However, knowledge of the effects on skin barrier function of long-term treatment with moisturizers is still scarce. OBJECTIVES: To investigate the impact of long-term treatment with moisturizers on the barrier function of normal skin, as measured by transepidermal water loss (TEWL) and susceptibility to an irritant, and to relate those effects to the composition of the designed experimental moisturizers. METHODS: Volunteers (n = 78) were randomized into five groups. Each group treated one volar forearm for 7 weeks with one of the following preparations: (i) one of three simplified creams, containing only a few ingredients in order to minimize the complexity of the system; (ii) a lipid-free gel; (iii) one ordinary cream, containing 5% urea, which has previously been shown to decrease TEWL. The lipids in the simplified creams were either hydrocarbons or vegetable triglyceride oil, and one of them also contained 5% urea. After 7 weeks, treated and control forearms were exposed for 24 h to sodium lauryl sulfate (SLS) using a patch test. TEWL, blood flow and skin capacitance of both SLS-exposed and undamaged skin were evaluated 24 h after removal of patches. Additionally, a 24-h irritancy patch test of all test preparations was performed on 11 volunteers in order to check their possible acute irritancy potential. RESULTS: Changes were found in the barrier function of normal skin after 7 weeks of treatment with the test preparations. The simplified creams and the lipid-free gel increased TEWL and skin response to SLS, while the ordinary cream had the opposite effect. One of the simplified creams also decreased skin capacitance. All test preparations were shown to be nonirritant, both by short-term irritancy patch test and by measurement of blood flow after long-term treatment. CONCLUSIONS: Moisturizers influence the skin barrier function of normal skin, as measured by TEWL and susceptibility to SLS. Moreover, the effect on skin barrier function is determined by the composition of the moisturizer. The ingredients which influence the skin barrier function need to be identified, and the mechanism clarified at the molecular level.
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7.
  • Buraczewska, Izabela, et al. (författare)
  • Long-term treatment with moisturizers affects the mRNA levels of genes involved in keratinocyte differentiation and desquamation
  • 2009
  • Ingår i: Archives of Dermatological Research. - : Springer Science and Business Media LLC. - 0340-3696 .- 1432-069X. ; 301:2, s. 175-181
  • Tidskriftsartikel (refereegranskat)abstract
    • In a recent study, we showed that long-term treatment with two different moisturizers affected TEWL in opposite directions. Therefore, we decided to examine the effect of these moisturizers on the cellular and molecular level. In a randomized controlled study on 20 volunteers, epidermal mRNA expression of genes essential for keratinocyte differentiation and desquamation after a 7-week treatment with two moisturizers was analyzed. Treatment with one test moisturizer increased gene expression of involucrin, transglutaminase 1, kallikrein 5, and kallikrein 7, while the other moisturizer affected only expression of cyclin-dependent kinase inhibitor 1A. Thus, moisturizers are able to modify the skin barrier function and change the mRNA expression of certain epidermal genes. Since the type of influence depends on the composition of the moisturizer, these should be tailored in accordance with the requirement of the barrier of each individual patient, which merits further investigations.
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8.
  • Buraczewska, Izabela, et al. (författare)
  • Moisturizers change the mRNA expression of enzymes synthesizing skin barrier lipids
  • 2009
  • Ingår i: Archives of Dermatological Research. - : Springer Science and Business Media LLC. - 0340-3696 .- 1432-069X. ; 301:8, s. 587-594
  • Tidskriftsartikel (refereegranskat)abstract
    • In a previous study, 7-week treatment of normal human skin with two test moisturizers, Complex cream and Hydrocarbon cream, was shown to affect mRNA expression of certain genes involved in keratinocyte differentiation. Moreover, the treatment altered transepidermal water loss (TEWL) in opposite directions. In the present study, the mRNA expression of genes important for formation of barrier lipids, i.e., cholesterol, free fatty acids and ceramides, was examined. Treatment with Hydrocarbon cream, which increased TEWL, also elevated the gene expression of GBA, SPTLC2, SMPD1, ALOX12B, ALOXE3, and HMGCS1. In addition, the expression of PPARG was decreased. On the other hand, Complex cream, which decreased TEWL, induced only the expression of PPARG, although not confirmed at the protein level. Furthermore, in the untreated skin, a correlation between the mRNA expression of PPARG and ACACB, and TEWL was found, suggesting that these genes are important for the skin barrier homeostasis. The observed changes further demonstrate that long-term treatment with certain moisturizers may induce dysfunctional skin barrier, and as a consequence several signaling pathways are altered.
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9.
  • Buraczewska, Izabela, 1976- (författare)
  • Skin barrier responses to moisturizers
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Moisturizers are used in various types of dry skin disorders, but also by people with healthy skin. It is not unusual that use of moisturizers is continued for weeks, months, or even years. A number of moisturizers have been shown to improve the skin barrier function, while others to deteriorate it, but the reason for observed effects remains unknown. Further understanding of the mechanism by which long-term treatment with moisturizers influences the skin barrier would have clinical implications, as barrier-deteriorating creams may enhance penetration of allergens or irritants and predispose to dry skin and eczema, while barrier-improving ones could reduce many problems. The present research combined non-invasive techniques with analyses of skin biopsies, allowing studies of the epidermis at molecular and cellular level. Test moisturizers were examined on healthy human volunteers for their effect on the skin barrier, with regard to such factors as pH, lipid type, and presence of a humectant, as well as complexity of the product. After a 7-week treatment with the moisturizers, changes in transepidermal water loss, skin capacitance, and susceptibility to an irritant indicated a modified skin barrier function. Moreover, the mRNA expression of several genes involved in the assembly, differentiation and desquamation of the stratum corneum, as well as lipid metabolism, was altered in the skin treated with one of the moisturizers, while the other moisturizer induced fewer changes. In conclusion, long-term use of moisturizers may strengthen the barrier function of the skin, but also deteriorate it and induce skin dryness. Moisturizers have also a significant impact on the skin biochemistry, detectable at molecular level. Since the type of influence is determined by the composition of a moisturizer, more careful selection of ingredients could help to design moisturizers generating a desired clinical effect, and to avoid ingredients with a negative impact on the skin.
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10.
  • Chamcheu, Jean Christopher, et al. (författare)
  • Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines : trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition
  • 2009
  • Ingår i: Journal of dermatological science (Amsterdam). - : Elsevier. - 0923-1811 .- 1873-569X. ; 53:3, s. 198-206
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Epidermolysis bullosa simplex (EBS) is an autosomal inherited mechano-bullous disease, characterized by intraepidermal blistering and skin fragility caused by mutations in the keratin (KRT) 5 or 14 genes. Despite a vast knowledge about the intermediate filament pathology in this disease, the progress in therapy has been slow. Animal models and well-characterized continuous cell culture models of EBS are needed prior to clinical testing. OBJECTIVES: Our aim was to generate immortalized cell lines as an in vitro model for the study of EBS and test a chemical chaperone, trimethylamine N-oxide (TMAO), as a putative novel therapy. METHODS: We generated four immortalized cell lines, two each from an EBS patient with a KRT5-mutation (V186L) and a healthy control, using human papillomavirus 16 (HPV16) E6E7 as transducer. Cell lines were established in serum-free and serum-containing medium and assessed for growth characteristics, keratin expression profiles, ability to differentiate in organotypic cultures, and response to heat stress with and without the presence of TMAO. RESULTS: All cell lines have been expanded >160 population doublings and their cellular characteristics are similar. However, the formation of cytoplasmic keratin filament aggregates in response to heat-shock treatment differed between EBS and normal cell lines. Notably, serum-free established EBS-cell line was most vulnerable to heat shock but both cell lines exhibited significant reduction in the number of keratin aggregates containing cells by TMAO. CONCLUSION: The immortalized cell lines represent a suitable model for studying novel therapies for EBS. TMAO is a promising new agent for future development as a novel EBS therapy.
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11.
  • Chamcheu, Jean Christopher, et al. (författare)
  • Chemical Chaperones Protect Epidermolysis Bullosa Simplex Keratinocytes from Heat Stress-Induced Keratin Aggregation : Involvement of Heat Shock Proteins and MAP Kinases
  • 2011
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 131:8, s. 1684-1691
  • Tidskriftsartikel (refereegranskat)abstract
    • Epidermolysis bullosa simplex (EBS) is a blistering skin disease caused by mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In other protein-folding disorders, involvement of molecular chaperones and the ubiquitin-proteasome system may modify disease severity. In this study, the effects of heat stress on keratin aggregation in immortalized cells from two patients with EBS (KRT5) and a healthy control were examined with and without addition of various test compounds. Heat-induced (43 °C, 30 minutes) aggregates were observed in all cell lines, the amount of which correlated with the donor phenotype. In EBS cells pre-exposed to proteasome inhibitor, MG132, and p38-mitogen-activated protein kinase (MAPK) inhibitor, SB203580, the proportion of aggregate-positive cells increased, suggesting a role of proteasomes and phosphorylation in removing mutated keratin. In contrast, aggregates were reduced by pretreatment with two chemical chaperones, trimethylamine N-oxide (TMAO) and 4-phenylbutyrate (4-PBA). TMAO also modulated stress-induced p38/c-jun N-terminal kinase (JNK) activation and expression of heat shock protein (HSPA1A), the latter of which colocalized with phosphorylated keratin 5 in EBS cells. Taken together, our findings suggest therapeutic targets for EBS and other keratinopathies.
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12.
  • Chamcheu, Jean Christopher, et al. (författare)
  • Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation: : Involvement of heat shock proteins and MAP kinases
  • Ingår i: Journal of Investigative Dermatology. - 0022-202X .- 1523-1747.
  • Tidskriftsartikel (refereegranskat)abstract
    • Epidermolysis bullosa simplex (EBS) is an inherited epithelial tissue fragility disorder due to mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In some protein folding disorders such as cystic fibrosis and Alzheimer’s disease, chaperones and the ubiquitin-proteasome system modify disease severity, suggesting a novel therapeutic approach even for EBS. In this study, the effects of two chemical chaperones (trimethylamine-N oxide (TMAO) and 4-phenylbutyrate (4-PBA)) on heat stress-induced keratin aggregation responses were examined in newly and previously established immortalized control and EBS patient-derived keratinocyte cell lines. Heat-induced keratin-positive aggregates were observed in all EBS cells, which were most prominent in severe keratin-defective cell lines and less so in normal cells. The proportion of cells containing aggregates were dramatically reduced by TMAO and 4-PBA pretreatment. Furthermore, heat stress greatly induced MAP kinase activation (p38 and JNK) and increased Hsp70/Hsc70 expression, and TMAO was able to transiently modulate these effects. The results suggest that TMAO rescue may involve components of the endogenous chaperone and MAPK machineries, which may represent novel targets for the development of more effective treatments for EBS and other keratin-related genetic disorders.
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13.
  • Chamcheu, Jean Christopher (författare)
  • Disease-causing Keratin Mutations and Cytoskeletal Dysfunction in Human Skin : In vitro Models and new Pharmacologic Strategies for Treating Epidermolytic Genodermatoses
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Epidermolysis bullosa simplex (EBS) and epidermolytic ichthyosis (EI) are rare skin fragility diseases characterized by intra-epidermal blistering due to autosomal dominant-negative mutations in basal (KRT5 or KRT14) and suprabasal (KRT1 or KRT10) keratin genes,  respectively. Despite vast knowledge in the disease pathogenesis, the pathomechanisms are not fully understood, and no effective remedies exist. The purpose of this work was to search for keratin gene mutations in EBS patients, to develop in vitro models for studying EBS and EI, and to investigate novel pharmacological approaches for both diseases. We identified both novel and recurrent KRT5 mutations in all studied EBS patients but one which did not show any pathogenic keratin mutations. Using cultured primary keratinocytes from EBS patients, we reproduced a correlation between clinical severity and cytoskeletal instability in vitro. Immortalized keratinocyte cell lines were established from three EBS and three EI patients with different phenotypes using HPV16-E6E7. Only cell lines derived from severely affected patients exhibited spontaneous keratin aggregates under normal culture conditions. However, heat stress significantly induced keratin aggregates in all patient cell lines. This effect was more dramatic in cells from patients with a severe phenotype. In organotypic cultures, the immortalized cells were able to differentiate and form a multilayered epidermis reminiscent of those observed in vivo. Addition of two molecular chaperones, trimethylamine N-oxide dihydrate (TMAO) and sodium 4-phenylbutyrate (4-PBA), reduced the keratin aggregates in both stressed and unstressed EBS and EI keratinocytes, respectively. The mechanism of action of TMAO and 4-PBA was shown to involve the endogenous chaperone system (Heat shock proteins e.g. Hsp70). Besides, MAPK signaling pathways also seemed to be incriminated in the pathogenesis of EBS. Furthermore, depending on which type of keratin is mutated, 4-PBA up-regulated Hsp70 and KRT4 (possibly compensating for mutated KRT1/5), and down-regulated KRT1 and KRT10, which could further assist in protecting EBS and EI cells against stress. In conclusion, novel and recurrent pathogenic keratin mutations have been identified in EBS. Immortalized EBS and EI cell lines that functionally reflect the disease phenotype were established. Two pharmacologic agents, TMAO and 4-PBA, were shown to be promising candidates as novel treatment of heritable keratinopathies in this in vitro model.
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14.
  • Chamcheu, Jean Christopher, et al. (författare)
  • Epidermolysis bullosa simplex due to KRT5 mutations : mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes
  • 2010
  • Ingår i: British Journal of Dermatology. - : Wiley InterScience. - 0007-0963 .- 1365-2133. ; 162:5, s. 980-989
  • Tidskriftsartikel (refereegranskat)abstract
    • Summary Background Epidermolysis bullosa simplex (EBS) is a mechanobullous skin fragility disease characterized by cytolysis of basal keratinocytes and intraepidermal blistering often caused by mutations in keratin genes (KRT5 or KRT14). No remedies exist for these disorders presenting a need for development of novel therapies. Objectives To identify new genotype-phenotype relationships in vivo and in cultured primary EBS keratinocytes in vitro, and to study the cytoskeletal stabilizing effects of trimethylamine N-oxide (TMAO) in heat-stressed EBS cells. Methods Genomic DNA and cDNA samples from three Swedish patients with EBS were analysed for keratin mutations. Primary EBS keratinocyte cultures were established, heat stressed with and without added TMAO, followed by evaluation of cellular fragility. Results In addition to the previously reported KRT5 mutation (V186L) in one patient, two patients were found to have a novel I183M and recurrent E475G replacements in KRT5. Cultured EBS keratinocytes did not exhibit keratin aggregates or cell loss, except in the patient with the p.I183M mutation who showed 3% aggregates and 2% cell loss. Upon transient heat stress the number of aggregate-containing cells increased to 21%, 27% and 13%, respectively, in the p.I183M, p.E475G and p.V186L mutant cells. Interestingly, pretreatment with TMAO prior to heat stress, dose dependently reduced the number of aggregate-containing cells and cell loss. Conclusion These results revealed a genotype-phenotype correlation in EBS keratinocytes upon heat stress and suggest protein stabilization as a new therapeutic strategy.
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15.
  • Chamcheu, Jean Christopher, et al. (författare)
  • Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype : A useful in vitro model for testing new treatments
  • 2011
  • Ingår i: British Journal of Dermatology. - : British Association of Dermatologists. - 0007-0963 .- 1365-2133. ; 164:2, s. 263-272
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Epidermolytic ichthyosis (EI) is a skin fragility disorder caused by mutations in genes encoding suprabasal keratins 1 and 10. While the aetiology of EI is known, model systems are needed for pathophysiological studies and development of novel therapies. Objectives To generate immortalized keratinocyte lines from patients with EI for studies of EI cell pathology and the effects of chemical chaperones as putative therapies. Methods We derived keratinocytes from three patients with EI and one healthy control and established immortalized keratinocytes using human papillomavirus 16-E6/E7. Growth and differentiation characteristics, ability to regenerate organotypic epidermis, keratin expression, formation of cytoskeletal aggregates, and responses to heat shock and chemical chaperones were assessed. Results The cell lines EH11 (K1-p.Val176-Lys197del), EH21 (K10-p.156Arg>Gly), EH31 (K10-p.Leu161-Asp162del) and NKc21 (wild-type) currently exceed 160 population doublings and differentiate when exposed to calcium. At resting state, keratin aggregates were detected in 9% of calcium-differentiated EH31 cells, but not in any other cell line. Heat stress further increased this proportion to 30% and also induced aggregates in 3% of EH11 cultures. Treatment with trimethylamine N-oxide and 4-phenylbutyrate (4-PBA) reduced the fraction of aggregate-containing cells and affected the mRNA expression of keratins 1 and 10 while 4-PBA also modified heat shock protein 70 (HSP70) expression. Furthermore, in situ proximity ligation assay suggested a colocalization between HSP70 and keratins 1 and 10. Reconstituted epidermis from EI cells cornified but EH21 and EH31 cells produced suprabasal cytolysis, closely resembling the in vivo phenotype. Conclusions These immortalized cell lines represent a useful model for studying EI biology and novel therapies.  
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17.
  • Dahlqvist, Johanna, 1979-, et al. (författare)
  • A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis
  • 2010
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 86:4, s. 596-603
  • Tidskriftsartikel (refereegranskat)abstract
    • KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis.
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18.
  • Dahlqvist, Johanna, 1979-, et al. (författare)
  • siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis
  • 2012
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29471-
  • Tidskriftsartikel (refereegranskat)abstract
    • Keratosis linearis with ichthyosis congenita and keratoderma (KLICK) is an autosomal recessive skin disorder associated with a single-nucleotide deletion in the 5'untranslated region of the proteasome maturation protein (POMP) gene. The deletion causes a relative switch in transcription start sites for POMP, predicted to decrease levels of POMP protein in terminally differentiated keratinocytes. To investigate the pathophysiology behind KLICK we created an in vitro model of the disease using siRNA silencing of POMP in epidermal air-liquid cultures. Immunohistochemical analysis of the tissue constructs revealed aberrant staining of POMP, proteasome subunits and the skin differentiation marker filaggrin when compared to control tissue constructs. The staining patterns of POMP siRNA tissue constructs showed strong resemblance to those observed in skin biopsies from KLICK patients. Western blot analysis of lysates from the organotypic tissue constructs revealed an aberrant processing of profilaggrin to filaggrin in samples transfected with siRNA against POMP. Knock-down of POMP expression in regular cell cultures resulted in decreased amounts of proteasome subunits. Prolonged silencing of POMP in cultured cells induced C/EBP homologous protein (CHOP) expression consistent with an activation of the unfolded protein response and increased endoplasmic reticulum (ER) stress. The combined results indicate that KLICK is caused by reduced levels of POMP, leading to proteasome insufficiency in differentiating keratinocytes. Proteasome insufficiency disturbs terminal epidermal differentiation, presumably by increased ER stress, and leads to perturbed processing of profilaggrin. Our findings underline a critical role for the proteasome in human epidermal differentiation.
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19.
  • Danielsson, Carina, et al. (författare)
  • Positive and negative interaction of 1,25-dihydroxyvitamin D3 and the retinoid CD437 on the induction of apoptosis of human melanoma cells
  • 1999
  • Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 81:3, s. 467-470
  • Tidskriftsartikel (refereegranskat)abstract
    • The natural ligands of the nuclear receptors vitamin D receptor (VDR) and retinoic acid receptor (RAR), i.e., 1alpha,25-dihydroxyvitamin D3 (VD) and all-trans retinoic acid, have important effects on the proliferation, differentiation and apoptosis of a variety of malignant cells, including melanoma. The therapeutic potential of the 2 nuclear hormones can be enhanced by the use of synthetic analogues. In this study, the 2 human melanoma cell lines WM1341 and MeWo were compared for the combined effect of VD and synthetic retinoids. Both cell lines expressed reasonable amounts of VDR, RARgamma and retinoid X receptor alpha and differed only in the relative expression of RARalpha and beta. From 9 functional variants of retinoids, only the RARgamma-selective retinoid CD437 showed, in both cell lines, a significant anti-proliferative effect. In MeWo cells, but not in WM1341 cells, VD induced growth arrest but showed no synergistic interaction with the effects of CD437. In contrast, VD induced apoptosis in WM1341, but not in MeWo, cells. CD437 was a strong inducer of apoptosis in both melanoma cell lines. Parallel treatment with CD437 and VD resulted in synergistic enhancement of apoptosis in WM1341 cells, whereas a clear decrease in induction of apoptosis in MeWo cells occurred. Our results indicate that a combined treatment of melanoma with VD and selected retinoids is promising but should be adapted to individual types of tumor.
  •  
20.
  • Elmabsout, Ali Ateia, et al. (författare)
  • Cloning and Functional Studies of a Splice Variant of CYP26B1 Expressed in Vascular Cells
  • 2012
  • Ingår i: Plos One. - San Francisco, USA : Public Library of Science (PLoS). - 1932-6203. ; 7:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene. Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells. Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.
  •  
21.
  •  
22.
  • Elmabsout, Ali, et al. (författare)
  • Cloning and functional studies of a splice variant of CYP26B1 : a cellular storage protein for all-trans retinoic acid
  • 2010
  • Ingår i: In Vivo. - 0258-851X .- 1791-7549. ; 24:3, s. 345-346
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundAll-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.Methodology/Principal FindingsThe coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.Conclusions/SignificanceVascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.
  •  
23.
  •  
24.
  • Gidlöf, Andreas C., et al. (författare)
  • Differences in retinol metabolism and proliferative response between neointimal and medial smooth muscle cells
  • 2006
  • Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1018-1172 .- 1423-0135. ; 43:4, s. 392-398
  • Tidskriftsartikel (refereegranskat)abstract
    • Vascular disease is multifactorial and smooth muscle cells (SMCs) play a key role. Retinoids have been shown to influence many disease-promoting processes including proliferation and differentiation in the vessel wall. Phenotypic heterogeneity of vascular SMCs is a well-known phenomenon and phenotypic modulation of SMCs precedes intimal hyperplasia. The SMCs that constitute the intimal hyperplasia demonstrate a distinct phenotype and differ in gene expression compared to medial SMCs. Cellular retinol-binding protein-1 (CRBP-I), involved in retinoid metabolism, is highly expressed in intimal SMCs, indicating altered retinoid metabolism in this subset of cells. The aim of this study was to evaluate the metabolism of all-trans ROH (atROH), the circulating prohormone to active retinoids, in vascular SMCs of different phenotypes. The results show an increased uptake of atROH in intimal SMCs compared to medial SMCs as well as increased expression of the retinoid-metabolizing enzymes retinol clehydrogenase-5 and retinal dehydrogenase-1 and, in conjunction with this gene expression, increased production of all-trans retinoic acid (atRA). Furthermore, the retinoic acid-catabolizing enzyme CYP26A1 is expressed at higher levels in medial SMCs compared to intimal SMCs. Thus, both retinoid activation and deactivation processes are in operation. To analyze if the difference in ROH metabolism was also correlated to differences in the biological response to retinol, the effects of ROH on proliferation of SMCs with this phenotypic heterogeneity were studied. We found that intimal SMCs showed a dose- and time-dependent growth inhibition when treated with atROH in contrast to medial SMCs, in which atROH had a mitogenic effect. This study shows, for the first time, that (1) vascular SMCs are able to synthesize biologically active atRA from the prohormone atROH, (2) intimal SMCs have a higher capacity to internalize atROH and metabolize atROH into atRA compared to medial SMCs and (3) atROH inhibits growth of intimal SMCs, but induces medial SMC growth.
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25.
  • Gidlöf, Andreas C., et al. (författare)
  • Increased retinoid signaling in vascular smooth muscle cells by proinflammatory cytokines
  • 2001
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 286:2, s. 336-342
  • Tidskriftsartikel (refereegranskat)abstract
    • Retinoids have been shown to modulate inflammation and the immune response in many cell types including macrophages, endothelial cells, and vascular smooth muscle cells. However, present knowledge of whether inflammatory mediators modulate vitamin A status in these cells is limited. To identify the role of inflammation on retinoid metabolism in vascular smooth muscle cells, the cells were exposed to a combination of proinflammatory cytokines: interleukin-1beta, interferon-gamma, and lipopolysaccharides. Without stimulation with proinflammatory cytokines, vascular smooth muscle cells expressed retinol dehydrogenases-2 and 5 mRNA detected by RT-PCR. Stimulation with the combination of cytokines induced a substantial increase of retinol dehydrogenase-5 mRNA. This was associated with increased production of ligands for retinoic acid receptors, when assayed in a retinoic acid receptor-dependent luciferase reporter system. Our results demonstrate that inflammatory mediators activate the retinoid metabolic pathway in vascular smooth muscle cells, which potentially may modulate the inflammatory response in the vascular wall.
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26.
  • Grängsjö, A., et al. (författare)
  • Different pathways in irritant contact eczema? Early differences in the epidermal elemental content and expression of cytokines after application of 2 different irritants
  • 1996
  • Ingår i: Contact Dermatitis. - 0105-1873 .- 1600-0536. ; 35:6, s. 355-360
  • Tidskriftsartikel (refereegranskat)abstract
    • The epidermal response to 2 different irritants, nonanoic acid (NAA) and sodium lauryl sulfate (SLS), was investigated with 2 different methods. NAA 80% and SLS 4% were applied under occlusion for up to 24 h. Elemental changes were determined in cryosections by x-ray microanalysis. Compared to unexposed skin a significantly higher sodium/potassium ratio was found after 6 h in NAA-exposed skin and a lower ratio in SLS-exposed. At 24 h both substances had induced similar changes, compatible with a cell injury. The findings demonstrate a time-dependent NAA and SLS response. With reverse transcription polymerase chain reaction, the mRNA expression of interleukin-1 alpha (IL-1 alpha), -1 beta (IL-1 beta), -6 (IL-6), and -8 (IL-8), tumor necrosis factor alpha (TNF alpha) and granulocyte macrophage colony stimulating factor (GM-CSF) in shave biopsies from irritated and unexposed skin was studied at 0. 4. 8 and 24 h. NAA, but not SLS, induced an increase in mRNA expression for IL-6 mRNA-expression for GM-CSF was increased after SLS exposure, but not after NAA. These findings indicate a time and substance dependent difference in the up-regulation of mRNA for different cytokines in epidermis during the first 24 h of the irritant reaction. This might be the effect of differences in the irritants action on the cell membranes, which is also reflected by the differences found in the elemental content at 6 h.
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27.
  • Gudmundsson, Sanna, et al. (författare)
  • Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
  • 2017
  • Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:6, s. 1070-1077
  • Tidskriftsartikel (refereegranskat)abstract
    • Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.
  •  
28.
  • Hellman, Per, et al. (författare)
  • Vitamin D and retinoids in parathyroid glands
  • 1999
  • Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 3:4, s. 355-361
  • Tidskriftsartikel (refereegranskat)abstract
    • Vitamin D and retinoids are important regulators of differentiation and proliferation in a number of tissues, and have been implicated as chemopreventive agents in several different tumors. While vitamin D is known to be important for regulation of parathyroid function and proliferation, it has recently been established that parathyroid cells also are targets for retinoids. Hyperparathyroidism (HPT) is a common disorder, and evaluation of the disease has indicated high prevalence of subclinical disease, as well as clear benefits of offering treatment for the disease. This review summarizes the data so far gathered concerning parathyroid cells, vitamin D and retinoids, with clear implication on prospects of possible medical treatment of hyperparathyroidism.
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29.
  • Hoppe, Torborg, et al. (författare)
  • Moisturizing treatment of patients with atopic dermatitis and ichthyosis vulgaris improves dry skin, but has a modest effect on gene expression regardless of FLG genotype
  • 2015
  • Ingår i: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 0926-9959 .- 1468-3083. ; 29:1, s. 174-177
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundLoss-of-function mutations in FLG (encoding filaggrin) are a predisposing factor for atopic dermatitis (AD) and cause ichthyosis vulgaris (IV). Patients with AD and IV display impaired skin barrier and dry skin, and altered epidermal expression of genes in pro-inflammatory and lipid metabolic pathways are often evident.ObjectivesTo evaluate the effect of three different moisturizers on skin barrier function and epidermal gene expression in patients with AD/IV in relation to FLG mutation status.MethodsPatients (n = 43) were classified according to their FLG status: AD with FLG+/+ (n = 14), AD with FLG+/− (n = 14), and AD/IV with FLG−/− (n = 15). Dryness score and transepidermal water loss (TEWL) were monitored on volar forearms, and punch biopsies were taken for analysis of gene expression. Measurements were repeated after 4 weeks of treatment with either of two moisturizers on each forearm.ResultsTreatment with any of the three moisturizers significantly reduced dryness score and TEWL in the group as a whole. FLG−/− patients displayed the largest reduction in dryness score. Only minute changes occurred in the mRNA expression of 15 selected epidermal genes.ConclusionsMoisturizing treatment improves dry skin and certain aspects of abnormal skin barrier function, especially in patients with AD/IV and dual FLG mutations, but does not normalize the epidermal gene expression profile.
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30.
  • Hoppe, Torborg, et al. (författare)
  • X-linked recessive ichthyosis : an impaired barrier function evokes limited gene responses before and after moisturizing treatments
  • 2012
  • Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 167:3, s. 514-522
  • Tidskriftsartikel (refereegranskat)abstract
    • Background X-linked recessive ichthyosis (XLRI) is due to deletions or inactivating mutations in the steroid sulfatase (STS) gene. This results in an accumulation of cholesterol sulphate affecting the packing of intercorneocyte lipids. XLRI is characterized by dry, scaly skin and increased skin barrier permeability; patients are often dependent on daily use of moisturizers.Objectives To examine the biophysical and molecular changes in the skin of patients with XLRI compared with healthy volunteers, and to analyse the effects of moisturizers on the patients' barrier function.Methods Patients with XLRI (n = 14) and healthy controls (n = 14) were included in the study. Skin dryness score, transepidermal water loss (TEWL) and skin surface pH were monitored at baseline, and punch biopsies were obtained for mRNA expression profiles determined by oligonucleotide arrays. Measurements were repeated in the patients with XLRI after a 4-week treatment with three different moisturizers on the volar forearms. Results  Patients with XLRI showed, compared with healthy controls, increased dryness and TEWL, equal skin pH and altered expression of 27 genes. There were no signs of activation of inflammation or repair pathways. Five selected genes were significantly altered also on quantitative polymerase chain reaction analysis. Treatment with the moisturizers showed similar effects: they improved skin dryness but had no effect on TEWL, pH or expression of selected genes.Conclusions  Despite a dysfunctional skin barrier, the limited number of genes altered in XLRI skin suggests that no inflammatory or repair mechanisms are triggered. Treatment with moisturizers does not have any major impact on the skin barrier properties of patients with XLRI.
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31.
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32.
  • Karlsson, Teresa, et al. (författare)
  • 13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4 : a mechanism for its anti-androgenic effects in sebaceous glands?
  • 2003
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - 0006-291X .- 1090-2104. ; 303:1, s. 273-278
  • Tidskriftsartikel (refereegranskat)abstract
    • Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione, which may stimulate sebum secretion. This oxidative 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity of RoDH-4 is competitively inhibited by retinol and 13-cis-retinol. Here, we further examine the substrate specificity of RoDH-4 and the inhibition of its 3 alpha-HSD activity by retinoids. Recombinant RoDH-4 oxidized 3,4-didehydroretinol-a major form of vitamin A in the skin-to its corresponding aldehyde. 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol, but not all-trans-retinoic acid or the synthetic retinoids acitretin and adapalene, were potent competitive inhibitors of the oxidative 3 alpha-HSD activity of RoDH-4, i.e., reduced the formation of dihydrotestosterone and androstandione in vitro. Extrapolated to the in vivo situation, this effect might explain the unique sebosuppressive effect of isotretinoin when treating acne.
  •  
33.
  • Karlsson, Teresa, et al. (författare)
  • Immunofluorescence localization of nuclear retinoid receptors in psoriasis versus normal human skin
  • 2004
  • Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 84:5, s. 363-369
  • Tidskriftsartikel (refereegranskat)abstract
    • Psoriasis responds favourably to treatment with retinoids but the cellular pathways mediating these effects are poorly understood. Retinoids regulate keratinocyte proliferation and maturation via binding to nuclear retinoic acid receptors (mainly RARalpha and RARgamma) which form heterodimers with the 9-cis-RA receptor, RXRalpha. We have previously shown that mRNA expression of RARalpha and RXRalpha is down-regulated in psoriatic lesions as compared with non-lesional human skin. In the present study, we investigated the protein expression of RARalpha, RARgamma and RXRalpha in normal and psoriatic skin using indirect immunofluorescence analysis. Epidermal keratinocytes of normal and non-lesional psoriatic skin displayed similar nuclear localization of all three receptors; RARalpha was detected with decreasing intensity from basal to suprabasal layers, RARgamma showed the opposite trend, whereas RXRalpha was evenly expressed throughout the epidermis. In lesional psoriatic skin, however, all three receptor proteins showed a much higher staining intensity in the lower half of the epidermis; in particular, RARalpha immunoreactivity was low or even absent in the upper layers of epidermis. The results support the idea that psoriasis is associated with abnormal retinoid signalling in lesional epidermis.
  •  
34.
  • Karlsson, Teresa, et al. (författare)
  • Keratinocyte differentiation induced by calcium, phorbol ester or interferon-γ elicits distinct changes in the retinoid signalling pathways
  • 2010
  • Ingår i: Journal of dermatological science (Amsterdam). - : Elsevier BV. - 0923-1811 .- 1873-569X. ; 57:3, s. 207-213
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Retinoids influence keratinocyte proliferation and differentiation via binding to nuclear retinoic acid receptors (RARα, -γ) and retinoid X receptor α (RXRα). The effect of keratinocyte differentiation on expression of nuclear retinoid receptors and on the conversion of retinol into retinoic acid has not been examined earlier in depth. Objectives: Our aim was to examine the expression of retinoid receptors and a retinoid-regulated gene CRABPII, as well as the metabolism of exogenous [3H]retinol in cultured human keratinocytes induced to differentiate by exposure to either calcium, phorbol 12-myristate 13-acetate (PMA), or interferon-γ (IFNγ). Methods: Normal human keratinocytes were cultured and exposed to differentiation-inducing agents. The mRNA and protein expression of retinoid receptors were examined using real-time PCR and Western blot. [3H]Retinol uptake and metabolism was monitored by HPLC with on-line radioactivity detection. Results: In calcium-exposed cells, increased expression of RARγ and RXRα, enhanced metabolism of [3H]retinol to 3,4-didehydro-RA (ddRA), and an induction of CRABPII mRNA and protein was noted. In contrast, treatment with PMA and IFNγ reduced the RARγ and RXRα protein expression (preventable by the proteasome inhibitor MG132), increased the accumulation of [3H]RA and/or [3H]ddRA in the cells, and changed the CRABPII transcription. Conclusions: Retinoid signalling is profoundly altered upon differentiation of keratinocytes and the effects depend on how cellular differentiation is initiated.
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35.
  • Karlsson, Teresa, et al. (författare)
  • Topical retinoic acid alters the expression of cellular retinoic acid-binding protein-I and cellular retinoic acid-binding protein-II in non-lesional but not lesional psoriatic skin
  • 2002
  • Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 11:2, s. 143-152
  • Tidskriftsartikel (refereegranskat)abstract
    • Therapeutic retinoids have profound effects on psoriatic skin pathology but their interactions with various retinoid-binding proteins in lesional vs non-lesional skin have not been investigated. Using quantitative real-time PCR the mRNA expression of cellular retinol-binding protein I (CRBPI) and retinoic acid-binding protein I/II (CRABPI/CRABPII) was studied in psoriatic and healthy control (=normal) skin after 4 days of occlusive RA/vehicle treatment (n=6). Untreated psoriatic lesions showed a markedly elevated CRABPII/CRABPI ratio, while the CRBPI level was reduced in lesional and non-lesional skin as compared to normal skin. In RA-treated normal and non-lesional skin, the mRNA expression of CRBPI was unaltered while that of CRABPI and CRABPII was reduced by approximately 80% and increased approximately 5-fold, respectively, as compared to vehicle-treated skin. In contrast, lesional skin exposed to RA showed an almost 90% increase in CRBPI transcripts but unaltered expression of CRABPI and CRABPII, yet, the mRNA expression of several inflammatory mediators, e.g. inducible nitric oxide synthase, interferon-gamma and interleukin-1beta, was clearly reduced. Immunohistochemistry localized CRABPII to suprabasal keratinocytes in normal skin and revealed markedly elevated levels in lesional skin. RA treatment induced CRABPII protein expression in normal and non-lesional skin, to similar levels as in untreated lesions. The results indicate that the effects of RA differ in normal/non-lesional psoriatic skin and lesional skin. Whether the high expression of CRABPII in psoriatic skin lesions is due to increased amounts of endogenous retinoids in lesional skin or reflects an abnormal regulation of the CRABPII gene in psoriasis remains to be studied.
  •  
36.
  • Kindmark, Andreas, et al. (författare)
  • Cellular retinoic acid-binding protein type II is expressed in adult humanosteoblasts and in adult liver
  • 1992
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - 0006-291X .- 1090-2104. ; 189:3, s. 1397-1403
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study we have used a reverse transcription polymerase chain reaction (RT-PCR) to demonstrate that adult primary human osteoblasts and SaOS-2, a human osteosarcoma-derived cell line with osteoblastic properties, express cellular retinol-binding protein I (CRBP I), cellular retinoic acid-binding protein II (CRABP II), and very low levels of CRABP I. We also show that CRABP II is expressed in the adult liver, which does not express CRABP I. The results suggest that CRABP II is the important isoform in the adult bone as well as in the adult liver. Since the 9-cis retinoic acid receptor (RXR) alpha previously has been shown to be expressed predominantly in the liver, CRABP II might be involved in the transport of 9-cis retinoic acid to its nuclear receptor.
  •  
37.
  • Kindmark, Andreas, et al. (författare)
  • Reverse transcription-polymerase chain reaction assay demonstrates thatthe 9-cis retinoic acid receptor alpha is expressed in human osteoblasts
  • 1993
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 192:3, s. 1367-1372
  • Tidskriftsartikel (refereegranskat)abstract
    • The 9-cis retinoic acid receptor (RXR) alpha, a co-regulator of the thyroid hormone and vitamin D receptors, has previously been shown to be expressed predominantly in metabolic organs such as the liver and the kidney. In this study we have used a reverse transcription polymerase chain reaction (RT-PCR) to examine the expression of retinoic acid (RA) nuclear receptors in primary human osteoblasts and in SaOS-2, a human osteosarcoma-derived cell line with osteoblastic characteristics. Our results demonstrate that human osteoblasts express RXR alpha, as well as the all-trans RA receptors (RAR) alpha, beta, and gamma. These data further establish bone as a major target for retinoids and suggest that RA can regulate vitamin D and thyroid hormone actions in osteoblasts.
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38.
  • Klar, Joakim, 1974-, et al. (författare)
  • Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome
  • 2009
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 85:2, s. 248-253
  • Tidskriftsartikel (refereegranskat)abstract
    • Ichthyosis prematurity syndrome (IPS) is an autosomal-recessive disorder characterized by premature birth and neonatal asphyxia, followed by a lifelong nonscaly ichthyosis with atopic manifestations. Here we show that the gene encoding the fatty acid transport protein 4 (FATP4) is mutated in individuals with IPS. Fibroblasts derived from a patient with IPS show reduced activity of very long-chain fatty acids (VLCFA)-CoA synthetase and a specific reduction in the incorporation of VLCFA into cellular lipids. The human phenotype is consistent with Fatp4 deficiency in mice that is characterized by a severe skin phenotype, a defective permeability barrier function, and perturbed VLCFA metabolism. Our results further emphasize the importance of fatty acid metabolism for normal epidermal barrier function illustrated by deficiency of a member in the FATP family of proteins.
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39.
  • Kolundzic, Nikola, et al. (författare)
  • Induced pluripotent stem cell (iPSC) line from an epidermolysis bullosa simplex patient heterozygous for keratin 5 E475G mutation and with the Dowling Meara phenotype
  • 2019
  • Ingår i: Stem Cell Research. - : ELSEVIER SCIENCE BV. - 1873-5061 .- 1876-7753. ; 37
  • Tidskriftsartikel (refereegranskat)abstract
    • We have generated MLi002-A, a new induced pluripotent stem cell (iPSC) line derived from keratinocytes of a skin punch biopsy of a female patient with the severe epidermolysis bullosa simplex Dowling-Meara phenotype and the keratin K5 E475G mutation. Keratinocytes were reprogrammed using non-integrating Sendai virus vectors, and xeno-free culture conditions were used throughout. The characterization of MLi002-A cell line consisted of molecular karyotyping, mutation screening using restriction enzyme digestion and Sanger sequencing, and testing of the pluripotency and differentiation potentials by immunofluorescence of associated markers both in vitro and in vivo. This is the first iPSC model of EB Simplex.
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40.
  • Koskela von Sydow, Anita, 1979- (författare)
  • Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α : studies in two- and three dimensional in vitro models
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. Reepithelialisation and epidermal wound coverage counteract excessive scar formation. We have previously shown that interleukin-1α (IL-1α) derived from keratinocytes conteracts TGF-β-stimulated CTGF-expression. The aim of this thesis was to further explore the effects of keratinocytes and IL-1α on gene and protein expression, as well as pathways, in TGF-β stimulated fibroblasts. Fibroblasts were studied in vitro by conventional two dimensional cell culture models and in a three dimensional keratinocyte-fibroblast organotypic skin culture model.The results showed that IL-1 suppresses basal and TGF-β-induced CTGF mRNA and protein, involving a possible TAK1 mechanism. Keratinocytes regulate the expression of fibroblast genes important for the turnover of the extracellular matrix. Most of the genes analysed (11/13) were regulated by TGF-β and counter regulated by keratinocytes. The overall results support a view that keratinocytes regulate fibroblasts to act catabolically (anti-fibrotic) on the extracellular matrix.Transcriptional microarray and gene set enrichment analysis showed that antagonizing effects of IL-1α on TGF-β were much more prominent than the synergistic effects. The most confident of these pathways was the interferon signaling, which were inhibited by TGF-β and activated by IL-1α. A proteomics study confirmed that IL-1α preferentially conteracts TGF-β effects. Six new fibroblast proteins involved in synthesis/ regulation were identified, being regulated by TGF-β and antagonized by IL-1α. Pathway analysis confirmed counter-regulation of interferon signaling by the two cytokines. These findings have implications for understanding the role of fibroblasts for inflammatory responses and development of fibrosis in the skin.
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41.
  • Krivospitskaya, Olesya, 1983-, et al. (författare)
  • A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
  • 2012
  • Ingår i: Molecular Medicine. - New York, USA : The Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 18:1, s. 712-718
  • Tidskriftsartikel (refereegranskat)abstract
    • All-trans retinoic acid, controlled by CYP26 enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26B1 in atherosclerosis and effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries and CYP26B1 and the macrophage marker CD68 co-localized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic than normal arteries. Databases were queried for non-synonymous CYP26B1 SNPs and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophage-like cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.
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42.
  • Lehmann, Sören, et al. (författare)
  • Retinoid receptor expression and its correlation to retinoid sensitivity in non-M3 acute myeloid leukemia blast cells
  • 2001
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 7:2, s. 367-372
  • Tidskriftsartikel (refereegranskat)abstract
    • All-trans-retinoic acid (ATRA) has significantly improved the treatment results in acute promyelocytic leukemia (M3). In non-M3 acute myeloid leukemia (AML), the effects are less clear, and there is a pronounced heterogeneity in the sensitivity to the growth-inhibitory effects of retinoids in leukemic cells from different non-M3 AML patients. Retinoids exert their effects through a number of nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. In this study, we determined the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha by real-time PCR in four cell lines and in blast cells from patients with non-M3 AML before and after ATRA incubation. All four receptors were expressed in cells from all 18 tested patient samples and in four myeloid cell lines. In the majority of the patient samples as well as in the cell lines, there was a pattern of high expression of RAR alpha and RXR alpha and low expression of RAR beta and RAR gamma. There was no correlation between the basal expression of any of the retinoid receptors and sensitivity to ATRA. A 24-h exposure to ATRA increased the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha in 46%, 77%, 30%, and 38% of the samples, respectively. The mean increase in receptor expression was most pronounced for RAR beta and RXR alpha. There was a significant correlation between an increase in RAR beta expression in response to ATRA and sensitivity to ATRA (P < 0.014). No such correlations were found for RAR alpha, RAR gamma, and RXR alpha. The expression of the monocytoid marker CD14 was significantly correlated with increased expression of RAR alpha (P = 0.03). We conclude that RAR alpha, RAR beta, RAR gamma, and RXR alpha are expressed in non-M3 AML blast cells and that ATRA-induced expression of RAR beta may be a marker for retinoid sensitivity.
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43.
  • Lehmann, Sören, et al. (författare)
  • The expression of cellular retinoid binding proteins in non-APL leukemic cells and its association with retinoid sensitivity
  • 2002
  • Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 43:4, s. 851-8
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Retinoic acid (RA) has important effects on cell differentiation and cell growth and on normal embryonic development. Intracellular retinoid signaling induced by endogenous or exogenous RA is regulated by retinoid binding proteins such as CRBPI, CRABPI and CRABPII and there are data suggesting that the expression of these proteins can influence the sensitivity to the growth inhibitory effects of ATRA. In this study, we investigated the basal and ATRA-induced expression of CRBPI and CRABPI and II in leukemic cell lines and in cells from patients with acute myeloid leukemia (AML). CRBPI as well as CRABPI and II were expressed in all tested cell lines and in leukemic cells from all 18 AML-patients. CRABPII mRNA expression was more abundant than CRBPI and CRABPI in both the cell lines and the patient cells but the levels compared the house keeping gene was lower in the patient cells. In all cell lines and in 69% of the patient samples, ATRA did upregulate CRABPII whereas CRBPI exhibited a varying response and CRABPI was more commonly downregulated. The sensitivity to the growth inhibitory effects of ATRA did not correlate with the basal expression of any of these proteins. However, ATRA-induced upregulation of CRABPII did significantly correlate with the ATRA sensitivity (p < 0.005) as well as with ATRA-induced upregulation of the retinoid receptor RARbeta (p < 0.05). We conclude that the retinoid binding proteins CRBPI and CRABPI and II are expressed in myeloid leukemic cells of non-M3 type but that the level of expression does not affect ATRA sensitivity.
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44.
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45.
  • Li, Hao, 1984- (författare)
  • In vitro Studies of Genodermatoses Affecting Cytoskeletal Integrity and Lipid Processing in Human Epidermis : Pathogenic Mechanisms and Effects of Retinoid Therapy
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Autosomal dominant epidermolytic ichthyosis (EI) is a rare disease characterized by intra-epidermal blistering due to mutations in either of two keratin genes, KRT1 and KRT10, expressed by suprabasal keratinocytes. Autosomal recessive congenital ichthyosis (ARCI) is a non-blistering, hyperkeratotic disease caused by mutations in one of the following genes: ABCA12, ALOX12B, ALOXE3, TGM1, CYP4F22, NIPAL4 and SLC27A4, which are all essential for skin barrier homeostasis. ARCI and EI often respond well to treatment with retinoids, but the mechanism of action is unclear. The aim of this thesis was to increase the knowledge of pathogenic pathways in ichthyosis and to find new explanations to the effect of retinoids.In vitro studies of immortalized keratinocytes from EI patients showed an abnormal keratin aggregation after heat stress, that could be partially inhibited by pre-treatment with all-trans retinoic acid (ATRA) or retinoic acid receptor α-agonists. ATRA treatment also reduced the relative expression of mutated vs wildtype KRT10. The clearance of ATRA in human keratinocytes was found to be mediated by CYP26B1.In skin biopsies from ARCI patients, immunofluorescence analysis of 12R-LOX, eLOX-3, TGM1, ichthyin and FATP4 showed altered expression, not only of the mutated protein, but also of the other proteins. These observations are consistent with a feedback regulatory mechanism by which the loss of one protein results in an up-regulation of other proteins. Furthermore, 12R-LOX, eLOX-3 and TGM1 were intimately co-localized in stratum corneum, as were ichthyin and FATP4, suggesting that the proteins are linked to the same metabolic pathway. When treated with a CYP26 inhibitor known to raise the endogenous ATRA level of the skin, two patients with NIPAL4 mutations, initially exhibiting increased co-localization signals for 12R-LOX and eLOX-3, displayed normalized lipoxygenase expressions and showed clinical improvement.In conclusion, mechanisms are proposed by which pathogenic keratin aggregations in EI and epidermal protein deficiencies in ARCI patients may be mitigated by retinoids. Furthermore, the vivid crosstalk between proteins incriminated in ARCI suggests that these enzymes operate along a common metabolic pathway essential for producing barrier lipids in stratum corneum. Any abrogation of this production may cause barrier failure, hence resulting in a compensatory hyperkeratosis characteristic of congenital ichthyosis.
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46.
  • Li, Hao, 1984-, et al. (författare)
  • Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis
  • 2013
  • Ingår i: Journal of dermatological science (Amsterdam). - : Elsevier BV. - 0923-1811 .- 1873-569X. ; 69:3, s. 195-201
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Autosomal recessive congenital ichthyosis (ARCI) is caused by mutations in 10 differentgenes, of which transglutaminase-1 (TGM1) predominates. A rare form is ichthyosis prematuritysyndrome (IPS) caused by mutations in SLC27A4 encoding fatty acid transporter protein 4 (FATP4),believed to be an acyl-CoA synthetase activating long- and very-long-chain FA. Another ARCI is caused bymutations in NIPAL4, coding for ichthyin, which is proposed to be a magnesium transporter or a transmembrane receptor. A possible interaction between FATP4 and ichthyin has not been studied before.Objective:To find common denominators in the pathogenesis of ARCI.Methods:FATP4 and ichthyin were analyzed by immunofluorescence and proximity ligation assay (PLA) in healthy and ARCI patient skin and in in vitro models of ARCI epidermis.Results:Both proteins were expressed in the upper stratum granulosum of normal epidermis and PLA confirmed a close interaction between FATP4 and ichthyin. In IPS skin lacking FATP4 we found reduced ichthyin expression and this finding could be reproduced in organotypic epidermis with siRNA silenced SLC27A4. In contrast, increased FATP4 staining was found in patients with ichthyin (NIPAL4) mutations and in organotypic epidermis with silenced NIPAL4. In patients with TGM1 mutations, the expression of both FATP4 and ichthyin was increased, but the PLA signal was low probably indicating a malfunctioning protein interaction.Conclusion:Our study suggests that FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function. It is also hypothesized that ichthyin serves as Mg2+-transporter for FATP4 in this process.
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47.
  • Li, Hao, 1984-, et al. (författare)
  • Retinoids Reduce Formation of Keratin Aggregates in Heat-stressed Immortalized Keratinocytes from an Epidermolytic Ichthyosis Patient with a KRT10 Mutation
  • 2013
  • Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 93:1, s. 44-49
  • Tidskriftsartikel (refereegranskat)abstract
    • Epidermolytic ichthyosis (EI) is an autosomal dominant epidermal skin fragility disorder caused by mutations in keratin 1 and 10 (K1 and K10) genes. Mutated keratins form characteristic aggregates in vivo and in vitro. Some patients benefit from retinoid therapy, although the mechanism is not fully understood. Our aim was to demonstrate whether retinoids affect the formation of keratin aggregates in immortalized EI cells in vitro. EI keratinocytes were seeded on cover slips, pre-treated or not with retinoids, heat-stressed, and keratin aggregate formation monitored. K10 aggregates were detected in 5% of cells in the resting state, whereas heat stress increased this proportion to 25%. When cells were pre-incubated with all-trans-retinoic acid (ATRA) or retinoic acid receptor (RAR)-α agonists the aggregates decreased in a dose-dependent manner. Furthermore, ATRA decreased the KRT10 transcripts 200-fold as well as diminished the ratio of mutant to wild-type transcripts from 0.41 to 0.35, thus providing a plausible rational for retinoid therapy of EI due to K10 mutations.
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48.
  • Li, Hao, 1984-, et al. (författare)
  • The expression of epidermal lipoxygenases and transglutaminase-1 is perturbed by NIPAL4 mutations : indications of a common metabolic pathway essential for skin barrier homeostasis
  • 2012
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 132:10, s. 2368-2375
  • Tidskriftsartikel (refereegranskat)abstract
    • Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin barrier diseases due inter alia to mutations in transglutaminase-1 (TGM1), in lipoxygenases (LOXs) of the hepoxilin pathway, and in ichthyin, a putative Mg2+ transporter encoded by the NIPAL4 gene. In search of a common pathogenic pathway for ARCI, we investigated the epidermal expression of TGM1, 12R-LOX, eLOX-3, and ichthyin in skin biopsies from four healthy controls and nine patients with ARCI. In healthy skin, TGM1, ichthyin, and the LOX enzymes were predominantly expressed in the upper epidermis where colocalization signals could also be demonstrated by in situ proximity ligation assay. In patients with ALOX12B mutations and abnormal 12R-LOX expression, the colocalization signal for eLOX-3 and TGM1 was increased 4-fold. In contrast, patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. Treatment of these patients with a retinoid-mimetic drug, liarozole, normalized the expression of 12R-LOX and attenuated the colocalization signal. Altogether, our data indicate that ichthyin and TGM1 are functionally closely related in the lipid processing and that this metabolic pathway can be modified by retinoids.
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49.
  • Löntz, Werner, et al. (författare)
  • Increased mRNA expression of manganese superoxide dismutase in psoriasis skin lesions and in cultured human keratinocytes exposed to IL-1 beta and TNF-alpha
  • 1995
  • Ingår i: Free Radical Biology & Medicine. - 0891-5849 .- 1873-4596. ; 18:2, s. 349-355
  • Tidskriftsartikel (refereegranskat)abstract
    • Because reactive oxygen species have been implicated in the pathogenesis of various hyperproliferative and inflammatory diseases, the mRNA expression of the antioxidant enzyme superoxide dismutase was studied in psoriatic skin tissue. By using reverse transcription-PCR we found similar expression of copper, zinc superoxide dismutase (CuZnSOD) in the involved vs. uninvolved psoriatic skin. In contrast, the level of the manganese superoxide dismutase (MnSOD) mRNA message was consistently higher in lesional psoriatic skin as compared to adjacent uninvolved skin and healthy control skin. Parallel investigation of those cytokines that are thought to be direct or indirect inducers of the MnSOD activity revealed an increased mRNA expression of IL-1 beta, TNF-alpha, and GM-CSF in lesional psoriatic skin. To study if these cytokines exert a direct effect on dismutase expression in epidermal cells, human keratinocytes in culture were challenged with IL-1 beta, TNF-alpha, and GM-CSF. It was found that IL-1 beta and TNF-alpha, but not GM-CSF, induced the mRNA expression of MnSOD, and an additive effect was demonstrated for the two former cytokines. Further, the expression of both CuZnSOD and MnSOD transcripts was similar in cultured keratinocytes maintained at low differentiation (low Ca2+ medium) and cells forced to terminal differentiation (by high Ca2+ medium). Our results indicate that the abnormal expression of MnSOD mRNA in lesional psoriatic skin is not directly linked to the pathologic state of keratinocyte differentiation in the skin. It seems more likely that the cutaneous overexpression of MnSOD in psoriatic epidermis represents a protective cellular response evoked by cytokines released from inflammatory cells invading the diseased skin.
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50.
  • Ocaya, Pauline Ajok, 1977-, et al. (författare)
  • CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells
  • 2011
  • Ingår i: Journal of Vascular Research. - : S. Karger. - 1018-1172 .- 1423-0135. ; 48:1, s. 23-30
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: The cytochrome P450 enzymes of the CYP26 family are involved in the catabolism of the biologically active retinoid all-trans-retinoic acid (atRA). Since it is possible that an increased local CYP26 activity would reduce the effects of retinoids in vascular injury, we investigated the role of CYP26 in the regulation of atRA levels in human aortic smooth muscle cells (AOSMCs).Methods: The expression of CYP26 was investigated in cultured AOSMCs using real-time PCR. The metabolism of atRA was analyzed by high-performance liquid chromatography, and the inhibitor R115866 or small interfering RNA (siRNA) was used to suppress CYP26 activity/expression.Results: AOSMCs expressed CYP26B1 constitutively and atRA exposure augmented CYP26B1 mRNA levels. Silencing of the CYP26B1 gene expression or reduction of CYP26B1 enzymatic activity by using siRNA or the inhibitor R115866, respectively, increased atRA-mediated signaling and resulted in decreased cell proliferation. The CYP26 inhibitor also induced expression of atRA-responsive genes. Therefore, atRA-induced CYP26 expression accelerated atRA inactivation in AOSMCs, giving rise to an atRA-CYP26 feedback loop. Inhibition of this loop with a CYP26 inhibitor increased retinoid signaling.Conclusion: The results suggest that CYP26 inhibitors may be a therapeutic alternative to exogenous retinoid administration. Copyright (C) 2010 S. Karger AG, Basel
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