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FEBS Letters Jan 2004Sphingosylphosphocholine (SPC), the N-deacylated form of sphingomyelin (SM), is a naturally occurring lipid mediator. However, little is known about the metabolism of...
Sphingosylphosphocholine (SPC), the N-deacylated form of sphingomyelin (SM), is a naturally occurring lipid mediator. However, little is known about the metabolism of SPC. We here report an in vitro assay system for SPC-phospholipase C (PLC). Using this assay system, we demonstrated that nSMase1 and nSMase2, human neutral sphingomyelinases (SMases), are capable of hydrolyzing SPC efficiently under detergent-free conditions. Bacterial and plasmodial neutral SMases also showed SPC-PLC activity. The substrate specificity of neutral SMases that hydrolyze SM, SPC, and monoradyl glycerophosphocholine, but not diradyl glycerophosphocholine, suggested that a hydrogen-bond donor at the C-2 or sn-2 position in the substrate is required for recognition by the enzymes.
Topics: Cell Line; Humans; Hydrolysis; Kidney; Kinetics; Molecular Sequence Data; Phospholipids; Phosphorylcholine; Sphingomyelin Phosphodiesterase; Sphingosine; Substrate Specificity; Type C Phospholipases
PubMed: 14741383
DOI: 10.1016/s0014-5793(03)01523-0 -
Biochimica Et Biophysica Acta.... Nov 2021Atomistic molecular dynamics simulations have reached a degree of maturity that makes it possible to investigate the lipid polymorphism of model bilayers over a wide...
Atomistic molecular dynamics simulations have reached a degree of maturity that makes it possible to investigate the lipid polymorphism of model bilayers over a wide range of temperatures. However if both the fluid L and tilted gel [Formula: see text] states are routinely obtained, the [Formula: see text] ripple phase of phosphatidylcholine lipid bilayers is still unsatifactorily described. Performing simulations of lipid bilayers made of different numbers of DPPC (1,2-dipalmitoylphosphatidylcholine) molecules ranging from 32 to 512, we demonstrate that the tilted gel phase [Formula: see text] expected below the pretransition cannot be obtained for large systems (equal or larger than 94 DPPC molecules) through common simulations settings or temperature treatments. Large systems are instead found in a disordered gel phase which display configurations, topography and energies reminiscent from the ripple phase [Formula: see text] observed between the pretransition and the main melting transition. We show how the state of the bilayers below the melting transition can be controlled and depends on thermal history and conditions of preparations. A mechanism for the observed topographic instability is suggested.
Topics: Gels; Lipid Bilayers; Molecular Dynamics Simulation; Phase Transition; Phosphorylcholine; Thermodynamics
PubMed: 34331947
DOI: 10.1016/j.bbamem.2021.183714 -
Tissue Engineering and Regenerative... Dec 2021One crucial factor in skin tissue engineering is to understand the hydration and barrier property of skin. We investigated the skin hydration and stabilization strategy...
Stabilization of Lipid Lamellar Bilayer Structure of Stratum Corneum Modulated by Poly (2-methacryloyloxyethyl phosphorylcholine) in Relation to Skin Hydration and Skin Protection.
BACKGROUND
One crucial factor in skin tissue engineering is to understand the hydration and barrier property of skin. We investigated the skin hydration and stabilization strategy of inter-lamellar structure of stratum corneum (SC) using poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC).
METHODS
The unique hydration and stabilization potency of PMPC on the barrier function of the SC examined using freshly excised hairless mouse skin as a model membrane and the relationship between the stabilization of the lipid lamellar bilayer (LLB) and its enhanced water holding capacity was established.
RESULTS
Differential scanning calorimeter based on the phase-transition temperature of lipid domain of SC demonstrated that PMPC stabilized the LLB. The ratio of the heat of lipid phase transition (△H) of SC exposed to water and PMPC for 24 h was 1.51. X-ray crystallography showed the presence of well- organized lipids in intercellular membranes exhibiting short and long periodicity of lamellar phases. The peak at 4.4 nm attributed to the long periodicity phase (LPP) was missing in water-treated SC, where, the presence of 4.2- 4.4 nm peak in PMPC treated SC indicated that PMPC stabilized LPP. Transmission electron microscopy study demonstrated that the LLB structure became more rigid and orderly in PMPC treated SC.
CONCLUSION
The unique ion paired structure of PMPC enhances the barrier function of the SC by stabilizing LLB structure and hydration by inducing weakly bound water. The unique hydration state and stabilization effect from extended water exposure could provide a valuable information to prepare reliable artificial skin matrix and skin tissue.
Topics: Animals; Epidermis; Lipid Bilayers; Methacrylates; Mice; Phosphorylcholine
PubMed: 34460064
DOI: 10.1007/s13770-021-00379-4 -
BMC Research Notes Apr 2012Designing efficient 'vectors', to deliver therapeutics across endothelial barriers, in a controlled manner, remains one of the key goals of drug development. Recently,...
BACKGROUND
Designing efficient 'vectors', to deliver therapeutics across endothelial barriers, in a controlled manner, remains one of the key goals of drug development. Recently, transcytosis of liposome encapsulated fluorescence marker calcein across a tight cell barrier was studied. The most efficient liposomes were found to be liposomes containing sufficient amount of alkyl phospholipid (APL) perifosine. APLs have similar structure as lysophosphatidyl choline (LPC), since APLs were synthesized as metabolically stable analogues of LPC, which increases endothelial permeability directly by inducing endothelial cell contraction, resulting in formation of gaps between endothelial cells. Since one of the unique properties of lysolipid, containing liposomal formulations is dynamic equilibrium of lysolipids, which are distributed among liposomes, micelles, and free form, such liposomes represent a reservoir of free lysolipids. On the other hand lysolipid containing liposomes also represent a reservoir of an encapsulated hydrophilic drug.
PRESENTATION OF THE HYPOTHESIS
We hypothesize that free lysolipids, with highest concentration in vicinity of drug carrying liposomes, compromise endothelial integrity, primarily where concentrations of liposomes is the highest, in a similar manner as LPC, by formation of gaps between endothelial cells. Liposome encapsulated drug, which leaks from liposomes, due to liposome destabilization, caused by lysolipid depletion, can therefore be efficiently transported across the locally compromised endothelial barrier.
TESTING THE HYPOTHESIS
This hypothesis could be verified: by measuring binding of perifosine and other lysolipids to albumin and to lysophospholipid receptor (LPL-R) group; formation of stress fibers and subsequent cell contraction; activation of RhoA, and endothelial barrier dysfunction; by a synthesis of other LPC analogues with high critical micellar concentration and measuring their effect on transendothelial permeability in presence and absence of albumin.
IMPLICATIONS OF THE HYPOTHESIS
We propose that lysolipid containing liposomal formulations might be used as nonspecific transendothelial transport vector, since leakage of liposome encapsulated active drug occurs simultaneously with the release of the lysolipids. The concentration of the active drug is therefore expected to be the highest at the site of compromised endothelial barrier. By appropriate choice of the lysolipids an endothelial barrier would stay open only for a short time. Use of such liposomes would potentially maximize the delivery of the drug while limiting the passage of toxic substances and pathogens across the endothelial barrier. Combining lysolipid containing liposomes with superparamagnetic iron oxide nanoparticles or a targeting ligand might be required to efficiently localize drug delivery to a disease affected tissue and to avoid endothelial disruption over the entire body.
Topics: Animals; Cell Membrane Permeability; Drug Delivery Systems; Endothelial Cells; Endothelium; Humans; Liposomes; Lysophosphatidylcholines; Models, Biological; Phosphorylcholine
PubMed: 22490670
DOI: 10.1186/1756-0500-5-179 -
The American Journal of Tropical... Apr 2017AbstractVisceral leishmaniasis (VL), popularly known as kala-azar, is essentially a disease of poverty. Kala-azar is caused by a parasite, . Recent review indicates that...
AbstractVisceral leishmaniasis (VL), popularly known as kala-azar, is essentially a disease of poverty. Kala-azar is caused by a parasite, . Recent review indicates that worldwide 98 countries are endemic for kala-azar. Approximately 0.2-0.4 million new VL cases occur each year worldwide. More than 90% of global VL cases occur in Bangladesh, Brazil, Ethiopia, India, South Sudan, and Sudan. This trend is slowly changing due to the progress in kala-azar elimination in southeast Asia, where Bangladesh has reported an average of some 600 new cases in 2014-2015. With the advancement in our knowledge about the disease and development of tools to diagnose and treat VL, it was considered that elimination of kala-azar was possible from India, Nepal, and Bangladesh. The three countries signed a memorandum of understanding in 2005 for collaboration. Miltefosine is the first ever oral drug developed to treat VL, which was later replaced by lipid amphotericin B. The main components of the strategy are early diagnosis using rK39 strip test and complete treatment utilizing miltefosine for 28 days. Dichlorodiphenyltrichloroethane or pyrethroids were deployed for vector control. There was much to be desired for better performance of the vector control activity. Pharmacovigilance and monitoring of drug resistance were the weakest part of the program. In the post-elimination phase, surveillance reinforced by active case finding will of a crucial factor for sustainability of the elimination. A strong political will is required to ensure elimination of kala-azar from the Indian subcontinent and its sustainability in the post-elimination phase.
Topics: Animals; Antiprotozoal Agents; Bangladesh; Humans; India; Insect Control; Insect Vectors; Insecticides; Internationality; Leishmaniasis, Visceral; Nepal; Phosphorylcholine; Preventive Health Services
PubMed: 28115678
DOI: 10.4269/ajtmh.16-0279 -
Diapeutic cancer-targeting alkylphosphocholine analogs may advance management of brain malignancies.CNS Oncology Oct 2016The following is a special report on alkylphosphocholine analogs as targeted imaging and therapy agents for cancer, and their potential role in diagnosis and treatment...
The following is a special report on alkylphosphocholine analogs as targeted imaging and therapy agents for cancer, and their potential role in diagnosis and treatment in glioblastoma and brain metastases. These novel cancer-targeting agents display impressive tumor avidity with low background in the normal brain, and multimodal diagnostic imaging and therapy capabilities. The use of these agents may significantly improve diagnosis, treatment and post-treatment follow-up in patients with brain malignancies.
Topics: Antineoplastic Agents; Brain Neoplasms; Disease Management; Glioblastoma; Humans; Multimodal Imaging; Phosphorylcholine
PubMed: 27616199
DOI: 10.2217/cns-2016-0017 -
Molecular Immunology Dec 2013Among the non-carbohydrate components of glycans, the addition of phosphocholine (ChoP) to the glycans of pathogens occurs more rarely than acetylation or methylation,... (Review)
Review
Among the non-carbohydrate components of glycans, the addition of phosphocholine (ChoP) to the glycans of pathogens occurs more rarely than acetylation or methylation, but it has far more potent biological consequences. These arise from ChoP's multiple interactions with host proteins, which are important at all stages of the infection process. These stages include initial adherence to cells, encountering the host's innate immune system and then the adaptive immune system. Thus, in the initial stages of an infection, ChoP groups are an asset to the pathogen, but they can turn into a disadvantage subsequently. In this review, we have focussed on structural aspects of these phenomena. We describe the biosynthesis of the ChoP modification, the structures of the pathogen glycans known to carry ChoP groups and the host proteins that recognize ChoP.
Topics: C-Reactive Protein; Host-Pathogen Interactions; Humans; Molecular Structure; Phosphorylcholine; Pneumococcal Infections; Polysaccharides; Protein Binding; Streptococcus pneumoniae
PubMed: 23911414
DOI: 10.1016/j.molimm.2013.05.237 -
Journal of Dentistry Feb 2015Biofilm acids contribute to secondary caries, which is a main reason for dental restoration failures. The objectives of this study were to: (1) develop a...
OBJECTIVES
Biofilm acids contribute to secondary caries, which is a main reason for dental restoration failures. The objectives of this study were to: (1) develop a protein-repellent and antibacterial composite, and (2) investigate the effects of combining 2-methacryloyloxyethyl phosphorylcholine (MPC) with quaternary ammonium dimethylaminohexadecyl methacrylate (DMAHDM) on composite mechanical properties and biofilm response for the first time.
METHODS
MPC, DMAHDM and glass particles were mixed into a dental resin composite. Mechanical properties were measured in three-point flexure. Protein adsorption onto the composites was measured by a micro bicinchoninic acid method. A human saliva microcosm model was used to grow biofilms on composites. Colony-forming unit (CFU) counts, live/dead assay, metabolic activity, and lactic acid production of biofilms were determined.
RESULTS
Incorporation of 3% MPC and 1.5% DMAHDM into composite achieved protein-repellent and antibacterial capabilities without compromising the mechanical properties. Composite with 3% MPC+1.5% DMAHDM had protein adsorption that was 1/10 that of a commercial composite (p<0.05). The composite with 3% MPC+1.5% DMAHDM had much greater reduction in biofilm growth than using MPC or DMAHDM alone (p<0.05). Biofilm CFU counts on composite with 3% MPC+1.5% DMAHDM were more than three orders of magnitude lower than that of commercial control.
CONCLUSIONS
Dental composite with a combination of strong protein-repellent and antibacterial capabilities was developed for the first time. Composite containing MPC and DMAHDM greatly reduced biofilm growth and lactic acid production, without compromising mechanical properties of the composite.
CLINICAL SIGNIFICANCE
Novel composite with MPC and DMAHDM greatly reduced biofilm activity and is promising to inhibit secondary caries. The dual agents of MPC plus DMAHDM may have wide applicability to other dental materials.
Topics: Acrylic Resins; Adsorption; Anti-Bacterial Agents; Biofilms; Colony Count, Microbial; Composite Resins; Dental Caries; Humans; Methacrylates; Microbial Viability; Phosphorylcholine; Polyurethanes; Proteins; Quaternary Ammonium Compounds
PubMed: 25478889
DOI: 10.1016/j.jdent.2014.11.008 -
Antimicrobial Agents and Chemotherapy Jul 2011In view of the severe immunosuppression in visceral leishmaniasis (VL), a rational approach to effectively combat the parasitic scourge would be to enhance the immune...
In view of the severe immunosuppression in visceral leishmaniasis (VL), a rational approach to effectively combat the parasitic scourge would be to enhance the immune status of the host. Use of CpG oligodeoxynucleotide (CpG-ODN) against leishmaniasis has previously been reported, especially as an immunomodulator and adjuvant with various immunogens. In the present study, experiments were carried out with BALB/c mice and hamsters infected with Leishmania donovani. Immunostimulating class B bacterial CpG-ODN namely, ODN-2006, was administered at various doses by the intraperitoneal (i.p.) route. The dose of CpG-ODN-2006 (1 nM/single dose) showing the most antileishmanial activity was given as free and liposomal forms with different doses of miltefosine, namely, 5 and 10 mg/kg of body weight, for 5 days in mice and hamsters, respectively. Among the various groups, mice coadministered liposomal CpG-ODN and miltefosine (5 mg/kg) showed the best inhibitory effect (97% parasite inhibition) compared with free CpG-ODN plus miltefosine and miltefosine, free CpG-ODN, and liposomal CpG-ODN given separately. Similar responses were observed in the case of hamsters, where the combination of liposomal CpG-ODN with miltefosine (10 mg/kg) gave 96% parasite inhibition. Promising antileishmanial efficacy was observed in animals treated with liposomal CpG-ODN and miltefosine.
Topics: Animals; Cricetinae; Drug Combinations; Female; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Phosphorylcholine; Trypanocidal Agents
PubMed: 21537026
DOI: 10.1128/AAC.00137-11 -
Parasites & Vectors Sep 2020The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of...
BACKGROUND
The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed-dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy.
METHODS
Two nanocombinations were prepared to provide 250 mg praziquantel-20 mg miltefosine/kg (higher fixed-dose) or 125 mg praziquantel-10 mg miltefosine/kg (lower fixed-dose), respectively. Their antischistosomal efficacy in comparison with a non-treated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral dose of either formulation was administered on the initial day of infection, and on days 21 and 42 post-infection. Scanning electron microscopic, parasitological, and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukey's post-hoc test for pairwise comparisons.
RESULTS
Lipid nanocapsules (~ 58 nm) showed high entrapment efficiency of both drugs (> 97%). Compared to singly loaded praziquantel-lipid nanocapsules, the higher nanocombination dose showed a significant increase in antischistosomal efficacy in terms of statistically significant decrease in mean worm burden, particularly against invasive and juvenile worms, and amelioration of hepatic granulomas (P ≤ 0.05). In addition, scanning electron microscopy examination showed extensive dorsal tegumental damage with noticeable deposition of nanostructures.
CONCLUSIONS
The therapeutic profile of praziquantel could be improved by a novel multiple approach integrating drug repurposing, combination therapy and nanotechnology. Multistage activity and amelioration of liver pathology could be achieved by a new praziquantel-miltefosine fixed-dose nanocombination providing 250 mg praziquantel-20 mg miltefosine/kg. To the best of our knowledge, this is the first report of a fixed-dose nano-based combinatorial therapy for schistosomiasis mansoni. Further studies are needed to document the nanocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.
Topics: Administration, Oral; Animals; Disease Models, Animal; Drug Combinations; Drug Compounding; Female; Humans; Male; Mice; Nanocapsules; Phosphorylcholine; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides
PubMed: 32933556
DOI: 10.1186/s13071-020-04346-1