Dysregulation of lipid metabolism plays a major role in the etiology and sequelae of inflammatory disorders, cardiometabolic and neurological diseases, and several forms of cancer. Recent advances in ...lipidomic methodology allow comprehensive lipidomic profiling of clinically relevant biological samples, enabling researchers to associate lipid species and metabolic pathways with disease onset and progression. The resulting data serve not only to advance our fundamental knowledge of the underlying disease process but also to develop risk assessment models to assist in the diagnosis and management of disease. Currently, clinical applications of in-depth lipidomic profiling are largely limited to the use of research-based protocols in the analysis of population or clinical sample sets. However, we foresee the development of purpose-built clinical platforms designed for continuous operation and clinical integration—assisting health care providers with disease risk assessment, diagnosis, and monitoring. Herein, we review the current state of clinical lipidomics, including the use of research-based techniques and platforms in the analysis of clinical samples as well as assays already available to clinicians. With a primary focus on MS-based strategies, we examine instrumentation, analysis techniques, statistical models, prospective design of clinical platforms, and the possible pathways toward implementation of clinical lipidomics.
Herein, we demonstrate a method for the functionalization of cubic phase lipid nanoparticles (cubosomes) with a series of magnetite (Fe3O4), copper oxide (Cu2O), and silver (Ag) nanocrystals, with ...prospective applications across a wide range of fields, including antimicrobial treatments. The resulting cubosomes are characterized using small-angle X-ray scattering and dynamic light scattering, demonstrating the retention of a typical cubic phase structure and particle size following nanocrystal encapsulation at concentrations up to 20% w/w. Cryogenic transmission electron microscopy reveals significant loading and association of each nanocrystal type with both monoolein- and phytantriol-based cubosomes. The antibiotic potential of these hybrid nanoparticles is demonstrated for the first time; cubosomes with embedded silver nanocrystals display a high level of antimicrobial activity against both Gram-positive and Gram-negative bacteria, with observed minimum inhibitory concentration values ranging from 15.6–250 μg/mL. Lastly, total internal reflection fluorescence microscopy is used to visualize cubosome–bacteria interactions, suggesting the involvement of particle interactions as a delivery mechanism.
•The particle size of EWP nanoparticle increased with addition of curcumin solution.•Ethanol would induce more α-helix transferred to β-sheet during heating treatment.•At pH 3.0, EWP behaved higher ...loading efficiency than pH 3.8.•EWP nanoparticle can effectively slow down curcumin degradation rate.
This study investigated the encapsulation of curcumin into egg white protein (EWP) nanoparticles. Processing conditions used to formulate the nanoparticles, including pH and the addition of ethanol, were used to control the unfolding and aggregation behavior of EWP. The curcumin loading capacity of the EWP nanoparticles was found to be strongly linked to the structural transitions of the protein during heat denaturation, and the microscopic properties of the particles such as particle size and zeta-potential. Fibrous particles were formed at lower pH (3.0) and were associated with a higher curcumin loading than the granular particles formed at pH 3.8. Ethanol leads to an increase in β-sheet structure, and the formation of a coarser gel structure during heat denaturation, resulted in an increase in particle diameter. The highest curcumin loading capacities were 11.53 and 9.89 mg/g protein (with a final curcumin concentration of 312.5 μM and 268 μM respectively), at pH 3.0 and 3.8, respectively. Encapsulation in EWP nanoparticles was shown to both effectively slow the degradation ratio as well as protect the antioxidant activity of encapsulated curcumin.
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Two-dimensional NOE (nuclear Overhauser effect) NMR spectroscopy was employed to investigate the dynamic properties of water within lyotropic bicontinuous lipidic cubic phases (LCPs) ...formed by monoolein (MO). Experiments observed categorically different effective residence times of water molecules: (i) in proximity to the glycerol moiety of MO, and (ii) adjacent to the hydrophobic chain towards the hydrocarbon tail of MO, as evidenced by the opposite signs of intermolecular NOE cross peaks between protons of water and those of MO in 2D 1H–1H NOESY spectra. Spectroscopic data delineating the different effective residence times of water molecules within both the gyroid (QIIG) and diamond (QIID) phase groups corresponding to hydration levels of 35 and 40 wt%, respectively, are presented. Additionally, an increase in effective residence time of water molecules in proximity to the glycerol moiety of MO in LCPs was observed upon storage at ambient temperature and in the presence of an additive lipid, cholesterol. Atom-specific NOE build-up curves for protons of water and those of MO are also given. The results presented herein provide new insight into the physicochemical properties and behaviour of water in LCPs, and demonstrate an additional avenue for experimental study of water–lipid interactions and hydration dynamics in model membranes and nanomaterials using 2D NOE NMR spectroscopy.
Abstract
Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body mass index (BMI). ...Conversely, not all obese individuals present with metabolic disorders giving rise to the concept of “metabolically healthy obese”. We use lipidomic-based models for BMI to calculate a metabolic BMI score (mBMI) as a measure of metabolic dysregulation associated with obesity. Using the difference between mBMI and BMI (mBMIΔ), we identify individuals with a similar BMI but differing in their metabolic health and disease risk profiles. Exercise and diet associate with mBMIΔ suggesting the ability to modify mBMI with lifestyle intervention. Our findings show that, the mBMI score captures information on metabolic dysregulation that is independent of the measured BMI and so provides an opportunity to assess metabolic health to identify “at risk” individuals for targeted intervention and monitoring.
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•Three antimicrobial peptides were encapsulated in various cubosome formulations.•Cubosomes were characterized using SAXS, cryo-TEM, circular dichroism and DLS.•Loading and mesophase ...structure varied significantly between formulations.•Changes in structural parameters depended on peptide and lipid properties.
The inverse bicontinuous lipidic cubic phase offers a simple and robust membrane mimetic with the ability to encapsulate peptides, potentially increasing bioavailability, while also offering a platform from which functionalized, targeted nanoparticles can be developed. Herein we have investigated the use of a number of cubic phase nanoparticle systems with encapsulated antimicrobial peptides gramicidin A’, melittin, and alamethicin. The optimal peptide loading ranges, over which cubic symmetry was retained, were determined using small angle X-ray scattering. A large variation in peptide loading capability of different cubosome formulations was confirmed using circular dichroism. Observations are supported by particle sizing using dynamic light scattering as well as by direct visualization of nanoparticle morphology using cryogenic transmission electron microscopy. The results are discussed in relation to bilayer properties such as the hydrophobic mismatch between bilayer and peptide, intrinsic surface curvature, and lateral pressure profile of each lipid system. The findings of this study should be of use in the further development of lipid-based peptide encapsulation systems, particularly in the field of drug delivery.
Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes ...in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC.
We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models.
The 3LS was associated with shorter OS in the discovery (hazard ratio HR 2.15, 95% confidence interval CI 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies.
Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.
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The growing global threat of antimicrobial resistance, combined with the slowed development of novel antibiotics, has resulted in a critical need for new antimicrobial therapies. ...Naturally occurring antimicrobial peptides (AMPs) can act as highly potent, broad-spectrum antibiotics which may be less likely to engender resistance in target organisms. However, their susceptibility to proteolysis and lack of specificity necessitates the use of a drug delivery vehicle to both protect the AMP from chemical degradation and provide a platform for further functionalization, enabling the development of targeted delivery and release systems. In this study, we have used lipid-based inverse bicontinuous cubic phase nanoparticles (cubosomes) as delivery vehicles for six different antimicrobial peptides. The phase stability, morphology, and peptide loading efficiency of the nanoparticles were characterized and rationalized according to lipid composition, buffer conditions, as well as peptide charge and hydrophobicity. The AMP loading efficiency within cubosomes was increased significantly through simple manipulation of electrostatic charge. Minimum inhibitory concentration (MIC) values were determined for formulations with high loading efficiency against Staphylococcus aureus, Bacilus cereus, Escherichia coli, and Pseudomonas aeruginosa. Encapsulation within a lipid nanocarrier was shown to increase antimicrobial activity for some formulations. We anticipate that the further development of these peptide loaded cubosomes will enable the design of potent and targeted antibiotic therapies.
Lipidic inverse bicontinuous cubic phases (LCPs), formed via the spontaneous self-assembly of lipids such as monoolein, have found increasing applications in the stabilization and crystallization of ...integral membrane proteins for structural characterization using X-ray crystallography. Their use as effective drug release matrices has also been demonstrated. Nuclear magnetic resonance (NMR) spectroscopy, both solution and solid-state, has previously been employed for the characterization of LCPs and related systems. Herein, we report a number of novel features of solution NMR for probing the fundamental composition and structural properties of monoolein-based LCPs. These include: (1) more complete assignments of both 1H and 13C chemical shifts, (2) direct quantification of hydration level in LCPs using 1D 1H NMR, and (3) monitoring longer term stability of LCPs and evaluating alterations introduced into standard LCPs at the sub-molecular level.
Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and ...immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.
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