Plasma Profiles Research Articles

Plasma Profiling of Acute Myeloid Leukemia With Fever- and Infection-Related Complications During Chemotherapy-Induced Neutropenia.

Acute myeloid leukemia (AML) is a heterogenous and complex blood cancer requiring aggressive treatment. Early identification and prediction of the complications following treatment is vital for effective disease management. We explored associations between plasma protein levels and fever- and infection-related complications in 26 AML patients during chemotherapy-induced neutropenia. Longitudinal plasma profiling was conducted using data-dependent mass spectrometry analysis. Mass spectrometry-based plasma profiling data correlated well with laboratory parameters, including C-reactive protein, and revealed a broader inflammation protein network associated with fever- and infection-related complications. These data indicate the potential of longitudinal plasma profiling in AML patients for identifying and predicting complications that may aid in improved disease monitoring and treatment.

Altered B-cell, plasma cell and antibody immune profiles in blood of systemic mastocytosis

Systemic mastocytosis (SM) is a heterogeneous disease characterised by an expansion of KIT-mutated constitutively activated mast cells (MC) which release MC mediators that might act on the tumour microenvironment including other immune cells. Here we investigated the blood distribution of B-cell, plasma cell (PC) and antibody-isotype compartments in SM. We used spectral flow cytometry and the EuroFlow Immunomonitoring panel and Lymphocyte Screening Tube to quantify B-cells, PC and their subsets in blood of 108 SM patients - 35 bone marrow mastocytosis (BMM), 64 indolent SM (ISM), 9 aggressive SM (ASM)- vs 117 age-matched healthy donors (HD) and paired bone marrow (BM) samples of 31 SM vs 17 controls, respectively. In parallel, immunoglobulin (Ig) M, IgD, IgG, IgA and IgE plasma levels of were measured. Compared to HD, SM patients showed an increased immature B-cell production in BM (P=0.003) associated with a greater release of pre-germinal center immature (P<0.001) and naive CD5+ B-lymphocytes (P<0.001) to blood, but a pronounced decrease in PC counts of all different IgH-isotypes and subclasses (P≤0.001) together with overall increased IgM (P=0.001) and IgD (P<0.001) plasma levels. Of note, different immune profiles were found per diagnostic subtype of the disease with progressively greater counts in blood of immature B-lymphocytes together with decreased IgMD+, IgG2+, IgA1+ and IgA2+ MBC (P≤0.032) and elevated IgM (P=0.017) plasma levels in ASM cases, increased IgM (P=0.001) and IgD (P=0.001) plasma levels in ISM patients and exacerbated IgE (P<0.001) with decreased IgG (P=0.008) plasma levels in BMM cases. Our results reveal a significant dysregulation of the B-cell and PC compartments in blood of SM patients, consistent with distinctly altered antibody-isotype profiles in plasma of BMM vs ISM vs ASM patients.

Circulating small non-coding RNA profiling for identification of older adults with low muscle strength and physical performance: A preliminary study

BackgroundSmall non-coding RNAs (ncRNAs) have recently emerged as potential biomarkers of sarcopenia. However, previous studies have rarely explored the association of small ncRNAs with sarcopenic components, especially muscle strength and physical performance. We aimed to examine circulating small ncRNA profiles to detect low muscle strength and physical performance in older adults. MethodsNinety-eight older adults were randomly selected from Korean Frailty and Aging Cohort Study and classified into the “Normal,” “Low muscle strength (MS) only,” “Low physical performance (PP) only,” and “Low MS and PP” groups by Asian Working Group for Sarcopenia 2019 criteria. We used high-throughput sequencing to delineate small ncRNA profiles in plasma. Differentially expressed small ncRNAs were analyzed to reveal distinct patterns based on muscle strength and physical performance status. ResultsIn “Low MS and PP” group, 119 miRNAs, 86 piRNAs, 92 snoRNAs, 106 snRNAs, and 15 tRNAs were differentially expressed compared to “Normal” group (p < 0.05). After Benjamini-Hochberg adjustment, 39 miRNAs, 2 piRNAs, 75 snoRNAs, 48 snRNAs, and 15 tRNAs showed differential expression in “Low MS and PP” group compared to than “Normal” group (adjusted p < 0.05). No significant differences were observed in comparisons between the other groups (adjusted p > 0.05). ConclusionThe expression of circulating small ncRNAs were comprehensively characterized, revealing distinct signatures in older adults with both low muscle strength and physical performance compared to normal individuals. Although preliminary, this characterization can advance small ncRNA research on age-related declines in muscle strength and physical performance by providing foundational data for further investigation.

Full-f gyrokinetic simulations of hydrogen isotope mixing in tokamak plasmas

Hydrogen isotope mixing phenomena in tokamak plasmas are analyzed using global full-f gyrokinetic simulations. Model plasma parameters are chosen based on hydrogen isotope pellet experiments on JET, in which fast hydrogen isotope mixing in the timescale of the energy confinement time τE occurred after injecting deuterium (D) pellets into hydrogen (H) plasmas. Two numerical experiments are conducted using plasma profiles before and after the pellet injection. In both cases, turbulent fluctuations in the plasma core are characterized by ion temperature gradient driven turbulence. In the former case, the density profile of bulk H ions is kept in a quasi-steady state, and the particle confinement time of bulk H ions τH is an order of magnitude longer than τE. In the latter case, the density profiles of bulk H ions and pellet D ions show transient relaxation in the timescale of τE, and both τH and the timescale of particle pinch τD become comparable to τE, indicating the fast hydrogen isotope mixing. In the toroidal angular momentum balance, it is found that the enhanced ion particle transport leading to the fast hydrogen isotope mixing is driven by the toroidal field stress.

Highly reliable LC-MS lipidomics database for efficient human plasma profiling based on NIST SRM 1950

Liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS)-based methods have become the gold standard methodology for the comprehensive profiling of the human plasma lipidome. However, both the complexity of lipid chemistry and LC-HRMS-associated data pose challenges to the characterization of this biological matrix. In accordance with the current consensus of quality requirements for LC-HRMS lipidomics data, we aimed to characterize the NIST® Standard Reference Material for Human Plasma (SRM 1950) using an LC-ESI(+/–)-MS method compatible with high-throughput lipidome profiling. We generated a highly curated lipid database with increased coverage, quality, and consistency, including additional quality assurance procedures involving adduct formation, within-method m/z evaluation, retention behavior of species within lipid chain isomers, and expert-driven resolution of isomeric and isobaric interferences. As a proof-of-concept, we showed the utility of our in-house LC-MS lipidomic database –consisting of 592 lipid entries– for the fast, comprehensive, and reliable lipidomic profiling of the human plasma from healthy human volunteers. We are confident that the implementation of this robust resource and methodology will have a significant impact by reducing data redundancy and the current delays and bottlenecks in untargeted plasma lipidomic studies.

Generation, expansion, gene delivery, and single-cell profiling in rhesus macaque plasma B cells.

A key step in developing engineered B cells for therapeutic purposes is evaluation in immunocompetent, large-animal models. Therefore, we developed methods to purify, expand, and differentiate non-human primate (NHP; rhesus macaque) B cells. After 7days in culture, B cells expanded 10-fold, differentiated into a plasma cell phenotype (CD38, CD138), and secreted immunoglobulin G. Using single-cell sequencing and flow cytometry, we verified the presence of plasma cell genes in differentiated NHP B cells and unearthed less-recognized markers, such as CD59 and CD79A. In contrast with human cells, we found that the immune checkpoint molecule CD274 (PD-L1) and major histocompatibility complex (MHC) class I molecules were upregulated in NHP plasma cells in the transcriptional data. Lastly, we established the conditions for efficient transduction of NHP B cells with adeno-associated virus (AAV) vectors, achieving a delivery rate of approximately 60%. We envision that this work will accelerate proof-of-concept studies using engineered B cells in NHPs.

Metabolomic Alterations Associated with Phthalate Exposures among Pregnant Women in Puerto Rico.

Although phthalate exposure has been linked with multiple adverse pregnancy outcomes, their underlying biological mechanisms are not fully understood. We examined associations between biomarkers of phthalate exposures and metabolic alterations using untargeted metabolomics in 99 pregnant women and 86 newborns [mean (SD) gestational age = 39.5 (1.5) weeks] in the PROTECT cohort. Maternal urinary phthalate metabolites were quantified using isotope dilution high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), while metabolic profiles in maternal and cord blood plasma were characterized via reversed-phase LC-MS. Multivariable linear regression was used in metabolome-wide association studies (MWAS) to identify individual metabolic features associated with elevated phthalate levels, while clustering and correlation network analyses were used to discern the interconnectedness of biologically relevant features. In the MWAS adjusted for maternal age and prepregnancy BMI, we observed significant associations between specific phthalates, namely, di(2-ethylhexyl) phthalate (DEHP) and mono(3-carboxypropyl) phthalate (MCPP), and 34 maternal plasma metabolic features. These associations predominantly included upregulation of fatty acids, amino acids, purines, or their derivatives and downregulation of ceramides and sphingomyelins. In contrast, fewer significant associations were observed with metabolic features in cord blood. Correlation network analysis highlighted the overlap of features associated with phthalates and those identified as differentiating markers for preterm birth in a previous study. Overall, our findings underscore the complex impact of phthalate exposures on maternal and fetal metabolism, highlighting metabolomics as a tool for understanding associated biological processes. Future research should focus on expanding the sample size, exploring the effects of phthalate mixtures, and validating identified metabolic features in larger, more diverse populations.

Investigating instabilities in magnetized low-pressure capacitively coupled RF plasma using particle-in-cell (PIC) simulations

The effect of a uniform magnetic field on particle transport in low-pressure radio frequency (RF) capacitively coupled plasma (CCP) has been studied using a particle-in-cell model. Three distinct regimes of plasma behavior can be identified as a function of the magnetic field. In the first regime at low magnetic fields, asymmetric plasma profiles are observed within the CCP chamber due to the effect of E→×B→ drift. As the magnetic field increases, instabilities develop and form self-organized spoke-shaped structures that are distinctly seen within the bulk plasma closer to the sheath. In this second regime, the spoke-shaped coherent structures rotate inside the plasma chamber in the −E→×B→ direction, where E→ and B→ are the DC electric and magnetic field vectors, respectively, and the DC electric field exists in the sheath and pre-sheath regions. The spoke rotation frequency is in the megahertz range. As the magnetic field strength increases further, the rotating coherent spokes continue to exist near the sheath. The coherent structures are, however, accompanied by new small-scale incoherent structures originating and moving within the bulk plasma region away from the sheath. This is the third regime of plasma behavior. The threshold values of the magnetic field between these regimes were found not to vary with changing plasma reactor geometry (e.g., area ratio between ground and powered electrodes) or the use of an external capacitor between the RF-powered electrode and the RF source. The threshold values of the magnetic field between these regimes shift toward higher values with increasing gas pressure. Analysis of the results indicates that the rotating structures are due to the lower hybrid instability driven by density gradients and electron-neutral collisions. This paper provides guidance on the upper limit of the magnetic field for instability-free operation in low-pressure CCP-based semiconductor deposition and etch systems that use the external magnetic field for plasma uniformity control.

MHD-induced beta limits in the Large Helical Device

Using the extended-magnetohydrodynamics code, M3D-C1, we perform a systematic numerical study of the effect of externally applied heating on the achievable plasma beta in a ten field-period heliotron. Heat sources of varying intensity are applied to a vacuum magnetic field that is representative of the standard configuration of the Large Helical Device, with R0=3.66 m, where R0 is the radial position of the magnetic axis in vacuum. As the system is driven to a state that is unstable to low-n magnetohydrodynamic (MHD) modes, nonlinear mode interactions lead to the formation of chaotic magnetic fields. With sufficiently strong heating, a collapse of the electron temperature profile is observed. This demonstrates the necessity of simulating the self-consistent evolution of plasma profiles, without imposing assumptions on the structure of the magnetic field, to accurately determine transport properties in stellarator plasmas. It also highlights the value of these advanced simulation capabilities for accelerating the development of high-performance stellarator operating scenarios.

A pilot study of microRNAs expression profile in plasma of patients with hydatid disease: potential immunomodulation of hydatid disease.

Echinococcosis is a zoonotic disease, which seriously endangers human health. The immune game between parasite and host is not fully understood. Exosomes are thought to be one of the ways of information communication between parasite and host. In this study, we attempted to explore the communication between Echinococcus granulosus and its host through the medium of exosomes. We collected plasma from E. granulosus patients (CE-EXO) and healthy donors (HD-EXO) and extracted exosomes from the plasma. The expression profile of miRNA in plasma was determined by second generation sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to annotate the function of target genes of differential miRNAs. Meanwhile, we co-cultured plasma exosomes from healthy donors and plasma exosomes from E. granulosus patients with Jurkat T cells with or without phytohaemagglutinin (PHA) stimulation. The expression of CD69 on Jurkat T cells was detected by flow cytometry. The results showed that the miRNA of exosomes between healthy donors and E. granulosus patients was significantly different. GO and KEGG were used to annotate the function of target genes of differential miRNAs. The results indicate that many important pathways are involved in inflammation, metabolism, and immune response after parasite infection, such as p53 signaling pathway, PI3K-Akt signaling pathway, and glycolysis/gluconeogenesis. Flow cytometry showed that CE-EXO reduced the expression of CD69 + on Jurkat T cells. Our present results suggest that these differentially expressed miRNAs may be important regulators of parasite-host interactions. Meanwhile, functional prediction of its target genes provides valuable information for understanding the mechanism of host-parasite interactions. These results provide clues for future studies on E. granulosus escape from host immune attack, which could help control E. granulosus infection.

Mass balance and pharmacokinetic characterization ofzavegepant in healthy male subjects.

Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, is approved as a nasal spray for acute treatment of migraine in adults. This phase I, open-label, single-center, single-period, nonrandomized study in six healthy male subjects assessed mass balance recovery after a single 15-min intravenous (IV) infusion dose of carbon-14 ([14C])-zavegepant. Blood, urine, and fecal samples were collected over 192 h for analysis of zavegepant in plasma and urine; total radioactivity (TR) in plasma, whole blood, urine, and feces; and zavegepant metabolite profiling and structural identification in plasma, urine, and feces. An average of 96.6% of radioactivity administered was recovered in excreta. Most TR (mean 84.9%) was recovered in the feces, indicating that biliary/fecal elimination was the main route. Volume of distribution of zavegepant based on the terminal phase (129 L) was higher than total body water (42 L), indicating substantial distribution into tissue. Total plasma clearance of zavegepant (220 mL/min) is identical to whole blood clearance given the blood/plasma partition ratio of 1, lower than typical hepatic blood flow (1450 mL/min). The observed plasma terminal half-life of zavegepant was 6.8 h. Exposure to zavegepant accounted for ~90% of circulating plasma TR, suggesting that very low levels of uncharacterized circulating metabolites were present. Metabolite profiling did not identify any metabolites representing ≥10% of radioactivity in plasma, urine, or feces. A single IV infusion of 5 mg [14C]-zavegepant was well tolerated in healthy male subjects. Disposition findings of IV [14C]-zavegepant are applicable to the disposition of the approved zavegepant nasal spray.

Proteolytic imbalance in plasma of patients with multiple sclerosis following COVID-19

Background. The present research was conducted with the following objectives: 1) to determine the plasma levels of five matrix metalloproteinases (MMPs), namely MMP-1, -2, -3, -8, -10, and tissue inhibitor of metalloproteinase-1 (TIMP-1); 2) to analyze protease activity profiles in plasma using a zymographic method; and 3) to perform preliminary analysis on plasma peptide pool composition in patients with multiple sclerosis (MS) with and without COVID-19 history. Materials and methods. We examined 97 patients with MS: 41 had been diagnosed with COVID-19 in the past 4–6 months (MS + COVID group), and 56 did not suffer from SARS-CoV-2 infection previously (MS group). The plasma of healthy volunteers (n = 30) with no evidence of disease was used as control. The enzyme-linked immunosorbent assay was used to measure MMP and TIMP-1 concentrations. Plasma MMP activity was verified by gelatin-substrate zymography. Peptide pools were extracted from the plasma of MS patients and healthy subjects. Then size exclusion chromatography was used to identify separate fractions present in peptide pools. Results. We found that plasma concentration of MMP-2 was remarkably increased in the MS group compared with healthy controls, while in the MS + COVID patients, the levels of two other MMPs, MMP-1 and -10, were elevated. Zymography showed four dominant gelatinolytic bands of 92, 84, 72, and 62 kDa in MS plasma samples, whereas only traces of MMP were detected in healthy subjects. Most of MS plasma samples showed MMP-2 lytic activity, but only a few contained MMP-9. Finally, we determined the concentration of circulating peptides. The levels of plasma peptides were higher in patients from both the MS and MS + COVID group compared to control subjects. According to our results, the development of MS was accompanied by changes in both quantity and quality of peptide pool composition compared to healthy controls. Conclusions. Thus, an advanced understanding of the role of MMPs in MS pathogenesis following infection is important in developing optimized interventions to improve health and clinical outcomes during COVID-19.

Effects of Superthermal Plasmas on Hiss Wave‐Driven Scattering Loss of Radiation Belt Electrons

AbstractPlasmaspheric hiss plays an important role in the loss of radiation belt electrons via cyclotron resonant interactions. The cold plasma approximation is widely used in the evaluation of hiss‐driven electron losses, which however can break down during disturbed periods of geomagnetic storms and substorms. The kappa particle velocity distribution, characterized by a pronounced high‐energy tail, is well‐established to model the profile of superthermal plasma under disturbed geomagnetic conditions. In the present study, by calculating the electron bounce‐averaged pitch angle diffusion coefficients with kappa plasma dispersion relations, we investigate the sensitivity of hiss‐induced cyclotron‐resonant electron scattering loss to the spectral index κ under a variety of superthermal plasma conditions. Our results demonstrate that, with increasing κ, the diffusion coefficients of ∼20–100 keV radiation belt electrons significantly decrease at lower pitch angles and increase at higher pitch angles. In contrast, for electrons at higher energies, the diffusion coefficients tend to increase at lower pitch angles and decrease at relatively higher pitch angles. We also find that decrease of L‐shell and increase of α* and temperature anisotropy tend to weaken the hiss‐driven pitch angle scattering efficiency of electrons at energies from tens to hundreds of keV with a dip at ∼30–50 keV, while the scattering of higher energy electrons can be enhanced. This study confirms the important role of superthermal plasmas in the hiss‐driven electron loss processes and should be carefully incorporated in future modeling of radiation belt electron dynamics.

Development and Evaluation of a Cost-Effective, Carbon-Based, Extended-Release Febuxostat Tablet.

This study outlines the development of a cost-effective, extended-release febuxostat (FEB) tablet using activated charcoal as an adsorbent to enhance drug release. FEB, a BCS Class II drug, presents formulation challenges due to low solubility and high lipophilicity. We evaluated eight formulations with varying FEB-to-charcoal ratios using FTIR and DSC for physical interactions and followed USP standards for overall assessment. The optimal 1:0.25 FEB-to-charcoal ratio demonstrated a consistent 12 h zero-order release pattern. In vivo studies indicated a significantly extended plasma profile compared to immediate-release tablets. The optimal tablets demonstrated acceptable hardness and disintegration times. This innovative approach enhances patient compliance, improves bioavailability, and reduces production costs, offering a promising solution for controlled FEB delivery.

Dynamic variations of plasma and urine metabolic profiles in left anterior descending coronary artery ligation-induced myocardial infarction rats and the regulatory effects of Chinese patent medicine Xin-Ke-Shu

Myocardial infarction (MI) is one of the most severe cardiovascular diseases (CVD). Traditional Chinese medicines have unique advantages in the treatment of CVD, with Xin-Ke-Shu (XKS) being a commonly used Chinese patent medicine for the prevention and treatment of MI patients. This study aimed to investigate the dynamic metabolic profiles of plasma and urine in left anterior descending coronary artery ligation (LAD) -induced MI rats at days 3, 12, and 21 after surgery, and to evaluate the regulatory effects of XKS at these time points using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) metabolomics. The metabolic profiles of plasma and urine in the LAD-induced MI rats showed significant variations at days 3, 12, and 21 after MI. We identified a total of 23 plasma metabolites and 12 urine metabolites as potential pathological markers related to MI progression. These metabolites were mainly involved in pathways such as TCA cycle, arachidonic acid metabolism, glutathione metabolism, glycerophospholipid metabolism, sphingolipid metabolism, and fatty acid metabolism, all of which were associated with imbalance of myocardial energy metabolism, oxidative stress, and calcium overload. Disturbances in the TCA cycle, arachidonic acid metabolism, glutathione metabolism, and purine metabolism in plasma and urine were observed as early as day 3 after MI. By day 12, we noted significant changes in fatty acid metabolism in plasma and urine, along with notable alterations in sphingolipid metabolism in plasma. Disorders in plasma glycerophospholipid metabolism were first evident at day 12 and reached their peak severity by day 21. Treatments with XKS significantly regulated the disturbances in the plasma and urine metabolic profiles of MI rats at days 3, 12, and 21, with medium dose of XKS displaying a particularly strong regulatory effect, especially at day 12. Our study demonstrates that host metabolism undergoes dynamical changes following MI with most metabolic disorders manifesting in the early stage of MI. XKS effectively regulates nearly all of these disturbances and can be administered as soon as possible after MI. These findings provide valuable insights into the metabolic progression of MI and highlight the therapeutic potential of XKS in the treatment of MI.

A Practical In Silico Method for Predicting Compound Brain Concentration-Time Profiles: Combination of PK Modeling and Machine Learning.

Given the aging populations in advanced countries globally, many pharmaceutical companies have focused on developing central nervous system (CNS) drugs. However, due to the blood-brain barrier, drugs do not easily reach the target area in the brain. Although conventional screening methods for drug discovery involve the measurement of (unbound fraction of drug) brain-to-plasma partition coefficients, it is difficult to consider nonequilibrium between plasma and brain compound concentration-time profiles. To truly understand the pharmacokinetics/pharmacodynamics of CNS drugs, compound concentration-time profiles in the brain are necessary; however, such analyses are costly and time-consuming and require a significant number of animals. Therefore, in this study, we attempted to develop an in silico prediction method that does not require a large amount of experimental data by combining modeling and simulation (M&S) with machine learning (ML). First, we constructed a hybrid model linking plasma concentration-time profile to the brain compartment that takes into account the transit time and brain distribution of each compound. Using mouse plasma and brain time experimental values for 103 compounds, we determined the brain kinetic parameters of the hybrid model for each compound; this case was defined as scenario I (a positive control experiment) and included the full brain concentration-time profile data. Next, we built an ML model using chemical structure descriptors as explanatory variables and rate parameters as the target variable, and we then input the predicted values from 5-fold cross-validation (CV) into the hybrid model; this case was defined as scenario II, in which no brain compound concentration-time profile data exist. Finally, for scenario III, assuming that the brain concentration is obtained at only one time point, we used the brain kinetic parameters from the result of the 5-fold CV in scenario II as the initial values for the hybrid model and performed parameter refitting against the observed brain concentration at that time point. As a result, the RMSE/R2-values of the brain compound concentration-time profiles over time were 0.445/0.517 in scenario II and 0.246/0.805 in scenario III, indicating the method provides high accuracy and suggesting that it is a practical method for predicting brain compound concentration-time profiles.

Development and Optimization of Gellan Gum-Based Gastro-Retentive Microbeads for Enhanced Controlled Release of Acyclovir.

Modified release systems offer enhanced spatial and temporal control over drug delivery, leading to better blood plasma profiles, targeted therapy, reduced side effects, and improved patient compliance. Recent advancements focus on using biocompatible polymers to achieve sustained or controlled drug release, particularly for gastroretentive systems that enhance oral bioavailability and minimize dose-dependent toxicity. This study explores the formulation of floating microbeads of acyclovir (ACV) using various hydrophilic polymers. The prototype oral formulations demonstrated superior micrometric properties, including bulk density, tapped density, Carr’s index, Hausner’s ratio, angle of repose, average particle size, yield, and drug content. In-vitro dissolution studies revealed controlled release characteristics, with optimal floating time and entrapment efficiency achieved using specific concentrations of olive oil and polymers. Drug release trailed the Korsmeyer-Peppas model, indicating a diffusioncontrolled mechanism. The formulations exhibited good storage stability, in-vivo floating ability, and higher bioavailability in rabbits compared to ACV solutions. The results suggest that hydrophilic polymers are effective for formulating floating microbeads with controlled release and reproducible profiles.

6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway

BackgroundTo delve into the precise mechanisms by which 6-gingerol ameliorates lipid metabolism disorders in skeletal muscle. MethodsThe level of triglycerides (TG) was used to evaluate lipid deposition. In skeletal muscle, transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. Additionally, PCR was applied to detect mitochondrial biogenesis, and levels of malondialdehyde (MDA), catalase (CAT), glutathione, r-glutamyl cysteingl+glycine (GSH) and nicotinamide adenine dinucleotide (NADH) were measured to assess mitochondrial oxidative stress levels. In vivo, flow cytometry and immunofluorescence assays were conducted to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Furthermore, the Seahorse XF assays was utilized to assess mitochondrial respiratory capacity. Fluorescence confocal microscopy and molecular docking were applied to analyze the binding of 6-gingerol and adiponectin receptor 1 (AdipoR1). The expression of AdipoR1, AMPK, PGC-1α and SIRT1 were detected by Western Blot. ResultsIn vivo, 6-gingerol could reduce body weight in mice induced by a high-fat diet, enhance metabolic profiles in plasma, decrease lipid accumulation in skeletal muscle and liver, and elevate adiponectin levels. In skeletal muscle, it could restore mitochondrial morphology, boost mitochondrial copy number and biogenesis, and mitigate oxidative stress. In vitro, 6-gingerol may directly interact with AdipoR1 to upregulate the expression of downstream proteins p-AMPK, SIRT1, and PGC-1α, leading to a reduction in lipid deposition, a decrease in ROS production, an increase in mitochondrial membrane potential, and an enhancement of mitochondrial respiratory capacity in C2C12 myotubes. Conclusion6-Gingerol ameliorated lipid metabolism in skeletal muscle by regulating the AdipoR1/AMPK signaling pathway.

Common Bean Suppresses Hepatic Ceramide Metabolism in a Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Background/Objectives: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition linked to the ongoing obesity pandemic, is rapidly increasing worldwide. In turn, its multifactorial etiology is consistently associated with low dietary quality. Changing dietary macronutrient and phytochemical quality via incorporating cooked common bean into an obesogenic diet formulation has measurable health benefits on the occurrence of both obesity and hepatic steatosis in C57BL/6 mice. Methods: A cohort of C57BL/6 mice were randomized into experimental diets containing multiple dietary concentrations of common bean. The primary endpoint of this study was comparing metabolomic analyses from liver and plasma of different treatment groups. Additionally, RNA sequencing and protein expression analysis via nanocapillary immunoelectrophoresis were used to elucidate signaling mediators involved. Results: Herein, global metabolomic profiling of liver and plasma identified sphingolipids as a lipid subcategory on which bean consumption exerted significant effects. Of note, C16 and C18 ceramides were significantly decreased in bean-fed animals. Hepatic RNAseq data revealed patterns of transcript expression of genes involved in sphingolipid metabolism that were consistent with metabolite profiles. Conclusions: Bean incorporation into an otherwise obesogenic diet induces effects on synthesis, biotransformation, and degradation of sphingolipids that inhibit the accumulation of ceramide species that exert pathological activity. These effects are consistent with a mechanistic role for altered sphingolipid metabolism in explaining how bean inhibits the development of MASLD.

Identification of amino acids metabolomic profiling in human plasma distinguishes lupus nephritis from systemic lupus erythematosus

Lupus nephritis (LN) is an immunoinflammatory glomerulonephritis associated with renal involvement in systemic lupus erythematosus (SLE). Given the close relationship between plasma amino acids (AAs) and renal function, this study aimed to elucidate the plasma AA profiles in LN patients and identify key AAs and diagnostic patterns that distinguish LN patients from those with SLE and healthy controls. Participants were categorized into three groups: normal controls (NC), SLE, and LN. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to quantify AA levels in human plasma. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to identify key AAs. The diagnostic capacity of the models was assessed using receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) values. Significant alterations in plasma AA profiles were observed in LN patients compared to the SLE and NC groups. The OPLS-DA model effectively separated LN patients from the SLE and NC groups. A joint model using histidine (His), lysine (Lys), and tryptophan (Trp) demonstrated exceptional diagnostic performance, achieving an AUC of 1.0 with 100% sensitivity, specificity, and accuracy in predicting LN. Another joint model comprising arginine (Arg), valine (Val), and Trp also exhibited robust predictive performance, with an AUC of 0.998, sensitivity of 93.80%, specificity of 100%, and accuracy of 95.78% in distinguishing between SLE and LN. The joint forecasting models showed excellent predictive capabilities in identifying LN and categorizing lupus disease status. This approach provides a novel perspective for the early identification, prevention, treatment, and management of LN based on variations in plasma AA levels.