南方医科大学学报杂志最新文献

Objectives: To assess the association between urinary levels of volatile organic compound metabolites (mVOCs) and risks of metabolic dysfunction-associated steatotic liver disease (MASLD) in the general adult population.

Methods: Based on 4 cycles of cross-sectional surveys from the 2011-2018 National Health and Nutrition Examination Survey (NHANES), generalized linear models were employed to evaluate the associations between individual mVOC exposures and the risk of MASLD. A two-stage Least Absolute Shrinkage and Selection Operator-Weighted Quantile Sum (LASSO-WQS) regression model was constructed to investigate the relationship between mixed mVOCs exposures and MASLD risk, and the relative contributions of the individual compounds were quantitatively analyzed.

Results: The single-exposure analysis revealed significant positive associations of 2-aminothiazoline-4-carboxylic acid (ATCA), N-acetyl-S‑(2-carboxyethyl)‑L-cysteine (CEMA), and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA) with MASLD risk after adjusting for confounders. In the two-stage mixed-exposure analysis, the first-stage LASSO regression identified 6 mVOCs with stronger association with MASLD risk. The second-stage WQS regression demonstrated a statistically significant positive association between mixed mVOCs exposures and MASLD risk (OR=1.306, 95% CI: 1.132-1.507; P<0.001), with CEMA contributing the highest weight (36%).

Conclusions: The study reveals a significant positive association between urinary levels of mVOCs mixtures and MASLD risk, suggesting potential hepatotoxic effects of VOC (especially CEMA) exposures, which urges future mechanistic studies of VOC mixture-related health impacts and listing of CEMA for health risk control.

Objectives: To evaluate the inhibitory effect of antitumor component-Ι in Agkistrodon halys venom (AHVAC-I) on proliferation and migration of cisplatin-resistant gastric cancer cells and explore the underlying mechanism.

Methods: Cisplatin-resistant MKN-28 (MKN-28/DDP) cells were obtained by continuous exposure of MKN-28 cells to stepwise-increasing concentrations of cisplatin. MKN-28/DDP cells were treated with different concentrations of AHVAC-I, and the changes in proliferation, migration and invasion of the cells were examined with colony-forming assay, CCK-8 assay wound-healing assay, and Transwell assay. Western blotting was performed to examine the effect of AHVAC-I on expressions of epithelial-mesenchymal transition (EMT) markers of MKN-28/DDP cells; the changes in protein and mRNA expression of retinoic acid induced 14 (RAI14) was detected with Western blotting and qRT-PCR.

Results: Treatment with 2, 4, and 8 μg/mL AHVAC-I significantly inhibited proliferative, migratory and invasion abilities and reduced the expressions of EMT markers in MKN-28/DDP cells. Compared with MKN-28 cells, MKN-28/DP cells showed an increased expression of RAI14, which was significantly lowered after treatment with AHVAC-I. Supplementation with exogenous RAI14 obviously attenuated the inhibitory effect of AHVAC-I on proliferation and migration of MKN-28/DDP cells.

Conclusions: AHVAC-I decreases proliferation and invasion of MKN-28/DDP cells by downregulating RAI14 expression.

Objectives: To explore the mechanism of Shihu Mixture (SHM) for improving diabetic cardiomyopathy.

Methods: Thirty male SD rats were randomized into 3 groups (n=10) for type 2 diabetes mellitus modeling by high-fat and -sugar feeding for 12 weeks and intraperitoneal streptozotocin injection, followed by treatment with daily gavage of normal saline (model group), metformin solution, or SHM extract for 4 weeks, with 10 normally fed rats as the normal control group. Fasting blood glucose and cardiac weight index of the rats were monitored, and their TG, TC, LDL-C, HDL-C, and LDH levels were determined; serum and myocardial levels of BNP, CRP, TNF‑α and IL-6 were detected with ELISA. Myocardial pathological changes and ultrastructures of myocardial mitochondria and autophagosomes were examined with HE and Masson staining and transmission electron microscopy. Myocardial expressions of Sirt3, FoxO3a, PINK1, Parkin, P62, and LC3 mRNAs and proteins were detected with RT-qPCR, Western blotting, and immunohistochemistry.

Results: Compared with those in the control group, the rats in the other 3 groups showed significantly increased fasting blood glucose, cardiac weight index, serum TC, TG, LDL-C, LDH, CRP and BNP levels and myocardial levels of TNF‑α and IL-6 with lowered HDL-C level, obvious myocardial and mitochondrial pathologies, and dysregulated expression of Sirt3, FoxO3a, p-FoxO3a, PINK1, Parkin, LC3 and P62. Treatment of the rat models with SHM extract significantly reduced fasting blood glucose level and cardiac weight index, lowered the levels of LDH, CRP, BNP, TNF‑α, IL-6, TC, TG, and LDL-C, increased HDL-C level, alleviated myocardial and mitochondrial damages, promoted autophagosome formation, and improved dysregulation of mitochondrial autophagy-related gene expression, showing similar effects to metformin.

Conclusions: SHM alleviates myocardial damage and improves mitochondrial function in rats with diabetic cardiomyopathy by regulating the mitochondrial autophagy pathway through Sirt3.

Depression is a complex and globally prevalent mental disorder, for which conventional antidepressant medications face limitations such as delayed onset and insufficient efficacy. Classic psychedelics, most notably psilocybin, have recently emerged as promising candidates for treatment of depression and demonstrated rapid, robust, and sustained antidepressant effects in controlled clinical settings. Their unique mechanisms of action and clinical prospects have become a key research focus in psychiatry and neuroscience. This review synthesizes the latest advances in the field over the past 5 years. Results from multiple randomized controlled trials indicate that a single or limited number of sessions of psychedelic-assisted psychotherapy can induce rapid and durable antidepressant effects in patients with treatment-resistant depression. At the mechanistic level, psychedelics rapidly promote the release of neurotrophic factors, enhance neuroplasticity, and facilitate brain network reorganization, thereby creating a critical "neuroplastic window" for psychotherapeutic intervention. However, the specific molecular and circuit-level mechanisms have not been fully understood with ongoing debate primarily over the 5-HT_2A receptor-dependent hypothesis versus the TrkB neurotrophic pathway-dependent hypothesis. Despite the promising outlook, translational applications of these substances faces several key challenges, including psychedelic-related risks, incomplete mechanistic understanding, lack of standardized treatment protocols, and insufficient long-term safety data. Future research should focus on elucidating the underlying neurobiological mechanisms, developing non-hallucinogenic derivatives, establishing standardized treatment frameworks, and identifying precise biomarkers to advance this therapeutic approach toward safer, more standardized, and personalized clinical implementation.

Objectives: To observe temporal changes of pain-related behaviors in mice with chronic postsurgical pain (CPSP) and identify its key mediators in the dorsal root ganglion (DRG).

Methods: In mouse models of CPSP induced by plantar incision (INC) followed by a dorsal foot injection of prostaglandin E2 (PGE2) and sham-operated mice, mechanical paw withdrawal thresholds (PWTs), thermal paw withdrawal latencies (PWLs), and cold withdrawal durations (WDs) were measured at different time points after modeling. Gene expression profiling of the DRG with RNA sequencing was performed on day 1 and day 8 after PGE2 injection. Bioinformatics analyses were conducted to explore the key mediators in the DRG for regulating CPSP, and the candidate genes and proteins were validated using RT-qPCR and ELISA. The effects of intrathecal injection of a CX3CL1-neuralizing antibody or JMS-17-2 (a CX3CR1 antagonist) on CPSP were observed.

Results: In CPSP mouse models, incision-induced pain was resolved within 14 days, and PWTs and WDs decreased progressively till day 10 and day 12 after PGE2 injection, respectively, without significant changes in PWLs. RNA-Seq identified 975 differentially expressed genes (DEGs) on day 1 and 895 on day 8 following CPSP modeling, including 524 intersecting DEGs enriched in cell membrane, plasma membrane, and CX3C chemokine receptor binding. Cx3cl1 and Cxcl14 were the top two upregulated chemokine-related DEGs in early CPSP, whose mRNA and protein expression increased significantly in the ipsilateral DRG on day 1 but declined on day 8. Intrathecal injection of the CX3CL1-neutralizing antibody before PGE2 injection prevented CPSP development, while JMS-17-2 partially reversed CPSP during the maintenance phase.

Conclusions: This CPSP mouse model shows persistent mechanical and cold allodynia for at least 10 days after PGE2 injection without significant changes in heat hypersensitivity. CX3CL1 and related chemokine signaling in the DRG may contribute to the development of CPSP.

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.