Plasma Profiles Research Articles

Sphingolipid metabolites as potential circulating biomarkers for sarcopenia in men.

Sarcopenia is an age-related progressive loss of muscle mass and function. Sarcopenia is a multifactorial disorder, including metabolic disturbance; therefore, metabolites may be used as circulating biomarkers for sarcopenia. We aimed to investigate potential biomarkers of sarcopenia using metabolomics. After non-targeted metabolome profiling of plasma from mice of an aging mouse model of sarcopenia, sphingolipid metabolites and muscle cells from the animal model were evaluated using targeted metabolome profiling. The associations between sphingolipid metabolites identified from mouse and cell studies and sarcopenia status were assessed in men in an age-matched discovery (72 cases and 72 controls) and validation (36 cases and 128 controls) cohort; women with sarcopenia (36 cases and 36 controls) were also included as a discovery cohort. Both non-targeted and targeted metabolome profiling in the experimental studies showed an association between sphingolipid metabolites, including ceramides (CERs) and sphingomyelins (SMs), and sarcopenia. Plasma SM (16:0), CER (24:1), and SM (24:1) levels in men with sarcopenia were significantly higher in the discovery cohort than in the controls (all P<0.05). There were no significant differences in plasma sphingolipid levels for women with or without sarcopenia. In men in the discovery cohort, an area under the receiver-operating characteristic curve (AUROC) of SM (16:0) for low muscle strength and low muscle mass was 0.600 (95% confidence interval [CI]: 0.501-0.699) and 0.647 (95% CI: 0.557-0.737). The AUROC (95% CI) of CER (24:1) and SM (24:1) for low muscle mass in men was 0.669 (95% CI: 0.581-0.757) and 0.670 (95% CI: 0.582-0.759), respectively. Using a regression equation combining CER (24:1) and SM (16:0) levels, a sphingolipid (SphL) score was calculated; an AUROC of the SphL score for sarcopenia was 0.712 (95% CI: 0.626-0.798). The addition of the SphL score to HGS significantly improved the AUC from 0.646 (95% CI: 0.575-0.717; HGS only) to 0.751 (95% CI: 0.671-0.831, P=0.002; HGS+SphL) in the discovery cohort. The predictive ability of the SphL score for sarcopenia was confirmed in the validation cohort (AUROC=0.695, 95% CI: 0.591-0.799). SM (16:0), reflecting low muscle strength, and CER (24:1) and SM (16:0), reflecting low muscle mass, are potential circulating biomarkers for sarcopenia in men. Further research on sphingolipid metabolites is required to confirm these results and provide additional insights into the metabolomic changes relevant to the pathogenesis and diagnosis of sarcopenia.

The assessment of pharmacokinetics and neuroprotective effect of berberine hydrochloride-embedded albumin nanoparticles via various administration routes: comparative in-vivo studies in rats.

The current study aimed to evaluate the pharmacokinetics and neuroprotective effect of well-characterised berberine-bovine serum albumin (BBR-BSA) nanoparticles. BBR-BSA nanoparticles were generated by desolvation method. Entrapment efficiency, loading capacity, particle size, polydispersity index, surface morphology, thermal stability, and in-vitro release were estimated. In-vitro pharmacokinetic and tissue distribution were conducted. Their neuroprotection was evaluated against lipopolysaccharides-induced neurodegeneration. BBR-BSA nanoparticles showed satisfactory particle size (202.60 ± 1.20 nm) and entrapment efficiency (57.00 ± 1.56%). Results confirmed the formation of spheroid-thermal stable nanoparticles with a sustained drug release over 48 h. Sublingual and intranasal routes had higher pharmacokinetic plasma profiles than other routes, with Cmax values at 0.75 h (444 ± 77.79 and 259 ± 42.41 ng/mL, respectively). BBR and its metabolite distribution in the liver and kidney were higher than in plasma. Intranasal and sublingual treatment improves antioxidants, proinflammatory, amyloidogenic biomarkers, and brain architecture, protecting the brain. In conclusion, neuroinflammation and neurodegeneration may be prevented by intranasal and sublingual BBR-BSA nanoparticles.

In vivo Imaging and Pharmacokinetics of Percutaneously Injected Ultrasound and X-ray Imageable Thermosensitive Hydrogel loaded with Doxorubicin versus Free Drug in Swine.

Intratumoral injections often lack visibility, leading to unpredictable outcomes such as incomplete tumor coverage, off-target drug delivery and systemic toxicities. This study investigated an ultrasound (US) and x-ray imageable thermosensitive hydrogel based on poloxamer 407 (POL) percutaneously delivered in a healthy swine model. The primary objective was to assess the 2D and 3D distribution of the hydrogel within tissue across three different needle devices and injection sites: liver, kidney, and intercostal muscle region. Secondly, pharmacokinetics of POL loaded with doxorubicin (POLDOX) were evaluated and compared to free doxorubicin injection (DOXSoln) with a Single End Hole Needle. Utilizing 2D and 3D morphometrics from US and x-ray imaging techniques such as Computed Tomography (CT) and Cone Beam CT (CBCT), we monitored the localization and leakage of POLDOX over time. Relative iodine concentrations measured with CBCT following incorporation of an iodinated contrast agent in POL indicated potential drug diffusion and advection transport. Furthermore, US imaging revealed temporal changes, suggesting variations in acoustic intensity, heterogeneity, and echotextures. Notably, 3D reconstruction of the distribution of POL and POLDOX from 2D ultrasound frames was achieved and morphometric data obtained. Pharmacokinetic analysis revealed lower systemic exposure of the drug in various organs with POLDOX formulation compared to DOXSoln formulation. This was demonstrated by a lower area under the curve (852.1 ± 409.1 ng/mL·h vs 2283.4 ± 377.2 ng/mL·h) in the plasma profile, suggesting a potential reduction in systemic toxicity. Overall, the use of POL formulation offers a promising strategy for precise and localized drug delivery, that may minimize adverse effects. Dual modality POL imaging enabled analysis of patterns of gel distribution and morphology, alongside of pharmacokinetics of local delivery. Incorporating hydrogels into drug delivery systems holds significant promise for improving the predictability of the delivered drug and enhancing spatial conformability. These advancements can potentially enhance the safety and precision of anticancer therapy.

Evaluating treatments for male androgenetic alopecia: clinical profile and comparative efficacy of platelet rich plasma and minoxidil with finasteride

Background: Androgenetic alopecia (AGA) is a common, hereditary, and androgen-dependent disorder characterized by progressive hair thinning on the scalp, affecting both men and women. It arises from follicular miniaturization, leading to the conversion of terminal hair into vellus hair. Methods: This study is a single-center, prospective, open-label, randomized, placebo-controlled trial with four parallel arms designed to evaluate treatments for male pattern baldness. Eighty patients were randomized into four groups: Group 1 received topical minoxidil and finasteride solution, group 2 received PRP alone, group 3 received PRP with minoxidil and finasteride solution, and group 4 received normal saline (NS). Interventions were administered monthly over three months, followed by a three-month follow-up period. Treatment effects were assessed using measures such as patient self-assessment, global photography, and the hair pull test. Results: Group 3 (combined treatment) showed the most significant improvement in the hair pull test after six months (73.33% negative tests), followed by group 2 (PRP treatment) with 60% improvement. Patient satisfaction scores were highest in group 3 across all follow-ups (F1 to F5), demonstrating superior treatment response compared to other groups (p&lt;0.001). Global photography assessments indicated varying results among groups, with group 4 recording the highest proportion of fair improvements (58.5%). Group 3 exhibited the highest percentage of patients with above-average improvement. Conclusions: Our study provides valuable insights into managing AGA, emphasizing the effectiveness of combining PRP with topical treatments compared to individual therapies and placebo.

P07-10 Differential impact of renewable diesel exhaust particles on protein profiles in bronchoalveolar lavage fluid and plasma after instillation exposure in mice

P07-10 Differential impact of renewable diesel exhaust particles on protein profiles in bronchoalveolar lavage fluid and plasma after instillation exposure in mice

Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling

Negative food effect refers to a reduction in bioavailability, when a drug is taken with food. Voclosporin, a highly lipophilic cyclic peptide drug for treatment of active lupus nephritis, has shown negative food effect in clinical trials. Here, the cause of the negative food effect of voclosporin was investigated using physiologically based pharmacokinetic (PBPK) modeling to understand the mechanism responsible for oral absorption of voclosporin. Voclosporin is a substrate for P-glycoprotein and CYP3A4, and it has been evaluated for intestinal membrane permeability in human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs). The membrane permeability in hiPSC-IECs is integrated into the PBPK model for simulating permeability accurately. The PBPK model simulated the systemic PK profile in fasted state in human. Then, the PBPK model with in vitro adsorption of voclosporin onto food simulated the systemic PK profile in fed state for food effect. In addition, the PBPK model for rats also simulated the plasma profile of voclosporin for the food effect. These results suggest that a possible cause of the negative food effect of voclosporin is the adsorption of voclosporin to food in gastrointestinal tract. These approaches could facilitate understanding of the mechanisms responsible for oral absorption of cyclic peptides.

Realization of a gas puff imaging system on the Wendelstein 7-X stellarator.

A system for studying the spatiotemporal dynamics of fluctuations in the boundary of the W7-X plasma using the "Gas-Puff Imaging" (GPI) technique has been designed, constructed, installed, and operated. This GPI system addresses a number of challenges specific to long-pulse superconducting devices, such as W7-X, including the long distance between the plasma and the vacuum vessel wall, the long distance between the plasma and diagnostic ports, the range of last closed flux surface (LCFS) locations for different magnetic configurations in W7-X, and management of heat loads on the system's plasma-facing components. The system features a pair of "converging-diverging" nozzles for partially collimating the gas puffed locally ≈135mm radially outboard of the plasma boundary, a pop-up turning mirror for viewing the gas puff emission from the side (which also acts as a shutter for the re-entrant vacuum window), and a high-throughput optical system that collects visible emission resulting from the interaction between the puffed gas and the plasma and directs it along a water-cooled re-entrant tube directly onto the 8 × 16 pixel detector array of the fast camera. The DEGAS 2 neutral code was used to simulate the Hα (656nm) and HeI (587nm) line emission expected from well-characterized gas-puffs of H2 and He and excited within typical edge plasma profiles in W7-X, thereby predicting line brightnesses used to reduce the risks associated with system sensitivity and placement of the field of view. Operation of GPI on W7-X shows excellent signal-to-noise ratios (>100 at 2 Mframes/s) over the field of view for minimally perturbing gas puffs. The GPI system provides detailed measurements of the two-dimensional (radial and poloidal) dynamics of plasma fluctuations in the W7-X edge and scrape-off layer and in and around the magnetic islands outside the LCFS that make up the island divertor configuration employed on W7-X.

2837: Metabolic profiling of plasma and tissue in breast cancer patients: uncovering therapeutic response

2837: Metabolic profiling of plasma and tissue in breast cancer patients: uncovering therapeutic response

Kidney effects of triple CFTR modulator therapy in people with cystic fibrosis.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a new cystic fibrosis transmembrane conductance regulator (CFTR) modulator that has transformed the respiratory prognosis of people with cystic fibrosis (pwCF). However, its impact on other organs such as the kidneys, where CFTR is expressed, remains unclear. Since pwCF are risk of both kidney disease and urolithiasis, we aimed to study the potential effects of ETI on renal function, volume status, and risk factors for urolithiasis. This prospective, observational, single-center, before-after cohort study, involved adult pwCF eligible for ETI. The changes in plasma and urinary profiles were assessed by comparing renal function (using 2021 CKD-EPIcreatinine and 2021 CKD-EPIcreatinine-cystatin C formulas), volume status (using aldosterone/renin ratio and blood pressure), and risk factors for urolithiasis, at the time of ETI introduction (M0) and 7 months after (M7). Nineteen pwCF were included. No significant change in renal function was observed between M0 and M7 (2021 CKD-EPIcreatinine: 105.5ml/min/1.73 m² at M0 vs. 103.3ml/min/1.73 m² at M7; P=.17). There was a significant reduction in aldosterone level (370.3pmol/l at M0 vs. 232.4pmol/l at M7; P=.02) and aldosterone/renin ratio (33.6 at M0 vs. 21.8 at M7; P=.03). Among the risk factors for urolithiasis, a significant reduction in magnesuria level was found (4.6mmol/d at M0 vs. 3.8mmol/d at M7; P=.01). These findings suggest that ETI seem to have no short-term impact on the renal function of adult pwCF and appears to correct secondary hyperaldosteronism due to excessive sweat losses. Further investigations are needed to determine the potential impact of decreased magnesuria observed under ETI therapy on the risk of urolithiasis.

Preliminary investigation on the impact of salty and sugary former foods on pig liver and plasma profiles using OMICS approaches

Replacing cereals with food leftovers could reduce feed-food competition and keep nutrients and energy in the food chain. Former food products (FFPs) are industrial food leftovers no more intended for human but still suitable as alternative and sustainable feedstuffs for monogastric. In this study, omics approaches were applied to evaluate the impact of dietary FFPs on pig liver proteome and plasma peptidome. Thirty-six Swiss Large White male castrated pigs were randomly assigned to three dietary treatments [control (CTR), 30% CTR replaced with salty FFP (SA), 30% CTR replaced with sugary FFP (SU)] from the start of the growing phase (22.4 ± 1.7 kg) until slaughtering (110 ± 3 kg). The low number of differentially regulated proteins in each comparison matrix (SA/SU vs. CTR) and the lack of metabolic interaction indicated a marginal impact on hepatic lipid metabolism. The plasma peptidomics investigation showed low variability between the peptidome of the three dietary groups and identified three possible bioactive peptides in the SA group associated with anti-hypertension and vascular homeostasis regulation. To conclude, the limited modulation of liver proteome and plasma peptidome by the SA and SU diets strenghtened the idea of reusing FFPs as feed ingredients to make pig production more sustainable.

Proteomic and Cytokine Profiling in Plasma from Patients with Normal-Tension Glaucoma and Ocular Hypertension

Primary open-angle glaucoma (POAG) is subdivided depending on eye pressure. Patients with normal-tension glaucoma (NTG) have never had high intraocular pressure (IOP) measured while patients with ocular hypertension (OHT) have high eye pressure but no signs of glaucoma. Although IOP is considered to be a risk factor for all glaucoma patients, it is reasonable to assume that other risk factors such as inflammation play a role. We aimed to characterize the proteome and cytokine profile during hypoxia in plasma from patients with NTG (n = 10), OHT (n = 10), and controls (n = 10). Participants were exposed to hypoxia for two hours, followed by 30 min of normoxia. Samples were taken before (“baseline”), during (“hypoxia”), and after hypoxia (“recovery”). Proteomics based on liquid chromatography coupled with mass spectrometry (LC–MS) was performed. Cytokines were measured by Luminex assays. Bioinformatic analyses indicated the involvement of complement and coagulation cascades in NTG and OHT. Regulation of high-density lipoprotein 3 (HDL3) apolipoproteins suggested that changes in cholesterol metabolism are related to OHT. Hypoxia decreased the level of tumor necrosis factor-α (TNF-α) in OHT patients compared to controls. Circulating levels of interleukin-1β (IL-1β) and C-reactive protein (CRP) were decreased in NTG patients compared to controls during hypoxia. After recovery, plasma interleukin-6 (IL-6) was upregulated in patients with NTG and OHT. Current results indicate an enhanced systemic immune response in patients with NTG and OHT, which correlates with pathogenic events in glaucoma. Apolipoproteins may have anti-inflammatory effects, enabling OHT patients to withstand inflammation and development of glaucoma despite high IOP.Graphical

Distinct protein patterns related to postnatal development in small for gestational age preterm infants.

Preterm infants, especially those born small for gestational age (SGA), are at risk of short-term and long-term health complications. Characterization of changes in circulating proteins postnatally in preterm infants may provide valuable fundamental insights into this population. Here, we investigated postnatal developmental patterns in preterm infants and explored protein signatures that deviate between SGA infants and appropriate for gestational age (AGA) infants using a mass spectrometry (MS)-based proteomics workflow. Longitudinal serum samples obtained at postnatal days 0, 3, 7, 14, and 28 from 67 preterm infants were analyzed using unbiased MS-based proteomics. 314 out of 833 quantified serum proteins change postnatally, including previously described age-related changes in immunoglobulins, hemoglobin subunits, and new developmental patterns, e.g. apolipoproteins (APOA4) and terminal complement cascade (C9) proteins. Limited differences between SGA and AGA infants were found at birth while longitudinal monitoring revealed 69 deviating proteins, including insulin-sensitizing hormone adiponectin, platelet proteins, and 24 proteins with an annotated function in the immune response. This study shows the potential of MS-based serum profiling in defining circulating protein trajectories in the preterm infant population and its ability to identify longitudinal alterations in protein levels associated with SGA. Postnatal changes of circulating proteins in preterm infants have not fully been elucidated but may contribute to development of health complications. Mass spectrometry-based analysis is an attractive approach to study circulating proteins in preterm infants with limited material. Longitudinal plasma profiling reveals postnatal developmental-related patterns in preterm infants (314/833 proteins) including previously described changes, but also previously unreported proteins. Longitudinal monitoring revealed an immune response signature between SGA and AGA infants. This study highlights the importance of taking postnatal changes into account for translational studies in preterm infants.

Application of Pattern Recognition and Mixture Methods in Exposome Profiling of Seminal Plasma and Associations with Semen Parameters

Application of Pattern Recognition and Mixture Methods in Exposome Profiling of Seminal Plasma and Associations with Semen Parameters

Inflammatory plasma profile in genetic symptomatic and presymptomatic Frontotemporal Dementia − A GENFI study

BackgroundInflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI). MethodsMesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)]. ResultsThe following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1β, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found.Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001).Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged. ConclusionWe showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease.

Benchmarking of hydrodynamic plasma waveguides for multi-GeV laser-driven electron acceleration

Hydrodynamic plasma waveguides initiated by optical field ionization have recently become a key component of multi-GeV laser wakefield accelerators. Here, we present the most complete and accurate experimental and simulation-based characterization to date, applicable to current multi-GeV experiments and future 100 GeV-scale laser plasma accelerators. Crucial to the simulations is the correct modeling of intense Bessel beam interaction with meter-scale gas targets, the results of which are used as initial conditions for hydrodynamic simulations. The simulations are in good agreement with our experiments measuring evolving plasma and neutral hydrogen density profiles using two-color short pulse interferometry, enabling realistic determination of the guided mode structure for application to laser-driven plasma accelerator design. Published by the American Physical Society 2024

Integration of epidemiological and blood biomarker analysis links haem iron intake to increased type 2 diabetes risk.

Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20-1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including L-valine and uric acid, potentially mediating the haem iron-T2D relationship, highlighting their pivotal role in T2D pathogenesis.

Bottom quark dynamics from nonprompt D0 and J/ψ production in Pb+Pb collisions at sNN=5.02 TeV

We study bottom quark energy loss via the nuclear modification factor (RAA) and elliptic flow (v2) of nonprompt D0 and J/ψ in relativistic heavy-ion collisions at the Large Hadron Collider (LHC). The space-time profile of quark-gluon plasma is obtained from the hydrodynamics simulation, the dynamical evolution of heavy quarks inside the color deconfined QCD medium is simulated using a linear Boltzmann transport model that combines Yukawa and string potentials of heavy-quark-medium interactions, the hadronization of heavy quarks is performed using a hybrid coalescence-fragmentation model, and the decay of B mesons is simulated via . Using this numerical framework, we calculate the transverse momentum (pT) dependent RAA and v2 of direct D mesons, B mesons, and nonprompt D0 and J/ψ from B meson decay in Pb+Pb collisions at sNN=5.02 TeV. We find the mass hierarchy of the nuclear modification of prompt D and B mesons depends on their pT. Both RAA and v2 of heavy flavor particles show strong pT and centrality dependences due to the interplay between parton energy loss, medium geometry and flow, and hadronization of heavy quarks. Nonprompt D0 and J/ψ share similar patterns of RAA and v2 to B mesons except for a pT shift during the decay processes. Therefore, future more precise measurements on nonprompt D0 and J/ψ can help further pin down the bottom quark dynamics inside the quark-gluon plasma. Published by the American Physical Society 2024

Prognostic and therapeutic monitoring value of plasma and urinary cytokine profile in primary membranous nephropathy: the STARMEN trial cohort

Abstract Background and hypothesis Primary membranous nephropathy (PMN) is usually caused by anti-PLA2R autoantibodies. There are different therapeutic options according to baseline risk. Novel biomarkers are needed to optimize risk stratification, and predict and monitor the response to therapy, as proteinuria responses may be delayed. We hypothesized that plasma or urinary cytokines may provide insight into the course and response to therapy in PMN. Methods Overall, 192 data-points from 34 participants in the STARMEN trial, randomized to tacrolimus-rituximab (TAC-RTX) or corticosteroids-cyclophosphamide (GC-CYC), were analyzed for plasma and urine cytokines using a highly sensitive chemiluminescence immunoassay providing a high-throughput multiplex analysis. Results Baseline (pretreatment) urinary CXCL13 predicted the therapeutic response to TAC-RTX. Cytokine levels evolved over the course of therapy. The levels of nine plasma and six urinary cytokines correlated with analytical parameters of kidney damage and disease activity, such as proteinuria, eGFR and circulating anti-PLA2R levels. The correlation with these parameters was most consistent for plasma and urinary GDF15, plasma TNF-α and urinary TWEAK. Decreasing plasma GDF15 levels were associated to response to GC-CYC. Four clusters of cytokines were associated to different stages of response to therapy in the full cohort, with the less inflammatory cluster associated to remission. Conclusion In conclusion, PMN displayed characteristic plasma and urine cytokine patterns that evolved over time as patients responded to therapy. Baseline urinary CXCL13 concentration could be a prognostic marker of response to TAC-RTX.

PBPK model of pegylated liposomal doxorubicin to simultaneously predict the concentration-time profile of encapsulated and free doxorubicin in tissues.

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict the concentrations of encapsulated and free doxorubicin in plasma and tissues in mice after intravenous injection of PEGylated liposomes (Doxil®). The PBPK model used in this study contains liposomes and free doxorubicin disposition components. The free doxorubicin disposition component was used to simulate the disposition of free doxorubicin produced by mononuclear phagocyte system (MPS)-degrading liposomes. The liver, spleen, kidneys, and lungs contain an additional MPS subcompartment. These compartments are interconnected through blood and lymphatic circulation. The model was validated strictly by four doses of external observed plasma and tissue concentration-time profiles. The fold error (FE) values were almost all within threefold. The sensitivity analysis revealed that the MPS-related parameters greatly influenced the model. The predicted in vivo distribution characteristics of the doxorubicin liposomes and doxorubicin solution were consistent with the observed values. The PBPK model was established based on the physiological mechanism and parameters of practical significance that can be measured in vitro. Thus, it can be used to study the pharmacokinetic properties of liposomes. This study also provides a reference for the establishment of liposome PBPK model.

Discovering novel plasma biomarkers for ischemic stroke: Lipidomic and metabolomic analyses in an aged mouse model

Ischemic stroke remains a leading cause of mortality and long-term disability worldwide, necessitating efforts to identify biomarkers for diagnosis, prognosis, and treatment monitoring. The present study aimed to identify novel plasma biomarkers of neurodegeneration and inflammation in a mouse model of stroke induced by distal middle cerebral artery occlusion. Using targeted lipidomic and global untargeted metabolomic profiling of plasma collected from aged male mice 24 h after stroke and weekly thereafter for 7 weeks, we discovered distinct acute and chronic signatures. In the acute phase, we observed elevations in myelin-associated lipids, including sphingomyelin (SM) and hexosylceramide (HCER) lipid species, indicating brain lipid catabolism. In the chronic phase, we identified 12-hydroxyeicosatetraenoic acid (12-HETE) as a putative biomarker of prolonged inflammation, consistent with our previous observation of a biphasic pro-inflammatory response to ischemia in the mouse brain. These results provide insight into the metabolic alterations detectable in the plasma after stroke and highlight the potential of myelin degradation products and arachidonic acid derivatives as biomarkers of neurodegeneration and inflammation, respectively. These discoveries lay the groundwork for further validation in human studies and may improve stroke management strategies.