ObjectiveTo integrate network pharmacology prediction with multi-level experimental verification methods， and to explore in depth the therapeutic efficacy and potential mechanism of luteolin in treating gout. MethodsDatabases were used to obtain potential pharmacodynamic targets of luteolin. Protein-protein interaction （PPI） network construction and network pharmacology analysis techniques were used to screen key core targets of luteolin in gout treatment. Further biological function enrichment analysis and signaling pathway analysis were performed on these targets. Molecular docking simulation was used to calculate the binding energy between luteolin and potential core targets， clarifying the strength of their interactions. In the in vivo experiment for hyperuricemia， 48 mice were randomly divided into a blank group， a model group， an allopurinol group （5 mg·kg^-1）， and low-dose （10 mg·kg^-1）， medium-dose （30 mg·kg^-1）， and high-dose （90 mg·kg^-1） luteolin groups. For the first three days， the blank and model groups were gavaged with an equal volume of normal saline， while the allopurinol group and luteolin groups were gavaged with corresponding drugs. From day 4 onwards， modeling was performed by intraperitoneal injection at 12：00 daily （normal saline for the blank group， and oxonic acid potassium-hypoxanthine mixture for other groups， with 300 mg·kg^-1 for each group）. Gavage intervention was administered at 18：00 daily （normal saline for the blank/model groups， and corresponding drugs for the treatment groups） until day 7. After sampling， levels of serum uric acid （UA）， alanine aminotransferase （ALT）， and aspartate aminotransferase （AST） were measured. Levels of xanthine oxidase （XO） in the liver and kidney， ATP-binding cassette transporter G2 （ABCG2） and malondialdehyde （MDA） in the kidney， and superoxide dismutase （SOD） in the liver were determined. Renal HE staining was also performed. In the pharmacodynamic study of gouty arthritis， 36 rats were randomly divided into a blank group， a model group， a colchicine group （0.315 mg·kg^-1）， and low-dose （7 mg·kg^-1）， medium-dose （21 mg·kg^-1）， and high-dose （63 mg·kg^-1） luteolin groups. The model was established by vertically injecting 100 µL of 25 g·L^-1 monosodium urate suspension into the posterior lateral aspect of the right ankle joint （the blank group was injected with an equal volume of normal saline）， with repeated injections every two days for reinforcement. From day 2 after modeling， daily gavage administration was performed （normal saline for the blank/model groups， and corresponding drugs for the treatment groups） for a total of 16 days. During the experiment， ankle swelling and pain threshold were measured regularly. After sampling， levels of serum tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and interleukin-1β （IL-1β） were determined. Ankle joints were subjected to HE， Masson， and safranin O-fast green staining， and HE staining was also performed on ankle synovial tissue and various organs. Western blot was used to determine the expression levels of key proteins in gout-related signaling pathways. ResultsNetwork pharmacology analysis predicted that luteolin may regulate over 20 core targets， such as XO， ABCG2， nuclear factor erythroid 2-related factor 2 （Nrf2）， and SOD， through acting on signaling pathways including NF-κB， phosphoinositide 3-kinase/protein kinase B （PI3K/Akt）， and ABC transporters， thereby affecting uric acid metabolism and inflammatory responses. In the hyperuricemia model， compared with the blank group， the model group showed significantly increased serum UA level， liver and kidney XO activity， renal ABCG2 expression， and liver SOD activity （P<0.01）. Compared with the model group， the high-dose luteolin group significantly reduced serum UA level （P<0.01）， inhibited liver and kidney XO activity （P<0.01）， and significantly increased renal ABCG2 expression and liver SOD activity （P<0.01）， effectively alleviating renal oxidative stress damage and improving renal histopathological status. In the gouty arthritis model， compared with the blank group， the model group showed significant ankle swelling， decreased pain threshold， and significantly increased levels of IL-6， IL-1β， and TNF-α in serum and synovial tissue （P<0.01）. The high-dose luteolin group significantly reduced ankle swelling， prolonged hot plate pain threshold， effectively decreased the levels of the above inflammatory factors in serum and synovial tissue （P<0.01）， and significantly improved ankle pathological damage， showing good analgesic and anti-inflammatory effects. Western blot results further confirmed that luteolin significantly upregulated Nrf2 protein expression and downregulated XO and nucleotide-binding oligomerization domain （NOD）-like receptor protein 3 （NLRP3） expression in animals. ConclusionLuteolin can improve symptoms of hyperuricemia and gouty arthritis， and its potential mechanism may be related to inhibiting XO activity， increasing ABCG2 and SOD levels， and regulating Nrf2-mediated oxidative stress-related pathways.

It is very limited that the benefit of perioperative chemotherapy in early non-small cell lung cancer (NSCLC), and the 5-year survival rate is only 5% higher than surgery. Antibodies that block programmed cell death protein 1/programmed death-ligand 1 significantly improve the survival of advanced NSCLC. The value of immunotherapy in early NSCLC is also being explored. This paper firstly summarized and analyzed the progress of immunotherapy in the perioperative period of NSCLC. Secondly, the safety and feasibility of surgical resection after neoadjuvant immunotherapy were discussed. Finally, the clinical value of different therapeutic efficacy prediction indicators was summarized, in order to clarify the current status of immunotherapy in the perioperative period, so as to improve the clinical benefits of early NSCLC patients.

Exercise fatigue is a complex physiological and psychological phenomenon that includes peripheral fatigue in the muscles and central fatigue in the brain. Peripheral fatigue refers to the loss of force caused at the distal end of the neuromuscular junction, whereas central fatigue involves decreased motor output from the primary motor cortex, which is associated with modulations at anatomical sites proximal to nerves that innervate skeletal muscle. The central regulatory failure reflects a progressive decline in the central nervous system’s capacity to recruit motor units during sustained physical activity. Emerging evidence highlights the critical involvement of central neurochemical regulation in fatigue development, particularly through neurotransmitter-mediated modulation. Alterations in neurotransmitter release and receptor activity could influence excitatory and inhibitory signal pathways, thus modulating the perception of fatigue and exercise performance. Increased serotonin (5-HT) could increase perception of effort and lethargy, reduce motor drive to continue exercising, and contribute to exercise fatigue. Decreased dopamine (DA) and noradrenaline (NE) neurotransmission can negatively impact arousal, mood, motivation, and reward mechanisms and impair exercise performance. Furthermore, the serotonergic and dopaminergic systems interact with each other; a low 5-HT/DA ratio enhances motor motivation and improves performance, and a high 5-HT/DA ratio heightens fatigue perception and leads to decreased performance. The expression and activity of neurotransmitter receptors would be changed during prolonged exercise to fatigue, affecting the transmission of nerve signals. Prolonged high-intensity exercise causes excess 5-HT to overflow from the synaptic cleft to the axonal initial segment and activates the 5-HT1A receptor, thereby inhibiting the action potential of motor neurons and affecting the recruitment of motor units. During exercise to fatigue, the DA secretion is decreased, which blocks the binding of DA to D1 receptor in the caudate putamen and inhibits the activation of the direct pathway of the basal ganglia to suppress movement, meanwhile the binding of DA to D2 receptor is restrained in the caudate putamen, which activates the indirect pathway of the basal ganglia to influence motivation. Furthermore, other neurotransmitters and their receptors, such as adenosine (ADO), glutamic acid (Glu), and γ‑aminobutyric acid (GABA) also play important roles in regulating neurotransmitter balance and fatigue. The occurrence of central fatigue is not the result of the action of a single neurotransmitter system, but a comprehensive manifestation of the interaction between multiple neurotransmitters. This review explores the important role of neurotransmitters and their receptors in central motor fatigue, reveals the dynamic changes of different neurotransmitters such as 5-HT, DA, NE, and ADO during exercise, and summarizes the mechanisms by which these neurotransmitters and their receptors regulate fatigue perception and exercise performance through complex interactions. Besides, this study presents pharmacological evidence that drugs such as agonists, antagonists, and reuptake inhibitors could affect exercise performance by regulating the metabolic changes of neurotransmitters. Recently, emerging interventions such as dietary bioactive components intake and transcranial electrical stimulation may provide new ideas and strategies for the prevention and alleviation of exercise fatigue by regulating neurotransmitter levels and receptor activity. Overall, this work offers new theoretical insights into the understanding of exercise central fatigue, and future research should further investigate the relationship between neurotransmitters and their receptors and exercise fatigue.

ObjectiveTo investigate the effect of video-based educational intervention combined with maternal presence on perioperative adverse outcomes in preschool children undergoing general anesthesia， including cooperation in anesthesia induction， perioperative anxiety， pain and agitation during recovery. MethodsA total of 300 preschool children scheduled for general anesthesia in our hospital from June to December 2023 were randomly assigned to control group （n=150） and intervention group （n=150）. The control group received routine recovery care. For the intervention group， in addition to routine recovery care， a preoperative visit was scheduled one day before surgery. During this visit， mothers were guided to watch anesthesia videos with their children. During the waiting period in the operating room and 30 minutes after awakening， the mothers were guided to accompany the children for more than 30 minutes. Recovery conditions were recorded using the surgical anesthesia information system， and the children’s anesthetic induction compliance， perioperative anxiety， pain， and agitation were evaluated and recorded using the modified Yale Preoperative Anxiety Scale （m-YPAS）， the Induction Compliance Scale （ICC）， the Children’s Pain Behavior Scale （FLACC）， and the Pediatric Agitation and Emergence Delirium Scale （PAED）. ResultsOn the preoperative visit day， there were no statistically significant differences in baseline data between the two groups （P > 0.05）. For perioperative anxiety， the m-YPAS scores of the intervention group were significantly lower than those of the control group， both when entering the operating room waiting area （35.27±6.48 vs. 41.79±6.68， P < 0.05） and 30 minutes after postoperative recovery （20.13±7.05 vs. 35.75±9.51， P < 0.05）. In terms of anesthesia induction cooperation， the ICC scores of the intervention group were significantly lower than those of the control group （1.84±0.95 vs. 3.17±0.62， P < 0.05）， and the proportion of good induction cooperation was significantly higher than that of the control group （24.00% vs. 12.67%， P < 0.05）. There was no significant difference in awakening duration between the two groups， but the intervention group had a significantly shorter length of stay in the post-anesthesia care unit than the control group （0.90±0.29 hours vs. 1.29±0.42 hours， P < 0.001）. For perioperative agitation， the PAED scores of the intervention group were significantly lower than those of the control group （entering in the operating room waiting area： 8.5 vs. 9.2， P < 0.05； 30 minutes after postoperative recovery： 4.2 vs. 7.8， P < 0.05）. In terms of pain scores， the FLACC scores of the intervention group were also significantly lower than those of the control group， both when entering the operating room waiting area （ 5.3 vs. 6.7， P < 0.05； 30 minutes after postoperative recovery： 2.1 vs. 4.9， P < 0.05）. ConclusionsVideo-based educational intervention combined with maternal presence reduces the perioperative anxiety， pain and agitation of preschool children undergoing general anesthesia， and improved the compliance of anesthesia induction. It is recommended to promote this intervention measure in clinical practice.

ObjectiveTo evaluate the effect of Suanzaoren Tang on the rat model of depression established by solitary culture combined with chronic unpredictable mild stress by reshaping the inflammatory microenvironment and mediating changes in hippocampal synaptic plasticity. MethodsSeventy-two male SD rats were randomized by a random number table into six groups： control group， model group， fluoxetine group （0.003 6 g·kg^-1）， and high-（10 g·kg^-1）， medium-（5 g·kg^-1）， low-dose （2.5 g·kg^-1）Suanzaoren Tang groups， with 12 rats per group. The sucrose preference rate and open field test scores of rats in each group were observed. Western blot was employed to determine the expression levels of the key proteins in the specificity protein 1 （SP1）/sphingosine kinase 1 （SK1）/sphingosine-1-phosphate receptor 1 （S1PR1） signaling pathway， as well as hippocampal proteins synaptophysin Ⅰ （SYNⅠ）， postsynaptic density protein-95 （PSD-95）， and family with sequence similarity 19， member A5 （FAM19A5）. Immunohistochemistry was employed to detect the positive expression of SP1， PSD-95， SYNⅠ， interleukin （IL）-10， and IL-6. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of SP1 and S1PR1. Finally， transmission electron microscopy was employed to observe the ultrastructural changes of hippocampal synapses. ResultsCompared with the control group， the model group exhibited a decrease in sucrose preference index （P<0.01） and reduced total scores for horizontal and vertical movements in the open field test （P<0.01）， which indicated the successful modeling of depression. Moreover， the model group showed reduced synaptic vesicles in the hippocampus （P<0.01）， up-regulated expression of SP1， SK1， S1PR1， and IL-6 （P<0.01）， and down-regulated expression of SYNⅠ， PSD-95， FAM19A5， and IL-10 （P<0.01）. Compared with the model group， high- and medium-dose Suanzaoren Tang and fluoxetine increased the sucrose preference index and the total scores for horizontal and vertical movements in the open field test （P<0.01）. All Suanzaoren Tang groups and the fluoxetine group demonstrated reductions in SP1， SK1， S1PR1， and IL-6 expression （P<0.05， P<0.01）， alongside restored synaptic vesicles in the hippocampus （P<0.05， P<0.01）. ConclusionSuanzaoren Tang modulates hippocampal expression of FAM19A5， SYNⅠ， PSD-95， IL-10， IL-6， and the SP1/SK1/S1PR1 pathway in the rat model of depression. The antidepressant effects may be related to the ability of reducing neuroinflammation and enhancing synaptic plasticity.

ObjectiveTo evaluate the effect of Suanzaoren Tang on the rat model of depression established by solitary culture combined with chronic unpredictable mild stress by reshaping the inflammatory microenvironment and mediating changes in hippocampal synaptic plasticity. MethodsSeventy-two male SD rats were randomized by a random number table into six groups： control group， model group， fluoxetine group （0.003 6 g·kg^-1）， and high-（10 g·kg^-1）， medium-（5 g·kg^-1）， low-dose （2.5 g·kg^-1）Suanzaoren Tang groups， with 12 rats per group. The sucrose preference rate and open field test scores of rats in each group were observed. Western blot was employed to determine the expression levels of the key proteins in the specificity protein 1 （SP1）/sphingosine kinase 1 （SK1）/sphingosine-1-phosphate receptor 1 （S1PR1） signaling pathway， as well as hippocampal proteins synaptophysin Ⅰ （SYNⅠ）， postsynaptic density protein-95 （PSD-95）， and family with sequence similarity 19， member A5 （FAM19A5）. Immunohistochemistry was employed to detect the positive expression of SP1， PSD-95， SYNⅠ， interleukin （IL）-10， and IL-6. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of SP1 and S1PR1. Finally， transmission electron microscopy was employed to observe the ultrastructural changes of hippocampal synapses. ResultsCompared with the control group， the model group exhibited a decrease in sucrose preference index （P<0.01） and reduced total scores for horizontal and vertical movements in the open field test （P<0.01）， which indicated the successful modeling of depression. Moreover， the model group showed reduced synaptic vesicles in the hippocampus （P<0.01）， up-regulated expression of SP1， SK1， S1PR1， and IL-6 （P<0.01）， and down-regulated expression of SYNⅠ， PSD-95， FAM19A5， and IL-10 （P<0.01）. Compared with the model group， high- and medium-dose Suanzaoren Tang and fluoxetine increased the sucrose preference index and the total scores for horizontal and vertical movements in the open field test （P<0.01）. All Suanzaoren Tang groups and the fluoxetine group demonstrated reductions in SP1， SK1， S1PR1， and IL-6 expression （P<0.05， P<0.01）， alongside restored synaptic vesicles in the hippocampus （P<0.05， P<0.01）. ConclusionSuanzaoren Tang modulates hippocampal expression of FAM19A5， SYNⅠ， PSD-95， IL-10， IL-6， and the SP1/SK1/S1PR1 pathway in the rat model of depression. The antidepressant effects may be related to the ability of reducing neuroinflammation and enhancing synaptic plasticity.

This paper presents an automatic acquisition and analytic procedure of acupuncture manipulation based on optical navigation, aiming at solving the shortcomings of existing acquisition methods of acupuncture manipulation. An acquisition holder installed at the handle tail of filiform needle was designed to display the movement trajectory of the needle during acupuncture delivery by collecting the movement trajectory of holder. The 3-month old male Bama miniature pig was selected as the experimental subject, and 6 points, "Bojian" "Qiangfeng" "Housanli" "Xiaokua" "Huiyang" (BL35) and "Baihui" (GV20), were selected during acupuncture manipulation. The optical navigation system was used to collect the real-time data, and these data were per-processed and analyzed using mean filtering and Fourier transform. The acupuncture procedure was divided into 3 stages, inserting, lifting-thrusting, and twisting. The results showed that the accuracy was 96.3% at lifting-thrusting stage, and that was 100.0% at twisting stage. The decomposition effect of the entire procedure was satisfactory. This study provides a new approach to the quantitative analysis of acupuncture manipulation. In the future, it needs to further optimize the algorithm and expand the sample size so as to improve the accuracy of this analytic technique.
Acupuncture Therapy/methods* ; Male ; Animals ; Swine ; Acupuncture Points ; Humans ; Swine, Miniature ; Needles

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

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