-
Heart, Lung & Circulation Nov 2023Mouse models have indicated that the pneumococcal polysaccharide vaccine (PPV) can reduce atherosclerosis. This is probably through a process of molecular mimicry, where... (Randomized Controlled Trial)
Randomized Controlled Trial
Persistence of Detectable Anti-Pneumococcal Antibodies 4 Years After Pneumococcal Polysaccharide Vaccination in a Randomised Controlled Trial: The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE).
AIM
Mouse models have indicated that the pneumococcal polysaccharide vaccine (PPV) can reduce atherosclerosis. This is probably through a process of molecular mimicry, where phosphorylcholine in the capsular polysaccharide of the vaccine elicits antibodies that cross-react with oxidised low-density lipoprotein and reduce plaque. We investigated whether a similar mechanism occurs in humans.
METHODS
A large national blinded, randomised, placebo-controlled trial of the PPV (Australian Study for the Prevention through Immunisation of Cardiovascular Events [AUSPICE]) is underway with fatal and nonfatal cardiovascular disease (CVD) events as the primary outcome. Participants at one centre agreed to a substudy measuring a number of biomarkers and surrogates of CVD over 4 years, including anti-pneumococcal antibodies (immunoglobulin G and immunoglobulin M), C-reactive protein, carotid intima-media thickness, pulse wave velocity, insulin, fasting blood glucose, glycated haemoglobin, and hepatorenal index.
RESULTS
Antipneumococcal immunoglobulin G and immunoglobulin M were both present and statistically significantly increased in the treated group compared to control at 4 years. However, there were no differences in any of the surrogate measures of CVD or metabolic markers at 4 years.
CONCLUSIONS
While there were prolonged differences in anti-pneumococcal antibody titres following PPV vaccination, these did not appear to provide any cardioprotective effect, as measured by a range of markers. Final results using the fatal and nonfatal CVD events await the completion of national health record linkage next year.
TRIAL REGISTRATION
ACTRN12615000536561.
Topics: Animals; Mice; Humans; Carotid Intima-Media Thickness; Pulse Wave Analysis; Australia; Streptococcus pneumoniae; Vaccination; Pneumococcal Vaccines; Immunoglobulin G; Immunoglobulin M; Cardiovascular Diseases
PubMed: 37919117
DOI: 10.1016/j.hlc.2023.09.006 -
Cell Proliferation Apr 2024Lung cancer is the leading global cause of cancer-related death, however, resistance to chemotherapy drugs remains a huge barrier to effective treatment. The elevated...
Lung cancer is the leading global cause of cancer-related death, however, resistance to chemotherapy drugs remains a huge barrier to effective treatment. The elevated recruitment of myeloid derived suppressor cells (MDSCs) to tumour after chemotherapy has been linked to resistance of chemotherapy drugs. Nevertheless, the specific mechanism remains unclear. oxPAPC is a bioactive principal component of minimally modified low-density lipoproteins and regulates inflammatory response. In this work, we found that cisplatin, oxaliplatin and ADM all increased oxPAPC release in tumour. Treating macrophages with oxPAPC in vitro stimulated the secretion of MCP-1 and LTB4, which strongly induced monocytes and neutrophils chemotaxis, respectively. Injection of oxPAPC in vivo significantly upregulated the percentage of MDSCs in tumour microenvironment (TME) of wild-type LL2 tumour-bearing mice, but not CCL2-/- mice and LTB4R-/- mice. Critically, oxPAPC acted as a pro-tumor factor in LL2 tumour model. Indeed, cisplatin increased oxPAPC level in tumour tissues of WT mice, CCL2-/- and LTB4R-/- mice, but caused increased infiltration of Ly6C monocytes and neutrophils only in WT LL2-bearing mice. Collectively, our work demonstrates cisplatin treatment induces an overproduction of oxPAPC and thus recruits MDSCs infiltration to promote the tumour growth through the MCP-1/CCL2 and LTB4/LTB4R pathways, which may restrict the effect of multiple chemotherapy. This provides evidence for a potential strategy to enhance the efficacy of multiple chemotherapeutic drugs in the treatment of lung cancer by targeting oxPAPC.
Topics: Animals; Mice; Myeloid-Derived Suppressor Cells; Cisplatin; Leukotriene B4; Lung Neoplasms; Tumor Microenvironment; Phosphatidylcholines
PubMed: 37905494
DOI: 10.1111/cpr.13570 -
The Journal of Physical Chemistry. B Nov 2023Improving drug delivery efficiency to solid tumor sites is a central challenge in anticancer therapeutic research. Our previous experimental study (Guo et al., , , 130)...
Improving drug delivery efficiency to solid tumor sites is a central challenge in anticancer therapeutic research. Our previous experimental study (Guo et al., , , 130) showed that soft, elastic liposomes had increased uptake and accumulation in cancer cells and tumors and respectively, relative to rigid particles. As a first step toward understanding how liposomes' molecular structure and composition modulates their elasticity, we performed all-atom and coarse-grained classical molecular dynamics (MD) simulations of lipid bilayers formed by mixing a long-tailed unsaturated phospholipid with a short-tailed saturated lipid with the same headgroup. The former types of phospholipids considered were 1,2-dioleoyl--glycero-3-phosphocholine (DOPC) and 1,2-dipalmitoleoyl--glycero-3-phosphocholine (termed here DPMPC). The shorter saturated lipids examined were 1,2-diheptanoyl--glycero-3-phosphocholine (DHPC), 1,2-didecanoyl--glycero-3-phosphocholine (DDPC), 1,2-dilauroyl--glycero-3-phosphocholine (DLPC), and 1,2-dimyristoyl--glycero-3-phosphocholine (DMPC). Several lipid concentrations and surface tensions were considered. Our results show that DOPC or DPMPC systems having 25-35 mol % of the shortest lipids DHPC or DDPC are the least rigid, having area compressibility moduli that are ∼10% smaller than the values observed in pure DOPC or DPMPC bilayers. These results agree with experimental measurements of the stretching modulus and lysis tension in liposomes with the same compositions. These mixed systems also have lower areas per lipid and form more uneven - interfaces with water, the tails of both primary and secondary lipids are more disordered, and the terminal methyl groups in the tails of the long lipid DOPC or DPMPC wriggle more in the vertical direction, compared to pure DOPC or DPMPC bilayers or their mixtures with the longer saturated lipid DLPC or DMPC. These observations confirm our hypothesis that adding increasing concentrations of the short unsaturated lipid DHPC or DDPC to DOPC or DPMPC bilayers alters lipid packing and thus makes the resulting liposomes more elastic and less rigid. No formation of lipid nanodomains was noted in our simulations, and no clear trends were observed in the lateral diffusivities of the lipids as the concentration, type of secondary lipid, and surface tension were varied.
Topics: Liposomes; Molecular Dynamics Simulation; Dimyristoylphosphatidylcholine; Phosphorylcholine; Phospholipids; Lipid Bilayers; Phosphatidylcholines
PubMed: 37879075
DOI: 10.1021/acs.jpcb.3c04386 -
Frontiers in Endocrinology 2023Obesity poses an increased risk for the onset of Nonalcoholic fatty liver disease (NAFLD). The influence of other factors, such as sex in the incidence and severity of...
OBJECTIVE
Obesity poses an increased risk for the onset of Nonalcoholic fatty liver disease (NAFLD). The influence of other factors, such as sex in the incidence and severity of this liver disease has not yet been fully elucidated. Thus, we aimed to identify the NAFLD serum metabolic signatures associated with sex in normal, overweight and obese patients and to associate the metabolite fluctuations across the increasing liver steatosis stages.
METHODS AND RESULTS
Using nuclear magnetic resonance (NMR) serum samples of 210 NAFLD cases and control individuals diagnosed with liver U/S, our untargeted metabolomics enquiry provided a sex distinct metabolic bouquet. Increased levels of alanine, histidine and tyrosine are associated with severity of NAFLD in both men and women. Moreover, higher serum concentrations of valine, aspartic acid and mannose were positively associated with the progression of NAFLD among the male subjects, while a negative association was observed with the levels of creatine, phosphorylcholine and acetic acid. On the other hand, glucose was positively associated with the progression of NAFLD among the female subjects, while levels of threonine were negatively related. Fluctuations in ketone bodies acetoacetate and acetone were also observed among the female subjects probing a significant reduction in the circulatory levels of the former in NAFLD cases. A complex glycine response to hepatic steatosis of the female subjects deserves further investigation.
CONCLUSION
Results of this study aspire to address the paucity of data on sex differences regarding NAFLD pathogenesis. Targeted circulatory metabolome measurements could be used as diagnostic markers for the distinct stages of NAFLD in each sex and eventually aid in the development of novel sex-related therapeutic options.
Topics: Humans; Female; Male; Non-alcoholic Fatty Liver Disease; Metabolomics; Obesity; Metabolome
PubMed: 37854184
DOI: 10.3389/fendo.2023.1230457 -
ACS Omega Oct 2023Nanofibrous mats as a wound dressing have received great attention in recent year. The development of biocompatible dressings with antibiofouling capability and...
Nanofibrous mats as a wound dressing have received great attention in recent year. The development of biocompatible dressings with antibiofouling capability and long-lasting antibacterial properties is important but challenging. Antibacterial photodynamic therapy (aPDT) effectively eliminates pathogens via a photodynamic process that can circumvent the emergence of antibiotic-resistant pathogens. In this study, we integrated the zwitterionic materials (2-methacryloyloxyethyl phosphorylcholine (MPC) moiety) and aPDT photosensitizer, methylene blue (MB), to fabricate a long-lasting antibacterial nanofibrous mat using electrospinning technology. The prepared nanofibers possessed an appropriate water absorption and retention ability, superior cytocompatibility, and antibiofouling ability against both proteins and L929 cell adhesion. MB-loaded nanofibrous mats have exhibited superior aPDT against Gram-positive compared to Gram-negative under moderate irradiation (100 W m) due to the presence of an extra outer membrane of Gram-negative bacteria serving as a protective barrier. In vitro release study demonstrated that the nanofibrous mat had a long-lasting drug release profile, which can efficiently suppress bacterial growth via aPDT. The antibacterial ability of the MB-loaded nanofibrous mat was commensurate or slightly inferior to antibiotics such as tetracycline and kanamycin, suggesting that it has the potential to be used as an antibiotic alternative. Overall, this zwitterionic nanofibrous mat with long-lasting aPDT function and nonadherent properties has potential as a promising antibacterial wound dressing.
PubMed: 37841143
DOI: 10.1021/acsomega.3c03964 -
International Journal of Molecular... Sep 2023Pathological mechanisms contributing to Alzheimer's disease (AD) are still elusive. Here, we identified the metabolic signatures of AD in human post-mortem brains. Using...
Pathological mechanisms contributing to Alzheimer's disease (AD) are still elusive. Here, we identified the metabolic signatures of AD in human post-mortem brains. Using H NMR spectroscopy and an untargeted metabolomics approach, we identified (1) metabolomic profiles of AD and age-matched healthy subjects in post-mortem brain tissue, and (2) region-common and region-unique metabolome alterations and biochemical pathways across eight brain regions revealed that BA9 was the most affected. Phenylalanine and phosphorylcholine were mainly downregulated, suggesting altered neurotransmitter synthesis. N-acetylaspartate and GABA were upregulated in most regions, suggesting higher inhibitory activity in neural circuits. Other region-common metabolic pathways indicated impaired mitochondrial function and energy metabolism, while region-unique pathways indicated oxidative stress and altered immune responses. Importantly, AD caused metabolic changes in brain regions with less well-documented pathological alterations that suggest degenerative progression. The findings provide a new understanding of the biochemical mechanisms of AD and guide biomarker discovery for personalized risk prediction and diagnosis.
Topics: Humans; Alzheimer Disease; Brain; Metabolomics; Metabolome; Magnetic Resonance Spectroscopy
PubMed: 37834217
DOI: 10.3390/ijms241914769 -
Pharmaceutical Research Dec 2023Miltefosine is the first and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with differences in exposure...
OBJECTIVES
Miltefosine is the first and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with differences in exposure patterns and cure rates among different population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure-response relationship of miltefosine in in silico clinical trials and evaluate the differences in population groups, particularly children and adults.
METHODS
The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under different dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUC > 535 µg⋅day/mL in the virtual population.
RESULTS
It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no significant difference in the predicted dose-exposure-response of the miltefosine treatment for different simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment.
CONCLUSIONS
The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the difference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials.
Topics: Adult; Humans; Child; Leukocytes, Mononuclear; Phosphorylcholine; Computer Simulation; Antiprotozoal Agents; Models, Biological
PubMed: 37816929
DOI: 10.1007/s11095-023-03610-0 -
Bioactive Materials Feb 2024Proteins, cells and bacteria adhering to the surface of medical devices can lead to thrombosis and infection, resulting in significant clinical mortality. Here, we...
Proteins, cells and bacteria adhering to the surface of medical devices can lead to thrombosis and infection, resulting in significant clinical mortality. Here, we report a zwitterionic polymers-armored amyloid-like protein surface engineering strategy we called as "armored-tank" strategy for dual functionalization of medical devices. The "armored-tank" strategy is realized by decoration of partially conformational transformed LZM (PCTL) assembly through oxidant-mediated process, followed by armoring with super-hydrophilic poly-2-methacryloyloxyethyl phosphorylcholine (pMPC). The outer armor of the "armored-tank" shows potent and durable zone defense against fibrinogen, platelet and bacteria adhesion, leading to long-term antithrombogenic properties over 14 days without anticoagulation. Additionally, the "fired" PCTL from "armored-tank" actively and effectively kills both Gram-positive and Gram-negative bacterial over 30 days as a supplement to the lacking bactericidal functions of passive outer armor. Overall, this "armored-tank" surface engineering strategy serves as a promising solution for preventing biofouling and thrombotic occlusion of medical devices.
PubMed: 37810990
DOI: 10.1016/j.bioactmat.2023.09.003 -
BioRxiv : the Preprint Server For... Sep 2023Glycans 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 exert immunomodulatory effects in a glycan-dependent manner. To better understand the mechanisms of these interactions, we prepared N-glycans from 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 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 are recognized by both the innate and adaptive immune systems, and also exhibit species-specific features distinguishing its glycome from those of other nematodes.
PubMed: 37790353
DOI: 10.1101/2023.09.21.557549 -
RSC Advances Sep 20232-Methacryloyloxyethyl phosphorylcholine (MPC) zwitterions were modified onto self-made graphene oxide (GO) through the atom transfer radical polymerization method. The...
2-Methacryloyloxyethyl phosphorylcholine (MPC) zwitterions were modified onto self-made graphene oxide (GO) through the atom transfer radical polymerization method. The chemical structures of the products were verified using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, nuclear magnetic resonance spectroscopy (NMR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), It was found that the modified GO (GO-PCn) is well dispersed in water with an average hydrodynamic diameter of about 170 nm. By utilizing the 2D planar structure of this modified graphene, the irinotecan@GO-PCn composite can be loaded with about 20% of irinotecan π-π stacking interaction and exhibit pH-sensitive drug release performance, releasing faster in the acidic environment. The cytotoxicity assessments confirmed that GO-PCn composed of phosphorylcholine moiety represented low cytotoxicity and acted as a certain effect on reducing the acute toxicity of irinotecan, which established a foundation for further studies of the system in oncology therapy.
PubMed: 37790105
DOI: 10.1039/d3ra04987f