1.Enlightenment of traditional Chinese medicine’s “preventive treatment of disease” thought on the home- and community-based integrated medical and elderly care services
Chinese Medical Ethics 2026;39(1):129-137
The thought of “preventive treatment of disease” in traditional Chinese medicine (TCM) is rooted in traditional Chinese culture. As one of the most influential theories in the theoretical system of TCM, it has played a crucial guiding role in the daily healthcare activities among the vast Chinese populace for thousands of years. Its health management concepts such as prevention first and prioritizing prevention over treatment, as well as holistic regulation and cause-based nourishment, exhibit significant inspirational and inheritance value for the construction and development of modern home- and community-based integrated medical and elderly care service models in China. Considering the current situation of population aging in China and the demand of residents for home-based elderly care services, this paper proposed that China should establish a home- and community-based integrated medical and elderly care service model with Chinese characteristics. This model should be co-built, co-governed, and shared by all populations, cover all aspects, and span the entire process of aging. The aim was to fully leverage the unique strengths of TCM culture, actively address ethical issues involved in China’s population aging and home- and community-based integrated medical and elderly care services, and meet the needs of elderly care. While promoting high-quality development of integrated medical and elderly care in China, it will also contribute to the construction of “healthy China.”
2.Exploring Mechanism of Glucose Metabolic Reprogramming-driven Macrophage Polarization in Regulating Metabolic Syndrome Based on Theory of "Spleen Qi Dispersing Essence"
Jinshun YOU ; Shijie QIAO ; Linzhen LI ; Lingfang ZHENG ; Shujie XIA
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(20):221-229
Metabolic syndrome (MS) is a clinical syndrome characterized by obesity, insulin resistance, and dyslipidemia, and chronic inflammation is closely associated with its pathogenesis. The imbalance between pro-inflammatory and anti-inflammatory macrophage polarization, as one of the core pathological mechanisms of chronic inflammation, is a crucial driver of MS progression. According to Essential Questions in Yellow Emperor's Inner Canon: Distinctive Theory on Meridians and Diseased Pulses, "the spleen Qi dispersing essence... along all the meridians and collaterals". When the spleen fails in transportation and transformation, the distribution of refined essence becomes disordered, leading to internal accumulation of phlegm-dampness, forming a dynamic pathological state of "root deficiency with branch excess". Accordingly, the core traditional Chinese medicine (TCM) pathogenesis of MS is closely related to "spleen failing in transportation and transformation coupled with the internal accumulation of phlegm-dampness"; however, its modern biological basis remains elusive. Therefore, based on the theory of "spleen Qi dispersing essence" and recent advances in immunometabolism, this paper explored the modern scientific connotation of the TCM pathogenesis of MS from the perspective of macrophage polarization driven by glucose metabolic reprogramming. Through theoretical analysis and literature integration, it was proposed that mitochondrial oxidative phosphorylation participates in the energy metabolism process of "spleen Qi dispersing essence". The dysfunction of the spleen's transportation and transformation prompts macrophage metabolism to shift toward glycolysis, resulting in the accumulation of lactate and succinate, which represents the microscopic manifestation of "refined essence deviating from proper transformation" and can be defined as "microscopic phlegm-dampness". These metabolites subsequently drive M1 macrophage polarization via the hypoxia-inducible factor-1α (HIF-1α)/nuclear factor-κB (NF-κB) signaling pathway, triggering the release of pro-inflammatory cytokines and inducing systemic chronic low-grade inflammation, ultimately manifesting as insulin resistance, lipid metabolic disorders, and other core components of MS, thus achieving immune amplification from local "microscopic phlegm-dampness" to systemic "internal accumulation of phlegm-dampness". Therefore, macrophage polarization driven by glucose metabolic reprogramming constitutes an important biological link connecting the TCM concept of "spleen failing to disperse essence" with the pathology of MS. Furthermore, this paper reviewed the potential mechanisms by which TCM herbal formulas and their monomeric components that "restore spleen transportation and resolve phlegm-dampness" ameliorate MS by modulating macrophage metabolic remodeling, thereby providing novel biological connotations for the modern interpretation of the theory of "spleen Qi dispersing essence". Future research should integrate multi-omics technologies with disease-syndrome animal models to elucidate the regulatory network of formulas that "restore spleen transportation and resolve phlegm-dampness". Additionally, the feasibility of utilizing macrophage metabolic phenotypes as objective diagnostic biomarkers for the phlegm-dampness syndrome in MS warrants further investigation.
3.Exploring Mechanism of Glucose Metabolic Reprogramming-driven Macrophage Polarization in Regulating Metabolic Syndrome Based on Theory of "Spleen Qi Dispersing Essence"
Jinshun YOU ; Shijie QIAO ; Linzhen LI ; Lingfang ZHENG ; Shujie XIA
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(20):221-229
Metabolic syndrome (MS) is a clinical syndrome characterized by obesity, insulin resistance, and dyslipidemia, and chronic inflammation is closely associated with its pathogenesis. The imbalance between pro-inflammatory and anti-inflammatory macrophage polarization, as one of the core pathological mechanisms of chronic inflammation, is a crucial driver of MS progression. According to Essential Questions in Yellow Emperor's Inner Canon: Distinctive Theory on Meridians and Diseased Pulses, "the spleen Qi dispersing essence... along all the meridians and collaterals". When the spleen fails in transportation and transformation, the distribution of refined essence becomes disordered, leading to internal accumulation of phlegm-dampness, forming a dynamic pathological state of "root deficiency with branch excess". Accordingly, the core traditional Chinese medicine (TCM) pathogenesis of MS is closely related to "spleen failing in transportation and transformation coupled with the internal accumulation of phlegm-dampness"; however, its modern biological basis remains elusive. Therefore, based on the theory of "spleen Qi dispersing essence" and recent advances in immunometabolism, this paper explored the modern scientific connotation of the TCM pathogenesis of MS from the perspective of macrophage polarization driven by glucose metabolic reprogramming. Through theoretical analysis and literature integration, it was proposed that mitochondrial oxidative phosphorylation participates in the energy metabolism process of "spleen Qi dispersing essence". The dysfunction of the spleen's transportation and transformation prompts macrophage metabolism to shift toward glycolysis, resulting in the accumulation of lactate and succinate, which represents the microscopic manifestation of "refined essence deviating from proper transformation" and can be defined as "microscopic phlegm-dampness". These metabolites subsequently drive M1 macrophage polarization via the hypoxia-inducible factor-1α (HIF-1α)/nuclear factor-κB (NF-κB) signaling pathway, triggering the release of pro-inflammatory cytokines and inducing systemic chronic low-grade inflammation, ultimately manifesting as insulin resistance, lipid metabolic disorders, and other core components of MS, thus achieving immune amplification from local "microscopic phlegm-dampness" to systemic "internal accumulation of phlegm-dampness". Therefore, macrophage polarization driven by glucose metabolic reprogramming constitutes an important biological link connecting the TCM concept of "spleen failing to disperse essence" with the pathology of MS. Furthermore, this paper reviewed the potential mechanisms by which TCM herbal formulas and their monomeric components that "restore spleen transportation and resolve phlegm-dampness" ameliorate MS by modulating macrophage metabolic remodeling, thereby providing novel biological connotations for the modern interpretation of the theory of "spleen Qi dispersing essence". Future research should integrate multi-omics technologies with disease-syndrome animal models to elucidate the regulatory network of formulas that "restore spleen transportation and resolve phlegm-dampness". Additionally, the feasibility of utilizing macrophage metabolic phenotypes as objective diagnostic biomarkers for the phlegm-dampness syndrome in MS warrants further investigation.
4.A Cross-Sectional Study on the Distribution of Traditional Chinese Medicine Constitutions and Factors Associated with Hyperuricemia
Zhongyi ZHANG ; Fangli LI ; Shiping HU ; Shujie AN ; Xihuan ZHU ; Jiahui ZHANG ; Luyao JIN ; Yuhan ZONG ; Mengru ZHOU ; Ji WANG ; Huaiyu WANG ; Qi WANG
Journal of Traditional Chinese Medicine 2026;67(20):2210-2218
ObjectiveTo analyze the distribution characteristics of traditional Chinese medicine (TCM) constitution and factors associated with hyperuricemia (HUA) in the HUA population, providing a reference for persona-lized prevention and management of HUA. MethodsA cross-sectional study was conducted among individuals who had completed both serum uric acid (SUA) testing and TCM constitution identification during health examinations. According to SUA levels, participants were divided into a hyperuricemia group and a normal SUA group; according to the constitution identification results, participants were classified into balanced constitution, single biased constitution, and mixed constitution. The distribution characteristics of TCM constitution were compared between the two groups; participants in the hyperuricemia group were stratified by sex and age (≥18 years and <40 years, ≥40 years), and the distribution characteristics of TCM constitution were compared across different sex and age groups. Logistic regression was used to analyze factors associated with HUA, with further stratified analyses by sex and age. ResultsA total of 10 920 participants were included, comprising 4170 cases (38.19%) in the hyperuricemia group and 6750 cases (61.81%) in the normal serum uric acid group. According to TCM constitution, there were 420 cases (3.85%) with balanced constitution, 6108 cases (55.93%) with single biased constitution, and 4392 cases (40.22%) with mixed constitution. In the hyperuricemia group, there were 80 cases (19.05%) with balanced constitution; 2275 cases (37.25%) with single biased constitution, among which damp-heat constitution (1205 cases, 52.97%), phlegm-dampness constitution (500 cases, 21.98%), and qi-stagnation constitution (181 cases, 7.96%) accounted for relatively high proportions; and 1815 cases (41.33%) with mixed constitution, among which mixed constitution involving phlegm-dampness (51.35%, 932 cases), mixed constitution involving blood stasis (47.00%, 853 cases), and mixed constitution involving damp-heat (41.21%, 748 cases) accounted for relatively high proportions. Logistic regression showed that qi-stagnation constitution (OR=1.68), mixed constitution involving qi-stagnation (OR=1.53), mixed constitution involving phlegm-dampness (OR=1.55), and mixed constitution involving blood stasis (OR=1.50) were independently associated with HUA (P<0.05). Sex-stratified analysis showed that mixed constitution involving phlegm-dampness was positively associated with HUA risk in females; age-stratified analysis showed that, among individuals aged ≥18 and <40 years, qi-stagnation constitution, mixed constitution involving qi stagnation, and mixed constitution involving phlegm-dampness were positively associated with HUA risk (all P<0.05). ConclusionThe prevalence of HUA differs markedly by sex and age. Mixed constitution accounts for a higher proportion of HUA patients. Qi-stagnation constitution, mixed constitution involving qi stagnation, mixed constitution involving phlegm-dampness, and mixed constitution involving blood stasis are associated with HUA. Notably, the specific association of mixed constitution involving phlegm-dampness in females and qi-stagnation constitution in young adults is particularly prominent.
5.Identification and validation of characterized gene NFE2L2 for ferroptosis in ischemic stroke
Mi WANG ; Shujie MA ; Yang LIU ; Rui QI
Chinese Journal of Tissue Engineering Research 2025;29(7):1466-1474
BACKGROUND:Ferroptosis is closely associated with the pathogenesis of ischemic stroke,and targeting ferroptosis is a promising regimen for the treatment of ischemic stroke,but the specific regulatory targets are unclear. OBJECTIVE:To screen ferroptosis-related characterized genes in ischemic stroke by bioinformatics and machine learning methods and validate them by cellular experiments to investigate the role of ferroptosis in ischemic stroke. METHODS:Eligible ischemic stroke-related datasets and ferroptosis expression datasets were selected based on GEO database and FerrDb database,and ferroptosis-related differential genes were screened by t-test.GO functional enrichment analysis with KEGG signaling pathway enrichment analysis was performed for ferroptosis-related differential genes.Characterized genes for ferroptosis in ischemic stroke were screened by PPI network analysis and machine learning.The reliability and biological functions of the characterized genes were explored using ROC analysis and GSEA analysis,followed by cell experiment.HT22 cells were divided into control and ischemic stroke groups.No intervention was made in the control group,and 0.1 mM H2O2 was added to the ischemic stroke group for 24 hours to simulate cellular oxidative stress injury and ferroptosis.The ferroptosis and the expression of characterized genes were verified by real-time fluorescence quantitative polymerase chain reaction(RT-PCR)and western blot assay. RESULTS AND CONCLUSION:(1)Forty-five ferroptosis-associated differential genes were obtained,and GO and KEGG enrichment analyses revealed that the differential genes were closely associated with oxidative stress,autophagy,ferroptosis,adipocytokine signaling pathway,and mitochondrial metabolism.(2)A total of one ferroptosis characterized gene,nuclear factor erythroid 2-related factor 2(NFE2L2),was identified by the MCODE plugin and cytoHubba plugin in the PPI network with the LASSO algorithm and SVM-RFE algorithm in machine learning.(3)Receiver operating characteristic curve analysis of NFE2L2 revealed that the diagnostic prediction models constructed in the training and validation sets had good accuracy and specificity.GSEA analysis of NFE2L2 revealed that the characterized gene was involved in the regulation of ischemic stroke pathogenesis through immunity,inflammatory response,amino acid metabolism,and neurofactor regulation.(4)RT-PCR and western blot analyses showed that the acyl coenzyme A synthetase long chain family,member 4(ACSL4)mRNA and protein expression levels were significantly higher in the ischemic stroke group compared with the control group(P<0.05),and the glutathione peroxidase 4(GPX4)mRNA and protein expression levels were significantly lower in the ischemic stroke group(P<0.05).Compared with the control group,the mRNA and protein expression levels of the characterized gene NFE2L2 were significantly higher in the ischemic stroke group(P<0.05).(5)It suggests that ischemic stroke is closely related to ferroptosis,and targeting the characterized gene NFE2L2 may provide certain ideas and directions for the study and treatment of ischemic stroke.
6.Analysis of Major Syndromes and Their Typical Related Symptoms and Signs in 135 Patients with Metabolic Syndrome:A Clinical Study Based on Syndrome Element Differentiation and Latent Class Analysis
Tong WANG ; Mingqian JIANG ; Lifen MI ; Shanyi SHEN ; Shujie XIA ; Candong LI
Journal of Traditional Chinese Medicine 2025;66(4):376-381
ObjectiveTo explore the typical syndromes and their characteristic of symptoms and signs with high diagnostic value in patients with metabolic syndrome (MS). MethodsTraditional Chinese medicine (TCM) diagnostic information was collected from 135 MS patients. Syndrome element differentiation and latent class analysis (LCA) were applied to identify the major TCM syndromes in MS patients. Symptoms were analyzed based on the differentiated syndromes, and a binary logistic regression model was constructed to determine symptoms and signs with high diagnostic value. ResultsA total of 135 MS patients were included, involving 163 symptoms and signs with a total frequency of 1749; twenty-three syndrome elements were extracted, 367 times frequency in total, among which 8 syndrome elements occurred ≥10 times with 323 frequencies (88.01% of the total). These included location-related elements such as kidney (48 times), spleen (14 times), and stomach (14 times), and nature-related elements such as phlegm (71 times), yin deficiency (64 times), dampness (57 times), heat (42 times), and qi deficiency (13 times). Based on LCA, the 135 patients were categorized into two groups distinguished by the syndrome elements of dampness and phlegm, forming the "phlegm-dampness syndrome" as the major syndrome type. Nine high-frequency symptoms and signs associated with the phlegm-dampness syndrome were identified,i.e. obesity (39 times), greasy coating (38 times), slippery pulse (33 times), white coating (31 times), preference for fatty and heavy foods (30 times), excessive urination (30 times), fatigue and lack of strength (29 times), wiry pulse (25 times), and dark red tongue (25 times). A binary logistic regression model was constructed combining these nine symptoms and signs with the LCA classification results, ultimately identifying obesity, greasy coating, fatigue and lack of strength, and white coating as independent factors associated with the phlegm-dampness syndrome in MS patients (P<0.05). ConclusionThe major TCM syndrome in MS patients is phlegm-dampness syndrome, and obesity, greasy coating, fatigue and lack of strength, and white coating are the typical symptoms and signs for diagnosing phlegm-dampness syndrome in MS patients.
7.The mechanism of Prim-O-glucosylcimifugin in improving cholesterol metabolism in osteoarthritis chondrocytes via lncRNA NEAT1/miR-128-3p
Yanming LIN ; Haishui TU ; Shujie LAN ; Chao LI ; Shiyu LU ; Yue CHEN ; Changlong FU
Journal of Beijing University of Traditional Chinese Medicine 2025;48(1):55-67
Objective:
To investigate the mechanism of action of Prim-O-glucosylcimifugin (POG) to improve cholesterol metabolism in osteoarthritic (OA) chondrocytes based on the long noncoding RNA nuclear-enriched transcript 1 (lncRNA NEAT1)/microRNA-128-3p (miR-128-3p) pathway.
Methods:
For in vivo experiments, 60 mice were divided into the normal, sham operation, model, and POG groups using the random number table method, with 15 mice per group. The osteoarthritis mouse model was constructed using the modified Hulth method in the model and POG groups. Mice in the POG group were administered 30 mg/(kg·d)POG by gavage. The other groups were administered an equal amount of normal saline for 8 weeks. The cartilage tissue structure of mice in each group was observed using hematoxylin and eosin staining. Real-time PCR was used to detect changes in the lncRNA NEAT1 and miR-128-3p mRNA expression levels in the cartilage tissues of mice. Western blotting was used to detect the protein expressions of ATP-binding cassette transporter A1 (ABCA1), liver X receptor β (LXRβ), matrix metalloprotein-3 (MMP-3), and B-lymphoblastoma-2-associated X protein (Bax) in articular cartilage of mice. An enzyme-linked immunosorbent assay was used to measure the tumor necrosis factor-α (TNF-α) content in the synovial fluid of mice. A biochemical microplate assay was used to measure the total cholesterol level in the synovial fluid of mice. The in vitro experiments were divided into the negative control, interleukin-1β(IL-1β), IL-1β+ POG, IL-1β+ oe-lncRNA NEAT1, IL-1β+ oe-lncRNA NEAT1 + POG, IL-1β + miR-128-3p inhibition, and IL-1β+ miR-128-3p inhibition+ POG groups. An OA model was established by inducing chondrocytes with IL-1β for 24 h, and 90 mg/L of POG and miR-128-3p inhibitor(50 nmol/L) were administered for 48 h as an intervention. lncRNA NEAT1 expression in chondrocytes was detected using fluorescence in situ hybridization. A dual luciferase assay was used to detect the targeting relationship between lncRNA NEAT1 and miR-128-3p. Lentiviral plasmids overexpressing lncRNA NEAT1 were used to transfect mouse chondrocytes. Real-time PCR was used to detect the effect of lncRNA NEAT1 overexpression on the mRNA level of miR-128-3p in chondrocytes. Western blotting was used to detect ABCA1, LXRβ, MMP-3, and Bax protein expression in chondrocytes after lncRNA NEAT1 overexpression and miR-128-3p inhibition.
Results:
POG significantly reduced OA cartilage tissue damage. Compared with the model group, the lncRNA NEAT1 mRNA level decreased, whereas the miR-128-3p mRNA level increased in the cartilage tissue of the POG group (P<0.05). Compared with the model group, ABCA1 and LXRβ protein expression increased in the POG group, whereas MMP-3 and Bax protein expression decreased (P<0.05). The TNF-α levels decreased in the POG group compared to the model group (P<0.05). Compared with the model group, the total cholesterol level in the synovial fluid of the joint of mice in the POG group decreased (P<0.05). The mean fluorescence intensity of lncRNA NEAT1 in the IL-1β+ POG group decreased compared with the IL-1β group (P<0.05). The relative luciferase activity in the miR-128-3p mimics group bound to the lncRNA NEAT1-WT plasmid decreased compared with the miR-128-3p negative control group (P<0.05). The lncRNA NEAT1 mRNA levels decreased, whereas the miR-128-3p mRNA levels increased in the IL-1β+ oe-lncRNA NEAT1 + POG group compared with the IL-1β+ oe-lncRNA NEAT1 group (P<0.05). Compared with the IL-1β+ POG group, ABCA1 and LXRβ protein expression decreased, whereas MMP-3 and Bax protein expression increased (P<0.05).
Conclusion
POG mediates lncRNA NEAT1/miR-128-3p to improve cholesterol metabolism in OA chondrocytes.
8.Emphasis on management of capsular embedded hyperplasia nodules
Shujie XIA ; Chenghao ZHENG ; Yiping ZHU ; Yifeng JING
Journal of Modern Urology 2025;30(2):95-98
Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men,and surgical treatment is one of the major therapeutic modalities.The management of prostatic hyperplasia nodules,especially capsular embedded hyperplasia nodules,is crucial to reduce the incidence of postoperative complications and rate of secondary surgery.In this essay,we summarize the sources of prostatic hyperplasia nodules,relationship between incidence of postoperative complications and capsular embedded hyperplasia nodules,advantages and disadvantages of various surgical procedures for the management of hyperplasia nodules and share our experience in the management of capsular embedded hyperplasia nodules in thulium laser enucleation of the prostate.
9.Investigation and multivariate analysis of humanistic care experience among patients visiting traditional Chinese medicine outpatient clinics
Hongxia WANG ; Xu CHE ; Haiying CAO ; Haixin ZHANG ; Shujie GUO ; Yilan LIU ; Heng ZHANG
Chinese Medical Ethics 2025;38(11):1498-1509
ObjectiveTo explore the current situation and influencing factors of humanistic care experience among patients visiting traditional Chinese medicine (TCM) outpatient clinics in China, and to provide a basis for optimizing TCM-characterized services in both TCM and Western medicine hospitals. MethodsA multi-center cross-sectional study was conducted using convenience sampling to select 35 hospitals across 13 provinces in China (including 3 TCM hospitals and 32 TCM outpatient clinics in general hospitals). A total of 3,430 patients were surveyed using the general information questionnaire and the Outpatient Humanistic Care Experience Questionnaire, with data collected via Questionnaire Star. Univariate analysis and multiple linear regression were employed to examine the impacts of patient characteristics, visit characteristics, hospital type (TCM hospital/general hospital), and geographic region (eastern/central/western) on humanistic care experience. ResultsThe total score of humanistic care experience was 194 (188, 233). Univariate analysis showed that gender, educational level, current residence, per capita monthly household income, location attribute of medical institutions, number of previous visits to this hospital, payment method of medical expenses, previous hospitalization history in this hospital, frequency of outpatient visits within the past 12 months, self-rated disease severity, familiarity with the outpatient procedures, implementation of the follow-up service provided by the hospital, satisfaction with follow-up services, the grade of the hospital visited, geographical region of the hospital visited, and the department visited had an impact on the humanistic care experience during outpatient visits (P<0.05). Multivariate analysis demonstrated that educational level (β=0.609, P=0.011), self-rated disease severity (β=-0.646, P=0.047), familiarity with outpatient procedures (β=4.784, P<0.001), satisfaction with follow-up services (β=6.365, P<0.001), and the grade of the hospital visited (β=-5.487, P<0.001) affected the humanistic care experience in outpatient medical treatment, explaining 24.4% of the total variation. ConclusionHumanistic care experience in TCM outpatient clinics is influenced by multiple factors. It is recommended to optimize the medical treatment process, strengthen doctor-patient communication training, and establish a precise follow-up mechanism, with a focus on improving care perceptions among patients with lower education levels and those attending primary-level hospitals, to refine the TCM-characterized service system.
10.Structure-Activity Relationship of NMDA Receptor Ligands and Their Activities on the ERK Activation through Metabotropic Signaling Pathway
Dooti KUNDU ; Mengling WANG ; Suresh PAUDEL ; Shujie WANG ; Choon-Gon JANG ; Kyeong-Man KIM
Biomolecules & Therapeutics 2025;33(2):278-285
The N-methyl-D-aspartate receptor (NMDA-R) subunit GluN2B is abundantly expressed in brain regions critical for synaptic plasticity and cognitive processes. This study investigated the structure-activity relationships (SAR) of NMDA-R ligands using GluN2B as a molecular target. Thirty potential NMDA-R antagonists were categorized into two structural classes: 1-(1-phenylcyclohexyl) amines (series A) and α-amino-2-phenylcyclohexanone derivatives (series B). In series A compounds, the phenyl ring and R1 substituents were positioned at the carbon center of the cyclohexyl ring, with R2 substituents at the para- or meta-positions of the phenyl ring. SAR analysis revealed optimal binding affinity when R1 was carbonyl (C=O) and R2 was 4-methoxy (4-OMe). Series B compounds featured a cyclohexanone scaffold with NH-R1 at the α-position and a phenyl ring bearing R2 substituents at ortho-, meta-, or para-positions. Maximum binding affinity was achieved with R1 as hydrogen (H) and R2 as hydroxyl (OH). Compounds were assessed for GluN2B-mediated ERK activation to evaluate potential metabotropic signaling properties. Approximately 50% of the compounds demonstrated ERK activation through a non-ionotropic signaling cascade involving Src, phosphatidylinositol 3-kinase, and protein kinase C. This study elucidated key structural determinants for NMDA-R binding and characterized a novel metabotropic signaling pathway. Notably, our findings suggest that compounds acting as antagonists at the ionotropic site may simultaneously function as agonists through non-ionotropic mechanisms.


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