南方医科大学学报杂志最新文献

Objectives: To evaluate the protective effect of Lonicerae Japonicae Flos (LJF) extract against doxorubicin (DOX)-induced cardiotoxicity (DIC) and explore the possible mechanisms.

Methods: Network pharmacology, bioinformatics analysis and molecular docking were used to predict the targets of the core components of LJF. In a mouse model of DOX-induced myocardial injury, the protective effects of different doses of LJF extract were evaluated and the underlying mechanisms were explored by detecting the changes in mouse myocardial functions, myocardial enzymes, myocardial pathologies, and the expressions of inflammatory factors and pyroptosis-related proteins.

Results: The 10 core ingredients of LJF showed strong binding to AKT, EGFR, and GSK3β. In the animal experiment, the DOX-treated mice, compared with the sham-treated mice, had significantly decreased cardiac output, stroke volume, left ventricular ejection fraction, left ventricular fraction shorting, elevated serum levels of CK-MB and LDH, increased myocardial expressions of IL-18 and IL-1β, obvious myocardial damage, increased expression levels of NLRP3, caspase-1, GSDMD and GSDMD-N, and reduced expressions of EGFR, p-AKT and p-GSK3β proteins in the myocardial tissues. LJF treatment obviously improved myocardial function, decreased myocardial expressions of IL-18, IL-1β, NLRP3, caspase-1, GSDMD and GSDMD-N proteins, and increased the expressions EGFR, p-AKT and p-GSK3β proteins in DOX-treated mice.

Conclusions: LJF extract alleviates DOX-induced myocardial injury in mice possibly by reducing myocardial inflammation and pyroptosis via targeting EGFR, AKT and GSK3β to regulate the ErbB signaling pathway.

Objectives: To investigate the expression of the 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) in gastric cancer and its impact on long-term patient prognosis. Methods Tumor and adjacent tissue samples were collected from a cohort of 94 gastric cancer patients treated at our hospital from January, 2016 to December, 2019. Immunohistochemistry was used to detect PSMD11 and Ki67 expression levels in the tissues, whose correlations with clinicopathological parameters and postoperative 5-year survival of the patients were analyzed. PSMD11 expression in gastric cancer was also analyzed using data from the GEPIA and UALCAN databases, while the KM-plotter database was used to predict 5-year survival rates. KEGG and GO enrichment analyses were employed to predict the biological functions and mechanisms of PSMD11. In cultured HGC-27 cells, the effects of PSMD11 knockdown and overexpression on cell migration, invasion and expressions of epithelial-mesenchymal transition (EMT) markers and TGF‑β/Smad pathway proteins were evaluated using scratch wound healing assay, Transwell assay, and Western blotting.

Results: Bioinformatic analysis showed that PSMD11 expression was significantly elevated in gastric cancer and positively correlated with Ki67 expression (r=0.73, P<0.05). Survival analysis suggested that high PSMD11 expression was correlated with a poorer prognosis in gastric cancer patients. Univariate and multivariate Cox regression analyses identified PSMD11 as an independent prognostic risk factor in gastric cancer (HR: 2.167, 95% CI: 1.159-4.051, P=0.015). Enrichment analysis suggested involvement of PSMD11 in EMT and TGF‑β signaling. In HGC-27 cells, PSMD11 overexpression significantly enhanced while PSMD11 knockdown suppressed cell migration and invasion. PSMD11 overexpression significantly increased the expression levels of vimentin, N-cadherin, TGF‑β, and p-Smad2/3 and reduced E-cadherin expression, and PSMD11 knockdown produced the opposite changes.

Conclusions: PSMD11 is overexpressed in gastric cancer and adversely affects patient prognosis likely by driving EMT via activation of the TGF-β/Smad signaling pathway.

Objectives: To investigate the mechanism of kahweol for promoting motor function recovery in mice with spinal cord injury (SCI).

Methods: Fifty-four 8- to 10- week-old C57BL/6J mice were randomized equally into sham operation (laminectomy only) group, SCI group (laminectomy with spinal cord contusion), and Kahweol treatment group (with daily intraperitoneal injection of 20 mg/kg Kahweol following SCI). Motor function of the mice was evaluated using BMS scores, footprint analysis, and swimming test, and SCI area, myelin integrity, and neuron survival were assessed using HE, LFB, and Nissl staining. In a co-culture system of lipopolysaccharide (LPS)‑stimulated BV2 cells and HT22 neurons, the effects of different concentrations of Kahweol and PMA, a NF-κB pathway activator, on the number of activated microglia and apoptotic neurons were evaluated with immunofluorescence staining, and the changes in apoptosis-related proteins and IκBα/NF‑κB pathway proteins were detected using Western blotting. The levels of inflammatory factors (TNF-α, IL-6, and IL-1β) were measured by qRT-PCR and ELISA.

Results: In the mice with SCI, kahweol treatment significantly promoted motor function recovery, reduced injury area in the spinal cord tissue, and increased the myelinated area and number of neurons. In both the mouse models and the cell co-culture system, kahweol treatment effectively alleviated neuronal apoptosis by inhibiting microglial activation and reducing the release of inflammatory factors. The results of Western blotting showed that kahweol significantly decreased the phosphorylation levels of NF‑κB and IκBα. In the cell co-culture system, PMA obviously attenuated the inhibitory effect of kahweol on BV2 cell activation and neuronal apoptosis.

Conclusions: Kahweol promotes motor function recovery of mice with SCI by suppressing microglial activation via inhibiting the NF‑κB pathway, which shed light on a new strategy for clinical treatment of SCI.

Objectives: To assess the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with ST-segment elevation myocardial infarction (STEMI) following percutaneous coronary intervention (PCI) by evaluating both the large coronary vessels and coronary microcirculation.

Methods: A total of 507 patients with STEMI undergoing successful percutaneous coronary intervention (PCI) were retrospectively enrolled from two centers. The optimal cut-off value (256.5 mmHg·s·m^-1) of angio-based microvascular resistance (AMR) for predicting MACCEs was determined by ROC analysis. Combined with a quantitative flow ratio (QFR) threshold of 0.80, the patients were classified into 4 groups: Group 1 (QFR≥0.8, AMR<256.5; n=271), Group 2 (QFR≥0.8, AMR≥256.5; n=140), Group 3 (QFR<0.8, AMR<256.5; n=77), and Group 4 (QFR<0.8, AMR≥256.5; n=19). The primary endpoint was cardiac death or heart failure readmission within 2 years.

Results: Patients with elevated AMR (≥256.5 mmHg·s·m^-1) had a significantly increased risk of MACCEs within two years after PCI (P<0.001). Kaplan-Meier analysis showed the lowest survival rate in patients with both QFR<0.8 and AMR≥256.5 mmHg·s·m^-1. Multiple linear regression analysis suggested that diabetes (P<0.001), hyperlipidemia (P<0.001), smoking (P<0.014), systemic inflammation response index (P<0.007), and platelet to lymphocyte ratio (P<0.001) were independently associated with elevated AMR levels. Restricted cubic spline regression revealed a non-linear relationship between AMR and MACCEs risk (non-linear P<0.001), and the hazard ratio for MACCEs increased markedly for an AMR beyond the threshold of 259.45 mmHg·s·m^-1.

Conclusions: The integrated assessment of QFR and AMR allows effective prediction of MACCEs risk in STEMI patients after PCI, and elevated AMR is an independent predictor of significantly increased risk of MACCEs.

Objectives: To investigate whether indole-3-acetic acid (IAA) alleviates Cryptococcus neoformans (Cn)‑induced pyroptosis in cerebral microvascular endothelial cells by modulating stress granules (SGs) formation and the NLRP3 inflammasome.

Methods: In vitro cultured cerebral microvascular endothelial cells were pretreated with different concentrations of IAA before Cn infection (10⁷/mL), and the changes in cellular expresisons of G3BP1, DDX3X, NLRP3 and pyroptosis-related proteins, cytokines, and cell viability were deceted using Western blotting, immunofluorescence staining, ELISA, and CCK-8 assay. In the animal experiment, C57BL/6 mice with cyclophosphamide-induced immunosuppression were pretreated with saline or IAA gavage for 7 days before intravenous Cn injection. The changes in blood-brain barrier (BBB) integrity of the mice was assessed with Evans blue assay, and the brain cortical tissues were analyzed for changes in protein expressions.

Results: Cn infection significantly downregulated G3BP1 expression and upregulated the expressions of DDX3X and NLRP3 in cultured cerebral microvascular endothelial cells. IAA intervention not only restored normal expressions of G3BP1, DDX3X, and NLRP3, but also effectively suppressed the activation of pyroptosis-related proteins, including NT-GSDMD/GSDMD and P20/caspase-1, and reduced the release of IL-18 and IL-1β. IAA treatment also inhibited the translocation of DDX3X to NLRP3 induced by Cn infection and promoted the binding between DDX3X and G3BP1. In Cn-infected C57BL/6 mice, IAA treatment significantly alleviated BBB injury, decreased the expression of ZO-1 in the cerebral cortex, and effectively ameliorated abnormal expressions of VEGFR2, G3BP1, DDX3X, NLRP3, NT-GSDMD/GSDMD and P20/caspase-1.

Conclusions: IAA effectively alleviates Cn infection-induced pyroptosis of cerebral microvascular endothelial cells by modulating the formation of SGs and activating the NLRP3 inflammasome.

Objectives: To quantitatively analyze setup errors of 4 immobilization devices in precision radiotherapy for prostate cancer, their accuracy differences, and the factors affecting their setup precisions.

Methods: We conducted a retrospective analysis of 240 prostate cancer patients undergoing image-guided radiotherapy at Sun Yat-sen University Cancer Center from May, 2016 to May, 2024. According to the immobilization devices used, the patients were divided into 1.2 m vacuum bag group (n=60), 1.8 m vacuum bag group (n=60), Orfit frame group (n=60), and customized prone board group (n=60). All the patients received pre-treatment cone-beam CT (CBCT) scans, and setup errors in the right-left (RL), superior-inferior (SI), and anterior-posterior (AP) directions were obtained through XVI system grayscale registration. Further subgroup analyses were performed based on patient stratifications by lymph node irradiation status (n=120 each), age (<65 years, n=80; ≥65 years, n=160), and BMI (BMI<24 kg/m², n=120; BMI≥24 kg/m², n=120).

Results: The setup errors differed significantly among the 4 groups in three-dimensional directions (P<0.05). The customized prone board group showed minimal errors in the RL (0.02±0.25 cm) and SI (0.01±0.32 cm) directions, but demonstrated the largest error in the AP direction (-0.28±0.36 cm). The patients with lymph node irradiation had significantly greater AP directional errors (-0.22±0.36 cm) than those without (-0.01±0.43 cm; P<0.001). BMI showed a negative correlation with SI directional errors (R=-0.45, P<0.001), while age was not significantly correlated with the setup errors (P>0.05).

Conclusions: The customized prone board demonstrates clinically significant advantages for its high setup accuracies in RL and SI directions in spite of its systematic AP directional errors. The setup accuracy in the SI direction is especially important for patients with lymph node irradiation or low BMI. Our findings provide quantitative evidence for immobilization device selection and individualized optimization of precision radiotherapy for prostate cancer.

Objectives: To develop and validate a risk prediction model for cognitive impairment in community-dwelling elderly individuals in China.

Methods: This cross-sectional study was based on data from the 2011 China Health and Retirement Longitudinal Study (CHARLS), and the data of 2228 individuals aged ≥60 years were analyzed. The participants were randomly divided into a training set (n=1560) and an internal validation set (n=668) in a 7∶3 ratio. Thirty-eight candidate variables were collected, covering sociodemographic characteristics, lifestyle and behavioral habits, chronic disease history, physical function, and self-rated health status. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO) regression, followed by multivariate logistic regression to identify independent risk factors for cognitive impairment. A nomogram was constructed based on these factors, its discrimination power and calibration were assessed using the receiver operating characteristic (ROC) curve and calibration plot, respectively, and its clinical utility was evaluated using decision curve analysis (DCA).

Results: Age, years of education, alcohol consumption, systolic blood pressure, grip strength, and depressive symptoms were identified as independent predictors of cognitive impairment in Chinese elderly individuals. The area under the ROC curve of the constructed nomogram was 0.839 (95% CI: 0.814-0.864) in the training set and 0.840 (95% CI: 0.801-0.879) in the validation set, indicating good predictive performance of the model. The calibration plots demonstrated good agreement between the predicted and observed outcomes, and the DCA showed good clinical utility of the model.

Conclusions: The nomogram developed in this study based on LASSO-selected predictors demonstrates high accuracy, discrimination power, and potential clinical applicability to facilitate early identification and intervention of cognitive impairment among rural elderly individuals in China.

Objectives: To investigate the association of preoperative serum magnesium (sMg) level with postoperative delirium (POD) in elderly surgical patients and the mediating role of systemic inflammation.

Methods: This retrospective cohort study was conducted among 12 876 patients aged ≥65 years undergoing non-cardiac, non-neurological surgeries at Chinese PLA General Hospital between January, 2014 and December, 2021. Preoperative sMg and C-reactive protein (CRP) levels were measured within 30 days before surgery. POD was identified within 7 days postoperatively using structured chart review based on the Confusion Assessment Method. Multivariate logistic regression and restricted cubic spline (RCS) models were used to evaluate the association between sMg and POD. Mediation analysis with structural equation modeling was used to quantify the indirect effect of CRP after adjusting for the confounding factors.

Results: POD was identified in 685 (5.3%) of the patients. A significant nonlinear association was observed between preoperative sMg levels and POD risk, and POD incidence was the lowest in patients with sMg levels of 0.90-0.94 mmol/L. Compared with those in the 4th quintile, the patients in the lowest quintile exhibited a markedly increased risk of POD (OR=1.81, 95% CI: 1.41-2.35) even after adjustment for multiple confounding factors. Mediation analysis suggested that CRP explained 17.1% of the total effect of sMg on POD risk, and a stronger mediating effect was observed in cancer as compared with the non-cancer patients (24.1% vs 11.9%). Subgroup analyses revealed a significant nonlinear relationship between sMg and POD particularly in cancer patients and patients beyond 75 years of age.

Conclusions: Preoperative sMg level is independently associated with an increased POD risk in elderly patients, mediated partly by systemic inflammation. sMg may serve as a modifiable biomarker for early risk stratification and prevention for POD in perioperative care.

Objectives: To explore therapeutic mechanism of Hugan Tang (Hugan Decoction, HGT) for alleviating non-alcoholic fatty liver disease (NAFLD) in rats.

Methods: Network pharmacology analysis was used to predict the active components of HGT against NAFLD and their potential targets, and the core targets were identified using the protein-protein interaction network, followed by GO and KEGG pathway enrichment analyses. A rat model of high-fat diet (HFD)-induced NAFLD was used to test the effects of saline, silymarin, and low-, moderate-, and high-dose HGT on serum levels of ALT, AST, LDL, LDH, TG and TC, liver histopathology, and protein and mRNA expressions of ACC1, FASN, AMPK and m-TOR. In free fatty acid (FFA)-induced HepG2 cells, the effects of blank and HGT-medicated sera, compound C (an AMPK inhibitor), and MHY1485 (a mTOR agonist) were tested on cell viability, intracellular lipid deposition, TC and TG levels, and expressions of ACC1, FASN, AMPK and m-TOR.

Results: We identified 130 active components in HGT, 267 common targets with NAFLD, and 53 core gene nodes, nearly half of which were involved in lipid metabolism. HGT treatment of NAFLD was closely associated with lipid and atherosclerosis signaling, insulin resistance signaling, and AMPK signaling. In rat models of NAFLD, HGT significantly alleviated liver injury and lipid accumulation, and suppressed mRNA and protein expressions of ACC1 and FASN. In FFA-induced HepG2 cells, HGT-medicated serum obviously reduced TG and TC levels and inhibited ACC1 and FASN mRNA and protein expressions. The results of in vitro and in vivo experiments both demonstrated that HGT activated the AMPK/mTOR signaling pathway by promoting p-AMPK expression and suppressing p-mTOR expression, and its regulatory effects on p-AMPK, p-mTOR, ACC1, and FASN were differentially modulated by compound C and MHY1485.

Conclusions: HGT alleviates NAFLD in rats by activating the AMPK/m-TOR signaling pathway and reducing lipid synthesis.

Objectives: To explore the role of Chi3l1 in human umbilical cord mesenchymal stem cell (hUC-MSCs) therapy of type 1 diabetes.

Methods: hUC-MSCs with stable Chi3l1 knockdown (sh-Chi3l1-MSCs) were constructed using a lentiviral vector and characterized by flow cytometry and adipogenic and osteogenic induction. In adult C57BL/6J mouse models of streptozotocin-induced T1DM, the therapeutic effects of sh-NC-MSCs and sh-Chi3l1-MSCs grafting were evaluated by observing changes in clinical manifestations, blood glucose, body weight and pancreatic tissue pathologies. Insulin content and macrophage infiltration in the islets were detected using immunohistochemistry and immunofluorescence staining. The effects of these two stem cells on induced polarization of co-cultured mouse bone marrow macrophages were assessed using flow cytometry by detecting the mRNA expressions of iNOS, Arg-1, TNF-α, IL-6, IL-10, IL-13, and IL-1β using qPCR.

Results: The constructed sh-Chi3l1-MSCs retained the characteristics of MSCs but showed reduced therapeutic efficacy in T1DM mice. Immunofluorescence staining showed that the number of macrophages in the pancreatic tissue of the mice treated with sh-Chi3l1-MSCs was higher than that in MSCs treatment group. In the co-culture experiments, sh-Chi3l1-MSCs exhibited a lowered capacity to suppress M1 polarization of the macrophages and a reduced efficacy to promote differentiation of M2-type macrophage subset. Analysis with qPCR showed that the expressions of M1 macrophage marker iNOS and the inflammatory factors TNF-α, IL-6, and IL-1β increased, while the expressions of M2 macrophage marker Arg-1 and the cytokines IL-13 and IL-10 were decreased significantly in sh-Chi3l1-MSCs group.

Conclusions: In T1DM mouse models, hUC-MSCs mitigate inflammatory responses by suppressing the production of pro-inflammatory M1-type macrophages via Chi3l1.