Abstract 230: Lipoprotein X Causes Renal Disease in LCAT Deficiency

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Edward B Neufeld ◽  
Alice Ossoli ◽  
Seth G Thacker ◽  
Boris Vaisman ◽  
Milton Pryor ◽  
...  
Keyword(s):  
Renal Disease ◽  
Plasma Clearance ◽  
Mesangial Cells ◽  
Chemical Properties ◽  
Low Hdl ◽  
Lcat Deficiency ◽  
Physical And Chemical ◽  
Dependent Pathway

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, and chemical properties, to wild-type and Lcat -/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat -/- mice, which have low HDL but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat -/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes, where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA 2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat -/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of LCAT induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.

CHARACTERIZATION OF A NEW LCAT MUTATION CAUSING FAMILIAL LCAT DEFICIENCY (FLD) AND THE ROLE OF APOE AS A MODIFIER GENE OF THE FLD PHENOTYPE

2009 ◽  
Vol 32 (6S) ◽  
pp. 3
Author(s):  
A Baass ◽  
H Wassef ◽  
M Tremblay ◽  
L Bernier ◽  
R Dufour ◽  
...  
Keyword(s):  
Modifier Gene ◽  
Size Exclusion ◽  
Plasma Lipoproteins ◽  
Lipoprotein Profile ◽  
Exclusion Chromatography ◽  
Low Hdl ◽  
Lcat Deficiency ◽  
Apoe Genotypes

Introduction: LCAT (lecithin:cholesterol acyltransferase ) is an enzyme which plays an essential role in cholesterol esterification and reverse cholesterol transport. Familial LCAT deficiency (FLD) is a disease characterized by a defect in LCAT resulting in extremely low HDL-C, premature corneal opacities, anemia as well as proteinuria and renal failure. Method: We have identified two brothers presenting characteristics of familial LCAT deficiency. We sequenced the LCAT gene, measured the lipid profile as well as the LCAT activity in 15 members of this kindred. We also characterized the plasma lipoproteins by agarose gel electrophoresis and size exclusion chromatography and sequenced several candidate genes related to dysbetalipoproteinemia in this family. Results: We have identified the first French Canadian kindred with familial LCAT deficiency. Two brothers affected by FLD, were homozygous for a novel LCAT mutation. This c.102delG mutation occurs at the codon for His35 causing a frameshift that stops transcription at codon 61 abolishing LCAT enzymatic activity both in vivo and in vitro. It has a dramatic effect on the lipoprotein profile, with an important reduction of HDL-C in both heterozygotes (22%) and homozygotes (88%) and a significant decrease in LDL-C in heterozygotes (35%) as well as homozygotes (58%). Furthermore, the lipoprotein profile differed markedly between the two affected brothers who had different APOE genotypes. We propose that APOE could be an important modifier gene explaining heterogeneity in lipoprotein profiles observed among FLD patients. Our results suggest that a LCAT-/- genotype associated with an APOE ?2 allele could be a novel mechanism leading to dysbetalipoproteinemia.

About Mechanisms of Biological Activity of the Nano- and Microparticles of Natural Minerals in the Experiment

10.12737/2753 ◽  
2013 ◽  
Vol 20 (4) ◽  
pp. 160-165
Author(s):  
Сергиевич ◽  
A. Sergievich ◽  
Чайка ◽  
Vladimir Chayka ◽  
Голохваст ◽  
...  
Keyword(s):  
Biological Activity ◽  
Biological Effects ◽  
Chemical Properties ◽  
Functional Condition ◽  
World Science ◽  
Natural Minerals ◽  
Physical Chemical ◽  
Physical And Chemical

There are both in the domestic and the world science a discussion about the biological activity of water-insoluble solid microparticles technogenous and natural. These interactions are studied in the context of the professional pathology, hygiene and nanotoxicology. The purpose of this research was to study the mechanisms of action of particles of natural minerals of various sizes on biological systems. The paper is based on the applied modern methods which allow to determine the degree of interaction of microelements with the functional systems of the organism. Analysis of the results showed that the application of these methods has a number of shortcomings in the experiments in vivo and in vitro, associated with the physical and chemical features of zeolites. It is established that under cultivation in 6- and 24-hole tablets, the zeolite in a dose of 50 mg/ml covers all the cells attached to the glass. In the fields of view of the cells are practically invisible. Thus, an assessment of toxic effects or functional condition of the cells is not possible. Zeolite being water-insoluble compound wich is not subjected to the pipetting. At the delete zeolite of culture, there is practically full elimination of cells from the hole. Accumulation of the primary information about the biological effects of nano - and microparticles is extremely important. This allows the authors to make some conclusions, but the decision of a question on the mechanism of biological activity, especially the prediction of some properties of particles without the study of physical-chemical properties of the particles isn´t possible.

scholarly journals Nanoparticle interaction with the immune system / Interakcije nanodelcev z imunskim sistemom

2015 ◽  
Vol 66 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Veno Kononenko ◽  
Mojca Narat ◽  
Damjana Drobne
Keyword(s):  
Immune System ◽  
Chemical Properties ◽  
The Body ◽  
Future Research ◽  
Molecular Response ◽  
Nanoparticle Interactions ◽  
Biological Environment ◽  
Physical And Chemical

Abstract When nanoparticles enter the body, their interactions with cells are almost unavoidable. Unintended nanoparticle interaction with immune cells may elicit a molecular response that can have toxic effects and lead to greater susceptibility to infectious diseases, autoimmune disorders, and cancer development. As evidenced by several studies, nanoparticle interactions with biological systems can stimulate inflammatory or allergic reactions and activate the complement system. Nanoparticles can also stimulate immune response by acting as adjuvants or as haptens. Immunosuppressive effects have also been reported. This article gives a brief review of in vitro and in vivo research evidencing stimulatory or suppressive effects of nanoparticles on the immune system of mammals. In order to ensure safe use of nanosized particles, future research should focus on how their physical and chemical properties influence their behaviour in the biological environment, as they not only greatly affect nanoparticle-immune system interactions but can also interfere with experimental assays

Functional Nanomaterials for the Detection and Control of Bacterial Infections

2019 ◽  
Vol 19 (27) ◽  
pp. 2449-2475 ◽  
Author(s):  
Huiqiong Jia ◽  
Mohamed S. Draz ◽  
Zhi Ruan
Keyword(s):  
Bacterial Infections ◽  
Chemical Properties ◽  
Multidrug Resistant ◽  
Optimal Time ◽  
Resistant Bacteria ◽  
Functional Nanomaterials ◽  
Detection Techniques ◽  
Physical And Chemical

Infections with multidrug-resistant bacteria that are difficult to treat with commonly used antibiotics have spread globally, raising serious public health concerns. Conventional bacterial detection techniques are time-consuming, which may delay treatment for critically ill patients past the optimal time. There is an urgent need for rapid and sensitive diagnosis and effective treatments for multidrug-resistant pathogenic bacterial infections. Advances in nanotechnology have made it possible to design and build nanomaterials with therapeutic and diagnostic capabilities. Functional nanomaterials that can specifically interact with bacteria offer additional options for the diagnosis and treatment of infections due to their unique physical and chemical properties. Here, we summarize the recent advances related to the preparation of nanomaterials and their applications for the detection and treatment of bacterial infection. We pay particular attention to the toxicity of therapeutic nanoparticles based on both in vitro and in vivo assays. In addition, the major challenges that require further research and future perspectives are briefly discussed.

Efficacy, safety, and physicochemical properties of a flowable hemostatic agent made from absorbable gelatin sponge via vacuum pressure steam sterilization

2020 ◽  
pp. 088532822095089
Author(s):  
Yuanxing Zhou ◽  
Xiaochi Ma ◽  
Zhonghai Li ◽  
Bo Wang
Keyword(s):  
Chemical Properties ◽  
Erythrocyte Aggregation ◽  
Hemostatic Agent ◽  
Gelatin Sponge ◽  
Toxicity Tests ◽  
Physical And Chemical Properties ◽  
Physical And Chemical ◽  
And Chemical Properties

An effective and viable hemostatic agent is important for stopping bleeding during surgery. However, it is difficult to achieve hemostasis at uneven or deep bleeding sites using a gelatin sponge. A flowable hemostatic agent has therefore been developed by processing and improving gelatin sponge, to address bleeding under these conditions. In this study, we evaluated the efficacy, safety, and physical and chemical properties of this flowable hemostatic agent in various experiments. We examined its efficacy for stopping bleeding in a rabbit model of liver abrasion in vivo, and compared its efficacy in dynamic coagulation and erythrocyte aggregation tests with gelatin sponge in vitro. We also investigated its safety in rat histocompatibility and acute systemic toxicity tests in mice in vivo, and in hemolysis tests in vitro, to determine if the flowable hemostatic agent induced any pathological reactions or adverse events. In terms of its physical and chemical properties, we analyzed the morphology and chemical bonds of the flowable hemostatic agent by optical and electron microscopy and infrared spectroscopy, and its absorbency and density. The flowable hemostatic agent resulted in a shorter mean bleeding time, less bleeding, greater likelihood of successful hemostasis, and reduced clotting time compared with gelatin sponge. The flowable agent produced some changes in physical morphology, but no pathological changes or undesirable outcomes were detected. This flowable topical hemostatic agent thus provides a safe and more effective hemostatic method than gelatin sponge, and more promising results for intraoperative hemostasis, especially on uneven or deep bleeding surfaces.

scholarly journals The Advantages of Polymeric Hydrogels in Calcineurin Inhibitor Delivery

Processes ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 1331
Author(s):  
Claudia Sandoval-Yañez ◽  
Leslie Escobar ◽  
Cristián A. Amador
Keyword(s):  
Drug Delivery ◽  
Adverse Effects ◽  
Chemical Properties ◽  
Calcineurin Inhibitors ◽  
Solid Organ ◽  
Drug Concentrations ◽  
Polymeric Hydrogels ◽  
Physical And Chemical

In recent years, polymeric hydrogels (PolyHy) have been extensively explored for their applications in biomedicine as biosensors, in tissue engineering, diagnostic processes, and drug release. The physical and chemical properties of PolyHy indicate their potential use in regulating drug delivery. Calcineurin inhibitors, particularly cyclosporine (CsA) and tacrolimus (TAC), are two important immunosuppressor drugs prescribed upon solid organ transplants. Although these drugs have been used since the 1970s to significantly increase the survival of transplanted organs, there are concerns regarding their undesirable side effects, primarily due to their highly variable concentrations. In fact, calcineurin inhibitors lead to acute and chronic toxicities that primarily cause adverse effects such as hypertension and nephrotoxicity. It is suggested from the evidence that the encapsulation of calcineurin inhibitors into PolyHy based on polysaccharides, specifically alginate (Alg), offers effective drug delivery with a stable immunosuppressive response at the in vitro and in vivo levels. This not only may reduce the adverse effects but also would improve the adherence of the patients by the effective preservation of drug concentrations in the therapeutic ranges.

Control of Inflammation by a Thermosensitive Lovastatin-Loaded Hydrogel

2021 ◽  
Author(s):  
Catherine Petit ◽  
Fareeha Batool ◽  
Louise Jacob ◽  
Nadia Benkirane-Jessel ◽  
Olivier Huck
Keyword(s):  
Wound Healing ◽  
Periodontal Diseases ◽  
Chemical Properties ◽  
Pleiotropic Effect ◽  
Local Application ◽  
Thermosensitive Gel ◽  
Physical And Chemical ◽  
Chitosan Gel

Objectives: Statins have been proposed as interesting pharmacological treatment for periodontal diseases because of their pleiotropic effect. Statins modulate bone metabolism, immuno-inflammatory complex and bacterial clearance. However, their systemic administration is associated to side effects. Therefore, their local administration has been suggested. The aim of this study was to evaluate the potential pro-regenerative effects of a thermosensitive gel functionalized by lovastatin on Porphyromonas gingivalis elicited inflammation in vitro and bone regeneration in vivo. Methods: Physical and chemical properties of a thermosensitive lovastatin loaded chitosan gel were evaluated. The anti-inflammatory effect of lovastatin was assessed in vitro by RT-qPCR and Elisa. In vivo, a model of calvarial defect was used to confirm the pro-regenerative effect on periodontal wound healing. Results: In vitro, lovastatin was able to decrease TNF-α secretion in P.gingivalis stimulated cells (p<0.05). In vivo, local application of chitosan gel functionalized with lovastatin improved wound healing at calvarial site in comparison with untreated controls and mice treated with systemic statin administration. Conclusions: This study demonstrates the potential regenerative effects of local application of a thermosensitive gel functionalized by lovastatin.

Titania Nanotubes: Novel Nanostructures for Improved Osseointegration

2010 ◽  
Vol 133 (3) ◽  
Author(s):  
Nathan Swami ◽  
Zhanwu Cui ◽  
Lakshmi S. Nair
Keyword(s):  
Chemical Properties ◽  
Orthopedic Implants ◽  
Titania Nanotubes ◽  
Bioactive Molecules ◽  
In Vivo Studies ◽  
Cellular Interactions ◽  
Wet Chemical Synthesis ◽  
Physical And Chemical

Nanostructured one dimensional titanium oxides such as nanotubes and nanowires have raised interest lately due to their unique electronic and optical properties. These materials also have shown significant potential as biomaterials because of their ability to modulate protein and cellular interactions. In this review, synthesis and modification of titania nanotubes have been discussed with emphasis on electrochemical synthesis and wet chemical synthesis and their heat treatment of resulting titania nanotubes. The biomedical applications of titania nanotubes were subsequently discussed in detail with a focus on osseointegration. The areas discussed are cell responses to titania nanotubes, effects of titania nanotubes on stem cell proliferation and differentiation, titania nanotubes as drug delivery vehicles, surface modification of titania nanotubes, and in vivo studies using titania nanotubes. It is concluded that the in vitro and in vivo study clearly demonstrates the efficacy of titania nanotube in enhancing osseointegration of orthopedic implants and much of the future work is expected to focus on improving implant functions by modulating the physical and chemical properties of the nanotubes and by locally delivering bioactive molecules in a sustained manner.

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