| 1. |
|
|
| 2. |
- Lundborg, Magnus, et al.
(författare)
-
Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation
- 2018
-
Ingår i: Journal of Structural Biology. - : Academic Press. - 1047-8477 .- 1095-8657. ; 203:2, s. 149-161
-
Tidskriftsartikel (refereegranskat)abstract
- In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.
|
|
| 3. |
- Lundborg, Magnus, et al.
(författare)
-
Predicting drug permeability through skin using molecular dynamics simulation
- 2018
-
Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 283, s. 269-279
-
Tidskriftsartikel (refereegranskat)abstract
- Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.
|
|
| 4. |
- Norlén, Filip, et al.
(författare)
-
Occupational exposure to inorganic particles during pregnancy and birth outcomes : A nationwide cohort study in Sweden
- 2019
-
Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9:2
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of this study was to investigate if occupational exposure to inorganic particles or welding fumes during pregnancy is associated with negative birth outcomes. Design A prospective national cohort study. Setting All single births from 1994 to 2012 in Sweden. Information on birth weight, preterm birth, small for gestational age, smoking habits, nationality, age, occupation, absence from work and education was obtained from nationwide registers. Exposure to inorganic particles (mg/m 3) was assessed from a job exposure matrix. Participants This study included all single births by occupationally active mothers (995 843). Outcome measures Associations between occupational exposures and negative birth outcomes in the form of low birth weight, preterm birth and small for gestational age. Results Mothers who had high exposure to inorganic particles and had less than 50 days (median) of absence from work during pregnancy showed an increased risk of preterm birth (OR 1.18; 95% CI 1.07 to 1.30), low birth weight (OR 1.32; 95% CI 1.18 to 1.48) as well as small for gestational age (OR 1.20; 95% CI 1.04 to 1.39). The increased risks were driven by exposure to iron particles. No increased risks were found in association with exposure to stone and concrete particles. High exposure to welding fumes was associated with an increased risk of low birth weight (OR 1.22; 95% CI 1.02 to 1.45) and preterm birth (OR 1.24; 95% CI 1.07 to 1.42). Conclusions The results indicate that pregnant women should not be exposed to high levels of iron particles or welding fumes.
|
|
| 5. |
- Norlén, Filip, et al.
(författare)
-
Occupational exposure to organic particles and combustion products during pregnancy and birth outcome in a nationwide cohort study in Sweden
- 2019
-
Ingår i: Occupational and environmental medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 76:8, s. 537-544
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To study if children of women exposed to organic particles and combustion products at work during pregnancy, have an increased risk of low birth weight, preterm birth or small for gestational age. Methods: A nationwide cohort of all occupationally active mothers and their children from single births during 1994 to the end of 2012 (1 182 138 observations) was formed. Information on birth outcome was obtained from the medical birth register. Information on absence from work, education, occupation, age, nationality and smoking habits was obtained from national registers. A job exposure matrix (FINJEM) was used to assess the exposure. Results: Pregnant women with low absence from work and high (>50th percentile) exposure to organic particles had an increased risk of giving birth to children with low birth weight (OR=1.19; 95% CI: 1.07 to 1.32), small for gestational age (OR=1.22; 95% CI: 1.07 to 1.38) or preterm birth (OR=1.17; 95% CI: 1.08 to 1.27). Subgroup analyses showed an increased risk of small for gestational age in association with exposure to oil mist. Exposure to oil mist and cooking fumes was associated with low birth weight. Paper and other organic dust was associated with preterm birth. Exposure to combustion products showed an increased risk of small for gestational age (OR=1.40; 95% CI: 1.15 to 1.71). Conclusions: The results indicate that occupational exposure to organic particles or combustion products during pregnancy is associated with restriction of fetal growth and preterm birth. More studies are needed to confirm a casual association.
|
|
| 6. |
- Wennberg, Christian, et al.
(författare)
-
Structural transitions in ceramide cubic phases during formation of the human skin barrier
- 2018
-
Ingår i: Biophysical Journal. - : Cell Press. - 0006-3495 .- 1542-0086.
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The stratum corneum is the outer-most layer of the human skin, and constitutes the primary barrier to penetration of external substances. The barrier function of the stratum corneum is primarily located to its extracellular space, which consists of long-chain ceramides, free fatty acids and cholesterol organised into a stacked lamellar bilayer structure. Recent experimental studies have shown that these lamellar structures are formed through a structural reorganization of glycosylceramide-based bilayers, folded in three dimensions with a cubic-like symmetry. Here we present coarse-grained molecular dynamics simulations of human ceramide- and glycosylceramide bilayer structures with gyroid cubic symmetry. The bilayer structures with glycosylceramides are able to maintain the cubic symmetry, while the bilayer structures with ceramides collapse into a stacked lamellar bilayer structure as the water content is reduced.
|
|
