Exposure to urban air pollution during early pregnancy is associated with increased risk for adverse pregnancy outcomes,such as preeclampsia(PE),and there is an urgent need to understand how air pollution affects biol...Exposure to urban air pollution during early pregnancy is associated with increased risk for adverse pregnancy outcomes,such as preeclampsia(PE),and there is an urgent need to understand how air pollution affects biological mechanisms in the placenta.Hofbauer cells(HBCs)are fetal placental macrophages that regulate immune tolerance in the placenta.They are normally polarized towards an anti-inflammatory M2 phenotype but display a more pro-inflammatory M1 phenotype in PE.The ex vivo dual placental perfusion approach uses full term human placentas to study physiological aspects of the placenta.In this study,effects of urban traffic-derived particles of size<2.5μm(PM_(2.5))on placental tissue and HBC polarization was deciphered.To study changes in placental microarchitecture and cell morphology,transmission electron microscopy was applied.In addition,changes in cell surface markers on HBCs were determined by immunohistochemistry.Exposure to PM_(2.5) caused disrupted collagen structures and affected cell organelles in multiple cell types inside placental villi.The resident HBC marker CD163 was not affected by PM_(2.5) exposure,while CD206 was reduced by 60%and CD209 remained unchanged,indicating altered M2 polarization.Additionally,the expression of pro-inflammatory M1 markers CD40(p=0.02)and CD80(p=0.03)in HBCs increased due to urban PM_(2.5) exposure.Urban PM_(2.5) showed detrimental effects on the placenta by disrupting tissue morphology and affecting HBC polarization specifically.These results extend the currently accepted view on properties of HBCs,by demonstrating their ability to react plastically and specifically to different exogenous stimuli.展开更多
Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiolo...Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells,leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species(ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or,and even more likely,due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress,however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover,molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signalingpathways involved in the regulation of immunological,metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response,interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase(IDO) in monocyte-derived macrophages,fibroblasts,endothelial and epithelial cells. Neopterin,a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase Ⅰ in macrophages and dendritic cells. Nitric oxide synthase(NOS) is induced in several cell types to generate nitric oxide(NO). NO,despite its low reactivity,is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin(BH4),which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite(ONOO-) is formed solely in the presence of superoxide anion(O2-). Neopterin and kynurenine to tryptophan ratio(Kyn/Trp),as an estimate of IDO enzyme activity,are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise,a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C,-E and-B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites,BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.展开更多
Lipids exhibit an extraordinary polymorphism in self-assembled mesophases, with lamellar phases as the most relevant biological representative. To mimic lipid lamellar phases with amphiphilic designer peptides, seven ...Lipids exhibit an extraordinary polymorphism in self-assembled mesophases, with lamellar phases as the most relevant biological representative. To mimic lipid lamellar phases with amphiphilic designer peptides, seven systematically varied short peptides were engineered. Indeed, four peptide candidates （V4D, V4WD, V4WD2, I4WD2） readily self-assembled into lamellae in aqueous solution. Small-angle X-ray scattering （SAXS） patterns revealed ordered lamellar structures with a repeat distance of 4-5 nm. Transmission electron microscopy （TEM） images confirmed the presence of stacked sheets. Two derivatives （V3D and V4D2） remained as loose aggregates dispersed in solution; one peptide （L4WD2） formed twisted tapes with internal lameUae and an antiparaUel -type monomer aligrtment. To understand the interaction of peptides with lipids, they were mixed with phosphatidylcholines. Low peptide concentrations （1.1 mM） induced the formation of a heterogeneous mixture of vesicular structures. Large multilamellar vesicles （MLV, d-spacing - 6.3 nm） coexisted with oligo- or unilamellar vesicles （- 50 nm in diameter） and bicelle-like structures （- 45 nm length, - 18 nm width）. High peptide concentrations （11 mM） led to unilamellar vesicles （ULV, diameter - 260-280 nm） with a homogeneous mixing of lipids and peptides. SAXS revealed the temperature-dependent fine structure of these ULVs. At 25 ℃ the bilayer is in a fully Interdigitated state （headgroup-to-headgroup distance dH, -2.9 nm）, whereas at 50 ℃this interdigitation opens up （dtm- 3.6 nm）. Our results highlight the versatility of self-assembled peptide superstructures. Subtle changes in the amino acid composition are key design elements in creating peptide- or lipid- peptide nanostructures with richness in morphology similar to that of naturally occurrin~ lioids.展开更多
Hierarchical self-assembly is a fundamental principle in nature, which gives rise to astonishing supramolecular architectures that are an inspiration for the development of innovative materials in nanotechnolog）a Her...Hierarchical self-assembly is a fundamental principle in nature, which gives rise to astonishing supramolecular architectures that are an inspiration for the development of innovative materials in nanotechnolog）a Here, we present the unique structure of a cone-shaped amphiphilic designer peptide. While tracking its concentration-dependent morphologies, we observed elongated bilayered single tapes at the beginning of the assembly process, which further developed into novel double-helix-like superstructures at high concentrations. This architecture is characterized by a tight intertwisting of two individual helices, resulting in a periodic pitch size over their total lengths of several hundred nanometers. Solution X-ray scattering data revealed a marked 2-layered internal organization. All these characteristics remained unaltered for the investigated period of almost three months. In their collective morphology, the assemblies are integrated into a network with hydrogel characteristics. Such a peptide-based structure holds promise as a building block for next-generation nanostructured biomaterials.展开更多
The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fa...The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity.To date,however,the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood.Here,we report that stearoyl-CoA desaturase-1(SCD1),an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors,acts as an endogenous brake on regulatory T-cell(Treg)differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner.Guided by RNA sequencing and lipidomics analysis,we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase(ATGL).ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma.Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity,with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.展开更多
基金supported by The Swedish Research Council(Vetenskapsrådet,No.314373.35.135949)ALF+3 种基金SUS FoundationRegion Skånes Foundations in Swedensupported through the PhD program Inflammatory Disorders in Pregnancy(DP-iDP)by the Austrian Science Fund FWF(No.Doc 31-B26)the Medical University of Graz,Austria.
文摘Exposure to urban air pollution during early pregnancy is associated with increased risk for adverse pregnancy outcomes,such as preeclampsia(PE),and there is an urgent need to understand how air pollution affects biological mechanisms in the placenta.Hofbauer cells(HBCs)are fetal placental macrophages that regulate immune tolerance in the placenta.They are normally polarized towards an anti-inflammatory M2 phenotype but display a more pro-inflammatory M1 phenotype in PE.The ex vivo dual placental perfusion approach uses full term human placentas to study physiological aspects of the placenta.In this study,effects of urban traffic-derived particles of size<2.5μm(PM_(2.5))on placental tissue and HBC polarization was deciphered.To study changes in placental microarchitecture and cell morphology,transmission electron microscopy was applied.In addition,changes in cell surface markers on HBCs were determined by immunohistochemistry.Exposure to PM_(2.5) caused disrupted collagen structures and affected cell organelles in multiple cell types inside placental villi.The resident HBC marker CD163 was not affected by PM_(2.5) exposure,while CD206 was reduced by 60%and CD209 remained unchanged,indicating altered M2 polarization.Additionally,the expression of pro-inflammatory M1 markers CD40(p=0.02)and CD80(p=0.03)in HBCs increased due to urban PM_(2.5) exposure.Urban PM_(2.5) showed detrimental effects on the placenta by disrupting tissue morphology and affecting HBC polarization specifically.These results extend the currently accepted view on properties of HBCs,by demonstrating their ability to react plastically and specifically to different exogenous stimuli.
文摘Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells,leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species(ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or,and even more likely,due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress,however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover,molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signalingpathways involved in the regulation of immunological,metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response,interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase(IDO) in monocyte-derived macrophages,fibroblasts,endothelial and epithelial cells. Neopterin,a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase Ⅰ in macrophages and dendritic cells. Nitric oxide synthase(NOS) is induced in several cell types to generate nitric oxide(NO). NO,despite its low reactivity,is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin(BH4),which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite(ONOO-) is formed solely in the presence of superoxide anion(O2-). Neopterin and kynurenine to tryptophan ratio(Kyn/Trp),as an estimate of IDO enzyme activity,are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise,a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C,-E and-B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites,BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.
文摘Lipids exhibit an extraordinary polymorphism in self-assembled mesophases, with lamellar phases as the most relevant biological representative. To mimic lipid lamellar phases with amphiphilic designer peptides, seven systematically varied short peptides were engineered. Indeed, four peptide candidates （V4D, V4WD, V4WD2, I4WD2） readily self-assembled into lamellae in aqueous solution. Small-angle X-ray scattering （SAXS） patterns revealed ordered lamellar structures with a repeat distance of 4-5 nm. Transmission electron microscopy （TEM） images confirmed the presence of stacked sheets. Two derivatives （V3D and V4D2） remained as loose aggregates dispersed in solution; one peptide （L4WD2） formed twisted tapes with internal lameUae and an antiparaUel -type monomer aligrtment. To understand the interaction of peptides with lipids, they were mixed with phosphatidylcholines. Low peptide concentrations （1.1 mM） induced the formation of a heterogeneous mixture of vesicular structures. Large multilamellar vesicles （MLV, d-spacing - 6.3 nm） coexisted with oligo- or unilamellar vesicles （- 50 nm in diameter） and bicelle-like structures （- 45 nm length, - 18 nm width）. High peptide concentrations （11 mM） led to unilamellar vesicles （ULV, diameter - 260-280 nm） with a homogeneous mixing of lipids and peptides. SAXS revealed the temperature-dependent fine structure of these ULVs. At 25 ℃ the bilayer is in a fully Interdigitated state （headgroup-to-headgroup distance dH, -2.9 nm）, whereas at 50 ℃this interdigitation opens up （dtm- 3.6 nm）. Our results highlight the versatility of self-assembled peptide superstructures. Subtle changes in the amino acid composition are key design elements in creating peptide- or lipid- peptide nanostructures with richness in morphology similar to that of naturally occurrin~ lioids.
文摘Hierarchical self-assembly is a fundamental principle in nature, which gives rise to astonishing supramolecular architectures that are an inspiration for the development of innovative materials in nanotechnolog）a Here, we present the unique structure of a cone-shaped amphiphilic designer peptide. While tracking its concentration-dependent morphologies, we observed elongated bilayered single tapes at the beginning of the assembly process, which further developed into novel double-helix-like superstructures at high concentrations. This architecture is characterized by a tight intertwisting of two individual helices, resulting in a periodic pitch size over their total lengths of several hundred nanometers. Solution X-ray scattering data revealed a marked 2-layered internal organization. All these characteristics remained unaltered for the investigated period of almost three months. In their collective morphology, the assemblies are integrated into a network with hydrogel characteristics. Such a peptide-based structure holds promise as a building block for next-generation nanostructured biomaterials.
基金supported by the Flemish Fund for Scientific Research(FWO Vlaanderen,12J9116N,12JG119N,12U7718N,1S15519N,and G099618N)the Belgian Charcot Foundation(FCS-2016-EG7,R-8676,and R-6832)+4 种基金the Interreg V‐A EMR program(EURLIPIDS,EMR23)the special research fund UHasselt(BOF)JMN is supported by a National Institutes of Health Grant(R01 DK062388)supported by the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(640116)by a SALK grant from the government of Flanders and by an Odysseus grant of the Research Foundation Flanders,Belgium(FWO).
文摘The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity.To date,however,the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood.Here,we report that stearoyl-CoA desaturase-1(SCD1),an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors,acts as an endogenous brake on regulatory T-cell(Treg)differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner.Guided by RNA sequencing and lipidomics analysis,we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase(ATGL).ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma.Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity,with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.
