Quantification of AICAR and study of metabolic markers after administration.

Objectives: AICAR (5-amino-4-imidazolecarboxyamide ribonucleoside) was reported as the first pharmacological AMPK (adenosine 5'-monophosphate (AMP)-activated protein kinase) activator, and it has been confirmed to exhibit a significant endurance enhancement effect and prohibited for doping by the World Anti-Doping Agency. Due to the fact that the human body can produce such substances, in order to ensure fairness in sports competition, methods for rapid detection and multi-type identification of AICAR drugs taken orally should be established. Methods: to assess AICAR levels, a new rapid, sensitive, efficient, and selective method was reported for the quantitative detection of AICAR in urine using LC-MS/MS. The method was validated for quantitative purposes based on the elemental selectivity, intra- (1.0-15.6%) and inter-day precision (1.3-16.3%), accuracy (99.9-112.8%), matrix effects (88.9-103.6%), recovery (87.4-106.5%), and stability at four different concentrations. The calibration curve was linear over a wide concentration range of 10-10,000 ng mL-1 with a high coefficient of determination (R 2 > 0.998). The limit of detection (LOD) and limit of quantification (LOQ) for the experiment were determined to be 1 and 10 ng mL-1, respectively. Simultaneously, metabolomics analysis was used to obtain the metabolic fingerprint of different populations and biomarkers to distinguish administration cases through partial least squares discriminant analysis (PLS-DA) and a receiver operating characteristic (ROC) curve. Results: the method enables easy quantitation for LC-MS/MS analysis with the best recovery yield maintained, and the method was applied to 122 Asian biological samples with an average concentration of 1310.5 ± 1031.4 ng mL-1. Through drug metabolism research, 734 and 294 variables were extracted for data analysis respectively in the positive and negative ion modes, and more than 100 metabolites with significant up- and down-regulation were found after the test. Conclusions: this research developed a fast, precise, effective, and specific approach for the qualitative and quantitative identification of AICAR in urine. Meanwhile, administration metabolism studies found that there were significant changes in AICAR levels and other compounds, such as PC types PC(18:1/16:0), PC(16:0/18:0), and PC(16:0/16:0), PE types PE(18:0/20:4), and LPE-type 18:1, which could better distinguish samples before and after AICAR administration. The analysis provides a multi-perspective reference for WADA to determine a positive criterion.

Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions.

BACKGROUND: Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical studies have demonstrated the association between EAT volume and increased risks for coronary artery disease (CAD). However, the cellular and molecular mechanisms underlying the association remain elusive. METHODS: We performed single-nucleus RNA sequencing on pericoronary EAT samples collected from 3 groups of subjects: patients undergoing coronary bypass surgery for severe CAD (n=8), patients with CAD with concomitant type 2 diabetes (n=8), and patients with valvular diseases but without concomitant CAD and type 2 diabetes as the control group (n=8). Comparative analyses were performed among groups, including cellular compositional analysis, cell type-resolved transcriptomic changes, gene coexpression network analysis, and intercellular communication analysis. Immunofluorescence staining was performed to confirm the presence of CAD-associated subclusters. RESULTS: Unsupervised clustering of 73 386 nuclei identified 15 clusters, encompassing all known cell types in the adipose tissue. Distinct subpopulations were identified within primary cell types, including adipocytes, adipose stem and progenitor cells, and macrophages. CD83high macrophages and FOSBhigh adipocytes were significantly expanded in CAD. In comparison to normal controls, both disease groups exhibited dysregulated pathways and altered secretome in the primary cell types. Nevertheless, minimal differences were noted between the disease groups in terms of cellular composition and transcriptome. In addition, our data highlight a potential interplay between dysregulated circadian clock and altered physiological functions in adipocytes of pericoronary EAT. ANXA1 and SEMA3B were identified as important adipokines potentially involved in functional changes of pericoronary EAT and CAD pathogenesis. CONCLUSIONS: We built a complete single-nucleus transcriptomic atlas of human pericoronary EAT in normal and diseased conditions of CAD. Our study lays the foundation for developing novel therapeutic strategies for treating CAD by targeting and modifying pericoronary EAT functions.

Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR.

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The "block and lock" approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the "block and lock" strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the "block and lock" strategy in the pursuit of an HIV-1 cure.

Health Qigong Mawangdui Guidance can improve pelvic floor muscle function and quality of life in females with stress urinary incontinence: A randomized controlled trial pilot study.

BACKGROUND: Urinary incontinence (UI) is a great problem of public health, especially for women's quality of life. UI afflicts at least 21.6% of the global population, and more than half of the UI is related to female stress urinary incontinence (SUI). Mawangdui Guidance plays an important role in preventing diseases and maintaining health. METHODS: Sixty female patients with SUI were randomly divided into a control group (n = 30) and an experimental group (n = 30). Patients in both groups were treated with basic rehabilitation therapy under the guidance of rehabilitation therapists who were trained in Mawangdui Guidance, based on the former, the experimental group was taught to exercise Mawangdui Guidance(including selected movements: "Qishi," "Longdeng," "Chishi," and "Yinyao"), while the control group performed Kegel exercise with a procedure of 20 min, six times per week for 6 weeks. The function was mainly evaluated by the 1 h pad-test, incontinence quality of life questionnaire (I-QOL), and international consultation on incontinence questionnaire urinary incontinence short form (ICI-Q-SF). In addition, evaluation of pelvic floor muscle function was also included in our assessment. RESULTS: The leakage of urine in the 1 h pad-test was significantly decreased in both two groups after treatment (P < .05), and the urine leakage in the experimental group was significantly less than that in the control group (P < .05). The muscle strength of type I and II muscle fibers of the pelvic floor, intravaginal pressure, and I-QOL score in both two groups were increased after treatment; moreover, the experimental group was more significant than the control group (P <.05). The fatigue degree of type I and type II muscle fibers of the pelvic floor, and the ICI-Q-SF score in both groups were significantly improved after treatment (P < .05); however, there were no differences between these two groups. The total effective rate of the experimental group was 90.00%, and 76.67% in the control group (P <.05). CONCLUSION: Mawangdui Guidance can effectively improve the function of pelvic floor muscle, improve the ability of urine storage and control, and alleviate the symptoms of female patients with SUI. However, the international research on Mawangdui Guidance is very limited, and more in-depth research is needed.

The role of 18F-FDG PET in minimizing variability in gross tumor volume delineation of soft tissue sarcomas.

BACKGROUND: Accurate gross tumor volume (GTV) delineation is a critical step in radiation therapy treatment planning. However, it is reader dependent and thus susceptible to intra- and inter-reader variability. GTV delineation of soft tissue sarcoma (STS) often relies on CT and MR images. PURPOSE: This study investigates the potential role of 18F-FDG PET in reducing intra- and inter-reader variability thereby improving reproducibility of GTV delineation in STS, without incurring additional costs or radiation exposure. MATERIALS AND METHODS: Three readers performed independent GTV delineation of 61 patients with STS using first CT and MR followed by CT, MR, and 18F-FDG PET images. Each reader performed a total of six delineation trials, three trials per imaging modality group. Dice Similarity Coefficient (DSC) score and Hausdorff distance (HD) were used to assess both intra- and inter-reader variability using generated simultaneous truth and performance level estimation (STAPLE) GTVs as ground truth. Statistical analysis was performed using a Wilcoxon signed-ranked test. RESULTS: There was a statistically significant decrease in both intra- and inter-reader variability in GTV delineation using CT, MR 18F-FDG PET images vs. CT and MR images. This was translated by an increase in the DSC score and a decrease in the HD for GTVs drawn from CT, MR and 18F-FDG PET images vs. GTVs drawn from CT and MR for all readers and across all three trials. CONCLUSION: Incorporation of 18F-FDG PET into CT and MR images decreased intra- and inter-reader variability and subsequently increased reproducibility of GTV delineation in STS.

A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs.

Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM-like organoid (LEGO: Laboratory Engineered Glioblastoma-like Organoid) models and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides new human GBM models and a research path toward effective GBM therapy.

Assembly of novel sequences for Chinese domestic pigs reveals new genes and regulatory variants providing new insights into their diversity.

There is an increasing understanding that a reference genome representing an individual cannot capture all the gene repertoire of a species. Here, we conduct a population-scale missing sequences detection of Chinese domestic pigs using whole-genome sequencing data from 534 individuals. We identify 132.41 Mb of sequences absent in the reference assembly, including eight novel genes. In particular, the breeds spread in Chinese high-altitude regions perform significantly different frequencies of new sequences in promoters than other breeds. Furthermore, we dissect the role of non-coding variants and identify a novel sequence inserted in the 3'UTR of the FMO3 gene, which may be associated with the intramuscular fat phenotype. This novel sequence could be a candidate marker for meat quality. Our study provides a comprehensive overview of the missing sequences in Chinese domestic pigs and indicates that this dataset is a valuable resource for understanding the diversity and biology of pigs.

Ionic Liquids in Pharmaceutical and Biomedical Applications: A Review.

The unique properties of ionic liquids (ILs), such as structural tunability, good solubility, chemical/thermal stability, favorable biocompatibility, and simplicity of preparation, have led to a wide range of applications in the pharmaceutical and biomedical fields. ILs can not only speed up the chemical reaction process, improve the yield, and reduce environmental pollution but also improve many problems in the field of medicine, such as the poor drug solubility, product crystal instability, poor biological activity, and low drug delivery efficiency. This paper presents a systematic and concise analysis of the recent advancements and further applications of ILs in the pharmaceutical field from the aspects of drug synthesis, drug analysis, drug solubilization, and drug crystal engineering. Additionally, it explores the biomedical field, covering aspects such as drug carriers, stabilization of proteins, antimicrobials, and bioactive ionic liquids.

MAGE: metafounders-assisted genomic estimation of breeding value, a novel additive-dominance single-step model in crossbreeding systems.

MOTIVATION: Utilizing both purebred and crossbred data in animal genetics is widely recognized as an optimal strategy for enhancing the predictive accuracy of breeding values. Practically, the different genetic background among several purebred populations and their crossbred offspring populations limits the application of traditional prediction methods. Several studies endeavor to predict the crossbred performance via the partial relationship, which divides the data into distinct sub-populations based on the common genetic background, such as one single purebred population and its corresponding crossbred descendant. However, this strategy makes prediction inaccurate due to ignoring half of the parental information of crossbreed animals. Furthermore, dominance effects, although playing a significant role in crossbreeding systems, cannot be modeled under such a prediction model. RESULTS: To overcome this weakness, we developed a novel multi-breed single-step model using metafounders to assess ancestral relationships across diverse breeds under a unified framework. We proposed to use multi-breed dominance combined relationship matrices to model additive and dominance effects simultaneously. Our method provides a straightforward way to evaluate the heterosis of crossbreeds and the breeding values of purebred parents efficiently and accurately. We performed simulation and real data analyses to verify the potential of our proposed method. Our proposed model improved prediction accuracy under all scenarios considered compared to commonly used methods. AVAILABILITY AND IMPLEMENTATION: The software for implementing our method is available at https://github.com/CAU-TeamLiuJF/MAGE.

[Research Progress of Indocyanine Green Fluorescence Laparoscopic Technique in Clinical Application].

Indocyanine green (ICG) is the most commonly used near-infrared fluorescent (NIRF) dye in clinical practice, and its mediated near-infrared fluorescence imaging technology is gradually applied in clinical practice. It has shown great potential in invasive surgery (MIS) and is expected to become the standard technology for surgical diagnosis and treatment of diseases. The clinical application of ICG fluorescence laparoscopy is reviewed here.

The therapeutic efficacy of guided therapy for PCI after acute myocardial infarction: A meta-analysis.

OBJECTIVE: To systematically evaluate the effects of lead therapies on percutaneous coronary intervention (PCI) after acute myocardial infarction (AMI). METHODS: A randomized controlled trial (RCT) in the CNKI, Wanfang, VIP, ProQuest, PubMed, Cochrane Library, Scopus, and Web of Science databases was searched until January 2023. Two researchers strictly screened and checked the included literature, extracted relevant data, and used the Cochrane Manual to assess the risk quality of the literature. Using RevMan 5.3 software, Meta-analysis of 4 main outcome measures [cardiac function-related indicators, 6-minute walking distance (6 MWT), quality of life (SF-36), Seattle angina pectoris scale (SAQ)], and 3 secondary outcome measures [adverse event incidence, death incidence, and readmission rate]. RESULTS: 22 studies were finally included with 1754 subjects, but the overall quality of the included studies was not high. The results of the meta-analysis showed that, in the cardiac function-related indicators compared to controls, improved left ventricular ejection fraction (LVEF) index (MD = 1.42, 95%CI [-0.94, 3.79], P < .00001); however, compared with the Baduanjin group, Tai Chi ball + Baduanjin group and control group, there was no significant difference (P > .05); compared with the control group, the guidance therapy group improved the left ventricular end-diastolic volume (LVEDV) index (MD = -4.67, 95%CI [-6.8, -2.71], P < .00001). In comparison, the lead group improved the 6 MWT (MD = 69.44, 95%CI [30.12, 108.76], P < .00001); the SF-36 score (MD = 10.05, 95%CI [8.68, 11.42], P < .00001])and the SAQ score (MD = 6.2, 95%CI [3.97, 8.44], P < .00001). Among the secondary outcome measures, the incidence of adverse events was statistically significant (RR = 0.17, 95%CI [0.1, 0.32], P < .00001); statistically significant (RR = 0.29, 95%CI (0.1, 0.87), P < .00001); readmission (RR = 0.39, 95%CI [0.17, 0.87, 0.89], P < .00001). CONCLUSION: Based on the current study, combining conventional therapy/ exercise or using simple lead therapy after PCI can improve the treatment effect and improve the quality of life.

Modified Kramers-Kronig receiver based on memory polynomial compensation for photonics-assisted millimeter-wave communications.

Photonics-assisted millimeter-wave (MMW) wireless communications are advancing rapidly driven by the escalating congestion in the lower-band spectrum and the growing demand for higher data rates. Concurrently, Kramers-Kronig (KK) receivers provide an economical solution ideally suited for cost-sensitive deployment and application. However, the conventional KK receiver is subject to performance degradation due to the nonlinearity and memory effects introduced by practical electronic devices. In this work, the performance degradation of the conventional KK receiver is investigated and quantitatively simulated, showing that the KK receiver exhibits greater sensitivity to nonlinearity and memory effects compared to the conventional coherent receiver. To enhance the performance of KK receivers deployed in MMW communication systems, we propose a modified KK receiver employing memory polynomial compensation, namely MP-KK receiver, capable of effectively compensating memory effects whilst simultaneously addressing nonlinearity. Crucially, the memory polynomial model is employed prior to the KK algorithm to prevent further signal degradation caused by the nonlinear operator in the KK algorithm in the scenario of photonics-assisted MMW wireless communication based on the KK receiver. For verification, we present a 95 GHz W-band MMW wireless transmission demonstration with 20 Gb/s QPSK and 40 Gb/s 16-QAM signals. The experimental results indicate that the MP-KK receiver can achieve more than 3.5 dB improvement in EVM and 71.25% reduction in BER compared to the conventional approaches.

Effect of repetition of rTMS at different frequencies on the efficacy of swallowing disorders after stroke: A systematic review and meta-analysis.

BACKGROUND: To systematically evaluate the curative effect of repeated transcranial magnetic stimulation at different frequencies on swallowing disorders after stroke. METHODS: A search was conducted for randomized controlled trials of repeated transcranial magnetic stimulation for stroke patients in CNKI, Wanfang, VIP, ProQuest, PubMed, Cochrane Library, Scopus, and Web of Science databases until December 2022. The 2 researchers strictly screened and checked the included documents, extracted relevant data, assessed the risk quality of the literature using the Cochrane manual, and conducted a network meta-analysis of the data using State16.0. RESULTS: Eighteen studies included 680 participants. The results of the reticular meta-analysis showed that in the leakage-aspiration scale (PAS) indicators, 1 Hz, 3 Hz, 5 Hz, and 10 Hz were all better treatment effects compared with the control group, and there was a statistically significant difference (P < .05). In the standard swallowing function assessment (SSA) index, 3 Hz, 5 Hz, and 10 Hz compared with the control group were statistically significant (P < .05); there was no difference between 1 Hz and the control group (P > .05). The cumulative probability ranking results showed that the intervention effect of 3 Hz was the best in the PAS index, much greater than that of other frequencies, and the intervention effects of 10 Hz and 5 Hz were similar. For the SSA index, the intervention effect was optimal at 10 Hz, followed by 5 Hz. Note that the treatment effect of 1 Hz ranked last, even lower than that of the control group. The results of the 5 Hz treatment site grouping analysis showed that the affected side was > bilateral > healthy in PAS and > bilateral > healthy in SSA. CONCLUSION SUBSECTIONS: Based on the current study, the optimal frequency and site selection results of the 2 evaluation indicators are not uniform, but from the combination of the 2 evaluation indicators, the treatment effect of 10H is good, and the effect of bilateral stimulation for the selection of stimulation sites is good. The above conclusions need to be verified in high-quality studies.

Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stress.

Accumulating evidence indicates that acetate is increased under energy stress conditions such as those that occur in diabetes mellitus and prolonged starvation. However, how and where acetate is produced and the nature of its biological significance are largely unknown. We observed overproduction of acetate to concentrations comparable to those of ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT12 and ACOT8 are dramatically upregulated in the liver to convert free fatty acid-derived acetyl-CoA to acetate and CoA. This conversion not only provides a large amount of acetate, which preferentially fuels the brain rather than muscle, but also recycles CoA, which is required for sustained fatty acid oxidation and ketogenesis. We suggest that acetate is an emerging novel 'ketone body' that may be used as a parameter to evaluate the progression of energy stress.

Analysis on the risk of myasthenia gravis related to immune checkpoint inhibitors based on the US FDA Adverse Event Reporting System.

OBJECTIVE: To evaluate the risk of myasthenia gravis (MG) associated with immune checkpoint inhibitors (ICI). METHODS: Adverse event (AE) reports related to MG, myasthenic syndrome, and MG crisis for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab in the US FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q3 2022 were collected. The proportional reporting odds ratio (PRR) method was used to evaluate the correlation between the six drugs and the three AEs. Statistical significance was defined as having reports ≥3, PRR ≥ 2, and chi-square (χ2 ) ≥ 4. RESULTS: A total of 36, 78, 276, 380, 5, and 53 AE reports were collected for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For myasthenic syndrome, the PRR values reflecting the correlation with the drugs were 27.83 (χ2 = 102.66), 26.20 (χ2 = 235.67), 44.17 (χ2 = 1313.98), 32.09 (χ2 = 1229.54), 21.31 (χ2 = 151.15), and 0 for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG, the PRR values reflecting the correlation with the drugs were 24.21 (χ2 = 682.04), 18.34 (χ2 = 900.27), 39.32 (χ2 = 7945.15), 26.93 (χ2 = 6636.45), 14.73 (χ2 = 566.47), and 15.69 (χ2 = 54.77) for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG crisis, there were no data for durvalumab, atezolizumab, avelumab, and ipilimumab; the PRR values reflecting the correlation with the drugs were 16.54 (χ2 = 225.23) and 9.20 (χ2 = 119.14) for pembrolizumab and nivolumab, respectively. All six drugs were statistically correlated with their corresponding AEs. CONCLUSIONS: ICI may lead to ICIs-associated MG during therapy. Analysis of FAERS data identified signals for AEs of MG with ICI regimens. Practitioners should consider the factors that may increase the likelihood of MG. The findings support a continued surveillance and risk factor identification.

Cost-sharing and horizontal compensation scheme of regional sulfur dioxide treatment: Evidence from China.

Establishing a reasonable cost-sharing and compensation mechanism for air pollution control is a prerequisite for realizing inter-regional cooperative treatment. Taking inter-provincial sulfur dioxide (SO2) emissions in China from 2005 to 2019 as the research object, this paper proposes a data-driven approach to establish a cost-sharing index system of regional SO2 treatment in four dimensions and construct a cost-sharing and compensation scheme using the entropy-TOPSIS method. The results revealed that there are significant spatial and temporal differences in the treatment cost of SO2 emission, and the total SO2 treatment costs at the national level increased first and then decreased during the study period, meanwhile, the regional SO2 treatment costs are much higher in the less economically developed regions such as the central and western regions than in economically developed eastern coastal regions. The design of the cost-sharing and compensation mechanism of SO2 treatment should consider the regional differences in abatement capacity, abatement potential, abatement responsibility, and development demands. The economically developed regions should share higher treatment costs according to their historical cumulative abatement responsibilities, and provide economic compensation and technical support to the less economically developed regions. Specifically, the marginal abatement cost in the more economically developed eastern region is much higher than that in the less economically developed central and western areas due to their large abatement responsibility and strong reduction capacity but insufficient abatement potential, so the eastern regions can transfer part of their abatement responsibility to the central and western regions using economic compensation. Reasonable cost sharing and horizontal compensation can help promote regional cooperation and synergistic management in air pollution abatement. Finally, corresponding policy recommendations are given to provide a decision basis for cross-regional cooperation in air pollution control.

Reduced Diversities and Clonally Expanded Sequences of T-Cell Receptors in Patients With Essential Hypertension and Subclinical Carotid Atherosclerosis.

BACKGROUND: It has long been hypothesized that the abnormal immune responses contribute to the essential hypertension (EH) and its subclinical target organ damage (STOD). However, the mechanism is unclear. This study aimed at exploring the potential association with abnormal T-cell responses and EH, STOD, and early atherosclerosis in patients with EH. METHODS: This cross-sectional study included 146 patients with EH and 73 age-matched normotensive individuals. The expressed peripheral TCR (T-cell receptor) ß repertoire was analyzed by high through-put sequencing. RESULTS: The TCRß repertoires of the patients with EH were significantly different, with significantly elevated certain TCR beta variable (TRBV) and joint (TRBJ) gene usages, significantly reduced TCRß diversity indexes (diversity 50s) and numbers of total TCRß clonal types, significantly elevated percentages of the biggest TCRß clones and numbers of clones accounting >0.1% sequences, compared with those in the normotensive controls. Decreased diversity 50s and increased biggest TCRß clone percentages were independently correlated with carotid intima-media thickness and subclinical carotid atherosclerosis (SCA) in the patients with EH. Moreover, the diversity 50s were further significantly reduced and the biggest TCRß clone percentages were significantly increased in the patients with EH with SCA (n=89) comparing to the patients with EH/patients without SCA (n=57), and in patients with EH/SCA with carotid plaque (n=22) comparing to patients with EH/SCA/patients without carotid plaque (n=67). Importantly, specific TCRß clones were identified in different subgroups of the patients with EH. CONCLUSIONS: These results reveal that abnormal T-cell responses may play important roles in the progression of EH and its SCA, especially the formation of carotid plaque. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2100054414.

Systems pharmacology-based mechanism exploration of Acanthopanax senticosusin for Alzheimer's disease using UPLC-Q-TOF-MS, network analysis, and experimental validation.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive cognitive dysfunction and memory loss. However, the disease-modifying treatments for AD are still lacking. Traditional Chinese herbs, have shown their potentials as novel treatments for complex diseases, such as AD. PURPOSE: This study was aimed at investigating the mechanism of action (MOA) of Acanthopanax senticosusin (AS) for treatment of AD. METHODS: In this study, we firstly identified the chemical constituents in Acanthopanax senticosusin (AS) utilizing ultra-high performance liquid chromatography coupled with Q-TOF-mass spectrometry (UPLC-Q-TOF-MS), and next built the drug-target network of these compounds. We also performed the systems pharmacology-based analysis to preliminary explore the MOA of AS against AD. Moreover, we applied the network proximity approach to identify the potential anti-AD components in AS. Finally, experimental validations, including animal behavior test, ELISA and TUNEL staining, were conducted to verify our systems pharmacology-based analysis. RESULTS: 60 chemical constituents in AS were identified via the UPLC-Q-TOF-MS approach. The systems pharmacology-based analysis indicated that AS might exert its therapeutic effects on AD via acetylcholinesterase and apoptosis signaling pathway. To explore the material basis of AS against AD, we further identified 15 potential anti-AD components in AS. Consistently, in vivo experiments demonstrated that AS could protect cholinergic nervous system damage and decrease neuronal apoptosis caused by scopolamine. CONCLUSION: Overall, this study applied systems pharmacology approach, UPLC-Q-TOF-MS, network analysis, and experimental validation to decipher the potential molecular mechanism of AS against AD.

Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.

BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,ß- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites. OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST. METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer. RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor. CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).

Global Research Trends of Exosomes in the Central Nervous System: A Bibliometric and Visualized Analysis.

OBJECTIVE: Exosomes in the central nervous system (CNS) have become an attractive area of research with great value. However, few bibliometric analysis has been conducted. The study aimed to visualize the scientific trends and research hotspots of exosomes in the CNS by bibliometric analysis. METHODS: All potential articles and reviews on exosomes in the CNS published in English from 2001 to 2021 were extracted from the Web of Science Core Collection. The visualization knowledge maps of critical indicators, including countries/regions, institutions, authors, journals, references, and keywords, were generated by CiteSpace and VOSviewer software. Besides, each domain's quantitative and qualitative analysis was also considered. RESULTS: A total of 2,629 papers were included. The number of exosomes-related publications and citations regarding CNS increased yearly. These publications came from 2,813 institutions in 77 countries/regions, led by the United States and China. Harvard University was the most influential institution, while the National Institutes of Health was the most critical funding source. We identified 14,468 authors, among which Kapogiannis D had the most significant number of articles and the highest H-index, while Théry C was the most frequently co-cited. The cluster analysis of keywords generated 13 clusters. In summary, the topic of biogenesis, biomarker, and drug delivery will serve as hotspots in future research. CONCLUSION: Exosomes-related CNS research has gained considerable attention in the past 20 years. The sources and biological functions of exosomes and their promising role in diagnosing and treating CNS diseases are considered hotspots in this field. The clinical translation of the results from exosomes-related CNS research will be of great importance in the future.