BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G-Protein-Coupled Receptor Kinase 2/metabolism* ; Arthritis, Rheumatoid/immunology* ; Animals ; Dendritic Cells/metabolism* ; Paroxetine/therapeutic use* ; Proto-Oncogene Proteins c-akt/metabolism* ; Mice ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Lymphocyte Activation/drug effects* ; Female ; T-Lymphocytes/metabolism* ; Middle Aged

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

General anesthesia, pivotal for surgical procedures, requires precise depth monitoring to mitigate risks ranging from intraoperative awareness to postoperative cognitive impairments. Traditional assessment methods, relying on physiological indicators or behavioral responses, fall short of accurately capturing the nuanced states of unconsciousness. This study introduces a machine learning-based approach to decode anesthesia depth, leveraging EEG data across different anesthesia states induced by propofol and esketamine in rats. Our findings demonstrate the model's robust predictive accuracy, underscored by a novel intra-subject dataset partitioning and a 5-fold cross-validation method. The research diverges from conventional monitoring by utilizing anesthetic infusion rates as objective indicators of anesthesia states, highlighting distinct EEG patterns and enhancing prediction accuracy. Moreover, the model's ability to generalize across individuals suggests its potential for broad clinical application, distinguishing between anesthetic agents and their depths. Despite relying on rat EEG data, which poses questions about real-world applicability, our approach marks a significant advance in anesthesia monitoring.
Animals ; Machine Learning ; Electroencephalography/methods* ; Ketamine/administration & dosage* ; Rats ; Male ; Propofol/administration & dosage* ; Rats, Sprague-Dawley ; Anesthesia, General/methods* ; Brain/physiology* ; Intraoperative Neurophysiological Monitoring/methods*

Long non-coding RNAs (lncRNAs) play a significant role in maintaining tissue morphology and functions, and their precise regulatory effectiveness is closely related to expression patterns. However, the spatial expression patterns of lncRNAs in humans are poorly characterized. Here, we constructed five comprehensive transcriptomic atlases of human lncRNAs covering thousands of major tissue samples in normal and disease states. The lncRNA transcriptomes exhibited high consistency within the same tissues across resources, and even higher complexity in specialized tissues. Tissue-elevated (TE) lncRNAs were identified in each resource and robust TE lncRNAs were refined by integrative analysis. We detected 1 to 4684 robust TE lncRNAs across tissues; the highest number was in testis tissue, followed by brain tissue. Functional analyses of TE lncRNAs indicated important roles in corresponding tissue-related pathways. Moreover, we found that the expression features of robust TE lncRNAs made them be effective biomarkers to distinguish tissues; TE lncRNAs also tended to be associated with cancer, and exhibited differential expression or were correlated with patient survival. In summary, spatial classification of lncRNAs is the starting point for elucidating the function of lncRNAs in both maintenance of tissue morphology and progress of tissue-constricted diseases.
Humans ; Gene Expression Profiling ; Neoplasms/genetics* ; Organ Specificity ; RNA, Long Noncoding/genetics* ; Transcriptome

This article reports a case of primary thyroid diffuse large B-cell lymphoma involving the superior mediastinum with Hashimoto's thyroiditis admitted to the Department of Otolaryngology and Head and Neck Surgery, First Hospital of Jilin University. This patient underwent right thyroid lobectomy and was transferred to the Department of Hematology of the Oncology Center for 6 courses of chemotherapy with R-CHOP protocol. The postoperative recovery was good, and the patient was regularly followed up for 12 months after the operation. The patient's condition was stable, and CT showed no abnormally high metabolism in the operation area indicating the inhibition of tumor activity, superficial lymph nodes and peripheral blood cells were normal. The case encountered many difficulties in the diagnosis process, and the diagnosis was not confirmed after puncture in two Grade III Class A hospitals in China. There are few patients with primary thyroid diffuse large B-cell lymphoma complicated with Hashimoto's thyroiditis, and it is particularly rare to invade the mediastinum. There is no report in China and abroad in the literature we reviewed. Therefore, this article reports the case and retrospectively analyzes the etiology, clinical symptoms, diagnosis and treatment of primary thyroid lymphoma.
Humans ; Mediastinum ; Retrospective Studies ; Hashimoto Disease ; Lymphoma, Large B-Cell, Diffuse ; Thyroid Neoplasms

Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.

It is a challenge to determine the cause of death in cases caused by both injury and disease in forensic pathology examinations.Here,we retrospectively analyzed 140 such cases enrolled in the Sun Yat-sen University Forensic Identification Center from 2013 to 2021.It was found that the cases caused by both injury and disease accounted for 2.89%of the total number of cases during the same period.The male-to-female ratio was 5.09.Cardiovascular disease accounted for 71.43%of the death-leading diseases,and coronary heart disease accounted for 49.29%.Among the three types of injury and disease relationship,the proportion of disease-based and injury-assisted cases accounted for more than half(65.86%),and the proportion of injury and disease with the same effect cases was the least(12.14%).Medical treatment was involved in as more as 82.86%of the cases.Re-identification were carried out in 10.71%of the cases,53.33%of which were with a≤24-hour-survival time,higher than the proportion(20.80%)of this survival time in initial identification cases(x2 = 13.84,P = 0.000 2).This study revealed the epidemiological characteristics of cases caused by both injury and disease,and supplied useful data for improving the level of forensic identification in such cases.

Objective:To introduce how to quickly set up a doctor team to achieve efficient treatment of batchs COVID-19 patients in Changchun GongTi shelter hospital.Methods:A cross-sectional study was conducted to analyze the basic situation of the doctors who supported the Changchun Gongti shelter hospital. The workload is the total number of patients from April 3 to 28, 2022. At the beginning of the task, the first week and the third week of the task, the five point scoring method was used to reflect the doctor's physical and mental state, stress state and rescue achievement. The time phased scheduling and disease grading management were fully implemented after 10 days of operation in the shelter. The doctors' ward round efficiency and self scoring changes before and after the implementation of the plan were compared, and the rescue results were summarized.Results:Total of 56 doctors (the Sichuan medical assistance team to Changchun), who undertook the work of Changchun Gongti shelter Hospital, came from 12 professional departments of 14 hospitals. By internal and external linkage-time phased scheduling and information-based patient zoning and grading management, the admission time of batch patients was shortened from (14.64±10.09) min to (6.80±5.10) min per person( P<0.05), the number of patients that each doctor can view per hour ranges from (28.50±12.26) to (68.43±19.95) ( P<0.01). A total of 1 293 patients were treated. There were no deaths, no accidents and no mild illness to severe illness in shelter hospital. 35 doctors completed a continuous survey. Before and after the implementation of those measures, the average physical state scores and the psychological state scores of doctors improved ( P=0.03), the self-score of stress feeling decreased ( P<0.01), and the self-score of professional achievement increased ( P<0.01). Conclusions:To adapt to the characteristics of emergency treatment for batch COVID-19 patients, the internal and external linkage-time phased scheduling and information-based patient zoning and grading management could help the temporarily convened doctors deal with a large number of patients efficiently, reduce work stress and exposure risk in shelter hospital.

Objective　To analyze the expression of miRNA-204 in hippocampus of epileptic mice based on gene chip.Methods　Differential genes were detected by microarray in hippocampal tissues of epileptic mice,and their target genes were enriched and pathway analyzed by bioinformatics.Results　The expression of miRNA-204,a differential gene associated with epilepsy,was down-regulated,and 457 related target genes were predicted.The function of 27 genes (P<0.01) and 16 signaling pathways (P<0.05) were obtained by enrichment analysis.Conclusion　Through analysis,the effect of miRNA-204 down-regulation on epileptic mice was clarified,and the miRNA-204 related pathway Wnt was analyzed,laying a foundation for further study on the regulation mechanism of miRNA-204 on epilepsy.

Objective To investigate the impact of four different collimator angle optimization techniques on the planning target volume (PTV) and organ at risk (OAR) during intensity-modulated radiotherapy (IMRT) for gastric cancer.Methods Ten patients with gastric cancer undergoing IMRT in Zhongnan Hospital of Wuhan University from 2015 to 2016 years were recruited in this study.All IMRT plans were designed by conventional five fields (330°,10°,45°,90°and 180°).In the Eclipse treatment planning system,four different collimator angle optimization techniques with consistent planning optimization parameters were employed to design the IMRT plan.Collimator angle optimization techniques included the following aspects.The collimator angle was set at 0 degree (CL0),collimator angle was set at 90 degree (CL90),Eclipse automatic collimator angle optimization (CLA) was adopted and collimator angle was set as the angle when the distance between X-Jaws and PTV (CLx) was the shortest.The dosimetric parameters mainly included the conformal index (CI) of PTV,the homogeneity index (HI),the mean dose (Mean),and the dosage of OAR.The treatment time (Time),monitor unit (MU),control point (CP),split field (SF) and conformal distance (Fx) were also considered.Results Regarding CL0 as the control,the CI,HI and Mean did not significantly differ among four collimator angle optimization techniques (all P＞0.05),whereas CLx could significantly increase the average dose of PTV in the target area (P＜0.05);CLx optimization reduced the liver (V30 reduction by 1.54％),left kidney (V12 decrease by 1.46％),right kidney and other OARs,whereas it slightly increased the maximum dose of the small intestine and spinal cord (＜1％).CLgo and CLA optimization elevated the dose of OAR in gastric cancer.Among four different collimator angle optimization techniques,CLx optimization reduced the MU (25.02％),CP (26.03％),Fx (20.27％) and SF (by 1.3separate fields on average) and treatment time (10.03％).CLgo and CLA optimization could decrease the MU,CP,Fx and SF.CL90 optimization had certain advantages in shortening the treatment time,whereas CLA optimization could prolong the treatment time by 5.04％.Conclusions During IMRT for gastric cancer,CL90,CLA and CLx collimator angle optimization techniques can obtain comparable dosimetry distribution to CL0 optimization technique,which can reduce the MU,decrease the radiation leakage,shorten the treatment time and improve treatment efficiency.