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Inhibition of mitochondrial reactive oxygen species reduces high glucose-induced pyroptosis and ferroptosis in H9C2 cardiac myocytes Journal of Southern Medical University    2021, 41 (7): 980-987.   DOI: 10.12122/j.issn.1673-4254.2021.07.03 Abstract （1185）   HTML （66）    PDF（pc） （1442KB）（1488）       Knowledge map    Save Objective To observe the effect of inhibiting mitochondrial oxidative stress and NLRP3 inflammasomes on high glucose (HG)-induced pyroptosis and ferroptosis in H9C2 cardiac muscle cells and explore the possible interactions between mitochondrial reactive oxygen species (ROS) and inflammasomes. Methods H9C2 cells exposed to high glucose (35 mmol/L) were treated with the mitochondrial antioxidant mitoquinone (MitoQ), the NLRP3 antagonist MCC950, or both MCC950 and rotenone (a mitochondrial electron transport antagonist), and the cell viability was measured with CCK-8 assay. The cellular and mitochondrial ROS levels were measured using CellRox and Mitosox fluorescent probes, respectively. The cellular NLRP3 inflammasome level was detected with immunofluorescence assay, and the expressions of the key proteins related with pyroptosis and ferroptosis were determined with Western blotting. Results HG exposure significantly lowered the viability of H9C2 cells (P<0.01), reduced the expression of GPX4 protein (a key protein related with ferroptosis) (P<0.01), and increased the fluorescence intensities of NLRP3 (P<0.01) and ROS (at both the cellular and mitochondrial levels, P<0.01) and the protein expressions of NLRP3 and GSDMD-NT (P<0.01). Treatment with either MitoQ or MCC950 significantly increased the viability of HG-exposed cells (P<0.01), increased GPX4 expression (P<0.01), and reduced the fluorescence intensities of NLRP3 (P<0.01) and cellular and mitochondrial ROS (P<0.01) and the protein expressions of NLRP3 and GSDMD-NT (P<0.05). Compared with MCC950 treatment, treatment with both MCC950 and rotenone significantly reduced the viability of HG-exposed cells (P<0.01), lowered GPX4 expression (P<0.01), and increased the fluorescence intensities of ROS and NLRP3 (P<0.01) and the protein levels of NLRP3 and GSDMD-NT (P<0.05). Conclusion MitoQ inhibits mitochondrial ROS production to reduce HG-induced NLRP3 inflammasome activation and thus suppress pyroptosis and ferroptosis of cardiac muscle cells. There may be an interaction between mitochondrial ROS and NLRP3 inflammasomes. Related Articles | Metrics | Comments（0）

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Expression of nicotinamide-N-methyltransferase in gastric cancer and its biological and clinicopathological significance Journal of Southern Medical University    2021, 41 (6): 828-838.   DOI: 10.12122/j.issn.1673-4254.2021.06.04 Abstract （328）   HTML （53）    PDF（pc） （2641KB）（1302）       Knowledge map    Save Objective To investigate the expression of nicotinamide-N-methyltransferase (NNMT) in gastric cancer (GC) and explore its biological and clinicopathological significance. Methods We screened the candidate genes associated with the classification and prognosis of gastric cancer by analyzing GEO, Oncomine and TCGA datasets. The molecular pathways and protein interaction network involving these candidate genes were analyzed using STRING, GSEA, David and Cytoscape software. The expressions of the candidate genes in 28 pairs of gastric cancer and adjacent tissues were detected with qRT-PCR, and CCK-8 assay, clone formation assay, wound healing assay and Transwell assay were carried out to analyze the effects of modulation of NNMT expression on proliferation, invasion and migration of different gastric cancer cell lines. Results NNMT was highly expressed in gastric cancer tissues and was negatively correlated with the prognosis of patients with gastric cancer. Pathway analysis showed that the high expression of NNMT was associated with adhesion-related pathway molecules such as extracellular matrix receptors, cell adhesion molecules, and cytokine receptors, while its low expression was associated with base mismatch repair and riboflavin metabolism. Protein interaction analysis showed that NNMT interacted with 16 differentially expressed proteins such as AURKA and was co-expressed with TAGLN, PTRF, AKAP12 and IGF2BP2. In clinical tissue specimens, qRT-PCR results showed that the expression of NNMT mRNA was significantly higher in gastric cancer tissues than in the adjacent tissues (P<0.05). In gastric cancer cell lines, overexpression of NNMT was found to significantly promote cell proliferation, invasion and migration, while NNMT knockdown produced obvious inhibitory effects on cell proliferation, invasion and migration. Conclusion NNMT is highly expressed in gastric cancer and negatively correlated with the prognosis of gastric cancer patients. The high expression of NNMT promotes the proliferation, invasion and metastasis of gastric cancer cells, suggesting the potential of NNMT as prognostic marker of gastric cancer. Related Articles | Metrics | Comments（0）

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Inhibiting ferroptosis attenuates myocardial injury in septic mice: the role of lipocalin-2 HUANG Yuhui, ZHANG Gongpeng, LIANG Huan, CAO Zhenzhen, YE Hongwei, GAO Qin Journal of Southern Medical University    2022, 42 (2): 256-262.   DOI: 10.12122/j.issn.1673-4254.2022.02.13 Abstract （1000）   HTML （26）    PDF（pc） （1734KB）（1268）       Knowledge map    Save Objective To explore the contribution of ferroptosis to myocardial injury in mouse models of sepsis and the role lipocalin-2 (Lcn2) in ferroptosis. Methods Adult male C57BL/6 mice were randomized equally into sham-operated group, cecal ligation and puncture (CLP)-induced sepsis group, and CLP + Fer-1 group where the mice received intraperitoneal injection of 5 mg/mL Fer-1 (5 mg/kg) 1 h before CLP. The left ventricular functions (including LVEF%, LVFS%, LVIDd and LVIDs) of the mice were assessed by echocardiography at 24 h after CLP. Myocardial injury in the mice was observed with HE staining, and the changes of myocardial ultrastructure and mitochondria were observed using transmission electron microscopy (TEM). Serum TNF-α level was measured with ELISA, and the changes of myocardial iron content were detected using tissue iron kit. The protein expressions of myocardial Lcn2, glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) were determined with Western blotting. Results The septic mice showed significantly decreased LVEF%, LVFS% and LVIDd and increased LVIDs at 24 h after CLP (P<0.05), and these changes were significantly improved by Fer-1 treatment. Sepsis caused obvious myocardial pathologies and changes in myocardial ultrastructure and mitochondria, which were significantly improved by Fer-1 treatment. Fer-1 treatment also significantly ameliorated sepsis-induced elevations of serum TNF-α level, myocardial tissue iron content, and Lcn2 protein expression and the reduction of GPX4 and FSP1 protein expression levels (P<0.05). Conclusion GPX4- and FSP1-mediated ferroptosis are involved in myocardial injury in mice with CLP-induced sepsis, and inhibition of ferroptosis can attenuate septic myocardial injury, in which Lcn2 may play a role. Related Articles | Metrics | Comments（0）

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Progress and prospect of application of traditional Chinese medicine fingerprint (specific chromatogram) in Chinese Pharmacopoeia (2010-2020) YAN Haiyan, ZOU Chuncai Journal of Southern Medical University    2022, 42 (1): 150-155.   DOI: 10.12122/j.issn.1673-4254.2022.01.19 Abstract （882）   HTML （61）    PDF（pc） （1604KB）（1208）       Knowledge map    Save The Chinese Pharmacopoeia began to apply fingerprints (specific chromatogram) to quality control of traditional Chinese medicine in its 2010 edition, and in its 2015 and 2020 editions, new fingerprints (specific chromatogram) were added for improvement of the Pharmacopoeia-based national standards for drugs. This review analyzes the traditional Chinese medicine fingerprints (specific chromatogram) in Chinese Pharmacopoeia (2010-2020) in terms of the number of varieties listed, application of fingerprints (specific chromatogram), selection of evaluation method, determination method, the selection of extraction or preparation solvents of the test samples. With the expansion of the application of fingerprints (specific chromatogram), the evaluation indicators are constantly improving. The future development of the fingerprints (specific chromatogram) is also discussed in light of the selection of appropriate extraction or preparation solvents to obtain effective substances, which is the basis for the establishment of the fingerprints; multiple fingerprints for one drug based on different functional indications or basic sources, which expands the application of the fingerprints; addition of technical guidelines for traditional Chinese medicine fingerprints to standardize the use of the fingerprints; and the regular revision, update and application expansion of the fingerprints to ensure its essential role in quality control of traditional Chinese medicine. Related Articles | Metrics | Comments（0）

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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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Pan-cancer analysis of the expression pattern of long non-coding RNA MIR22HG WANG Hui, LI Wenwen, ZHANG Dongyan Journal of Southern Medical University    2022, 42 (4): 473-485.   DOI: 10.12122/j.issn.1673-4254.2022.04.03 Abstract （331）   HTML （190）    PDF（pc） （5766KB）（1165）       Knowledge map    Save Objective To conduct a pan-cancer analysis of the expression of long non-coding RNA (lncRNA) MIR22HG and explore its association with clinical characteristics. Methods We analyzed the expression of MIR22HG in different tumors and its association with clinical staging, lymph node metastasis, tumor mutation burden (TMB) and microsatellite instability (MSI) using R package based on the Cancer Genome Atlas (TCGA) datasets. The relationship between MIR22HG expression and infiltrating immune cells was analyzed using TIMER algorithm. The association of MIR22HG gene alteration frequency with the clinical outcomes was examined using cBioPortal online software. Data form Genomics of Drug Sensitivity in Cancer (GDSC) were used to analyze the relationship between MIR22HG and the sensitivity of chemotherapy drugs. We specifically analyzed MIR22HG expression in hepatocellular carcinoma (HCC) and its correlation with sorafenib treatment using GEO database and verified the results in 12 pairs of HCC specimens. Kaplan-Meier analysis was performed to analyze the correlation of MIR22HG with the outcomes of sorafenib treatment. We also tested the effects of MIR22HG overexpression and knockdown on IC50 of sorafenib in HCC cells. Results MIR22HG was downregulated in most tumors (P<0.05), where its deletion mutations were frequent, and associated with a poor prognosis (P<0.05). In many tumors, MIR22HG expression level was correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, immune checkpoint-related genes, and sensitivity to common chemotherapeutic drugs (P<0.05). Among the 6 common infiltrating immune cells in cancers, neutrophil infiltration had the strongest correlation with MIR22HG expression level, especially in breast cancer, rectal cancer and kidney renal papillary cell carcinoma (P<0.05). MIR22HG was downregulated in HCC in association with HCC progression (P<0.05). In HCC patients, a low MIR22HG expression was associated with a favorable outcome after sorafenib treatment (HR=2.94, P=0.075) and was capable of predicting the response to sorafenib treatment (AUC=0.8095). Compared with the negative control, MIR22HG overexpression obviously reduced sorafenib sensitivity (with IC50 of 7.731 vs 15.61) while MIR22HG knockdown increased sorafenib sensitivity of HCC cells (with IC50 of 7.986 vs 5.085). Conclusion MIR22HG expression level is correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, and chemosensitivity in most cancer, suggesting its potential as an immunotherapeutic target and also a prognostic biomarker for tumors. Related Articles | Metrics | Comments（0）

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Exploring the therapeutic mechanism of quercetin for heart failure based on network pharmacology and molecular docking TAN Xin, XIAN Wei, CHEN Yongfeng, LI Xiaorong, WANG Qiyi, KANG Pinfang, WANG Hongju Journal of Southern Medical University    2021, 41 (8): 1198-1206.   DOI: 10.12122/j.issn.1673-4254.2021.08.11 Abstract （584）   HTML （53）    PDF（pc） （2242KB）（1140）       Knowledge map    Save Objective To investigate the molecular mechanism of quercetin in the treatment of heart failure (HF) based on network pharmacology and molecular docking. Methods Quercetin and HF-related targets were obtained using TCMSP, PharmMapper, CTD and GeneCards databases, and quercetin-HF intersection targets were obtained through the online website Venn; the protein interaction network was constructed and imported into Cytoscape 3.7.2 to identify the core targets of quercetin in the treatment of HF. GO and KEGG pathway enrichment analyses were performed using R package, and molecular docking was performed using Auto Dock Vina. The protein levels of AKT1, phospho-AKT (Ser473), eNOS, MMP9, and caspase-3 in quercetin-treated HF cell models were detected using protein immunoblotting. Results We identified 80 quercetin-HF intersectional targets (AKT1, CASP3, MAPK1, MMP9, and MAPK8) and 5 core targets of quercetin for treatment of HF. GO analysis suggested that the therapeutic effect of quercetin for HF was mediated mainly by such biological processes as responses to peptide hormones, phosphatidylinositol-mediated signalling, responses to lipopolysaccharides, responses to molecules of bacterial origin and regulation of inflammatory responses. KEGG pathway enrichment analysis identified lipid and atherosclerosis pathway, proteoglycans in cancer, PI3K-AKT signaling pathway, diabetic cardiomyopathy and MAPK signaling pathway as the most significantly enriched signaling pathways. Molecular docking showed a good binding activity of quercetin to the 5 core targets. The results of protein immunoblotting showed that 100 μmol/L quercetin significantly reduced AKT1, phospho-AKT (Ser473), eNOS, MMP9 and caspase-3 levels in the cell models of HF (P<0.01). Conclusion Quercetin improves the pathological changes in HF possibly by regulating the AKT1-eNOS-MMP9 pathway to inhibit cell apoptosis. Related Articles | Metrics | Comments（0）

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Macrophage migration inhibitory factor meditates MPP+/MPTP-induced NLRP3 inflammasome activation in microglia cells Journal of Southern Medical University    2021, 41 (7): 972-979.   DOI: 10.12122/j.issn.1673-4254.2021.07.02 Abstract （826）   HTML （72）    PDF（pc） （1754KB）（1121）       Knowledge map    Save Objective To explore the mechanisms of macrophage migration inhibitory factor (MIF)/nucleus factor-κB (NF-κB) in mediating 1-methyl-4-phenylpyridinium iodide (MPP + )/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced activation of Nod-like receptor protein 3 (NLRP3) inflammasome in microglials and the its effects on neurons. Methods Murine microglial cell line Bv-2 was infected with a lentivirus carrying MIF shRNA for MIF knockdown and then treated with MPP+. The total protein levels of NLRP3, caspase-1, p65 and p65 in the cell nuclei and cytoplasm were detected. ELISA was used to detect the levels of IL-1β and IL-18 in the culture supernatant, which served as the conditioned culture medium for MN9D cells, whose TH expression level was detected using Western blotting. The effect of stereotactic injection of an adeno-associated virus (AAV) carrying MIF shRNA on behaviors was assessed in a C57BL/6 mouse model of Parkinson disease (PD) induced by intraperitoneal MPTP injection. TH and Iba-1 immunohistochemistry was used to evaluate the number of substantia nigraneurons and the activation of microglia cells, and the protein expressions of MIF, NLRP3 and TH in the substantia nigra were detected with Western blotting. Results MPP+ significantly increased NLRP3 and MIF expressions in Bv-2 cells (P<0.05). MIF knockdown in Bv-2 cells significantly lowered NLRP3 and caspase-1 protein expressions and IL-1β and IL-18 levels in the culture supernatant (P<0.05) without affecting total protein level of p65. Bv-2 cells with MIF knockdown showed significantly lowered p65 protein expression in the nuclei but increased p65 expression in the cytoplasm (P<0.05). The conditioned medium derived from Bv-2 cells with MIF knockdown, as compared with that from than MPP +-treated Bv-2 cells, significantly increased TH expression in MN9D cells (P=0.01). Compared with those in MPTP group, the mice receiving injections of AAV-MIF-shRNA had higher scores in pole test and open field test with lower scores in traction test, and showed increased TH-positive neurons, decreased Iba-1 microglia cell activation, reduced expressions of MIF and NLRP3, and increased expression of TH in the substantia nigra (all P<0.05). Conclusion Inhibition of MIF can reduce the expression of NLRP3 inflammasomes and inflammatory factor caused by MPP+ in microglia cells to relieve the damage of dopaminergic neurons and alleviate microglia cell activation, thus offering protection against neuroinflammation in Parkinson's disease. Related Articles | Metrics | Comments（0）

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Liuwei Buqi capsule modulates immune function by targeting multiple immune cell subsets in lung tissue of patients with COPD WANG Xiaole, ZHU Jie, GAO Yating, WU Fan, YANG Qinjun, TONG Jiabing, ZHANG Xingxing, WANG Chuanbo, WU Di, LI Zegeng Journal of Southern Medical University    2021, 41 (10): 1492-1500.   DOI: 10.12122/j.issn.1673-4254.2021.10.07 Abstract （405）   HTML （36）    PDF（pc） （2383KB）（1101）       Knowledge map    Save Objective To investigate the characteristics of immune cell subsets in the lung tissues of patients with chronic obstructive pulmonary disease (COPD) and the mechanism of Liuwei Buqi capsule in modulating immune and inflammatory imbalance in COPD. Methods We downloaded COPD-related single-cell RNA sequencing data from Gene Expression Omnibus (GEO) and identified COPD immune cell subsets using the Seurat package in the R software to construct an immune cell subsets-differential genes network. The target genes and active ingredients of Liuwei Buqi capsule were obtained from the Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), and the Liuwei Buqi capsule-immune cell subsets-target genes network was constructed by mapping the target genes to the differentially expressed genes in each immune cell subset. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to analyze significantly enriched pathways of the target genes, and the key genes involved in the top 20 pathways were identified. In a rat model of COPD, we investigated the effects of Liuwei Buqi capsule on pulmonary function, lung tissue pathology, serum levels of IL-1β, NF-κB, and TNF-α, and expressions of IKBα, JNK, c-JUN, and c-FOS proteins in the lung tissue. Results A total of 18 immune-related cell subsets, including macrophages and alveolar macrophages, were identified in both COPD patients and healthy control subjects, and the patients with COPD showed significant changes the percentages of macrophages, cDC1, pDC, mast cells, T cells, and mature dendritic cells (P<0.05). Liuwei Buqi capsules targeted multiple immune cell subsets, and the identified target genes were enriched mostly in such immune and inflammation-related signaling pathways as lipids and atherosclerosis, IL-17 signaling pathway, Toll-like receptor signaling pathway, and TNF signaling pathway; the genes CXCL8, IL1B, JUN, NFKBIA, MAPK8, and FOS were the key genes involved in the significantly enriched pathways. In the rat models of COPD, treatment with Liuwei Buqi capsule significantly improved pulmonary function, alleviated lung pathologies, reduced serum levels of IL-1β, TNF-α, and NF-κB (P<0.05) and pulmonary expressions of JNK, c-JUN, and c-FOS (P<0.01) protein, and increased pulmonary expression of IκBα (P<0.01). Conclusion Liuwei Buqi capsule may play an immunomodulatory role by targeting multiple immune cell subsets in the lung tissue of COPD patients. Related Articles | Metrics | Comments（0）

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Advances in research of Musashi2 in solid tumors YANG Yinggui, ZHAO Min, DING Tengteng, NI Chuping, ZHENG Qingyou, LI Xin Journal of Southern Medical University    2022, 42 (3): 448-456.   DOI: 10.12122/j.issn.1673-4254.2022.03.20 Abstract （498）   HTML （49）    PDF（pc） （932KB）（1099）       Knowledge map    Save RNA binding protein (RBP) plays a key role in gene regulation and participate in RNA translation, modification, splicing, transport and other important biological processes. Studies have shown that abnormal expression of RBP is associated with a variety of diseases. The Musashi (Msi) family of mammals is an evolutionarily conserved and powerful RBP, whose members Msi1 and Msi2 play important roles in the regulation of stem cell activity and tumor development. The Msi family members regulate a variety of biological processes by binding and regulating mRNA translation, stability and downstream cell signaling pathways, and among them, Msi2 is closely related to embryonic growth and development, maintenance of tumor stem cells and development of hematological tumors. Accumulating evidence has shown that Msi2 also plays a crucial role in the development of solid tumors, mainly by affecting the proliferation, invasion, metastasis and drug resistance of tumors, involving Wnt/β-catenin, TGF-β/SMAD3, Akt/mTOR, JAK/STAT, Numb and their related signaling pathways (Notch, p53, and Hedgehog pathway). Preclinical studies of Msi2 gene as a therapeutic target for tumor have achieved preliminary results. This review summarizes the molecular structure, physiological function, role of Msi2 in the development and progression of various solid tumors and the signaling pathways involved. 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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miR-483-5p aggravates cisplatin-induced premature ovarian insufficiency in rats by targeting FKBP4 Journal of Southern Medical University    2021, 41 (6): 801-810.   DOI: 10.12122/j.issn.1673-4254.2021.06.01 Abstract （373）   HTML （65）    PDF（pc） （5563KB）（1083）       Knowledge map    Save Objective To investigate the role of FKBP4 protein in cisplatin-induced premature ovarian insufficiency (POI). Methods We performed ITRAQ assay of the ovarian tissues from 4 mice with cisplatin-induced POI and 4 control mice, and identified FKBP4 as a significantly down-regulated protein in the oocytes and granulosa cells following cisplatin treatment. TargetScan software was used for target analysis of FKBP4, and qRT-PCR and Western blotting were used to verify the expression levels of miR-483-5p and FKBP4 in the mouse models. Serum samples were collected from patients with POI and healthy women for detecting miR-483-5p level with qRT-PCR. Cell transfection and dual-luciferase assay were performed to determine the relationship between miR-483-5p and FKBP4. In primary granulosa cells and KGN cells, we examined the effect of miR-483-5p alone, miR-483-5p and cisplatin, and miR-483-5p combined with both cisplatin and FKBP4 on cell apoptosis. We also assessed ovarian function in a transgenic mouse model with ovarian miR-483-5p overexpression in comparison wigh wild-type mice using immunofluorescence assay, in situ hybridization and ELISA. Results Ovarian FKBP4 expression was significantly decreased in mice with cisplatin-induced POI. Analysis using TargetScan software indicated that FKBP4 was the potential target of miR-483-5p, which was highly expressed in the ovaries and serum of POI mice and in the serum of patients with POI. In vitro experiments further confirmed that FKBP4 was the target of miR-483-5p. In KGN and primary granulosa cells, FKBP4 overexpression significantly reduced cell apoptosis induced by both cisplatin and miR-483-5p overexpression (P= 0.0045 and 0.0177, respectively). In the transgenic mice with miR-483-5p overexpression in the oocytes, cisplatin induced more severe ovarian damages as compared with those in the wild-type mice. Conclusion miR-483-5p/FKBP4 is a new and important pathway in cisplatin-induced POI, in which cisplatin increases ovarian miR- 483-5p expression to result in targeted down-regulation of FKBP4. Up-regulation of miR-483-5p may increase ovarian sensitivity to cisplatin and cause severe ovarian dysfunction. Detection of serum miR-483-5p level may help to predict the occurrence and development of POI. Related Articles | Metrics | Comments（0）

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TRIM21 suppresses invasion of hepatocellular carcinoma cells by promoting β-catenin ubiquitylation and degradation ZHANG Zhihong, ZHU Zhenru, SHENG Hailong, SUN Jingyuan, CAO Chuanhui Journal of Southern Medical University    2022, 42 (1): 55-62.   DOI: 10.12122/j.issn.1673-4254.2022.01.06 Abstract （525）   HTML （31）    PDF（pc） （4913KB）（1065）       Knowledge map    Save Objective To explore the role of TRIM21 in modulating the invasive phenotype of hepatocellular carcinoma (HCC) cells and its mechanism of action.Methods RNA interference technique was used to knock down the expression of TRIM21 and β-catenin, alone or in combination, in HCC cell lines 97H and LM3, and the interfering efficiency and the activity of closely related pathways were determined using Western blotting. The two cells with TRIM21 knockdown (siTRIM21 97H and siTRIM21 LM3 cells) were assessed for their invasion ability in vitro using Transwell invasion assay, and the lung metastasis capacity of siTRIM21 LM3 cells following tail vein injection was evaluated in nude mice. The binding of TRIM21 with β-catenin and the ubiquitylation level of β-catenin in TRIM21-overexpressing HEK293 cells were determined with Western blotting and co-immunoprecipitation assay. We also compared the overall survival of patients with CTNNB1highTRIM21high and CTNNB1highTRIM21low HCC subtypes using Kaplan-Meier method based on filtrated and grouped HCC clinical data from TCGA database.Results TRIM21 knockdown significantly enhanced the invasion ability of 97H and LM3 cells in vitro (P<0.01 or 0.05) and the lung metastasis ability of LM3 cells in nude mice (P<0.01), and simultaneous knockdown of β -catenin obviously suppressed the in vitro invasiveness of the cells (P<0.0001 or 0.05). Co-immunoprecipitation assay showed that TRIM21 was capable of directly binding with β-catenin protein to accelerate the ubiquitination and degradation of the latter, leading to inhibition of nuclear translocation of β-catenin and hence reduced invasiveness of HCC cells. Bioinformatic analysis showed that compared patients with CTNNB1highTRIM21low HCC subtype where Wnt pathway was activated, the patients with CTNNB1highTRIM21high HCC subtype had a significantly better survival outcomes (P<0.05).Conclusion A high expression of TRIM21 suppresses the invasion of HCC cells by promoting β-catenin ubiquitylation and degradation, which possibly explains the poor prognosis of CTNNB1highTRIM21low HCC patients. Related Articles | Metrics | Comments（0）

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MicroRNA-132 promotes atherosclerosis by inducing mitochondrial oxidative stress-mediated ferroptosis LIU Zexin, CAO Sai, CHEN Qing, FU Fangyong, CHENG Meirong, HUANG Xianying Journal of Southern Medical University    2022, 42 (1): 143-149.   DOI: 10.12122/j.issn.1673-4254.2022.01.18 Abstract （320）   HTML （22）    PDF（pc） （2350KB）（1062）       Knowledge map    Save Objective To explore the expression of microRNA-132 (miR-132) and its potential role in the development of atherosclerosis (AS). Methods Thirty AS samples and 30 samples of normal peripheral vessels were collected from atherosclerotic patients undergoing peripheral angiostomy in our hospital for detecting the expression level of miR-132 using RT-qPCR. The expression of miR-132 in human umbilical vein endothelial cells (HUVEC) was up-regulated by liposome transfection, and intracellular reactive oxygen species (ROS), localization relationship between ROS and mitochondria, functional changes of mitochondrial reactive oxygen superoxide species (mtROS), mitochondrial membrane potential (MMP) and opening of mitochondrial permeability transition pore (mPTP) were analyzed by flow cytometry and laser confocal microscopy. The activity of mitochondrial redox respiratory chain complex (type I, II, III, IV and V) in HUVECs was detected using ELISA, and the expression levels of key iron death proteins were detected with Western blotting. Results RT-qPCR results showed that miR-132 was significantly up-regulated in atherosclerotic plaques compared with normal vascular samples (P<0.001). Compared with control HUVECs, HUVECs overexpressing miR-132 showed a significantly increased level of intracellular ROS (P<0.001), and most of ROS was colocalized with mitochondria. HUVECs overexpressing miR-132 also showed significantly decreased MMP (P<0.001) and obviously increased mtROS (P<0.001) and opening of mPTP (P<0.001), which led to mitochondrial REDOX respiratory chain stress disorder. The key iron death protein GPX4 was significantly down-regulated and the oxidized protein NOX4 was significantly increased in miR-132-overexpressing HUVECs (P<0.001). Conclusion MiR-132 promotes atherosclerosis by inducing mitochondrial oxidative stress-mediated ferroptosis, which may serve as a promising therapeutic target for AS. Related Articles | Metrics | Comments（0）

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Application of DNA origami in nanobiomedicine Journal of Southern Medical University    2021, 41 (6): 960-964.   DOI: 10.12122/j.issn.1673-4254.2021.06.22 Abstract （609）   HTML （65）    PDF（pc） （636KB）（1054）       Knowledge map    Save The development of DNA nanotechnology make it possible to artificially generate complex nucleic acid nanostructures with controllable sizes and shapes. DNA origami emerges as an effective and versatile approach to construct two- and three-dimensional programmable nanostructures, and represents a milestone in the development of structural DNA nanotechnology. Due to its high degree of controllable geometry, spatial addressability, easy chemical modification and good biocompatibility, DNA origami has great potentials for applications in many fields. In this review, we briefly summarize the applications of DNA origami in antigen-antibody interaction, targeted drug delivery and the synthesis of biomaterials. Related Articles | Metrics | Comments（0）

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A 3D hydrogel loaded with exosomes derived from bone marrow stem cells promotes cartilage repair in rats by modulating immunological microenvironment GUAN Pengfei, CUI Ruiwen, WANG Qiyou, SUN Yongjian Journal of Southern Medical University    2022, 42 (4): 528-537.   DOI: 10.12122/j.issn.1673-4254.2022.04.08 Abstract （705）   HTML （41）    PDF（pc） （2380KB）（1044）       Knowledge map    Save Objective To assess the efficacy of GelMA hydrogel loaded with bone marrow stem cell-derived exosomes for repairing injured rat knee articular cartilage. Methods The supernatant of cultured bone marrow stem cells was subjected to ultracentrifugation separate and extract the exosomes, which were characterized by transmission electron microscopy, particle size analysis and Western blotting of the surface markers. The changes in rheology and electron microscopic features of GelMA hydrogel were examined after loading the exosomes. We assessed exosome release from the hydrogel was detected by BCA protein detection method, and labeled the exosomes with PKH26 red fluorescent dye to observe their phagocytosis by RAW264.7 cells. The effects of the exosomes alone, unloaded hydrogel, and exosome-loaded hydrogel on the polarization of RAW264.7 cells were detected by q-PCR and immunofluorescence assay. We further tested the effect of the exosome-loaded hydrogel on cartilage repair in a Transwell co-culture cell model of RAW264.7 cells and chondrocytes in a rat model of knee cartilage injury using q-PCR and immunofluorescence assay and HE and Masson staining. Results GelMA hydrogel loaded with exosomes significantly promoted M2-type polarization of RAW264.7 cells (P<0.05). In the Transwell co-culture model, the exosome-loaded GelMA hydrogel significantly promoted the repair of injured chondrocytes by regulating RAW264.7 cell transformation from M1 to M2 (P<0.05). HE and Masson staining showed that the exosome-loaded hydrogel obviously promoted cartilage repair in the rat models damage. Conclusion GelMA hydrogel loaded with bone marrow stem cell-derived exosomes can significantly promote the repair of cartilage damage in rats by improving the immune microenvironment. Related Articles | Metrics | Comments（0）

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Characteristics of gut virome and microbiome in patients with stroke Journal of Southern Medical University    2021, 41 (6): 862-869.   DOI: 10.12122/j.issn.1673-4254.2021.06.08 Abstract （390）   HTML （51）    PDF（pc） （1953KB）（1036）       Knowledge map    Save Objective To explore the differences in gut virome and microbiome between patients with stroke and healthy volunteers. Methods Fifteen patients with acute ischemic stroke treated in the Department of Neurology of Nanfang Hospital between February, 2014 and February, 2016 and 15 healthy volunteers matched for age and sex were enrolled in this study. Virome sequencing and 16S rRNA sequencing were performed on stool samples of all the participants, and the composition and structures of the virome and microbiome were compared between the two groups. Results No significant difference was found in the overall diversity of virome between the stroke patients and the healthy volunteers (alpha diversity: P=0.320; beta diversity: P=0.169, R2=0.037), but virome composition differed significantly between the two groups. The relative abundance of Bacteroides phage B40_8 and Cronobacter phage CS01 increased significantly in patients with stroke. The structures and composition of the microbiome in patients with stroke also differed significantly from those of the healthy volunteers (alpha diversity: P=0.950; beta diversity: P=0.005, R2=0.117). The relative abundance of Megasphaera increased while that of Bifidobacterium decreased in patients with stroke. Correlation analysis showed that in the virome of stroke patients, the relative abundance of the phage preying Streptococcus was positively correlated with that of their hosts (r=0.550, P=0.036), while in the virome of healthy volunteers, the relative abundance of the phage preying Faecalibacterium (r=0.520, P=0.049), Bilophila (r=0.541, P=0.040) and Roseburia (r=0.526, P=0.046) were positively correlated with that of their respective hosts. Conclusion Stroke patients have similar overall diversity of the virome to healthy volunteers but different virome composition and interaction patterns between the virome and microbiome. The gut microbiome also differs between stroke patients and healthy volunteers. The relative abundance of opportunistic pathogens increases but that of symbiotic bacteria decreases in stroke patients. Related Articles | Metrics | Comments（0）

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Puerarin alleviates insulin resistance in type 2 diabetic mice by modulating fetuin B-AMPK/ACC signaling pathway in the liver Journal of Southern Medical University    2021, 41 (6): 839-846.   DOI: 10.12122/j.issn.1673-4254.2021.06.05 Abstract （324）   HTML （50）    PDF（pc） （1679KB）（1032）       Knowledge map    Save Objective To explore the role of fetuin B-AMPK/ACC signaling pathway in mediating the effect of puerarin on hepatic insulin resistance in mice with type 2 diabetes mellitus (T2DM). Methods Forty C57BL/6J mouse models of T2DM induced by high-fat diet and intraperitoneal injection of streptozotocin were randomized into diabetic model (HFD) group and 3 puerarin groups for treatment with low- , moderate- and high- dose puerarin (50, 100 and 200 mg/kg, respectively), with another 10 mice fed a normal diet as the control group. After treatment for 8 weeks, the mice were examined for fasting blood glucose (FBG), fasting insulin (FINS), liver triglycerides (TG), cholesterol (TC) and free fatty acids (FFA) levels. The expression of fetuin B in the liver was detected by immunohistochemistry. RT-qPCR was used to detect the expressions of fetuin B, AMPK, and ACC mRNA in the liver, and the protein expressions of fetuin B, AMPKα1, ACC, P-AMPKαT183/T172, and P-ACC S79 were determined with Western blotting. Results Treatment with moderate- and high-dose puerarin significantly lowered TG, TC, FFA and FBG levels in diabetic mice (P<0.01). Puerarin at all the 3 doses significantly lowered FINS and HOMA-IR of the mice (P<0.01). In diabetic mice, hepatic expressions of fetuin B and ACC mRNA increased and AMPK mRNA decreased significantly (P<0.01); the protein expressions of fetuin B and ACC increased while those of AMPKα1, P-AMPKαT183/T172 and P-ACC S79 decreased significantly (P<0.01). Puerarin dose-dependently inhibited the mRNA and protein expressions of fetuin B and ACC, increased AMPK mRNA and protein expressions of AMPKα1, P-AMPKαT183/ T172, and P-ACC S79, and lowered fetuin B content in the liver of diabetic mice (P<0.01). Conclusion Puerarin alleviates insulin resistance and improves glucolipid metabolism in T2DM mice by modulating hepatic fetuin B-AMPK/ACC signaling pathway. Related Articles | Metrics | Comments（0）

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Identification of potential hub genes of Alzheimer's disease by weighted gene co-expression network analysis XUE Jiguo, LIU Jing, GENG Miao, YUE Jingwei, HE Haochen, FAN Jiao Journal of Southern Medical University    2021, 41 (12): 1752-1762.   DOI: 10.12122/j.issn.1673-4254.2021.12.01 Abstract （786）   HTML （86）    PDF（pc） （583KB）（1032）       Knowledge map    Save Objective To investigate the differential expression gene modules and hub genes associated with Alzheimer's disease (AD) by weighted gene co-expression network analysis (WGCNA) and annotate the biological functions of these modules. Methods We downloaded transcriptome sequencing data from the GEO database, and according to the correlation of the genes, a gene co-expression network was constructed with the parameter setting of β=8 and a correlation coefficient threshold of 0.85. Pearson correlation test was used to calculate the correlation between the module genes and clinical traits to screen the gene modules significantly associated with AD and identify the hub genes according to the connectivity within modules. GO functional enrichment analysis and KEGG pathway analysis were used to annotate the functions of the modules. A cell model of AD was established in SH-SY5Y cells by Aβ1-42 treatment, and the mRNA expression levels of the hub genes were compared between the Aβ1-42-treated cells and the control cells. Results Ten gene co-expression modules were constructed based on the correlations of gene expression, in which the brown (r=0.66, P<0.001) and turquoise modules (r=-0.68, P<0.001) were significantly correlated with the AD group. Forty-eight genes were identified as the hub genes in the co-expression network. Function annotation revealed that the genes in both modules were mainly enriched in DNA damage and repair pathways and metabolism-related pathways. Differential expression analysis of the genes revealed that the genes DNASE1, TEKT2 and MTSS1L were highly expressed while ACP2, LANCL2 and GMPR2 were lowly expressed in AD group. The results of cell experiment confirmed the up-regulation of DNASE1, TEKT2 and MTSS1L genes and the down-regulation of ACP2, LANCL2, and GMPR2 in Aβ1-42-treated SH-SY5Y cells (P<0.01). Conclusion The brown and turquoise modules are closely correlated with AD. The hub genes including MTSS1L, GMPR2, ACP2, ACTG1 and LANCL2 selected from the modules may participate in AD pathogenesis by regulating DNA damage and repair. Related Articles | Metrics | Comments（0）

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CDK1, CCNB1 and NDC80 are associated with prognosis and progression of hepatitis B virus-associated hepatocellular carcinoma: a bioinformatic analysis LI Yujie, WU Dengqiang, WEI Changhong, YANG Xuejia, ZHOU Sufang Journal of Southern Medical University    2021, 41 (10): 1509-1518.   DOI: 10.12122/j.issn.1673-4254.2021.10.09 Abstract （424）   HTML （53）    PDF（pc） （1965KB）（994）       Knowledge map    Save Objective To identify the key genes involved in the transformation of hepatitis B virus (HBV) into hepatocellular carcinoma (HCC) and explore the underlying molecular mechanisms. Methods We analyzed the mRNA microarray data of 119 HBV-related HCC tissues and 252 HBV-related non-tumor tissues in GSE55092, GSE84044 and GSE121248 from the GEO database, and the "sva" R package was used to remove the batch effects. Integration analysis was performed to identify the differentially expressed genes (DEGs) in HBV-related liver cancer and liver tissues with HBV infection. The significant DEGs were functionally annotated using GO and KEGG analyses, and the most important modules and hub genes were explored with STRING analysis. Kaplan-Meier and Oncomine databases were used to verify the HCC gene expression data in the TCGA database to explore the correlations of the hub genes with the occurrence, progression and prognosis of HCC. We also examined the expressions of the hub genes in 17 pairs of surgical specimens of HCC and adjacent tissues using RT-qPCR. Results We identified a total of 121 DEGs and 3 genetic markers in HCC (P<0.01). These DEGs included cyclin1 (CDK1), cyclin B1 (CCNB1), and nuclear division cycle 80 (NDC80), which participated in cell cycle, pyrimidine metabolism and DNA replication and were highly correlated (P<0.05). Analysis of the UALCAN database confirmed high expressions of these 3 genes in HCC tissues, which were correlated with a low survival rate of the patients, as shown by Kaplan-Meier analysis of the prognostic data from the UALCAN database. CDK1, CCNB1 and NDC80 were all correlated with the clinical grading of HCC (P<0.05). The results of RT-qPCR on the surgical specimens verified significantly higher expressions of CDK1, CCNB1 and NDC80 mRNA in HCC tissues than in the adjacent tissues. Conclusion CDK1, CCNB1 and NDC80 genes can be used as prognostic markers of HBV-related HCC and may serve as potential targets in preclinical studies and clinical treatment of HCC. Related Articles | Metrics | Comments（0）