南方医科大学学报杂志最新文献

Objectives: To explore pathological and immune cell infiltration characteristics of pigmented pretibial patches in diabetic patients.

Methods: Forty-two diabetic patients undergoing thigh amputation at Tianjin Medical University Chu Hsien-I Memorial Hospital were enrolled. Before the operation, the pretibial skin of the patients were examined and sampled for HE and Masson staining. The thickness of the epidermis and the density of blood vessels in the dermis were compared between patients with and without pigmented pretibial patches. The expressions of VEGFA and VEGFR2 in the skin tissues were detected using Western blotting, and CD4⁺ and CD8⁺ cells and the CD4/CD8 ratio were analyzed with immunohistochemical staining.

Results: Compared with the patients without pigmented pretibial patches, the patients with pigmented pretibial patches showed obvious thickening of the epidermal spinous layer, irregular downward extension of the epidermal projections, hyperkeratosis, melanin deposition in the basal layer, increased capillaries in the dermis, and localized, well-defined inflammatory cell infiltration around the blood vessels. In pigmented pretibial patches group, Masson staining revealed irregular arrangement, thickening and hyaline degeneration of collagen fibers, significantly increased epidermal thickness and blood vessel density in the dermis, increased CD4⁺ cells and the CD4/CD8 ratio, and reduced CD8⁺ cells.

Conclusions: The pigmented pretibial patches in diabetic patients show obvious pathological changes possibly due to vascular and immune abnormalities.

Objectives: To explore the role of miR-221-3p in mediating the positive effects of aerobic exercise on macrophage polarization in the adipose tissues and insulin resistance (IR).

Methods: Sixteen normal C57BL/6J mice and 16 mice with IR induced by high-fat diet (HFD) feeding for 12 weeks were both randomized into sedentary group and exercise group with aerobic exercise training on a treadmill (5 times per week for 8 consecutive weeks). All the mice were examined for changes in body weight, body composition, fasting blood glucose, blood lipid levels, insulin levels, miR-221-3p expression level, mRNA levels of Socs1, Tnf-α and Arg-1, and protein levels of SOCS1, JAK1, p-STAT1, and p-STAT3 in the adipose tissues, and the targeting relationship between miR-221-3p and SOCS1 was validated using dual-luciferase reporter gene assay. In RAW264.7 macrophages, the effects of transfection with miR-221-3p mimic or inhibitor on macrophage polarization were observed.

Results: In mice with normal feeding, aerobic exercise significantly decreased body weight, fat mass, fat percent, fasting blood glucose, serum insulin level, HOMA-IR, and TC and TG levels, and reduced miR-221-3p levels in both the plasma and the adipose tissues. The sedentary IR mice showed significantly increased miR-221-3p levels in both the plasma and adipose tissue, increased protein levels of iNOS, JAK1, and p-STAT1/STAT1, and decreased protein levels of Arg-1, SOCS1 and p-STAT3/STAT3, which were significantly reversed after aerobic exercise intervention. Dual-luciferase reporter gene assays validated the targeting relationship between miR-221-3p and SOCS1. In RAW264.7 macrophages, miR-221-3p overexpression significantly reduced Socs1 and Arg-1 mRNA expression, whereas miR-221-3p inhibition obviously promoted M2 polarization of the macrophages.

Conclusions: Aerobic exercise improves HFD-induced IR in mice possibly by inhibiting miR-221-3p to activate the SOCS1 and JAK/STAT signaling pathway, thereby promoting macrophage M2 polarization and alleviating chronic inflammation in the adipose tissue.

Objectives: To evaluate the effect of exosomes derived from folic acid (FA)-treated infrapatellar fat pad mesenchymal stem cells (IPFP-MSCs) on M1 and M2 polarization of macrophages in vitro.

Methods: Infrapatellar fat pad tissues were obtained from surgical patients without knee osteoarthritis to isolate IPFP-MSCs. The exosomes were extracted from the cell cultures with or without FA treatment and identified by transmission electron microscopy, TEM, NTA and Western blotting. RAW264.7 cells were induced with lipopolysaccharide (LPS) and incubated with exosomes from FA-treated or untreated IPFP-MSCs for 12 h, and Exos uptake was observed using confocal microscopy. The changes in expression levels of IL-1β, IL-6, TNF-α, iNOS, ARG1, MRC1, and CD206 in the macrophages were detected using qRT-PCR, ELISA, flow cytometry and immunofluorescence staining.

Results: The exosomes derived from IPFP-MSCs showed a typical cup shape, were positive for CD9 and CD81, and could be uptaken by macrophages. In LPS-induced macrophages, incubation with exosomes from FA-treated IPFP-MSCs significantly decreased the expressions of IL-1β, IL-6, TNF‑α, and NOS2, and increased the expressions of ARG1 and MRC1. Treatment of the macrophages with exosomes from FA-treated IPFP-MSCs significantly lowered CD86-positive cell percentage, increased CD206-positive cells and the CD206/CD86 ratio, lowered cellular expression of iNOS, and enhanced the expression of CD206.

Conclusions: Exosomes from FA-treated IPFP-MSCs promotes M2 polarization of macrophages more effectively than exosomes from unmodified IPFP-MSCs, suggesting a new exosome modification strategy for targeted treatment of knee osteoarthritis.

Objectives: To explore the therapeutic mechanism of Jiangzhi Quban Recipe (JZQBR) for type 2 diabetes mellitus (T2DM) complicated with hyperlipidemia and validate its clinical efficacy and safety.

Methods: The active components and disease targets of JZQBR were screened using TCMSP and GeneCards databases, followed by protein-protein interaction analysis and GO and KEGG enrichment analyses. In the animal experiments, ApoE^-/- mice were randomized into blank control, model, simvastatin treatment, and low- and high-dose JZQBR groups. In the latter 4 groups, the mice were fed a high-fat diet for 24 weeks with corresponding treatments from Weeks 9 to 24. The changes in body weight, blood glucose, lipids, liver pathology, and inflammatory cytokine expressions of the mice were examined. In the clinical study, 72 T2DM patients with hyperlipidemia were randomized equally into control group for treatment with metformin plus empagliflozin and JZQBR group with additional JZQBR for 12 consecutive weeks.

Results: Network pharmacology identified 65 potential targets, with quercetin, kaempferol, and luteolin as the core components and IL-6, IL-1β, and TNF‑α as the key targets. The targets were enriched mainly in the pathways involving inflammatory responses and diabetic complications. In the ApoE^-/- mouse models, JZQBR treatment dose-dependently improved body weight, blood glucose, and blood lipid profiles, and high-dose JZQBR produced a stronger effect than simvastatin for improving hepatic steatosis and significantly reduced inflammatory cytokine levels. In the clinical trial, 29 patients in JZQBR group and 31 in the control group completed the trial. The patients in JZQBR group showed significant improvements in body weight, FBG, TG, HbA1c, and liver enzymes with significantly lower fasting blood glucose level than the control group. The total effective rates were comparable between the two groups.

Conclusions: JZQBR improves T2DM complicated with hyperlipidemia possibly by multi-target regulation of the inflammation-metabolism network.

Objectives: To explore the therapeutic mechanism of Qingjie Fuzheng granules (QFG) for alleviating 5-fluorouracil (5-FU)-induced skeletal muscle atrophy.

Methods: Male BALB/c mice bearing subcutaneous colorectal cancer CT26 cell xenografts were randomized into control group, model group, and treatment group. The mice in model and treatment groups were given intraperitoneal 5-FU injections every 3 days and treated with daily gavage of saline and QFG for 21 days, respectively; the mice in the control group and normally fed mice were given only saline gavage. Gripping test and hanging test of the mice were performed before and after the treatment, and on day 21, tumor weight and gastrocnemius muscle weight were measured, and histopathology and cell apoptosis in the gastrocnemius muscle were examined with HE staining, transmission electron microscopy and TUNEL assay. ATP content in the muscle was measured, and protein expressions of AMPK, PGC-1α, Cyt c, AIF, Apaf-1, Smac, Bcl-2, Bax, cleaved caspase-3 and cleaved caspase-9 were determined with immunohistochemistry.

Results: The tumor-bearing mice in the control group showed significantly decreased gastrocnemius muscle weight and grip and suspension test scores. The gastrocnemius muscle showed ultrastructure injuries with lowered ATP content, obvious cell apoptosis, decreased expressions of AMPK, PGC-1 α, and Bcl-2, and increased expressions of Bax, Cyto C, AIF, Apaf-1, Smac, cleaved caspase-3 and cleaved caspase-9. These changes were obviously worsened in 5-FU-treated mice, while QFG treatment significantly increased gastrocnemius muscle weight and strength, ameliorated its ultrastructural injuries, reduced cell apoptosis, and reversed the abnormal protein expressions.

Conclusions: QFG alleviates 5-FU-induced skeletal muscle fatigue in tumor-bearing mice by activating the AMPK/PGC-1α pathway and inhibiting mitochondria-dependent apoptosis in the gastrocnemius muscle.

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.