Abstract 126: Effects of Rosuvastatin on the Protein Composition of Lipoprotein Subfractions

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Scott M Gordon ◽  
Georgina Kemeh ◽  
Michael B Fessler ◽  
Alan T Remaley
Keyword(s):  
Lipoprotein Metabolism ◽  
Protein Composition ◽  
Protein Detection ◽  
Fold Increase ◽  
Cholesterol Content ◽  
Vascular Lesions ◽  
Lipid Lowering ◽  
Lipoprotein Subfractions ◽  
The Impact

Introduction: Statins, by inhibiting HMG-CoA reductase and up regulating hepatic LDL receptors, effectively lower plasma LDL-C by as much as 50%, thus reducing future CVD events. However, the physiological effects of statins are diverse and not all are related to lowering of LDL-C. Goal: The goal of this study was to test our hypothesis that some of these pleiotropic alternative effects from statins may be driven by compositional changes to lipoproteins distinct from their cholesterol content. We, therefore, performed a small clinical pilot study to assess the impact of statins on lipoprotein associated proteins in healthy individuals. Methods: Ten subjects with normal LDL-C (<130 mg/dL) were given rosuvastatin (20 mg/day) for 28 days. Plasma samples collected at baseline and after treatment were used for lipid measurement, nuclear magnetic resonance (NMR) lipoprotein profiling and lipoprotein proteomics. Results: The effects of rosuvastatin treatment on clinical lipid measures and NMR profile were consistent with established findings. Proteomic analysis of FPLC fractions representing LDL, HDL-1 (large) and HDL-2 (small) identified a total of 124 different proteins. Spectral counting was used to compare relative protein detection before and after statin therapy. Significant protein changes were found in each lipoprotein pool: LDL = 9, HDL-1 = 9 and HDL-2 = 4. These changes included both increases and decreases in proteins involved in lipoprotein metabolism, complement regulation and acute phase response. The most dramatic effect of the treatment was a profound increase in alpha-1-antirypsin (A1AT) spectral counts association with HDL-1 particles. Quantitative measurement by ELISA revealed an average 5.7 fold increase in HDL-1 associated A1AT. Preliminary in vitro studies indicate a potential functional role for A1AT enriched HDL in the formation of neutrophil extracellular traps (NETs), a pro-inflammatory component of vascular lesions. Summary: Based on these results, statins can significantly change the protein composition of both LDL and HDL. Some of these changes, such as the up regulation of A1AT on HDL, may convey anti-inflammatory functionality on lipoproteins and might contribute to some of the non-lipid lowering effects of statins.

scholarly journals Natural Variation Can Significantly Alter the Sensitivity of Influenza A (H5N1) Viruses to Oseltamivir

2006 ◽  
Vol 50 (11) ◽  
pp. 3809-3815 ◽  
Author(s):  
M. A. Rameix-Welti ◽  
F. Agou ◽  
P. Buchy ◽  
S. Mardy ◽  
J. T. Aubin ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza Pandemic ◽  
Fold Increase ◽  
Influenza Viruses ◽  
Control Measures ◽  
Inhibition Assay ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
The Impact

ABSTRACT Geographic spread of highly pathogenic avian H5N1 influenza viruses may give rise to an influenza pandemic. During the first months of a pandemic, control measures would rely mainly on antiviral drugs, such as the neuraminidase (NA) inhibitors oseltamivir and zanamivir. In this study, we compare the sensitivities to oseltamivir of the NAs of several highly pathogenic H5N1 viruses isolated in Asia from 1997 to 2005. The corresponding 50% inhibitory concentrations were determined using a standard in vitro NA inhibition assay. The Km for the substrate and the affinity for the inhibitor (Ki ) of NA were determined for a 1997 and a 2005 virus, using an NA inhibition assay on cells transiently expressing the viral enzyme. Our data show that the sensitivities of the NAs of H5N1 viruses isolated in 2004 and 2005 to oseltamivir are about 10-fold higher than those of earlier H5N1 viruses or currently circulating H1N1 viruses. Three-dimensional modeling of the N1 protein predicted that Glu248Gly and Tyr252His changes could account for increased sensitivity. Our data indicate that genetic variation in the absence of any drug-selective pressure may result in significant variations in sensitivity to anti-NA drugs. Although the clinical relevance of a 10-fold increase in the sensitivity of NA to oseltamivir needs to be investigated further, the possibility that sensitivity to anti-NA drugs could increase (or possibly decrease) significantly, even in the absence of treatment, underscores the need for continuous evaluation of the impact of genetic drift on this parameter, especially for influenza viruses with pandemic potential.

scholarly journals Targeting the Inflammatory Niche in MDS By Tasquinimod Restores Hematopoietic Support and Suppresses Immune-Checkpoint Expression in Vitro

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2596-2596
Author(s):  
Manja Wobus ◽  
Ekaterina Balaian ◽  
Uta Oelschlaegel ◽  
Russell Towers ◽  
Kristin Möbus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mrna Expression ◽  
Immunohistochemical Staining ◽  
Research Funding ◽  
Fold Increase ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
Healthy Donors ◽  
The Impact

Abstract Introduction Myelodysplastic syndromes (MDS) belong to the most common hematological neoplasms in the elderly population, characterized by ineffective hematopoiesis, peripheral cytopenia and the risk of transformation into acute myeloid leukemia. There is increasing evidence that an aberrant innate immune response and a proinflammatory bone marrow (BM) microenvironment play a critical role in the pathogenesis of MDS. The alarmin S100A9, a key player for regulation of inflammatory responses, has been shown to be elevated in MDS patients. It directs an inflammatory cell death (pyroptosis) by increased NF-kB mediated transcription and secretion of proinflammatory, hematopoiesis-inhibitory cytokines and production of reactive oxygen species. Tasquinimod (TASQ, Active Biotech) is a novel, oral small molecular drug with S100A9 inhibitory activity and it is currently investigated in a phase Ib/IIa trial in relapsed/refractory multiple myeloma (NCT04405167). TASQ has demonstrated anti-angiogenic, antitumor and immunomodulatory properties in a broad range of preclinical solid tumor models; however, little is known about its effects in myeloid malignancies. Aim We investigated the role of S100A9 in cellular models of MDS and the potential of TASQ to target S100A9 within the MDS stroma in vitro. Methods Immunohistochemical staining of S100A9, CD271+ mesenchymal stromal cells (MSCs), CD68+ macrophages and CD66b+ neutrophils in BM tissues from MDS patients and healthy donors was performed with multiplex immunohistochemistry and analyzed with the VECTRA imaging system. MSCs from patients with either low-risk MDS, CMML or age-adjusted healthy donors were exposed to S100A9 (1.5µg/ml) in the presence or absence of TASQ (10µM). Subsequently, TLR4 downstreaming molecules such as IRAK1, gasdermin and NF-kB-p65 were analyzed by Western blot. Moreover, the mRNA expression of further proinflammatory molecules (IL-1b, IL-18, caspase1) and PD-L1 was quantified by real-time PCR. To study the impact on the hematopoietic support, MSCs were pre-treated for one week with S100A9 ± TASQ before CD34+ hematopoietic stem and progenitor cells (HSPCs) were seeded on the stromal layer. The colony formation (CAF-C) was analyzed weekly followed by a CFU-GEMM assay in methylcellulose medium. Additionally, PD-1 mRNA expression was quantified in cocultured HSPCs. Results Immunohistochemical staining of BM tissue demonstrated S100A9 expression mainly by CD66b+ neutrophils and with less extent by CD68+ macrophages. In line with this, we could not detect relevant S100A9 mRNA expression in cultured MDS or healthy MSCs in vitro. Exposure of MDS and healthy MSCs with S100A9 induced TLR4 downstream signalling as demonstrated by increased expression of IRAK1 and NF-kB-p65. We further detected a higher expression of gasdermin, an inductor of pyroptosis, in S100A9 exposed MSCs. Addition of TASQ abolished these effects and inhibited the expression of the mentioned proteins, indicating an alleviation of inflammation. Furthermore, we detected a 2-fold increase of mRNA expression of the proinflammatory cytokines IL-1b and IL-18 as well as a 5-fold increase of their activator caspase 1 in MSCs after treatment with S100A9, which could be prevented by TASQ. Interestingly, PD-L1 as a potential downstream target was induced by S100A9 by 2.5-fold and could be suppressed by TASQ to about 50%. To evaluate the impact on the hematopoietic support of MSCs, we analysed MSC/HSPC cocultures after treatment with S100A9. We observed a decreased number of cobblestone area forming cells (CAF-C) as well as reduced numbers of colonies (CFU) in a subsequent clonogenic assay, indicating a disturbed hematopoietic support by S100A9 treated MSCs. Interestingly, both the number of CAF-C and CFU could be increased by TASQ pre-treatment. Finally, the PD-1 expression in co-cultured HSPCs was regulated in the same way as its ligand in treated MSCs, nominating this interaction as a potential target of S100A9/TASQ in the MDS BM. Conclusion In summary, we provide evidence that the pathological inflammasome activation in the myelodysplastic bone marrow can be rescued by TASQ at least in part by inhibition of the S100A9 mediated TLR4 downstream signalling including NF-kB-p65 transcription and PD-L1 expression. These effects result in an improved hematopoietic support by MSCs, suggesting a potential efficacy to improve cytopenia in low-risk MDS patients. Disclosures Balaian: Novartis: Honoraria. Törngren: Active Biotech: Current Employment. Eriksson: Active Biotech: Current Employment. Platzbecker: AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Geron: Honoraria. Röllig: Novartis: Honoraria, Research Funding; Jazz: Honoraria; Janssen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

scholarly journals Current and Emerging Reconstituted HDL-apoA-I and HDL-apoE Approaches to Treat Atherosclerosis

2018 ◽  
Vol 8 (4) ◽  
pp. 34 ◽  
Author(s):  
Eftaxia-Konstantina Valanti ◽  
Katerina Dalakoura-Karagkouni ◽  
Despina Sanoudou
Keyword(s):  
Therapeutic Potential ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Research Direction ◽  
Lipid Lowering ◽  
Therapeutic Approaches ◽  
Low Density Lipoprotein Cholesterol ◽  
Native Plasma

Atherosclerosis affects millions of people worldwide. However, the wide variety of limitations in the current therapeutic options leaves much to be desired in future lipid-lowering therapies. For example, although statins, which are the first-line treatment for coronary heart disease (CHD), reduce the risk of cardiovascular events in a large percentage of patients, they lead to optimal levels of low density lipoprotein-cholesterol (LDL-C) in only about one-third of patients. A new promising research direction against atherosclerosis aims to improve lipoprotein metabolism. Novel therapeutic approaches are being developed to increase the levels of functional high density lipoprotein (HDL) particles. This review aims to highlight the atheroprotective potential of the in vitro synthesized reconstituted HDL particles containing apolipoprotein E (apoE) as their sole apolipoprotein component (rHDL-apoE). For this purpose, we provide: (1) a summary of the atheroprotective properties of native plasma HDL and its apolipoprotein components, apolipoprotein A-I (apoA-I) and apoE; (2) an overview of the anti-atherogenic functions of rHDL-apoA-I and apoA-I-containing HDL, i.e., natural HDL isolated from transgenic Apoa1−/− × Apoe−/− mice overexpressing human apoA-I (HDL-apoA-I); and (3) the latest developments and therapeutic potential of HDL-apoE and rHDL-apoE. Novel rHDL formulations containing apoE could possibly present enhanced biological functions, leading to improved therapeutic efficacy against atherosclerosis.

scholarly journals The Positive Association between Plasma Myristic Acid and ApoCIII Concentrations in Cardiovascular Disease Patients Is Supported by the Effects of Myristic Acid in HepG2 Cells

2020 ◽  
Vol 150 (10) ◽  
pp. 2707-2715 ◽  
Author(s):  
Oliviero Olivieri ◽  
Giulia Speziali ◽  
Annalisa Castagna ◽  
Patrizia Pattini ◽  
Silvia Udali ◽  
...  
Keyword(s):  
Myristic Acid ◽  
Hepg2 Cells ◽  
Plasma Lipids ◽  
Plasma Concentrations ◽  
Plasma Lipid ◽  
Positive Association ◽  
Fold Increase ◽  
Lipid Lowering ◽  
In Vitro Experiments

ABSTRACT Background In the settings of primary and secondary prevention for coronary artery disease (CAD), a crucial role is played by some key molecules involved in triglyceride (TG) metabolism, such as ApoCIII. Fatty acid (FA) intake is well recognized as a main determinant of plasma lipids, including plasma TG concentration. Objectives The aim was to investigate the possible relations between the intakes of different FAs, estimated by their plasma concentrations, and circulating amounts of ApoCIII. Methods Plasma samples were obtained from 1370 subjects with or without angiographically demonstrated CAD (mean ± SD age: 60.6 ± 11.0 y; males: 75.8%; BMI: 25.9 ± 4.6 kg/m2; CAD: 73.3%). Plasma lipid, ApoCIII, and FA concentrations were measured. Data were analyzed by regression models adjusted for FAs and other potential confounders, such as sex, age, BMI, diabetes, smoking, and lipid-lowering therapies. The in vitro effects of FAs were tested by incubating HepG2 hepatoma cells with increasing concentrations of selected FAs, and the mRNA and protein contents in the cells were quantified by real-time RT-PCR and LC-MS/MS analyses. Results Among all the analyzed FAs, myristic acid (14:0) showed the most robust correlations with both TGs (R = 0.441, P = 2.6 × 10−66) and ApoCIII (R = 0.327, P = 1.1 × 10−31). By multiple regression analysis, myristic acid was the best predictor of both plasma TG and ApoCIII variability. Plasma TG and ApoCIII concentrations increased progressively at increasing concentrations of myristic acid, independently of CAD diagnosis and gender. Consistent with these data, in the in vitro experiments, an ∼2-fold increase in the expression levels of the ApoCIII mRNA and protein was observed after incubation with 250 μM myristic acid. A weaker effect (∼30% increase) was observed for palmitic acid, whereas incubation with oleic acid did not affect ApoCIII protein or gene expression. Conclusions Plasma myristic acid is associated with increased ApoCIII concentrations in cardiovascular patients. In vitro experiments indicated that myristic acid stimulates ApoCIII expression in HepG2 cells.

Abnormalities in Lipoprotein Metabolism Provide Insight into Novel Therapeutic Approaches for Waldenstrom’s Macroglobulinemia (WM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4749-4749 ◽  
Author(s):  
Christopher J. Patterson ◽  
Anne Sophie Moreau ◽  
Xavier Leleu ◽  
Jacob Soumerai ◽  
Zachary Hunter ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Surrogate Marker ◽  
Lipoprotein Metabolism ◽  
Median Number ◽  
Lipid Lowering ◽  
Dependent Manner ◽  
Growth And Survival ◽  
Lipid Lowering Agent ◽  
Induced Apoptosis ◽  
The Impact

Abstract WM is an incurable B-cell disorder characterized by the presence of lymphoplasmacytic cells in the bone marrow and an IgM monoclonal protein. The presence of hypocholesterolemia has often been observed in WM patients, though the incidence and significance has not been investigated. As part of these studies, we evaluated lipoprotein levels in 110 patients with WM. The median age for this cohort was 62, and median number of prior therapies was 1. Twenty-one (19.1%) patients were on a lipid-lowering agent (lovastatin, simvastatin, pravastatin). We observed decreased total cholesterol (&lt;160 mg/dL), LDL (&lt;100 mg/dL) and VLDL (&lt;40 mg/dL) levels in 41 (37.3%), 68 (61.8%) and 90 (81.8%) patients, respectively. Among the 41 patients with a cholesterol level of &lt;160 mg/dL, only 7 patients were on a lipid lowering agent. Importantly, median serum IgM levels which serve as a surrogate marker for WM disease burden were higher among patients with hypocholesterolemia (3440 vs. 1587 mg/dL; p=0.0004). Moreover, significantly lower levels of serum IgM (885 vs. 1960 mg/dL; p=0.004) were observed among patients on a lipid-lowering agent. Given these results, which suggested a possible disease dependency on cholesterol metabolism, as well as possible anti-tumor effect of statins, we explored the impact of two statins (lovastatin, simvastatin) on the growth and survival of BCWM.1 WM cells. The studies demonstrated that both lovastatin and simvastatin inhibited proliferation (by MTT assay), and induced apoptosis (by Annexin-PI assay) in a dose dependent manner (0.5–50 um) at concentrations that overlapped pharmacologically achievable levels. Taken together, these studies suggest that lipoprotein metabolism may be essential for WM growth and survival, and that statin agents may represent clinically useful agents for the treatment of WM.

scholarly journals Improved Tissue Culture Conditions for Engineered Skeletal Muscle Sheets

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Sara Hinds ◽  
Natalia Tyhovych ◽  
Clint Sistrunk ◽  
Louis Terracio
Keyword(s):  
Skeletal Muscle ◽  
Fold Increase ◽  
Culture Conditions ◽  
Neonatal Rat ◽  
Skeletal Myoblasts ◽  
Potential Clinical Utility ◽  
Cell Subpopulations ◽  
The Impact ◽  
Muscle Precursor Cells

The potential clinical utility of engineered muscle is currently restricted by limitedin vitrocapacity of expanded muscle precursor cells to fuse and form mature myofibers. The purpose of this study was to use isotropic skeletal muscle sheets to explore the impact of (1) fibroblast coculture and (2) fibroblast-conditioned media (fCM) onin vitromyogenesis. Muscle sheets were prepared by seeding varying ratios of skeletal myoblasts and fibroblasts on a biomimetic substrate and culturing the resulting tissue in either control media or fCM. Muscle sheets were prepared from two cell subpopulations, (1) C2C12 and NOR-10 and (2) primary neonatal rat skeletal muscle cells (nSKM). In C2C12/Nor-10 muscle sheets fCM conferred a myogenic advantage early in culture; at D1 a statistically significant 3.12 ± 0.8-fold increase in myofiber density was observed with fCM. A high purity satellite cell population was collected from an initially mixed population of nSKMs via cell sorting for positiveα7-integrin expression. On D6, tissue sheets with low fibroblast concentrations (0 & 10%) cultured in fCM had increased average myofiber density (4.8 ± 0.2 myofibers/field) compared to tissue sheets with high fibroblast concentrations (50%) cultured in control media (1.0 ± 0.1 myofibers/field). Additionally, fCM promoted longer, thicker myofibers with a mature phenotype.

Lenalidomide Administered for the Initial Treatment of Chronic Lymphocytic Leukemia (CLL) Patients- In Vivo Modulation of the Leukemia Cell Surface Phenotype and Association with Tumor Flare Reaction (TFR).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3440-3440
Author(s):  
Danelle James ◽  
Esther D Avery ◽  
Ling Zhang ◽  
Jamie Gould ◽  
Andrew Greaves ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Chemokine Receptors ◽  
Cell Activation ◽  
Fold Increase ◽  
Cxcr4 Expression ◽  
Leukemia Cells ◽  
B Cell Activation ◽  
The Impact

Abstract Abstract 3440 Poster Board III-328 Lenalidomide (L), an oral immunomodulatory agent used for the treatment of MM and MDS and has clinical activity in patients (pts) with relapsed/refractory CLL. When administered to CLL pts L is often associated with a TFR. TFR is painful enlargement of the lymph nodes and/or spleen. The mechanism of TFR is unknown. Previous reports have demonstrated upregulation of costimulatory molecules on leukemia cells with in-vitro L exposure. This led to the hypothesis that B cell activation is responsible for the TFR, possibly allowing for greater immune responses and infiltration of the lymph nodes/ spleen with inflammatory cells. Another hypothesis is that TFR results from the modulation of chemokine receptors allowing malignant lymphocytes to experience greater homing to the lymph nodes. We designed a phase II study to evaluate the efficacy and tolerability of L and rituximab as initial therapy of CLL. This previously untreated pt population provides a fairly homogenous population to assess the impact of in-vivo L treatment on CLL cells and test these hypotheses. To assess the impact of L on the CLL cells we designed a 3 week L run-in and performed ex-vivo analysis of the CLL cells prior to rituximab. All pts received L 2.5mg daily for the first 7 days and were escalated to 5 mg if they lacked significant toxicity on day 8. 20 pts have been enrolled on study and received at least 3 weeks of L. We report the early results of corollary science phenotyping the leukemia cells of 12 pts through the relative expression of a number of surface markers prior to and 21 days post initiation L. 9 of these pts experienced the TFR and 3 did not. 7 pts were on 5mg of L on day 21 and 5 on 2.5mg. Leukemia cells were stained for CD19, CD20 and chemokine receptors CXCR4, CXCR5, and CCR7 and for costimulatory molecules CD40, CD80, CD86, and CD54. Mean fluorescent intensity (MFI) was determined on CD19+ lymphocytes. MFI ratio (MFIR) was calculated by dividing the MFI for each stain by the isotype control of the respective sample. Two-sided student t test were used to assess statistical significance. Increased expression of CD40 was observed in 9/12 pts, (MFIR p 0.09) including 7/9 pts with TFR. Mean fold increase of CD40 MFIR for those with TFR was 1.13 compared with 1.26 in those without TFR (p = NS). CD86 increased in 6/12 including all 3 pts who did not experience TFR. Mean fold increase of CD86 MFIR for those with TFR was 1.11 and 1.6 in those without TFR (p = NS). CD80 MFIR increased slightly above pretreatment levels in 3/12 pts (3/9 with TFR). CD54 (ICAM) was evaluated in 9 pts and increased in 6. Median MFIR of CD54 following in vivo L increased from 14.7 to 24.8 (p = 0.066). Mean fold increase of CD54 MFIR for 2 pts without TFR was 2.08 compared with 1.82 for those with TFR (p= NS). MFIR for CXCR4 decreased in 10/12 pts during L including 8/9 pts with TFR. Median MFIR for CXCR4 prior to treatment was 67.9 and decreased to 37.5 (p = 0.024). Pts who experienced TFR had a more pronounced decrease in CXCR4 expression with MFIRs following L treatment mean 56% of pretreatment levels compared to the pts without TFR at 72% (p = NS). To assess if decreased CXCR4 expression could be the result of CLL cells mobilized from microenvironment niches we assessed the density of CXCR4 on 4 pts. All 4 pts had an increase in the population of CD19+ cells with dim CXCR4 expression from 10.2% prior to therapy to 26.4% following L (p = 0.058). MFIR for CXCR5 decreased in 9/12 pts (7/9 with TFR). For the 12 pts median CXCR5 MFIR 122.8 prior to treatment and 75.3 following 21 days of L (p = 0.045). Median MFIR for those who did or did not experience TFR was 79% and 80% of pretreatment levels respectively. There was not a significant change in CCR7 for the 12 pts or clear relationship to TFR. Previous studies reported in vitro downmodulation of CD20 on CLL cells exposed to L. As this clinical study is evaluating the combination of L and rituximab, we assessed CD20 levels on CLL cells exposed to L in vivo. Median MFIR for CD20 prior to treatment was 10.5 and was 8.5 following 21 days of L (p = 0.064). In the 12 pts evaluated CD20 expression increased in 5 pts (mean increase 24% (range 5-58%)) and decreased in the other 7 (mean decrease 31% (range 5-42%)). All pts clinically responded to the addition of rituximab with decrease in absolute lymphocyte count. These data show no clear relationship to the upregulation of markers of B cell activation on circulating CLL cells and the occurrence of TFR. There is early evidence of in-vivo down modulation of chemokine receptors CXCR4 and CXCR5, however this phenomenon is not markedly different in pts who have experienced TFR. Disclosures Off Label Use: Lenalidomide is not approved for the treatment of CLL.

scholarly journals The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art

2019 ◽  
Vol 20 (4) ◽  
pp. 867 ◽  
Author(s):  
Ruben Esse ◽  
Madalena Barroso ◽  
Isabel Tavares de Almeida ◽  
Rita Castro
Keyword(s):  
Amino Acid ◽  
Endothelial Dysfunction ◽  
Molecular Basis ◽  
Methylation Status ◽  
Lipoprotein Metabolism ◽  
Negative Regulator ◽  
Vascular Lesions ◽  
Antioxidant Systems ◽  
Vascular Toxicity ◽  
The Impact

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcy-induced vascular toxicity, a mechanism that has merited our attention in particular. AdoHcy is the metabolic precursor of Hcy, which accumulates in the setting of HHcy and is a negative regulator of most cell methyltransferases. In this review, we examine the biosynthesis and catabolism of Hcy and critically revise recent findings linking disruption of this metabolism and endothelial dysfunction, emphasizing the impact of HHcy on endothelial cell methylation status.

scholarly journals Mildly Pasteurized Whey Protein Promotes Gut Tolerance in Immature Piglets Compared with Extensively Heated Whey Protein

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3391
Author(s):  
Marit Navis ◽  
Lauriane Schwebel ◽  
Susanne Soendergaard Kappel ◽  
Vanesa Muncan ◽  
Per Torp Sangild ◽  
...  
Keyword(s):  
Human Milk ◽  
Whey Protein ◽  
Transit Time ◽  
Protein Composition ◽  
In Vitro Digestion ◽  
Whey Protein Concentrate ◽  
Milk Formula ◽  
The Impact ◽  
Β Lactoglobulin

Human milk is the optimal diet for infant development, but infant milk formula (IMF) must be available as an alternative. To develop high-quality IMF, bovine milk processing is required to ensure microbial safety and to obtain a protein composition that mimics human milk. However, processing can impact the quality of milk proteins, which can influence gastro-intestinal (GI) tolerance by changing digestion, transit time and/or absorption. The aim of this study was to evaluate the impact of structural changes of proteins due to thermal processing on gastro-intestinal tolerance in the immature GI tract. Preterm and near-term piglets received enteral nutrition based on whey protein concentrate (WPC) either mildly pasteurized (MP-WPC) or extensively heated (EH-WPC). Clinical symptoms, transit time and gastric residuals were evaluated. In addition, protein coagulation and protein composition of coagulates formed during in vitro digestion were analyzed in more detail. Characterization of MP-WPC and EH-WPC revealed that mild pasteurization maintained protein nativity and reduced aggregation of β-lactoglobulin and α-lactalbumin, relative to EH-WPC. Mild pasteurization reduced the formation of coagulates during digestion, resulting in reduced gastric residual volume and increased intestinal tract content. In addition, preterm piglets receiving MP-WPC showed reduced mucosal bacterial adherence in the proximal small intestine. Finally, in vitro digestion studies revealed less protein coagulation and lower levels of β-lactoglobulin and α-lactalbumin in the coagulates of MP-WPC compared with EH-WPC. In conclusion, minimal heat treatment of WPC compared with extensive heating promoted GI tolerance in immature piglets, implying that minimal heated WPC could improve the GI tolerance of milk formulas in infants.

scholarly journals Protective Effects of Medicinal Plant Decoctions on Macrophages in the Context of Atherosclerosis

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 280
Author(s):  
Eloïse Checkouri ◽  
Stéphane Ramin-Mangata ◽  
Nicolas Diotel ◽  
Wildriss Viranaicken ◽  
Claude Marodon ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Medicinal Plant ◽  
Lipid Lowering ◽  
Protective Effects ◽  
Lipid Uptake ◽  
E Coli ◽  
Ldl Uptake ◽  
Anti Inflammatory ◽  
The Impact

Atherosclerosis is a hallmark of most cardiovascular diseases. The implication of macrophages in this pathology is widely documented, notably for their contribution to lipid accumulation within the arterial wall, associated with oxidative stress and inflammation processes. In order to prevent or limit the atherosclerosis damage, nutritional approaches and medicinal plant-based therapies need to be considered. In Reunion Island, medicinal plant-based beverages are traditionally used for their antioxidant, lipid-lowering and anti-inflammatory properties. The aim of our study was to assess the protective effects of eight medicinal plant decoctions in an in vitro model of RAW 264.7 murine macrophages exposed to pro-atherogenic conditions (oxidized low-density lipoproteins—ox-LDL—E. coli Lipopolysaccharides—LPS). The impact of polyphenol-rich medicinal plant decoctions on cell viability was evaluated by Neutral Red assay. Fluorescent ox-LDL uptake was assessed by flow cytometry and confocal microscopy. Activation of NF-κB was evaluated by quantification of secreted alkaline phosphatase in RAW-Blue™ macrophages. Our results show that medicinal plant decoctions limited the cytotoxicity induced by ox-LDL on macrophages. Flow cytometry analysis in macrophages demonstrated that medicinal plant decoctions from S. cumini and P. mauritianum decreased ox-LDL uptake and accumulation by more than 70%. In addition, medicinal plant decoctions also inhibited NF-κB pathway activation in the presence of pro-inflammatory concentrations of E. coli LPS. Our data suggest that medicinal plant decoctions exert protective effects on ox-LDL-induced cytotoxicity and limited macrophage lipid uptake. Moreover, herbal preparations displayed anti-inflammatory properties on macrophages that can be of interest for limiting the atherosclerotic process.

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