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Ultrasound-guided stellate ganglion block improves sleep quality in elderly patients early after thoracoscopic surgery for lung cancer: a randomized controlled study GU Cuifang, ZHAI Mingjian, LÜ Aijun, LIU Lu, HU Huan, LIU Xi, LI Xuan, CHENG Xiangyang Journal of Southern Medical University    2022, 42 (12): 1807-1814.   DOI: 10.12122/j.issn.1673-4254.2022.12.08 Abstract （308）   HTML （23）    PDF（pc） （1443KB）（1197）       Knowledge map    Save Objective To investigate the effects of ultrasound-guided stellate ganglion block (SGB) on sleep quality in elderly patients with lung cancer early after thoracoscopic surgery. Methods A total of 86 patients with lung cancer (ASA class I-III, aged 60-80 years) undergoing elective thoracoscopic surgery were randomized into stellate ganglion block (SGB) group (n=43) and control group (n=43) to receive ultrasound-guided right SGB with 7 mL of 0.5% ropivacaine at the C6-7 level and injection of 7 mL saline at the same site 30 min before anesthesia induction, respectively. On the day before surgery and the first two days after the surgery, sleep duration, sleep efficiency index (SEI) and N3 sleep stage of the patients were monitored using a BIS-Vista monitor, and Athens Insomnia Scale (AIS) scores were recorded. The plasma levels of norepinephrine and cortisol of the patients were measured before SGB (T1), at 5 min after extubation (T2) and at 6:00 on the first morning after the surgery (T4). Urine levels of 6-hydroxysulfate melatonin (6-HMS) were measured at 6:00 in the morning for 3 consecutive days starting on the day of surgery (T3, T4 and T5, respectively). VAS score, incidences of postoperative delirium and depression, sufentanil consumption after surgery, and discharge time of the patients were recorded. Results Thirty-six patients in SGB group and 35 in the control group were analyzed. In both groups, most of the patients had insomnia after surgery, but compared with those in the control group, the patients in SGB group had significantly longer sleep duration (P<0.05) with a higher sleep efficiency index (P<0.05) and a longer sleep time in N3 stage (P<0.05) on the first two nights after surgery. The mean postoperative AIS score and incidence of insomnia were significantly lower in SGB group than in the control group (P<0.05). Compared with the control group, SGB group showed significantly lower plasma levels of norepinephrine and cortisol at T2 and T4 (P<0.05), a higher urine level of 6-HMS at T5 (P<0.05), and a shorter discharge time after the surgery (P<0.05). The VAS scores, postoperative incidences of delirium and depression, or postoperative sufentanil consumption did not differ significantly between the two groups. Conclusion Ultrasound-guided SGB improves objective and subjective sleep quality in elderly patients early after thoracoscopic surgery for lung cancer to alleviate stress responses and sleep disorders, reduce postoperative hospital stay, and accelerate postoperative recovery of the patients. Related Articles | Metrics | Comments（0）

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Huangqi Sijunzi decoction for treating cancer-related fatigue in breast cancer patients: a randomized trial and network pharmacology study CUI Yixin, MI Jiwei, FENG Yu, LI Lingsheng, WANG Yujia, HU Jian, WANG Haiming Journal of Southern Medical University    2022, 42 (5): 649-657.   DOI: 10.12122/j.issn.1673-4254.2022.05.04 Abstract （775）   HTML （24）    PDF（pc） （6179KB）（1090）       Knowledge map    Save Objective To evaluate the clinical efficacy of Huangqi Sijunzi decoction (HQSJZD) for treating cancer-related fatigue (CRF) of spleen and stomach Qi deficiency type after chemotherapy in patients with breast cancer. Methods A total of 94 breast cancer patients who developed CRF of spleen and stomach Qi deficiency type after chemotherapy were randomized into chemotherapy group (n=47) and traditional Chinese medicine (TCM) + chemotherapy group (n=47). The patients in chemotherapy group received the AC or EC regimen and non-drug interventions including psychological counseling, and those in TCM + chemotherapy group received oral administration of HQSJZD in addition to chemotherapy for 21 days as a treatment cycle, after which improvement of fatigue was assessed using Modified Piper Fatigue Scale. The active ingredients and targets of HQSJZD were screened using the TCM System Pharmacology Analysis Platform (TCMSP); the CRF- and breast cancer-related disease targets were retrieved based on data from the GeneCards, NCBI gene and OMIM databases to construct the component-target network and the protein-protein interaction (PPI) network. GO functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes KEGG pathway enrichment analysis of the target genes were performed to construct the component-disease-pathway- target biological network. The binding strength of the major drug ingredients and CRF key targets were predicted using AutoDock software. Results The scores for somatic fatigue, emotional fatigue and cognitive fatigue, along with the overall fatigue score, showed more significant improvements in TCM+chemotherapy group than in chemotherapy group (P<0.001), and the response rate reached 89.4% in the combined treatment group. We identified 250 targets for HQSJZD, 2653 CRF-related genes, 15 329 breast cancer-related genes and 161 prescription-disease intersected targets, from which topological analysis identified 66 potential key targets. GO and KEGG enrichment analyses predicted multiple pathways related with the disease. Molecular docking results suggested that the core ingredients of HQSJZD showed high affinities to the key targets AKT1, CASP3, IL6, JUN and VEGFA, among which AKT1 might be the most important target for HQSJZD to treat CRF. Conclusion HQSJZD can obviously improve CRF symptoms in breast cancer patients possibly by regulating multiple signaling pathways including PI3K-Akt through AKT1. Related Articles | Metrics | Comments（0）

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Berberine inhibits erastin-induced ferroptosis of mouse hippocampal neuronal cells possibly by activating the Nrf2-HO-1/GPX4 pathway HUANG Qingyang, JI Dongdong, TIAN Xiuyun, MA Linyan, SUN Xiaojin Journal of Southern Medical University    2022, 42 (6): 937-943.   DOI: 10.12122/j.issn.1673-4254.2022.06.19 Abstract （1147）   HTML （32）    PDF（pc） （1245KB）（975）       Knowledge map    Save Objective To explore the mechanism by which berberine inhibits ferroptosis of mouse hippocampal neuronal cells (HT22). Methods Cultured HT22 cells were pretreated with 30 or 60 μmol/L berberine for 2 h before exposure to 0.5 μmol/L erastin for 8 h, and the cell proliferation, intracellular ferric iron level, changes in intracellular reactive oxygen species (ROS) and cell apoptosis were detected using CCK-8, Fe2 + fluorescent probe, fluorescent dye (DAPI) and fluorescent probe (H2DCFH-DA). RT-qPCR and Western blotting were used to detect the mRNA and protein expressions of Nrf2, HO-1 and GPX4 in the cells. We further tested the effects of treatments with 2 μmol/L ML385 (a Nrf2 inhibitor), 60 μmol/L berberine and erastin in the cells to explore the protective mechanism of berberine against erastin-induced ferroptosis in the neuronal cells. Results Treatment with 0.5 μmol/L erastin significantly lowered the viability of HT22 cells (P<0.05) and increased the production of ROS, cell apoptosis rate and ferric iron level (P<0.05). Pretreatment with 30 and 60 μmol/L berberine both significantly increased the vitality of erastin-exposed cells (P<0.05) and lowered the levels of intracellular ROS and ferric iron content (P<0.05). RT-qPCR and Western blotting showed that berberine obviously promoted the expressions of Nrf2, HO-1 and GPX4 in the cells (P<0.05), and treatment with ML385 significantly inhibited the Nrf2-HO-1/GPX4 pathway, increased intracellular ROS and ferric iron contents and mitigated the protective effect of berberine against erastin-induced ferroptosis (P<0.05). Conclusion Berberine can inhibit erastin-induced ferroptosis in HT22 cells possibly by activating the Nrf2-HO-1/GPX4 pathway. Related Articles | Metrics | Comments（0）

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m7G-lncRNAs are potential biomarkers for prognosis and tumor microenvironment in patients with colon cancer CHEN Shuran, DONG Rui, LI Yan, WU Huazhang, LIU Mulin Journal of Southern Medical University    2022, 42 (5): 681-689.   DOI: 10.12122/j.issn.1673-4254.2022.05.08 Abstract （697）   HTML （39）    PDF（pc） （3587KB）（796）       Knowledge map    Save Objective To assess the value of m7G-lncRNAs in predicting the prognosis and microenvironment of colorectal cancer (CRC). Methods We screened m7G- lncRNAs from TCGA to construct an m7G-lncRNAs risk model using multivariate Cox analysis, which was validated using ROC and C-index curves. Calibration and nomogram were used to predict the prognosis of CRC patients. Point-bar charts and K-M survival curves were used to assess the correlation of risk scores with the patients' clinical staging and prognosis. CIBERSORT and ESTIMATE were used to explore the association between the tumor microenvironment and immune cell infiltration in patients in high and low risk groups and the correlation of risk scores with microsatellite instability, stem cell index and immune checkpoint expression. A protein-protein interaction network was constructed, and the key targets regulated by m7G-lncRNAs were identified and validated in paired samples of CRC and adjacent tissues by immunoblotting. Results We identified a total of 1722 m7G-lncRNAs from TCGA database, from which 12 lncRNAs were screened to construct the risk model. The AUCs of the risk model for predicting survival outcomes at 1, 3 and 5 years were 0.727, 0.747 and 0.794, respectively. The AUC of the nomogram for predicting prognosis was 0.794, and the predicted results were consistent with actual survival outcomes of the patients. The patients in the high- risk group showed more advanced tumor stages and a greater likelihood of high microsatellite instability than those in the low-risk group (P<0.05). The tumor stemness index was negatively correlated with the risk score (r=- 0.19; P=7.3e-05). Patients in the high-risk group had higher stromal cell scores (P=0.0028) and higher total scores (P=0.007) with lowered expressions of activated mast cells (r=-0.11; P=0.045) and resting CD4+ T cells (r=-0.14; P=0.01) and increased expressions of most immune checkpoints (P<0.05). ATXN2 (P= 0.006) and G3BP1 (P=0.007) were identified as the key targets regulated by m7G-lncRNAs, and their expressions were both higher in CRC than in adjacent tissues. Conclusion The risk model based on 12 m7G-lncRNAs has important prognostic value for CRC and can reflect the microenvironment and the efficacy of immunotherapy in the patients. Related Articles | Metrics | Comments（0）

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Exploration of the therapeutic mechanism of Yiqi Jiedu recipe for treatment of primary liver cancer based on network pharmacology and molecular docking XU Meng, ZHANG Peng, ZHANG Guoliang Journal of Southern Medical University    2022, 42 (6): 805-814.   DOI: 10.12122/j.issn.1673-4254.2022.06.03 Abstract （581）   HTML （39）    PDF（pc） （3256KB）（754）       Knowledge map    Save Objective To explore the effective components of Yiqi Jiedu recipe and the main biological processes and signal pathways involved in the therapeutic mechanism of the recipe in treatment of primary liver cancer through network pharmacology and molecular docking approaches. Methods TCMSP, Uniport, Genecards and String databases were searched to obtain the target genes of drugs and disease using Cytoscape 3.8.2 software. GO and KEGG enrichment analyses were performed to identify the common genes in the target genes of the drugs and disease. Using Pubcham, RCSB and Autoduck, the effective components of the drugs were connected with the final core genes. The effects of different concentrations of Yiqi Jiedu recipe on the expressions of the core genes DHX9, HNRNPK, NCL and PABPC1 in HepG2 cells were analyzed with Western blotting and real- time fluorescence quantitative PCR. Results We finally identified 8 core genes from the drug and disease targets, including DDX5, HNRNPK, PABPC1, DHX9, RPS3A, RPS3, RPL13, and NCL. GO analysis showed that these core genes were involved mainly in the biological processes of adrenaline receptor signal communication, movement of cellular or subcellular components, blood particles, adhesion class and iron ion binding. KEGG analysis showed that the Ras signaling pathway had the greatest gene enrichment. The results of molecular docking suggested that the effective components of the recipe were capable of docking with the core genes under natural conditions, and PABPC1 and stigmasterol had the highest binding energy. In HepG2 cells, treatment with 10% medicated serum for 48 h had the strongest effect on the expression of DHX9, HNRNPK, NCL and PABPC1 (P<0.05). Conclusion Yiqi Jiedu recipe is capable of regulating viral expression of primary liver cancer multiple effective components that bind to DHX9, HNRNPK, NCL and PABPC1. Related Articles | Metrics | Comments（0）

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Honokiol reduces doxorubicin-induced cardiotoxicity in vitro by inhibiting pyroptosis via activating AMPK/Nrf2 signaling XIONG Fengmei, LIU Ruiping, LI Yang, SUN Na Journal of Southern Medical University    2022, 42 (8): 1205-1211.   DOI: 10.12122/j.issn.1673-4254.2022.08.13 Abstract （425）   HTML （36）    PDF（pc） （1560KB）（746）       Knowledge map    Save Objective To investigate the effect of honokiol (HKL) for reducing doxorubicin (DOX)-induced cardiotoxicity in H9c2 cells and the underlying mechanisms. Methods H9c2 cells were divided into control group, DOX group, HKL + DOX group, and HKL+compound C+DOX group. After 24 h of corresponding treatment, the cells were examined for morphological changes and cell viability using CCK-8 assay. The mRNA expressions of the inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by RT-PCR, and the protein levels of cleaved caspase-3, cytochrome c, NOD-like receptor pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), p-AMPK and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) were detected with Western blotting; the expressions of NLRP3 and p-AMPK also detected with immunofluorescence staining. Results DOX treatment caused swelling and significantly lowered the viability of H9c2 cells (P<0.05), resulting also in increased mRNA expressions of TNF-α, IL-6 and IL-1β (P<0.05) and protein expressions of cleaved caspase-3, cytochrome c, NLRP3, caspase-1 and ASC (P<0.05) but reduced protein levels of p-AMPK and Nrf2 (P<0.05); fluorescence staining showed significantly increased NLRP3 expression and decreased expression of p-AMPK in DOX-treated cells (P<0.05). All these changes in COX-treated cells were significantly alleviated by HKL treatment (P<0.05). The application of compound C obviously mitigated the protective effects of HKL against DOX-induced cardiotoxicity in H9c2 cells. Conclusions HKL can alleviate DOX-induced cardiotoxicity by inhibiting pyroptosis in H9c2 cells, and this effect is mediated by activation of AMPK to regulate Nrf2 signaling. Related Articles | Metrics | Comments（0）

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SOX2-OT/SOX2 axis regulates lung cancer H520 cell migration via Gli1-mediated epithelial-mesenchymal transition DONG Hongliang, ZENG Lili, WU Yan, MIAO Shuang, NI Na, LIU Naiguo, CHEN Weiwei, DU Jing Journal of Southern Medical University    2022, 42 (10): 1431-1439.   DOI: 10.12122/j.issn.1673-4254.2022.10.01 Abstract （577）   HTML （283）    PDF（pc） （2150KB）（730）       Knowledge map    Save Objective To explore the regulatory role of SOX2-OT in migration of lung squamous cell carcinoma H520 cells and the underlying mechanisms. Methods Wound- healing and Transwell migration assays were performed to examine the changes in migration and invasion capacity of lung squamous cell line H520, which expressed higher levels of SOX2-OT than other lung cancer cell lines, following RNA interference-mediated SOX2-OT knockdown. The transcription levels of epithelial-mesenchymal transition (EMT)-related components was detected by qRT-PCR and immunoblotting. Gli1 gain-of-function analysis was performed in H520 cells with SOX2-OT knockdown and the changes in EMT phenotype of the cells were examined. miR-200c mimic and inhibitor were used to analyze the mechanism by which SOX2-OT positively regulates Gli1 and the mediating role of SOX2. Results SOX2-OT knockdown significantly lowered the invasiveness and migration capacity of H520 cells and caused changes in EMT phenotype of the cells. Overexpression of Gli1, which was positively regulated by SOX2-OT, reversed the inhibitory effect of SOX2-OT knockdown on migration of H520 cells. Transfection of the cells with miR-200c inhibitor effectively reversed SOX2-OT knockdown-induced down-regulation of SOX2. Conclusion The SOX2-OT/SOX2 axis positively regulates migration of lung squamous H520 cells via Gli1-mediated EMT. Related Articles | Metrics | Comments（0）

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Role of myelin and lymphocyte protein in regulating pulmonary artery smooth muscle cell proliferation and apoptosis in pulmonary hypertension LIU Jinjun, LI Qingqing, ZENG Chaochao, WANG Yuexiang, HU Qingtian, WANG Hongju, WU Shili Journal of Southern Medical University    2022, 42 (10): 1572-1577.   DOI: 10.12122/j.issn.1673-4254.2022.10.19 Abstract （256）   HTML （39）    PDF（pc） （1260KB）（716）       Knowledge map    Save Objective To investigate the role of myelin and lymphocyte protein (MAL) in pulmonary hypertension (PAH). Methods Blood samples were collected from 50 patients with PAH (PAH group) and 50 healthy individuals for detection of plasma MAL expression using ELISA. According to the echocardiographic findings, the patients were divided into moderate/severe group (n=18) and mild group (n=32), and the correlation between MAL protein level and the severity of PAH was analyzed. In a pulmonary artery smooth muscle cell model of PAH with hypoxia-induced abnormal proliferation, the effects of mal gene knockdown and overexpression on cell growth, proliferation and starvation-induced apoptosis were observed; the changes in NK-κB signaling pathway in the transfected cells were detected to explore the molecular mechanism by which MAL regulates PAMSC proliferation and apoptosis. Results The plasma level of MAL was significantly higher in patients with PAH than in healthy individuals (P<0.05), and the patients with moderate/severe PAH had significantly higher MAL level than those with mild PAH (P<0.001). In PAMSCs, exposure to hypoxia significantly increased the mRNA and protein expression levels of MAL (P<0.05), and MAL knockdown obviously inhibited hypoxia- induced proliferation and promoted starvationinduced apoptosis of the PAMSCs (P<0.05). Knocking down mal significantly inhibited the activation of NK-κB signaling pathway that participated in regulation of PAMSC proliferation (P<0.05). Conclusion The plasma level of MAL is elevated in PAH patients in positive correlation with the disease severity. MAL knockdown inhibits abnormal proliferation and promotes apoptosis of PAMSCs by targeted inhibition of the NF-κB signaling pathway to improve vascular remodeling in PAH. Related Articles | Metrics | Comments（0）

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WP1130 relieves septic shock in mice by inhibiting NLRP3 inflammasome activation LU Li, LIU Didi, YANG Yanqing, WANG Fengchao Journal of Southern Medical University    2022, 42 (12): 1747-1754.   DOI: 10.12122/j.issn.1673-4254.2022.12.01 Abstract （493）   HTML （83）    PDF（pc） （1981KB）（716）       Knowledge map    Save Objective To investigate the mechanism by which the small molecule compound WP1130 inhibits NLRP3 inflammasome activation and alleviates septic shock. Methods Mouse bone marrow-derived macrophages (BMDM) and human THP-1 cells were pre-treated with WP1130 before stimulation with different NLRP3 inflammasome agonists (Nigericin, ATP, MSU and intracellular LPS transfection), and AIM2 inflammasomes were activated with poly A: T. The levels of caspase-1 and IL-1β in the cell culture supernatant were determined using Western blotting and ELISA, and mitochondrial damage in the cells was observed using confocal microscopy. In the animal experiment, male C57BL/6 mice were randomized into blank control group, septic shock group (LPS group) and WP1130 treatment group (WP1130+LPS group), and the levels of IL-1β and TNF-α in the serum and peritoneal cavity were detected using ELISA. Results In murine BMDM and human THP-1 cells, WP1130 significantly inhibited NLRP3 agonists-induced caspase-1 and IL-1β secretion in a dose-dependent manner (P<0.05) but did not obviously affect the secretion of such inflammatory factors as IL-6 and TNF-α that were not associated with inflammasomes (P>0.05). Treatment with WP1130 did not significantly affect poly A:T-induced activation of AIM2 inflammasomes (P>0.05) or induce obvious changes in mitochondrial damage, an upstream signal of NLRP3 inflammasome activation. In the mouse model of LPS-induced septic shock, WP1130 treatment significantly reduced the level of IL-1β (P<0.05) without obviously affecting TNF-α level either in the serum or in the peritoneal cavity (P>0.05). Conclusion WP1130 specifically inhibits NLRP3 inflammasome activation to alleviate LPS-induced septic shock in mice. Related Articles | Metrics | Comments（0）

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P4HA2 promotes occurrence and progression of liver cancer by regulating the PI3K/Akt/mTOR signaling pathway SHANG Ling, JIANG Wendi, ZHANG Junli, WU Wenjuan Journal of Southern Medical University    2022, 42 (5): 665-672.   DOI: 10.12122/j.issn.1673-4254.2022.05.06 Abstract （773）   HTML （36）    PDF（pc） （2408KB）（712）       Knowledge map    Save Objective To investigate the role of proline 4-hydroxylase II (P4HA2) in the occurrence and progression of liver cancer. Methods GEPIA and Human Protein Atlas database were used to predict the expression of P4HA2 in hepatocellular carcinoma (HCC), and K-M plotter online database was used to analyze the relationship between P4HA2 expression and the prognosis of HCC. We also examined the expressions of P4HA2 in HCC cells and normal hepatocytes using qRT-PCR and Western blotting. With lentivirus-mediated RNA interference, P4HA2 expression was knocked down in hepatoma SNU-449 and Hep-3B cells, and the changes in cell proliferation, migration and invasion were assessed using cell counting kit-8 (CCK-8) assay, colony formation test, scratch test and Transwell assay. The changes in the expressions of epithelial-mesenchymal transition (EMT) and PI3K/Akt/mTOR signal pathway-related proteins were detected using Western blotting. Results Online database analysis showed that the expression of P4HA2 was significantly higher in HCC tissues than in normal liver tissues (P< 0.05). The expression levels of P4HA2 mRNA and protein were also significantly higher in HCC cell lines than in normal hepatocytes (P<0.01). Lentivirus-mediated RNA interference of P4HA2 significantly lowered the expression levels of P4HA2 mRNA and protein in the hepatoma cells (P<0.05) and caused obvious inhibition of cell proliferation, migration and invasion. P4HA2 knockdown significantly increased the expression of E-cadherin protein, lowered the expressions of N-cadherin and Snail, and obviously decreased the expressions of phosphorylated PI3K, AKT and mTOR (P<0.05). Conclusion P4HA2 enhances the proliferation, migration, invasion, and EMT of hepatoma cells by activating the PI3K/Akt/mTOR signaling pathway to promote the occurrence and progression of liver cancer. Related Articles | Metrics | Comments（0）

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Interference of P2X4 receptor expression in tumor-associated macrophages suppresses migration and invasion of glioma cells YANG Xuezhi, SHEN Hong, LI Qun, DAI Zichao, YANG Rongqiang, HUANG Guobin, CHEN Rui, WANG Fang, SONG Jingling, HUA Hairong Journal of Southern Medical University    2022, 42 (5): 658-664.   DOI: 10.12122/j.issn.1673-4254.2022.05.05 Abstract （218）   HTML （32）    PDF（pc） （2228KB）（675）       Knowledge map    Save Objective To investigate the effect of interference of P2X4 receptor expression in tumor-associated macrophages (TAMs) on invasion and migration of glioma cells. Methods C57BL/6 mouse models bearing gliomas in the caudate nucleus were examined for glioma pathology with HE staining and expressions of Iba-1 and P2X4 receptor with immunofluorescence assay. RAW264.7 cells were induced into TAMs using conditioned medium from GL261 cells, and the changes in mRNA expressions of macrophage polarization-related markers and the mRNA and protein expressions of P2X4 receptor were detected with RT-qPCR and Western blotting. The effect of siRNA-mediated P2X4 interference on IL-1β and IL-18 mRNA and protein expressions in the TAMs was detected with RT-qPCR and Western blotting. GL261 cells were cultured in the conditioned medium from the transfected TAMs, and the invasion and migration abilities of the cells were assessed with Transwell invasion and migration experiment. Results The glioma tissues from the tumor-bearing mice showed a significantly greater number of Iba-1-positive cells, where an obviously increased P2X4 receptor expression was detected (P=0.001), than the brain tissues of the control mice (P<0.001). The M2 macrophage markers (Arg-1 and IL-10) and M1 macrophage markers (iNOS and TNF-α) were both significantly up-regulated in the TAMs derived from RAW264.7 cells (all P<0.01), but the up-regulation of the M2 macrophage markers was more prominent; the expression levels of P2X4 receptor protein and mRNA were both increased in the TAMs (P<0.05). Interference of P2X4 receptor expression significantly lowered the mRNA（P<0.01）and protein （P<0.01, P<0.05）expression levels of IL-1β and IL-18 in the TAMs and obviously inhibited the ability of the TAMs to promote invasion and migration of the glioma cells (P<0.05). Conclusion Interference of P2X4 receptor in the TAMs suppresses the migration and invasion of glioma cells possibly by lowering the expressions of IL-1β and IL-18. Related Articles | Metrics | Comments（0）

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Cold stress reduces lifespan and mobility of C. elegans by mediating lipid metabolism disorder and abnormal stress response SHI Hao, ZHANG Chao, ZHAO Jiamin, LI Yiwen, LI Yunjia, LI Junjie, ZENG Zhiyun, GAO Lei Journal of Southern Medical University    2022, 42 (8): 1159-1165.   DOI: 10.12122/j.issn.1673-4254.2022.08.07 Abstract （1780）   HTML （48）    PDF（pc） （1178KB）（675）       Knowledge map    Save Objective To investigate the changes of lipid metabolism and stress response of adult C. elegans exposed to non-freezing low temperature and explore the possible mechanism. Methods The survival rate and activity of adult C. elegans cultured at 20 ℃ or 4 ℃ were observed. Lipid metabolism of the cultured adult C. elegans was evaluated using oil red O staining and by detecting the expressions of the genes related with lipid metabolism. The effects of low temperature exposure on stress level of adult C. elegans were evaluated using mitochondrial fluorescence staining and by detecting the expression levels of stress-related genes and antioxidant genes at both the mRNA and protein levels. Results The lifespan and activity of adult C. elegans exposed to low temperature were significantly reduced with decreased lipid accumulation (P<0.05) and decreased expressions of genes related with fatty acid synthesis and metabolism (fat-5, fat-6, fat-7, fasn-1, nhr-49, acs-2 and aco-1; P<0.01). Cold stress significantly increased the expressions of heat shock proteins hsp-70 and hsp16.2 (P<0.05) but lowered the number of mitochondria (P<0.0001) and the expressions of atfs-1, sod-2, sod-3 and gpx-1 (P<0.05). Knockout of fat-5, nhr-49 or both fat-5 and fat-6 obviously enhanced the sensitivity of C. elegans to cold stress as shown by further reduced activity (P<0.05) and reduced survival rate at 24 h (P<0.0001) under cold stress. Conclusion Exposure to a low temperature at 4 ℃ results in lowered lipid metabolism of adult C. elegans accompanied by a decreased mitochondrial number and quality control ability, which triggers high expressions of stress-related genes and causes reduction of antioxidant capacity, thus callsing lowered activity and reduced lifespan of C. elegans. Related Articles | Metrics | Comments（0）

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Clinical features of children with Cunninghamella spp. infection: a case report and literature review WU Feifeng, TIAN Jidong, SHE Zhou, LIU Ying, WAN Wuqing, WEN Chuan Journal of Southern Medical University    2022, 42 (5): 780-784.   DOI: 10.12122/j.issn.1673-4254.2022.05.22 Abstract （791）   HTML （24）    PDF（pc） （1201KB）（667）       Knowledge map    Save We report a case of mucormycosis induced by Cunninghamella spp. infection in a ten-year-old girl with acute lymphoblastic leukemia, who developed fever and respiratory symptoms after chemotherapy and was diagnosed with invasive fungal disease. Peripheral blood DNA sequences were analyzed using metagenomic next-generation sequencing (mNGS), and by comparison with the Pathogens Metagenomics Database (PMDB), we identified Cunninghamella spp. with sequence number 514 as the pathogen. The patient was treated with amphotericin B combined with posaconazole and showed a favorable response. We searched Pubmed, Embase, CNKI, and Wanfang database for reports of cases of Cunninghamella spp. infection in children and retrieved 22 reported cases (including 12 males) with a median age of 13.5 (3-18) years. In these 22 cases, hematological malignancy was the most common underlying condition (19/22), and most of patients experienced an acute onset and rapid progression with respiratory symptoms (14/20) and fever (16/20) as the most common symptoms. CT imaging often showed unilateral lesions with varying imaging findings, including pulmonary nodules or masses, infiltrative changes, and pleural effusion. Definite diagnoses were established in 18 of the cases, and 4 had probable diagnoses; the lungs and skin were the most frequent organs compromised by the infection. A definite diagnosis of Cunninghamella spp. infection still relied on histopathological examination and fungal culture, but the molecular techniques including PCR and mNGS had shown potentials in the diagnosis. Almost all the cases received antifungal treatment after diagnosis (21/22), and 13 patients also underwent surgeries. Death occurred in 9 (42% ) of the cases at a median of 19 (4-54) days after onset of the signs or symptoms. The patients receiving antifungal therapy combined with surgery had a high survival rate (9/13, 69% ) than those with antifungal therapy alone (3/8, 37%). Invasive fungal disease is a common complication in immunoco-mpromised patients, but Cunninghamella spp. infection is rare and has a high mortality rate. In cases highly suspected of this disease, active diagnosis and early treatment are critical to improve the survival outcomes of the patients. Related Articles | Metrics | Comments（0）

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Fucoxanthin regulates Nrf2/Keap1 signaling to alleviate myocardial hypertrophy in diabetic rats ZHENG Dongxiao, CHEN Linlin, WEI Qihui, ZHU Ziran, LIU Zilue, JIN Lin, YANG Guanyu, XIE Xi Journal of Southern Medical University    2022, 42 (5): 752-759.   DOI: 10.12122/j.issn.1673-4254.2022.05.18 Abstract （570）   HTML （31）    PDF（pc） （3710KB）（651）       Knowledge map    Save Objective To investigate the protective effect of fucoxanthin (FX) against diabetic cardiomyopathy and explore the underlying mechanism. Methods Rat models of diabetes mellitus (DM) induced by intraperitoneal injection of streptozotocin (60 mg/kg) were randomized into DM model group, fucoxanthin treatment (DM+FX) group and metformin treatment (DM+Met) group, and normal rats with normal feeding served as the control group. In the two treatment groups, fucoxanthin and metformin were administered after modeling by gavage at the daily dose of 200 mg/kg and 230 mg/kg, respectively for 12 weeks, and the rats in the DM model group were given saline only. HE staining was used to examine the area of cardiac myocyte hypertrophy in each group. The expression levels of fibrotic proteins TGF-β1 and FN proteins in rat hearts were detected with Western blotting. In the cell experiment, the effect of 1 μmol/L FX on H9C2 cell hypertrophy induced by exposure to high glucose (HG, 45 mmol/L) was evaluated using FITC-labeled phalloidin. The mRNA expression levels of the hypertrophic factors ANP, BNP and β-MHC in H9C2 cells were detected using qRT-PCR. The protein expressions of Nrf2, Keap1, HO-1 and SOD1 proteins in rat heart tissues and H9C2 cells were determined using Western blotting. The DCFH-DA probe was used to detect the intracellular production of reactive oxygen species (ROS). Results In the diabetic rats, fucoxanthin treatment obviously alleviated cardiomyocyte hypertrophy and myocardial fibrosis, increased the protein expressions of Nrf2 and HO-1, and decreased the protein expressions of Keap1 in the heart tissue (P<0.05). In H9C2 cells with HG exposure, fucoxanthin significantly inhibited the enlargement of cell surface area, lowered the mRNA expression levels of ANP, BNP and β-MHC (P<0.05), promoted Nrf2 translocation from the cytoplasm to the nucleus, and up-regulated the protein expressions its downstream targets SOD1 and HO-1 (P<0.05) to enhance cellular antioxidant capacity and reduce intracellular ROS production. Conclusion Fucoxanthin possesses strong inhibitory activities against diabetic cardiomyocyte hypertrophy and myocardial fibrosis and is capable of up-regulating Nrf2 signaling to promote the expression of its downstream antioxidant proteins SOD1 and HO-1 to reduce the level of ROS. Related Articles | Metrics | Comments（0）

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Screening and identification of key genes ATP1B3 and ENAH in the progression of hepatocellular carcinoma: based on data mining and clinical validation YANG Xuejia, LI Yujie, WU Dengqiang, MA Yili, ZHOU Sufang Journal of Southern Medical University    2022, 42 (6): 815-823.   DOI: 10.12122/j.issn.1673-4254.2022.06.04 Abstract （333）   HTML （43）    PDF（pc） （1898KB）（644）       Knowledge map    Save Objective To explore the marker genes correlated with the prognosis, progression and clinical diagnosis of hepatocellular carcinoma (HCC) based on bioinformatics methods. Methods The TCGA-LIHC, GSE84432, GSE143233 and GSE63898 datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed. The differentially expressed genes (DEGs) shared by different disease types were obtained using GEO2R and edge R packages, and Gene Ontology (GO) and Kyoto Gene and Genome Encyclopedia (KEGG) enrichment analyses of the DEGs were performed. The expression levels of these DEGs in normal and cancerous tissues were verified in TCGA-LIHC to identify the upregulated genes in HCC. Survival analysis, receiver-operating characteristic (ROC) curve analysis, and correlation analysis between the key genes and the clinical features of the patients were carried out using the R language. The differential expressions of 15 key genes were verified in clinical samples of HCC and adjacent tissues using RT-qPCR. Results A total of 118 common DEGs were obtained in the database, and among them two genes, namely ATPase Na +/K + transport subunit beta 3 (ATP1B3) and actin regulator (ENAH), showed increased expressions with disease progression. Survival analysis combined with the TCGA-LIHC dataset suggested that high expressions of ATP1B3 and ENAH were both significantly correlated with a poor prognosis of HCC patients (P<0.05), and their AUC values were 0.821 and 0.933, respectively. A high expression of ATP1B3 was correlated with T stage, pathological stage and pathological grade of the tumors (P<0.05), while that of ENAH was associated only with an advanced tumor grade (P<0.05). The results of RT-qPCR showed that ATP1B3 and ENAH were both significantly upregulated in clinical HCC tissues (P<0.05). Conclusion ATPIB3 and ENAH are both upregulated in HCC, and their high expressions may serve as biomarkers of progression of liver diseases and a poor prognosis of HCC. Related Articles | Metrics | Comments（0）

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Protective effect of ulinastatin combined with dexmedetomidine against hepatic ischemia-reperfusion injury in laparoscopic hepatectomy for liver cancer and cirrhosis: a randomized controlled trial OU Yi, LIU Gang, YIN Fengwei , YANG Yang, ZHANG Fangyuan Journal of Southern Medical University    2022, 42 (12): 1832-1838.   DOI: 10.12122/j.issn.1673-4254.2022.12.11 Abstract （269）   HTML （20）    PDF（pc） （1073KB）（639）       Knowledge map    Save Objective To investigate the protective effect of ulinastatin combined with dexmedetomidine against ischemia-reperfusion injury (IRI) of the liver in patients undergoing laparoscopic hepatectomy (LH) for liver cancer with cirrhosis. Methods Eighty patients with liver cancer and cirrhosis undergoing elective LH were randomized into ulinastatin (administered immediately before hepatectomy) group, dexmedetomidine (administered before anesthesia induction) group, ulinastatin plus dexmedetomidine group, and saline group (groups U, D, UD, and C, respectively). Venous blood samples were collected before the operation (T0) and at 30 min (T1), 24 h (T2), 3 days (T3), and 5 days (T4) after the operation. Serum levels of α-GST, MDA, TNF-α and IL-6 were analyzed at T0-T2. Serum levels of ALT, AST, BUN and Cr were measured at T0 and T2-T4, and the incidence of liver dysfunction, complications and postoperative hospital stay of the patients were recorded. Results At T1, serum α-GST, MDA, TNF-α and IL-6 levels increased significantly in groups U, D and UD compared with those in group C, and were significantly higher in groups U and D than in group UD (all P<0.05). At T2, the levels of MDA, TNF-α and IL-6 were significantly decreased in groups U, D and UD compared with those in group C, and were significantly higher in groups U and D than in group UD (all P<0.05). At T2-T4, the levels of ALT and AST were significantly lower in groups U, D and UD than in group C, and were higher in groups U and D than in group UD (all P<0.05). The patients in group UD had significantly shortened postoperative hospital stay as compared with those in group C (P<0.05). The incidences of complications or postoperative renal or liver insufficiency did not differ significantly among the 4 groups. However, there was no significant difference in the incidence of renal function, liver insufficiency and complications among the four groups (all P> 0.05). Conclusion In patients undergoing LH for liver cancer with cirrhosis, ulinastatin combined with dexmedetomidine provides enhanced protection against hepatic IRI possibly through a synergistic effect against oxidative stress and inflammatory response, thereby reducing perioperative liver injury and accelerating postoperative recovery Related Articles | Metrics | Comments（0）

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LRG1 inhibits hepatic macrophage activation by enhancing TGF-β1 signaling to alleviate MAFLD in mice XU Longfei, HAN Jing, YANG Zhe, YANG Yanping, CHEN Jinhui, WU Xijun, WANG Qi, HONG Yan Journal of Southern Medical University    2023, 43 (7): 1164-1171.   DOI: 10.12122/j.issn.1673-4254.2023.07.13 Abstract （166）   HTML （17）    PDF（pc） （8437KB）（636）       Knowledge map    Save Objective To explore the effect of leucine- rich α-2-glycoprotein (LRG1) derived from hepatocytes on activation of hepatic M1 Kupffer cells. Methods A metabolic dysfunction-associated fatty liver disease (MAFLD) model was established in BALB/c mice by high-fat diet (HFD) feeding for 16 weeks. Oleic acid was used to induce steatosis in primary cultures of mouse hepatocytes. The mRNA and protein expressions of LRG1 in mouse liver tissues and hepatocytes were detected by real-time PCR and Western blotting. Primary hepatic macrophages were stimulated with the conditioned medium (CM) from steatotic hepatocyte along with LRG1 or transforming growth factor-β1 (TGF-β1), or both for 24 h, and the expression levels of inducible nitric oxide synthase (iNOS) was detected with Western botting, and the mRNA expressions of iNOS, chemokine ligand 1 (CXCL-1) and interleukin-1β (IL-1β) were measured by RT-PCR. The MAFLD mice were injected with LRG1 (n=6), TGF-β1 (n=6), or both (n=6) through the caudal vein, and the live tissues were collected for HE staining and immumohistochemical detection of F4/80 expression; the mRNA expressions of iNOS, CXCL-1 and IL-1β in liver tissues were detected using RT-PCR. Results The mRNA and protein expression levels of LRG1 were significantly downregulated in the liver tissues of MAFLD mice and steatotic hepatocytes (P<0.05). Treatment of the hepatic macrophages with CM from steatosis hepatocytes significantly enhanced the mRNA expression levels of iNOS, CXCL-1 and IL-1β, and these changes were significantly inhibited by the combined treatment with TGF-β1 and LRG1 (P<0.05). In MAFLD mice, injections with either LRG1 or TGF-β1 alone reduced hepatic lipid deposition and intrahepatic macrophage infiltration, and these effects were significantly enhanced by their combined treatment, which also more strongly inhibited the mRNA expression levels of iNOS, CXCL-1 and IL-1β (P<0.05). Conclusion LRG1 inhibits hepatic macrophage infiltration by enhancing TGF-β1 signaling to alleviate fatty liver inflammation in MAFLD mice. Related Articles | Metrics | Comments（0）

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VIPR1 promoter methylation promotes transcription factor AP-2α binding to inhibit VIPR1 expression and promote hepatocellular carcinoma cell growth in vitro NING Shiyu, HE Chunmei, GUO Zehao, ZHANG Hao, MO Zhijing Journal of Southern Medical University    2022, 42 (7): 957-965.   DOI: 10.12122/j.issn.1673-4254.2022.07.01 Abstract （1684）   HTML （85）    PDF（pc） （2191KB）（610）       Knowledge map    Save Objective To explore the transcriptional regulation mechanism and biological function of low expression of vasoactive intestinal peptide receptor 1 (VIPR1) in hepatocellular carcinoma (HCC). Methods We constructed plasmids carrying wild-type VIPR1 promoter or two mutant VIPR1 promoter sequences for transfection of the HCC cell lines Hep3B and Huh7, and examined the effect of AP-2α expression on VIPR1 promoter activity using dual-luciferase reporter assay. Pyrosequencing was performed to detect the changes in VIPR1 promoter methylation level in HCC cells treated with a DNA methyltransferase inhibitor (DAC). Chromatin immunoprecipitation was used to evaluate the binding ability of AP-2α to VIPR1 promoter. Western blotting was used to assess the effect of AP-2α knockdown on VIPR1 expression and examine the differential expression of VIPR1 in the two cell lines. The effects of VIPR1 overexpression and knockdown on the proliferation, cell cycle and apoptosis of HCC cells were analyzed using CCK8 assay and flow cytometry. We also observed the growth of HCC xenograft with lentivirus-mediated over-expression of VIPR1 in nude mice. Results Compared with the wild-type VIPR1 promoter group, co-transfection with the vector carrying two promoter mutations and the AP-2α-over-expressing plasmid obviously restored the luciferase activity in HCC cells (P<0.05). DAC treatment of the cells significantly decreased the methylation level of VIPR1 promoter and inhibited the binding of AP-2α to VIPR1 promoter (P<0.01). The HCC cells with AP-2α knockdown showed increased VIPR1 expression, which was lower in Huh7 cells than in Hep3B cells. VIPR1 overexpression in HCC cells caused significant cell cycle arrest in G2/M phase (P<0.01), promoted cell apoptosis (P<0.001), and inhibited cell proliferation (P<0.001), while VIPR1 knockdown produced the opposite effects. In the tumor-bearing nude mice, VIPR1 overexpression in the HCC cells significantly suppressed the increase of tumor volume (P<0.001) and weight (P<0.05). Conclusion VIPR1 promoter methylation in HCC promotes the binding of AP-2α and inhibits VIPR1 expression, while VIPR1 overexpression causes cell cycle arrest, promotes cell apoptosis, and inhibits cell proliferation and tumor growth. Related Articles | Metrics | Comments（0）

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Establishment of a culture system for human nasal mucosa organoids with controllable differentiation WANG Ke, YU Yan, HAN Ri, WANG Xianwen, ZHAO Yunteng, TANG Haocheng, LI Gang Journal of Southern Medical University    2022, 42 (6): 868-877.   DOI: 10.12122/j.issn.1673-4254.2022.06.10 Abstract （722）   HTML （30）    PDF（pc） （2828KB）（609）       Knowledge map    Save Objective To establish a culture system for human nasal mucosal organoids with controllable differentiation to reproduce the structure and function of the source tissue through staged expansion-differentiation culture. Methods Fresh samples of surgically resected middle turbinate and nasal polyp tissues were collected, from which the nasal mucosa epithelial cells were isolated by enzymatic digestion and filtration for continuous culture at the air-liquid interface for expansion (EO group) or staged culture for expansion and differentiation (DO group). Immunohistochemical staining was used to characterize the structure, cellular composition and ciliary function of nasal mucosal organoids in the two groups. The secretion function of the differentiated nasal mucosal organoids in DO group was evaluated using PAS staining. Results Both of the two organoid culture systems yielded vacuolar or solid spherical 3D organoids, and their diameters increased progressively with time. On day 16 of culture, more vacuolar organoids occurred in DO group, while more solid spherical organoids were seen in EO group, and the proportion of vacuoles was significantly greater in DO group than in EO group [(54.67±13.26)% vs (21.67±8.57)%, P<0.05]. Short tandem repeat (STR) test of the nasal mucosal organoids and the source tissue showed a 100% match between them. On day 21 of culture, scanning and transmission electron microscopy of the nasal mucosal organoids identified ultrastructure of cilia in DO group and short villi structure in most of the organoids in EO group. Immunohistochemical staining showed positivity for P63 (basal cells), β-tubulin (ciliated columnar cells), and MUC5AC (goblet cells) in the organoids. Compared with those in EO group, the organoids in DO group showed significantly greater percentages of ciliated cells [(7.95±1.81)% vs (27.04±5.91)%, P<0.05] and goblet cells [(14.46±0.93)% vs (39.85±5.43)%, P<0.05) with a similar percentage of basal cells [(56.91±14.12)% vs (53.42±15.77)%, P>0.05]. The differentiated nasal mucosal organoids in DO group were positively stained for glycogen. Conclusion The staged expansion-differentiation culture method allows more stable and prolonged growth of the cultured cells in vitro to produce organoids with controllable differentiation closely resembling the morphological structure and functions (ciliary function and secretory function) of the source tissue. Related Articles | Metrics | Comments（0）

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A nomogram based on systemic inflammation markers can predict adverse outcomes in patients with heart failure LIU Zhaojun, ZHOU Xiaoli Journal of Southern Medical University    2022, 42 (8): 1149-1158.   DOI: 10.12122/j.issn.1673-4254.2022.08.06 Abstract （1105）   HTML （44）    PDF（pc） （1123KB）（609）       Knowledge map    Save Objective To construct a nomogram based on systemic inflammation markers for assessing the risk of adverse outcomes in patients with heart failure (HF). Methods We retrospectively collected the clinical data from 430 patients with HF hospitalized in our hospital from June, 2017 to June, 2019. The patients were randomized into derivation group (n=286) and validation group (n=144) at a 7∶3 ratio using R software. The risk factors for adverse prognosis of HF were screened using COX regression analysis to establish the nomogram. The predictive accuracy of the nomogram was assessed using calibration curves. Decision curve analysis (DCA) and Kaplan-Meier curves were used to evaluate the clinical utility of the nomogram. Results The results of COX multivariate regression analysis showed that age (P=0.030), body mass index (BMI, P=0.002), New York Heart Association classification (NYHA, P<0.001), hypertension (P=0.004), lymphocyte count (P<0.001), platelet-to-lymphocyte ratio (PLR, P=0.007), neutrophil-to-lymphocyte ratio (NLR, P<0.001) and system inflammation response index (SIRI, P<0.001) were prognostic factors for HF patients. The nomogram was constructed using these prognostic factors. The C-indexes of the derivation and validation cohorts were 0.719 (95% CI: 0.680-0.758) and 0.732 (95% CI: 0.693-0.771), respectively. The calibration curves showed a good concordance of the nomogram for predicting adverse outcomes in patients with HF. Conclusion The nomogram constructed based on the systemic inflammation markers and the conventional risk factors can predict adverse outcomes (mortality and readmission) in patients with HF. Related Articles | Metrics | Comments（0）