Endothelial Lipase Modulates Paraoxonase 1 Content and Arylesterase Activity of HDL

Endothelial lipase (EL) is a strong modulator of the high-density lipoprotein (HDL) structure, composition, and function. Here, we examined the impact of EL on HDL paraoxonase 1 (PON1) content and arylesterase (AE) activity in vitro and in vivo. The incubation of HDL with EL-overexpressing HepG2 cells decreased HDL size, PON1 content, and AE activity. The EL modification of HDL did not diminish the capacity of HDL to associate with PON1 when EL-modified HDL was incubated with PON1-overexpressing cells. The overexpression of EL in mice significantly decreased HDL serum levels but unexpectedly increased HDL PON1 content and HDL AE activity. Enzymatically inactive EL had no effect on the PON1 content of HDL in mice. In healthy subjects, EL serum levels were not significantly correlated with HDL levels. However, HDL PON1 content was positively associated with EL serum levels. The EL-induced changes in the HDL-lipid composition were not linked to the HDL PON1 content. We conclude that primarily, the interaction of enzymatically active EL with HDL, rather than EL-induced alterations in HDL size and composition, causes PON1 displacement from HDL in vitro. In vivo, the EL-mediated reduction of HDL serum levels and the consequently increased PON1-to-HDL ratio in serum increase HDL PON1 content and AE activity in mice. In humans, additional mechanisms appear to underlie the association of EL serum levels and HDL PON1 content.

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Liver X Receptor Nuclear Receptors Are Transcriptional Regulators of Dendritic Cell Chemotaxis

Molecular and Cellular Biology ◽

10.1128/mcb.00534-17 ◽

2018 ◽

Vol 38 (10) ◽

Cited By ~ 13

Author(s):

Susana Beceiro ◽

Attila Pap ◽

Zsolt Czimmerer ◽

Tamer Sallam ◽

Jose A. Guillén ◽

...

Keyword(s):

Nuclear Receptors ◽

Low Density Lipoprotein ◽

Myeloid Cells ◽

Density Lipoprotein ◽

Loss Of Function ◽

Transcriptional Responses ◽

Cd38 Expression ◽

The Impact

ABSTRACTThe liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DCs), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migrationin vitroandin vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished the LXR-dependent induction of DC chemotaxis. Using the low-density lipoprotein receptor-deficient (LDLR−/−) LDLR−/−mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for the efficient emigration of DCs in response to chemotactic signals during inflammation.

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Bovine sperm-oviduct interactions are characterized by specific sperm behaviour, ultrastructure and tubal reactions which are impacted by sex sorting

Scientific Reports ◽

10.1038/s41598-020-73592-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Miguel Camara Pirez ◽

Heather Steele ◽

Sven Reese ◽

Sabine Kölle

Keyword(s):

Beat Frequency ◽

Ciliary Beat Frequency ◽

Sperm Binding ◽

Tail Movement ◽

Bovine Spermatozoa ◽

Sperm Reservoir ◽

And Function ◽

The Impact

Abstract To date sperm-oviduct interactions have largely been investigated under in vitro conditions. Therefore we set out to characterize the behaviour of bovine spermatozoa within the sperm reservoir under near in vivo conditions and in real-time using a novel live cell imaging technology and a newly established fluorescent sperm binding assay. Sperm structure and tubal reactions after sperm binding were analysed using scanning and transmission electron microscopy and histochemistry. As a model to specify the impact of stress on sperm-oviduct interactions, frozen-thawed conventional and sex-sorted spermatozoa from the same bulls (n = 7) were co-incubated with oviducts obtained from cows immediately after slaughter. Our studies revealed that within the oviductal sperm reservoir agile (bound at a tangential angle of about 30°, actively beating undulating tail), lagging (bound at a lower angle, reduced tail movement), immotile (absence of tail movement) and hyperactivated (whip-like movement of tail) spermatozoa occur, the prevalence of which changes in a time-dependent pattern. After formation of the sperm reservoir, tubal ciliary beat frequency is significantly increased (p = 0.022) and the epithelial cells show increased activity of endoplasmic reticula. After sex sorting, spermatozoa occasionally display abnormal movement patterns characterized by a 360° rotating head and tail. Sperm binding in the oviduct is significantly reduced (p = 0.008) following sexing. Sex-sorted spermatozoa reveal deformations in the head, sharp bends in the tail and a significantly increased prevalence of damaged mitochondria (p < 0.001). Our results imply that the oviductal cells specifically react to the binding of spermatozoa, maintaining sperm survival within the tubal reservoir. The sex-sorting process, which is associated with mechanical, chemical and time stress, impacts sperm binding to the oviduct and mitochondrial integrity affecting sperm motility and function.

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IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients

Blood ◽

10.1182/blood-2005-06-2399 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2409-2414 ◽

Cited By ~ 433

Author(s):

Mojgan Ahmadzadeh ◽

Steven A. Rosenberg

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Interleukin 2 ◽

Selective Inhibition ◽

High Dose ◽

Protein Levels ◽

And Function ◽

The Impact

Abstract Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

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Paraoxonase-1 (PON-1) genotype and activity and in vivo oxidized plasma low-density lipoprotein in Type II diabetes

Clinical Science ◽

10.1042/cs20050089 ◽

2005 ◽

Vol 109 (2) ◽

pp. 189-197 ◽

Cited By ~ 26

Author(s):

Mike J. Sampson ◽

Simon Braschi ◽

Gavin Willis ◽

Sian B. Astley

Keyword(s):

Type Ii Diabetes ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Paraoxonase 1 ◽

Ldl Oxidation ◽

Phenyl Acetate ◽

Low Density ◽

Type Ii

The HDL (high-density lipoprotein)-associated enzyme PON (paraoxonase)-1 protects LDL (low-density lipoprotein) from oxidative modification in vitro, although it is unknown if this anti-atherogenic action occurs in vivo. In a cross-sectional study of 58 Type II diabetic subjects and 50 controls, we examined the fasting plasma LDL basal conjugated diene concentration [a direct measurement of circulating oxLDL (oxidatively modified LDL)], lipoprotein particle size by NMR spectroscopy, PON-1 polymorphisms (coding region polymorphisms Q192R and L55M, and gene promoter polymorphisms −108C/T and −162G/A), PON activity (with paraoxon or phenyl acetate as the substrates) and dietary antioxidant intake. Plasma oxLDL concentrations were higher in Type II diabetic patients (males, P=0.048; females, P=0.009) and unrelated to NMR lipoprotein size, PON-1 polymorphisms or PON activity (with paraoxon as the substrate) in any group. In men with Type II diabetes, however, there was a direct relationship between oxLDL concentrations and PON activity (with phenyl acetate as the substrate; r=0.611, P=0.0001) and an atherogenic NMR lipid profile in those who were PON-1 55LL homozygotes. Circulating oxLDL concentrations in vivo were unrelated to PON-1 genotypes or activity, except in male Type II diabetics where there was a direct association between PON activity (with phenyl acetate as the substrate) and oxLDL levels. These in vivo data contrast with in vitro data, and may be due to confounding by dietary fat intake. Male Type II diabetic subjects with PON-1 55LL homozygosity have an atherogenic NMR lipid profile independent of LDL oxidation. These data do not support an in vivo action of PON on LDL oxidation.

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Long term exposure of human gut microbiota with high and low emulsifier sensitivity to soy lecithin in M-SHIME model.

10.1101/2021.12.16.472798 ◽

2021 ◽

Author(s):

Lisa Miclotte ◽

Ellen De Paepe ◽

Qiqiong Li ◽

Andreja Rajkovic ◽

John Van Camp ◽

...

Keyword(s):

Gut Microbiota ◽

Day Treatment ◽

Treatment Phase ◽

Microbial Composition ◽

Soy Lecithin ◽

Potential Health ◽

And Function ◽

The Impact

In the context of the potential health hazards related to food processing, dietary emulsifiers have been shown to alter the structure and function of the gut microbial community, both in vivo and in vitro. In mouse models, these emulsifier exposed gut microbiota were shown to contribute to gut inflammation. Several knowledge gaps remain to be addressed though. As such, the impact from a longer timeframe of exposure on the gut microbiota is not known and interindividual variability in microbiome response needs to be measured. To answer these research questions, in this study the faecal microbiota from two individuals, previously selected for high and low emulsifier sensitivity, were exposed to two concentrations of soy lecithin during a 7 day treatment phase in the dynamic mucosal simulator of the human intestinal microbial ecosystem (M-SHIME). The results showed mild effects from soy lecithin on the composition and functionality of these microbial communities, which depended on the original microbial composition. The effects also mostly levelled off after 3 days of exposure. The emulsifier sensitivity for which the microbiota were selected, was preserved. Some potentially concerning effects were also registered: butyrate levels, positively correlating with Faecalibacterium abundance, were lowered by soy lecithin. Also the abundance of the beneficial Bifidobacterium genus was lowered, while the abundance of the notorious unclassified Enterobacteriaceae was increased. Within the family of the unclassified Lachnospiraceae, several genera were either suppressed or stimulated. The effects that these microbial alterations would have on a living host is not yet certain, especially given the fact that large fractions of soy lecithins constituents can be absorbed. Nevertheless, choline and phosphatidylcholine, both primary and absorbable constituents of soy lecithin, have recently been linked to cardiovascular disease via the generation of TMA by the gut microbiota. Further studies that validate our findings and link them to potential health outcomes are thus justified.

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Dysfunctional high-density lipoprotein: the role of myeloperoxidase and paraoxonase-1

Current Medicinal Chemistry ◽

10.2174/0929867327999200716112353 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Tiziana Bacchetti ◽

Gianna Ferretti ◽

Federico Carbone ◽

Stefano Ministrini ◽

Fabrizio Montecucco ◽

...

Keyword(s):

Metabolic Syndrome ◽

Protective Factor ◽

Density Lipoprotein ◽

High Density ◽

Paraoxonase 1 ◽

High Density Lipoproteins ◽

Atherosclerotic Cardiovascular Disease ◽

Potential Marker ◽

And Function

: Low circulating high-density lipoproteins (HDL) are not only a defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte-derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation, and then acts as a protective factor against ASCVD. Noteworthy, recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview on in vitro and experimental animal models, finally focusing on clinical evidence from cohort of patients with ASCVD and metabolic syndrome.

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Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0227 ◽

2014 ◽

Vol 92 (11) ◽

pp. 927-935 ◽

Cited By ~ 21

Author(s):

Wenhe Zhu ◽

Changwen Wang ◽

Lei Liu ◽

Yan Li ◽

Xiaokun Li ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Cell Damage ◽

Density Lipoprotein ◽

Serum Levels ◽

Lipoprotein Cholesterol ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth

Fibroblast growth factor 21 (FGF-21), which is a modulator of glucose and lipid homeostasis, acts as a novel therapeutic reagent for many metabolic perturbations. However, its potential as a treatment for cardiovascular disease, especially atherosclerosis (AS) has not been fully explored. Here, we report that recombinant FGF-21 improves resistance to cell damage from oxidative stress in vitro, and from atherosclerosis in vivo. Human umbilical vein endothelial cells (HUVECs) were induced with H2O2, followed by treatment with high purity recombinant FGF-21. The results indicated that FGF-21 significantly enhanced cell viability and decreased the degree of DNA fragmentation in HUVECs, as caused by H2O2 stress induction. Further studies revealed that FGF-21 inhibited H2O2-induced cell apoptosis by preventing the activation of mitogen-activated protein kinase (MAPK) signaling pathways. In an established rat model, FGF-21 dramatically improved the condition of atherosclerotic rats by decreasing serum levels of total triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and total cholesterol (TC), and by increasing the serum levels of high density lipoprotein cholesterol (HDL-C). FGF-21 also has antioxidant effects in the atherosclerotic rat, such that increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde were observed. These data provide novel insight into the potential use of FGF-21 in the prevention and treatment of human cardiovascular diseases.

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The Cholesterol-Lowering Effect of Alisol Acetates Based on HMG-CoA Reductase and Its Molecular Mechanism

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/4753852 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Fei Xu ◽

Hui Yu ◽

Cai Lu ◽

Jun Chen ◽

Wei Gu

Keyword(s):

Molecular Simulation ◽

Reductase Activity ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Hmg Coa Reductase ◽

Coa Reductase ◽

The Impact

This study measured the impact of alisol B 23-acetate and alisol A 24-acetate, the main active ingredients of the traditional Chinese medicine Alismatis rhizoma, on total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) levels of hyperlipidemic mice. The binding of alisol B 23-acetate and alisol A 24-acetate to the key enzyme involved in the metabolism of TC, 3-hydroxy-3-methylglutary-coenzyme A (HMG-CoA) reductase, was studied using the reagent kit method and the western blotting technique combined with a molecular simulation technique. According to the results, alisol acetates significantly lower the TC, TG, and LDL-C concentrations of hyperlipidemic mice, while raising HDL-C concentrations. Alisol acetates lower HMG-CoA reductase activity in a dose-dependent fashion, both in vivo and in vitro. Neither of these alisol acetates significantly lower the protein expression of HMG-CoA. This suggests that alisol acetates lower the TC level via inhibiting the activity of HMG-CoA reductase by its prototype drug, which may exhibit an inhibition effect via directly and competitively binding to HMG-CoA. The side chain of the alisol acetate was the steering group via molecular simulation.

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Development and Physiological Functions of the Lymphatic System - Insights from Genetic Studies of Lymphedema

Physiological Reviews ◽

10.1152/physrev.00006.2020 ◽

2021 ◽

Author(s):

Silvia Martin-Almedina ◽

Peter Mortimer ◽

Pia Ostergaard

Keyword(s):

Lymphatic System ◽

Imaging Techniques ◽

The Body ◽

Genetic Studies ◽

Disease Mechanisms ◽

Primary Lymphedema ◽

And Function ◽

The Impact

Primary lymphedema is a long-term (chronic) condition characterized by tissue lymph retention and swelling that can affect any part of the body, although it usually develops in the arms or legs. Due to the relevant contribution of the lymphatic system to human physiology, while this review mainly focusses on the clinical and physiological aspects related to the regulation of fluid homeostasis and edema, clinicians need to know that the impact of lymphatic dysfunction with a genetic origin can be wide ranging. Lymphatic gene dysfunction can affect immune function so leading to infection; it can influence cancer development and spread; and it can determine fat transport so impacting on nutrition and obesity. Genetic studies and the development of imaging techniques for the assessment of lymphatic function have enabled the recognition of primary lymphedema as a heterogenic condition in terms of genetic causes and disease mechanisms. In this review, the known biological function of several genes crucial to the development and function of the lymphatic system are used as a basis for understanding normal lymphatic biology. The disease conditions originating from mutations in these genes are discussed together with a detailed clinical description of the phenotype and the up-to-date knowledge in terms of disease mechanisms acquired from in vitro and in vivo research models.

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Artificial skin composites

Annales Universitatis Mariae Curie-Sklodowska sectio AA – Chemia ◽

10.17951/aa.2018.73.1.51-60 ◽

2019 ◽

Vol 73 (1) ◽

pp. 51

Author(s):

Agata Ładniak

Keyword(s):

Wound Dressings ◽

Skin Damage ◽

Skin Substitutes ◽

Significant Deterioration ◽

Form And Function ◽

Potential Applications ◽

And Function ◽

The Impact

Skin injuries are a health problem and can lead to serious, significant deterioration in the quality of life and, consequently, even illness and disability. Therefore, after wounding, immediate regeneration of the tissue is necessary to avoid further complications and pathogenesis. Consequently, many wound healing strategies have been developed, leading to the progress in constructing of multifunctional tissue substitutes for the skin, biomembranes, scaffolds and intelligent dressings. The field of science focusing on the creation of the above-mentioned products is tissue engineering (TE). Its main goal is to find a system that is able to replace or be a model that perfectly mimics the form and function of the skin. Research carried out on such constructs is mainly based on the analysis of mechanical properties (porosity, elasticity), as well as the assessment of the impact of individual components on processes related to the formation of new tissue as cell proliferation and differentiation, proliferation, angiogenesis - through in vivo studies (using animal models: mice, New Zealand rabbits) and in vitro (most often using mouse fibroblasts - L929). Skin constructions may have potential applications as wound dressings or skin substitutes in cases of severe skin damage.

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