南方医科大学学报杂志最新文献

Objective: To observe the effects of restricted and high-fat diets on behavioral changes of wild-type (Adrb1^+/+) and transgenic mice carrying Adrb1-A187V mutation (Adrb1^+/m) with short sleep durations.

Methods: Adrb1^+/+ and Adrb1^+/m C57BL/6 mice were randomized into normal chow group (25 Adrb1^+/+ and 26 Adrb1^+/m mice for behavioral monitoring), odor retention fasting group (17 Adrb1^+/+ and 19 Adrb1^+/m mice for behavioral monitoring; 6 Adrb1^+/+ mice and 6 Adrb1^+/m mice for EEG/EMG monitoring), absolute fasting group (6 Adrb1^+/+ and 4-5 Adrb1^+/m mice for behavioral monitoring; 6 Adrb1^+/+ and 6 Adrb1^+/m mice for EEG/EMG monitoring), and high-fat diet group (6 Adrb1^+/+ and 7 Adrb1^+/m mice for behavioral monitoring; 6 Adrb1^+/+ and 6 Adrb1^+/m mice for EEG/EMG monitoring). Electrodes for EEG and muscle activity monitoring were implanted on the skulls of the mice. After 24 h of odor retention fasting, absolute fasting, or high-fat feeding, the mice were observed for behavioral changes adapted to diet changes.

Results: In odor retention fasting experiment, Adrb1^+/m mice exhibited more stable fluctuations of activities with mildly reduced movement and prolonged sleep duration, indicating enhanced starvation resistance. In absolute fasting experiment, Adrb1^+/m mice showed significantly increased nighttime water intake, improved rhythmicity in water intake (frequent intakes in small amounts), and increased duration of non-rapid eye movement sleep (NREM). In the high-fat diet experiment, Adrb1^+/m mice showed higher levels of activity with increased instances of nighttime rearing, longer movement distances, and increased rapid eye movement sleep during daytime.

Conclusion: Adrb1^+/m mice can quickly respond to environmental changes and under restricted dietary conditions, they can conserve energy by increasing sleep to maintain energy homeostasis but show higher levels of activity under high-fat dietary conditions.

Objective: To establish a predictive model for survival outcomes of glioma patients based on both brain radiomics features from preoperative MRI multi-sequence images and clinical features.

Methods: We retrospectively analyzed the MRI images and clinical data of 388 glioma patients and extracted the radiomics features from the peritumoral edema zone, tumor core, and whole tumor on T1, T2, and T1-weighted contrast-enhanced (T1CE) and fluid attenuated inversion recovery (FLAIR) sequences. The cases were divided into a training set (271 cases) and a test set (117 cases). Random survival forest algorithms were used to select the radiomics features associated with overall survival (OS) in the training set to construct a radiomic score (Rad-score), based on which the patients were classified into high- and low-risk groups for Kaplan-Meier survival analysis. Cox proportional hazard regression models for the 3 different tumor zones were constructed, and their performance for predicting 1- and 3-year survival rates was evaluated using 5-fold cross-validation and AUC analysis followed by external validation using data from another 10 glioma patients. The best-performing model was used for constructing a nomogram for survival predictions.

Results: Five radiomics features from the tumor core, 7 from the peritumoral edema zone, and 5 from the whole tumor were selected. In both the training and test sets, the high- and low-risk groups had significantly different OS (P < 0.05), and age, IDH status and Rad-score were independent factors affecting OS. The combined model showed better performance than the Rad-score model with AUCs for 1-year and 3-year survival prediction of 0.750 and 0.778 in the training set, 0.764 and 0.800 in the test set, and 0.938 and 0.917 in external validation, respectively.

Conclusion: The predictive model combining preoperative multi-modal MRI radiomics features and clinical features can effectively predict survival outcomes of glioma patients.

Objective: To investigate the mechanism behind the protective effects of gastrodin against microglia-mediated inflammatory responses following hypoxic-ischemic brain damage (HIBD) in neonatal mice.

Methods: Thirty-six 10-day-old C57BL/6J mice were randomized into sham-operated group, HIBD (induced by ligation of the left common carotid artery followed by hypoxia for 40 min) group, and HIBD with gastrodin treatment groups (n=12). In gastrodin treatment group, 100 mg/kg gastrodin was injected intraperitoneally 1 h before and at 2 and 12 h after hypoxia. After the treatments, the expressions of CCR5, AKT, p-AKT, and TNF-α and the co-expression of IBA1 and CCR5 in the corpus callosum of the mice were detected with Western blotting and immunofluorescence double staining. In a BV2 microglial cell model of oxygen-glucose deprivation (OGD), the effects of pretreatment with gastrodin and Maraviroc (an CCR5 antagonist) on protein expressions of CCR5, AKT, p-AKT, TNF-α and IL-1β were evaluated using Western blotting and immunofluorescence double staining.

Results: The neonatal mice with HIBD showed significantly increased expressions of CCR5 and TNF-α with lowered p-AKT expression in the brain tissues, and GAS treatment obviously reversed these changes. HIBD also significantly increased the co-expression of IBA1 and CCR5 in the corpus callosum of the mice, which was obviously lowered by gastrodin treatment. In BV2 cells, OGD significantly increased the expressions of CCR5, TNF-α, and IL-1β and decreased the expression of p-AKT, and these changes were inhibited by treatment with gastrodin, Maraviroc or their combination; the inhibitory effect of the combined treatment did not differ significantly from that of gastrodin or Maraviroc alone.

Conclusion: Gastrodin can produce neuroprotective effects in neonatal mice with HIBD by inhibiting inflammatory cytokine production and activate AKT phosphorylation via inhibiting CCR5.

Objective: To investigate whether cisplatin induces tumor necrosis factor-α (TNF-α) secretion in human head and neck squamous cell carcinoma (HNSCC) cells to trigger RIP1/RIP3/MLKL-dependent necroptosis of the cells.

Methods: HNSCC cell lines HN4 and SCC4 treated with cisplatin (CDDP) or the combined treatment with CDDP and z-VAD-fmk (a caspase inhibitor) or Nec-1 (a necroptosis inhibitor) for 24 h were examined for changes in cell viability using CCK8 assay and expressions of caspase-8 and necroptosis pathway proteins (RIP1/RIP3/MLKL) using Western blotting. The changes in migration of the cells were assessed with cell scratch assay, and the expressions of epithelial-mesenchymal transition (EMT) marker proteins N-cadherin, vimentin, and E-cadherin as well as the expressions of NF-κB (p65) and TNF-α were detected with Western blotting.

Results: The IC₅₀ of cisplatin was 10 μg/mL in HN4 cells and 15 μg/mL in SCC4 cells. Cisplatin treatment significantly decreased the expressions of caspase-8, N-cadherin and vimentin and increased the expressions of Ecadherin, the necroptosis pathway proteins (RIP1/RIP3/MLKL), TNF-α, and NF-κB (p65), and these changes were obviously inhibited by treatment with Nec-1. Cisplatin stimulation also significantly lowered migration of the cells, and this inhibitory effect was strongly attenuated by Nec-1 treatment.

Conclusion: Cisplatin activates nuclear factor-κB signaling in HNSCCs to promote TNF-α autocrine and induce RIP1/RIP3/MLKL-dependent necroptosis, thus leading to inhibition of cell proliferation.

Methods: To investigate how the timing of cooling therapy affects organ injuries in rats with exertional heat stroke (EHS) and explore the possible mechanisms.

Methods: A total of 60 adult male Wistar rat models of EHS were randomized into model group without active cooling after modeling, immediate cooling group with cold water bath immediately after modeling, delayed cooling groups with cold water bath at 5, 15 and 30 min after modeling, with another 12 mice without EHS as the normal control group. The changes in core body temperature of the mice were recorded and the cooling rate was calculated. After observation for 24 h, the mice were euthanized and blood samples were collected for detection of interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-10, and interferon-γ, followed by pathological examination of the vital organs. The rats that died within 24 h were immediately dissected for examination.

Results: The number of deaths of the model rats within 24 h increased significantly with the time of delay of cooling treatment. The delay of cooling was positively correlated (r=0.996, P=0.004) while the cooling rate negatively correlated with the mortality rate (r=-0.961, P=0.009). The inflammatory cytokine levels presented with different patterns of variations among the cooling intervention groups. All the rat models of EHS had significant organ damages characterized mainly by epithelial shedding, edema, effusion, and inflammatory cell infiltration, and brain and renal injuries reached the peak level at 24 h after EHS.

Conclusion: EHS causes significant nonspecific pathologies of varying severities in the vital organs of rats, and the injuries worsen progressively with the delay of cooling. There is a significant heterogeneity in changes of serum inflammatory cytokines in rats with different timing of cooling intervention following EHS.

Objective: To investigate the molecular mechanism of lipid metabolism disorder in mouse spleen tissues due to high-altitude hypoxia.

Methods: Ten C57BL/6 male mice were randomly divided into normoxia group (maintained at an altitude of 400 m) and high-altitude hypoxia group (maintained at 4200 m) for 30 days (n=5). Lipidomics and metabolomics analyses of the spleen tissue of the mice were conducted using liquid chromatography-mass spectrometry (LC-MS) to identify the differential metabolites, which were further analyzed by KEGG enrichment and pathway analyses, and the differential genes were screened through transcriptome sequencing. Bioinformatics analysis was conducted to identify the upstream target genes of the differential metabolites in specific metabolic pathways. RT-qPCR and Western blotting were used to detect mRNA expressions of 11β-hydroxysteroid dehydrogenase 1 (HSD11B1), steroid 5α reductase 1 (SRD5A1), prostaglandin-endoperoxide synthase 1 (PTGS1), hematopoietic prostaglandin D synthetase (HPGDS), xanthine dehydrogenase (XDH), purine nucleoside phosphorylase (PNP), hypoxanthine guanine-phosphoribosyltransferase (HPRT) and extracellular 5'-nucleotidase (NT5E) and protein expressions of HSD11B1, SRD5A1, XDH, PNP and HPRT in the mouse spleens.

Results: We identified a total of 41 differential lipid metabolites in the mouse spleens, and these metabolites and the differential genes were enriched in steroid hormone biosynthesis, arachidonic acid metabolism, and purine metabolism pathways. Compared to the mice kept in normoxic conditions, the mice exposed to high-altitude hypoxia showed significantly upregulated expressions of adrenosterone, androsterone, prostaglandin D2, prostaglandin J2, xanthine, xanthosine, and uric acid in the spleen with also changes in the expression levels of HSD11B1, SRD5A1, PTGS1, HPGDS, XDH, PNP, HPRT, and NT5E.

Conclusion: High-altitude hypoxia can result in lipid metabolism disorder in mouse spleen tissue by affecting steroid hormone biosynthesis, arachidonic acid metabolism, and purine metabolism pathways.

Objective: To propose a dual-domain CBCT reconstruction framework (DualSFR-Net) based on generative projection interpolation to reduce artifacts in sparse-view cone beam computed tomography (CBCT) reconstruction.

Methods: The proposed method DualSFR-Net consists of a generative projection interpolation module, a domain transformation module, and an image restoration module. The generative projection interpolation module includes a sparse projection interpolation network (SPINet) based on a generative adversarial network and a full-view projection restoration network (FPRNet). SPINet performs projection interpolation to synthesize full-view projection data from the sparse-view projection data, while FPRNet further restores the synthesized full-view projection data. The domain transformation module introduces the FDK reconstruction and forward projection operators to complete the forward and gradient backpropagation processes. The image restoration module includes an image restoration network FIRNet that fine-tunes the domain-transformed images to eliminate residual artifacts and noise.

Results: Validation experiments conducted on a dental CT dataset demonstrated that DualSFR-Net was capable to reconstruct high-quality CBCT images under sparse-view sampling protocols. Quantitatively, compared to the current best methods, the DualSFR-Net method improved the PSNR by 0.6615 and 0.7658 and increased the SSIM by 0.0053 and 0.0134 under 2-fold and 4-fold sparse protocols, respectively.

Conclusion: The proposed generative projection interpolation-based dual-domain CBCT sparse-view reconstruction method can effectively reduce stripe artifacts to improve image quality and enables efficient joint training for dual-domain imaging networks in sparse-view CBCT reconstruction.

Objective: To investigate whether activation of mitochondrial acetal dehydrogenase 2 (ALDH2) alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.

Methods: Thirty 8-week-old C57 BL/6 mice were randomized into control, hypoxia, and hypoxia +Alda-1 (an ALDH2 activator) group (n=10), and the mice in the latter two groups, along with 10 ALDH2 knockout (ALDH2^-/-) mice, were exposed to hypoxia (10% O₂, 90% N₂) with or without daily intraperitoneal injection of Alda-1 for 4 weeks. The changes in right ventricular function and pressure (RVSP) of the mice were evaluated by echocardiography and right ventricular catheter test, and pulmonary artery pressure was estimated based on RVSP. Pulmonary vascular remodeling, right ventricular injury, myocardial α -SMA expression, distal pulmonary arteriole muscle normalization, right ventricular cross-sectional area, myocardial cell hypertrophy, and right cardiac hypertrophy index were assessed with HE staining, immunofluorescence staining and WGA staining, and the expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21^CIP1 were detected. In pulmonary artery smooth muscle cells with hypoxic exposure, the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.

Results: The wild-type mice with hypoxic exposure showed significantly increased RVSP, right ventricular free wall thickness and myocardial expressions of P16^INK4A and P21^CIP1, which were effectively lowered by treatment with Alda-1 but further increased in ALDH2^-/- mice. In cultured pulmonary artery smooth muscle cells, hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16^INK4A and P21^CIP1, which were all lowered by treatment with Alda-1, but its effect was obviously attenuated by EX527 treatment.

Conclusion: ALDH2 alleviates hypoxiainduced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Objective: To investigate the effects of Shenqi Tiaoshen Formula (SQTSF) for alleviating airway inflammation in rats with both chronic obstructive pulmonary disease (COPD) and lung-kidney qi deficiency syndrome and explore its therapeutic mechanism.

Methods: Forty-eight SD rats were randomly divided into control group, model group, low-, medium-, and high-dose SQTSF groups, and aminophylline (APL) group. In all but the control group, rat models of COPD with lung-kidney qi deficiency syndrome were established and treated with saline, SQTSF or APL via daily gavage as indicated (starting from day 30). The rats were observed for changes in body weight, grip strength, lung function, lung pathology, inflammatory cytokines in bronchoalveolar lavage fluid (BALF), oxidative stress levels, iron ion metabolism, cellular and mitochondrial ultrastructural changes in the lung tissue, and expressions of Nrf2/SLC7A11/GPX4 signaling pathway and ferroptosis-related proteins.

Results: The rats in the model group exhibited obvious symptoms of lung-kidney qi deficiency syndrome with significantly decreased body weight, grip strength, and lung function parameters. Examination of the lung tissue revealed showed significant inflammatory cell infiltration and emphysema with obvious bronchial, perivascular, and alveolar inflammation and alveolar destruction, significantly increased IL-1β, TNF-α, IL-6, and IL-13 levels in BALF, and elevated pulmonary oxidative stress levels and Fe²⁺ and total iron ion concentrations. The rat models also showed characteristic ultrastructural changes of ferroptosis in the lung tissue cells under transmission electron microscope and significantly decreased Nrf2, GPX4, and SLC7A11 and increased ACSL4 expressions in the lung tissue. Treatment with SQTSF significantly improved these pathological changes in the rat models with a better effect than APL.

Conclusion: SQTSF can effectively improve airway inflammation and oxidative stress in COPD rats with lung-kidney qi deficiency possibly by inhibiting ferroptosis via regulating the Nrf2/SLC7A11/GPX4 signaling pathway.

Objective: To explore the mechanism by which Yigong San (YGS) improves learning and memory abilities of APP/PS1 transgenic mice in light of cerebral fluid metabolism regulation.

Methods: Three-month-old male APP/PS1 transgenic mice and wild-type C57BL/6 mice were both randomized into control group, model group, donepezil (1.67 mg/kg) group, and YGS (7.5 g/kg) group and received the corresponding treatments via gavage once daily for one month. After the treatments, the mice were assessed for learning and memory functions using Morris water maze test and examined for hippocampal and cortical pathologies and amyloid plaques using HE, immunohistochemical and thioflavin S staining; ELISA and Evans blue method were used for detecting Aβ_1-40 and Aβ_1-42 levels in the brain tissue and serum and assessing blood-brain barrier (BBB) integrity. Immunofluorescence colocalization was used to investigate AQP4 polarization on astrocytes. Western blotting was performed to detect the expressions of VE-cadherin, ZO-1, occludin, β-amyloid precursor protein (APP), BACE1, insulin-degrading enzyme (IDE), LRP1, RAGE, and AQP4 proteins.

Results: Compared with the control mice, APP/PS1 mice showed significant impairment of learning and memory abilities, increased degeneration or necrosis of hippocampal and cortical neurons, pathological scores, Aβ-positive plaques, elevated Aβ_1-40 and Aβ_1-42 levels in the brain tissue and serum, increased BBB permeability, upregulated RAGE expression, lowered expressions of VE-cadherin, LRP1, ZO-1, occludin, and AQP4 proteins, and reduced AQP4- expressing GFAP-positive cells. YGS treatment significantly improved the performance of the transgenic mice in Morris water maze test, reduced hippocampal and cortical pathologies and Aβ-positive plaques, and ameliorated the abnormal changes in Aβ_1-40 and Aβ_1-42 levels, BBB permeability, protein expressions of RAGE, VE-cadherin, LRP1, ZO-1, occludin and AQP4, and the number of AQP4-expressing GFAP-positive cells.

Conclusion: YGS improves learning and memory changes in APP/PS1 mice by ameliorating neuronal damage and Aβ pathology in the brain and regulating brain fluid metabolism.