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Scientific Reports Jan 2024Various drugs have been used for the treatment of leishmaniasis, but they often have adverse effects on the body's organs. In this study, we aimed to explore the effects...
Various drugs have been used for the treatment of leishmaniasis, but they often have adverse effects on the body's organs. In this study, we aimed to explore the effects of one type of drug, Miltefosine (MIL), and its analogue or modifier, liposomal Miltefosine (NMIL), on several fetal organs using both in silico analysis and practical tests on chicken embryos. Our in silico approach involved predicting the affinities of MIL and NMIL to critical proteins involved in leishmaniasis, including Vascular Endothelial Growth Factor A (VEGF-A), the Kinase insert domain receptor (KDR1), and apoptotic-regulator proteins (Bcl-2-associate). We then validated and supported these predictions through in vivo investigations, analyzing gene expression and pathological changes in angiogenesis and apoptotic mediators in MIL- and NMIL-treated chicken embryos. The results showed that NMIL had a more effective action towards VEGF-A and KDR1 in leishmaniasis, making it a better candidate for potential operative treatment during pregnancy than MIL alone. In vivo, studies also showed that chicken embryos under MIL treatment displayed less vascular mass and more degenerative and apoptotic changes than those treated with NMIL. These results suggest that NMIL could be a better treatment option for leishmaniasis during pregnancy.
Topics: Chick Embryo; Animals; Leishmaniasis, Visceral; Antiprotozoal Agents; Vascular Endothelial Growth Factor A; Phosphorylcholine
PubMed: 38291076
DOI: 10.1038/s41598-024-52620-4 -
Nanomaterials (Basel, Switzerland) Jan 2024Sodium- (Na) and potassium- (K) ion batteries are cost-effective alternatives to lithium-ion (Li) batteries due to the abundant sodium and potassium resources. Solid...
Sodium- (Na) and potassium- (K) ion batteries are cost-effective alternatives to lithium-ion (Li) batteries due to the abundant sodium and potassium resources. Solid polymer electrolytes (SPEs) are essential for safer and more efficient Na and K batteries because they often exhibit low ionic conductivity at room temperature. While zwitterionic (ZW) materials enhance Li battery conductivity, their potential for Na and K transport in batteries remains unexplored. In this study, we investigated the effect of three ZW molecules (ChoPO4, i.e., 2-methacryloyloxyethyl phosphorylcholine, ImSO3, i.e., sulfobetaine ethylimidazole, and ImCO2, i.e., carboxybetaine ethylimidazole) on the dissociation of Na and K coordination with ethylene oxide (EO) chains in EO-based electrolytes through molecular dynamics simulations. Our results showed that ChoPO4 possessed the highest cation-EO dissociation ability, while ImSO3 exhibited the lowest. Such dissociation ability correlated with the cation-ZW molecule coordination strength: ChoPO4 and ImSO3 showed the strongest and the weakest coordination with cations. However, the cation-ZW molecule coordination could slow the cationic diffusion. The competition of these effects resulted in accelerating or decelerating cationic diffusion. Our simulated results showed that ImCO2 enhanced Na diffusion by 20%, while ChoPO4 and ImSO3 led to a 10% reduction. For K, ChoPO4 reduced its diffusion by 40%, while ImCO2 and ImSO3 caused a similar decrease of 15%. These findings suggest that the ZW structure and the cationic size play an important role in the ionic dissociation effect of ZW materials.
PubMed: 38276737
DOI: 10.3390/nano14020219 -
Polymers Jan 2024The 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers are mimetic to phospholipids, being widely used as biocompatible polymers. In our previous study, MPC polymer...
The 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers are mimetic to phospholipids, being widely used as biocompatible polymers. In our previous study, MPC polymer hydrogels proved more effective for optical tissue clearing compared to acrylamide (AAm) polymer hydrogels. In the present study, 2-acryloyloxyethyl phosphorylcholine (APC) was synthesized and employed to create hydrogels for a comparative analysis with methacrylic MPC-based hydrogels. APC, an acrylic monomer, was copolymerized with AAm in a similar reactivity. In contrast, MPC, as a methacrylic monomer, demonstrated higher copolymerization reactivity than AAm, leading to a spontaneously delayed two-step polymerization behavior. This suggests that the polymer sequences and network structures became heterogeneous when both methacrylic and acrylic monomers, as well as crosslinkers, were present in the copolymerization system. The molecular weight of the APC polymers was considerably smaller than that of the MPC polymers due to the formation of mid-chain radicals and subsequent β-scission during polymerization. The swelling ratios in water and strain sweep profiles of hydrogels prepared using acrylic and methacrylic compounds differed from those of hydrogels prepared using only acrylic compounds. This implies that copolymerization reactivity influences the polymer network structures and crosslinking density in addition to the copolymer composition. APC-based hydrogels are effective for the optical clearing of tumor tissues and are applicable to both passive and electrophoretic methods.
PubMed: 38257040
DOI: 10.3390/polym16020241 -
Cell Communication and Signaling : CCS Jan 2024The Ca-independent contraction of vascular smooth muscle is a leading cause of cardiovascular and cerebrovascular spasms. In the previous study, we demonstrated the...
BACKGROUND
The Ca-independent contraction of vascular smooth muscle is a leading cause of cardiovascular and cerebrovascular spasms. In the previous study, we demonstrated the involvement of Src family protein tyrosine kinase Fyn and Rho-kinase in the sphingosylphosphorylcholine (SPC)-induced abnormal and Ca-independent contraction of vascular smooth muscle, but the specific mechanism has not been completely clarified.
METHODS
Paxillin knockdown human coronary artery smooth muscle cells (CASMCs) and smooth muscle-specific paxillin knockout mice were generated by using paxillin shRNA and the tamoxifen-inducible Cre-LoxP system, respectively. CASMCs contraction was observed by time-lapse recording. The vessel contractility was measured by using a myography assay. Fyn, Rho-kinase, and myosin light chain activation were assessed by immunoprecipitation and western blotting. The paxillin expression and actin stress fibers were visualized by histological analysis and immunofluorescent staining.
RESULTS
The SPC-induced abnormal contraction was inhibited in paxillin knockdown CASMCs and arteries of paxillin knockout mice, indicating that paxillin is involved in this abnormal contraction. Further study showed that paxillin knockdown inhibited the SPC-induced Rho-kinase activation without affecting Fyn activation. In addition, paxillin knockdown significantly inhibited the SPC-induced actin stress fiber formation and myosin light chain phosphorylation. These results suggest that paxillin, as an upstream molecule of Rho-kinase, is involved in the SPC-induced abnormal contraction of vascular smooth muscle.
CONCLUSIONS
The present study demonstrated that paxillin participates in the SPC-induced abnormal vascular smooth muscle contraction by regulating Rho-kinase activation. Video Abstract.
Topics: Animals; Humans; Mice; Actins; Mice, Knockout; Muscle, Smooth, Vascular; Myosin Light Chains; Paxillin; Phosphorylcholine; rho-Associated Kinases; Sphingosine
PubMed: 38254202
DOI: 10.1186/s12964-023-01404-w -
Journal of Lipid Research Feb 2024Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of...
Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), glutathione peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.
Topics: Animals; Mice; Humans; Phospholipids; Phosphorylcholine; Phospholipid Ethers; Ferroptosis; Mice, Inbred C57BL; Atherosclerosis; Human Umbilical Vein Endothelial Cells; Endothelium; Glutathione; Iron; Fatty Acid Binding Protein 3; Cyclohexylamines; Phenylenediamines
PubMed: 38218337
DOI: 10.1016/j.jlr.2024.100499 -
International Journal of Molecular... Dec 2023The present study compares two groups of locally advanced patients with head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (cCHRT),...
The present study compares two groups of locally advanced patients with head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (cCHRT), specifically those for whom it is a first-line treatment and those who have previously received induction chemotherapy (iCHT). The crucial question is whether iCHT is a serious burden during subsequent treatment for LA-HNSCC and how iCHT affects the tolerance to cCHRT. Of the 107 LA-HNSCC patients, 54 received cisplatin-based iCHT prior to cCHRT. The patients were clinically monitored at weekly intervals from the day before until the completion of the cCHRT. The 843 blood samples were collected and divided into two aliquots: for laboratory blood tests and for nuclear magnetic resonance (NMR) spectroscopy (a Bruker 400 MHz spectrometer). The NMR metabolites and the clinical parameters from the laboratory blood tests were analyzed using orthogonal partial least squares analysis (OPLS) and the Mann-Whitney U test (MWU). After iCHT, the patients begin cCHRT with significantly (MWU -value < 0.05) elevated blood serum lipids, betaine, glycine, phosphocholine, and reticulocyte count, as well as significantly lowered NMR inflammatory markers, serine, hematocrit, neutrophile, monocyte, red blood cells, hemoglobin, and CRP. During cCHRT, a significant increase in albumin and psychological distress was observed, as well as a significant decrease in platelet, N-acetyl-cysteine, tyrosine, and phenylalanine, in patients who received iCHT. Importantly, all clinical symptoms (except the decreased platelets) and most metabolic alterations (except for betaine, serine, tyrosine, glucose, and phosphocholine) resolve until the completion of cCHRT. In conclusion, iCHT results in hematological toxicity, altered lipids, and one-carbon metabolism, as well as downregulated inflammation, as observed at the beginning and during cCHRT. However, these complications are temporary, and most of them resolve at the end of the treatment. This suggests that iCHT prior to cCHRT does not pose a significant burden and should be considered as a safe treatment option for LA-HNSCC.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Induction Chemotherapy; Phosphorylcholine; Head and Neck Neoplasms; Chemoradiotherapy; Betaine; Serine; Tyrosine; Lipids
PubMed: 38203359
DOI: 10.3390/ijms25010188 -
Molecular & Cellular Proteomics : MCP Feb 2024Glycans are key to host-pathogen interactions, whereby recognition by the host and immunomodulation by the pathogen can be mediated by carbohydrate binding proteins,...
Glycans are key to host-pathogen interactions, whereby recognition by the host and immunomodulation by the pathogen can be mediated by carbohydrate binding proteins, such as lectins of the innate immune system, and their glycoconjugate ligands. Previous studies have shown that excretory-secretory products of the porcine nematode parasite Trichuris suis exert immunomodulatory effects in a glycan-dependent manner. To better understand the mechanisms of these interactions, we prepared N-glycans from T. suis and both analyzed their structures and used them to generate a natural glycan microarray. With this array, we explored the interactions of glycans with C-type lectins, C-reactive protein, and sera from T. suis-infected pigs. Glycans containing LacdiNAc and phosphorylcholine-modified glycans were associated with the highest binding by most of these proteins. In-depth analysis revealed not only fucosylated LacdiNAc motifs with and without phosphorylcholine moieties but phosphorylcholine-modified mannose and N-acetylhexosamine-substituted fucose residues, in the context of maximally tetraantennary N-glycan scaffolds. Furthermore, O-glycans also contained fucosylated motifs. In summary, the glycans of T. suis are recognized by both the innate and adaptive immune systems and also exhibit species-specific features distinguishing its glycome from those of other nematodes.
Topics: Animals; Swine; Trichuris; Phosphorylcholine; Polysaccharides; Glycosylation; Immune System
PubMed: 38182041
DOI: 10.1016/j.mcpro.2024.100711 -
Molecular Biology of the Cell Mar 2024Fatty acids stored in triacylglycerol-rich lipid droplets are assembled with a surface monolayer composed primarily of phosphatidylcholine (PC). Fatty acids stimulate PC...
Fatty acids stored in triacylglycerol-rich lipid droplets are assembled with a surface monolayer composed primarily of phosphatidylcholine (PC). Fatty acids stimulate PC synthesis by translocating CTP:phosphocholine cytidylyltransferase (CCT) α to the inner nuclear membrane, nuclear lipid droplets (nLD) and lipid associated promyelocytic leukemia (PML) structures (LAPS). Huh7 cells were used to identify how CCTα translocation onto these nuclear structures are regulated by fatty acids and phosphorylation of its serine-rich P-domain. Oleate treatment of Huh7 cells increased nLDs and LAPS that became progressively enriched in CCTα. In cells expressing the phosphatidic acid phosphatase Lipin1α or 1β, the expanded pool of nLDs and LAPS had a proportional increase in associated CCTα. In contrast, palmitate induced few nLDs and LAPS and inhibited the oleate-dependent translocation of CCTα without affecting total nLDs. Phospho-memetic or phospho-null mutations in the P-domain revealed that a 70% phosphorylation threshold, rather than site-specific phosphorylation, regulated CCTα association with nLDs and LAPS. In vitro candidate kinase and inhibitor studies in Huh7 cells identified cyclin-dependent kinase (CDK) 1 and 2 as putative P-domain kinases. In conclusion, CCTα translocation onto nLDs and LAPS is dependent on available surface area and fatty acid composition, as well as threshold phosphorylation of the P-domain potentially involving CDKs.
Topics: Phosphorylcholine; Lipid Droplets; Oleic Acid; Nuclear Envelope; Phosphatidylcholines; Fatty Acids; Choline-Phosphate Cytidylyltransferase
PubMed: 38170618
DOI: 10.1091/mbc.E23-09-0354 -
Frontiers in Immunology 2023Mice develop pathology in the lungs as they age and this may be accelerated by a high calorie diet (HCD). ES-62 is a protein secreted by the parasitic worm that is...
Mice develop pathology in the lungs as they age and this may be accelerated by a high calorie diet (HCD). ES-62 is a protein secreted by the parasitic worm that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties. In this study, we show that weekly treatment of C57BL/6J mice with ES-62 protected against pathology in the lungs in male but not female mice fed a HCD from 10 weeks of age as shown by reductions in cellular infiltration and airway remodelling, particularly up to 160 days of age. ES-62 also reduced gene expression of the cytokines IL-4 and IL-17 and in addition the TLR/IL-1R adaptor MyD88, in the lungs of male mice although HCD-induced increases in these inflammatory markers were not detected until between 340 and 500 days of age. A combination of two drug-like ES-62 PC-based small molecule analogues (SMAs), produced broadly similar protective effects in the lungs of male mice with respect to both lung pathology and inflammatory markers, in addition to a decrease in HCD-induced IL-5 expression. Overall, our data show that ES-62 and its SMAs offer protection against HCD-accelerated pathological changes in the lungs during ageing. Given the targeting of Th2 cytokines and IL-17, we discuss this protection in the context of ES-62's previously described amelioration of airway hyper-responsiveness in mouse models of asthma.
Topics: Male; Animals; Mice; Interleukin-17; Mice, Inbred C57BL; Cytokines; Obesity; Aging; Acanthocheilonema; Lung
PubMed: 38077318
DOI: 10.3389/fimmu.2023.1285069 -
Medicine Dec 2023The purpose of this study was to evaluate the mid-term clinical results and polyethylene wear of vitamin E-diffused highly cross-linked polyethylene (HXLPE) and...
The purpose of this study was to evaluate the mid-term clinical results and polyethylene wear of vitamin E-diffused highly cross-linked polyethylene (HXLPE) and 2-methacryloyloxyethyl phosphorylcholine (MPC)-grafted HXLPE in cementless total hip arthroplasty (THA). Thirty-four THAs with vitamin E-diffused HXLPE (VEPE) and 32-mm cobalt-chromium head, and 116 THAs with MPC-grafted HXLPE and 32-mm alumina head were evaluated. The Merle d'Aubigné and Postel scores were administered. Kaplan-Meier survivorship was analyzed. Annual radiographs were analyzed using computerized method and linear steady-state wear rate was measured. The mean duration of follow-up was 9 years (range, 7-11 years) in VEPE group and 8 years (range, 7-10 years) in MPC group. The mean Merle d'Aubigné and Postel scores improved postoperatively in both groups. Kaplan-Meier survivorship with endpoint of revision was 100% (95% confidence interval, 100%-100%) in VEPE group and 98.3% (95% confidence interval, 93.4%-99.6%) in MPC group at 10 years (P = .44). The mean steady-state wear rate was 0.007 mm/year in VEPE group and 0.006 mm/year in MPC group (P = .60). The clinical results of both groups were good and wear rates of both liners were very low.
Topics: Humans; Arthroplasty, Replacement, Hip; Polyethylene; Hip Prosthesis; Vitamin E; Prosthesis Failure; Prosthesis Design; Follow-Up Studies
PubMed: 38050300
DOI: 10.1097/MD.0000000000036257