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ARL67156, a small-molecule CD39 inhibitor, enhances natural killer cell cytotoxicity against gastric cancer cells in vitro and in nude mice GONG Ying, AIMAITI Ailifeire, HE Zongzhong Journal of Southern Medical University    2023, 43 (12): 2006-2014.   DOI: 10.12122/j.issn.1673-4254.2023.12.03 Abstract （270）   HTML （39）    PDF（pc） （2268KB）（2995）       Knowledge map    Save Objective To investigate the effect of ARL67156, a small-molecule inhibitor of CD39, on cytotoxicity of natural killer (NK) cells against gastric cancer cells. Methods Human peripheral blood-derived primary NK cells isolated and purified using a magnetic bead antibody method were treated with 100 μmol/L ARL67156 for 24 h, and the signaling pathway of NK cell activation was detected by Western blotting. The level of interferon-γ (IFN-γ) in the supernatant of NK cells co-cultured with gastric cancer cells was detected using ELISA, and NK cell CD107a degranulation was measured with flow cytometry. The cytotoxicity of NK cells against co-cultured gastric cancer cells was evaluated using flow cytometry. In a nude mouse model bearing subcutaneous gastric cancer xenografts, the therapeutic effect of intravenous transfusion of NK cells and intraperitoneal injection of ARL67156 was assessed by measuring the changes in tumor volume. Results (25.97±5.69) % of peripheral blood NK cells from healthy individuals positive for CD39 expression. Treatment with ARL67156 significantly upregulated the activation molecules including NKG2D, DAP10, CD57, and CD16 and reduced the expressions of the inhibitory receptors TIGIT and KIR, thereby promoting the secretion of IFN-γ and CD107a degranulation in NK cells (P<0.05). In both the in vitro and in vivo experiments, ARL67156 significantly enhanced the cytotoxicity of NK cells against gastric cancer cells (P<0.05). Conclusion ARL67156 activates NK cells through the vav1-Syk signaling pathway to enhance their cytotoxicity against gastric cancer cells, which may serve as a new strategy for NK cell immunotherapy for gastric cancer. Related Articles | Metrics | Comments（0）

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Linagliptin improves diabetic kidney disease in rats by promoting mitochondrial biogenesis through the AMPK/PGC-1α/TFAM pathway WAN Lu, QIAN Yuchi, NI Wenjing, LU Yuxin, LI Wei, PAN Yan, CHEN Weidong Journal of Southern Medical University    2023, 43 (12): 2053-2060.   DOI: 10.12122/j.issn.1673-4254.2023.12.09 Abstract （467）   HTML （24）    PDF（pc） （5421KB）（2377）       Knowledge map    Save Objective To investigate whether linagliptin improves diabetic kidney disease (DKD) by promoting mitochondrial biosynthesis via activating adenosine monophosphate activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α/mitochondrial transcription factor A (AMPK/PGC-1α/TFAM) pathway. Methods With 6 male SD rats feeding normal chow as the control group, 16 SD rat models of DKD induced by intraperitoneal injection of 45 mg/kg STZ and high-fat and high-glucose feeding for 4 weeks were randomized into DKD model group and linagliptin treatment group. The rats in the latter two groups were subjected to daily intragastric administration of vehicle or 5 mg/kg linagliptin (dissolved in 5 g/L sodium carboxymethylcellulose, final concentration of 2 mg/mL) for 12 weeks with further high-fat and high- glucose feeding. After the treatments, the rats were sacrificed and blood samples from the abdominal aorta and kidney tissues were collected for testing blood glucose, liver function and lipid metabolism; HE, PAS, Masson, Sirius red staining and electron microscopy were used to observe renal tissue damage. Renal expressions of transforming growth factor β1 (TGF-β1), fibronectin (FN) and collagen I (Col I) were detected by immunohistochemistry, and the changes in membrane potential (ΔψM) and ATP enzyme content were analyzed to assess mitochondrial damage; The expressions of AMPK/PGC-1α/TFAM pathway proteins were detected using Western blotting. Results Compared with DKD model rats, the rats receiving linagliptin treatment showed significantly decreased blood glucose level (P<0.01) and improved proteinuria (P<0.05) with obviously alleviated renal ultrastructural damage and fibrosis, increased ATPase content and ΔψM (P<0.0001), and enhanced renal expressions of P-AMPK/AMPK, PGC-1α and TFAM (P<0.05). Conclusions Linagliptin improves proteinuria and renal fibrosis in rat models of DKD possibly by activating the AMPK/PGC-1α/TFAM pathway to promote mitochondrial biosynthesis. Related Articles | Metrics | Comments（0）

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Hmga2 knockdown enhances osteogenic differentiation of adipose-derived mesenchymal stem cells and accelerates bone defect healing in mice Zhiyong KE, Zicheng HUANG, Ruolin HE, Qian ZHANG, Sixu CHEN, Zhong-Kai CUI, Jing DING Journal of Southern Medical University    2024, 44 (7): 1227-1235.   DOI: 10.12122/j.issn.1673-4254.2024.07.02 Abstract （356）   HTML （813）    PDF（pc） （5574KB）（2263）       Knowledge map    Save Objective To investigate the role of high-mobility group AT-hook 2 (HMGA2) in osteogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) and the effect of Hmga2 knockdown for promoting bone defect repair. Methods Bioinformatics studies using the GEO database and Rstudio software identified HMGA2 as a key factor in adipogenic-osteogenic differentiation balance of ADSCs. The protein-protein interaction network of HMGA2 in osteogenic differentiation was mapped using String and visualized with Cytoscape to predict the downstream targets of HMGA2. Primary mouse ADSCs (mADSCs) were transfected with Hmga2 siRNA, and the changes in osteogenic differentiation of the cells were evaluated using alkaline phosphatase staining and Alizarin red S staining. The expressions of osteogenic markers Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcein (OCN) in the transfected cells were detected using RT-qPCR and Western blotting. In a mouse model of critical-sized calvarial defects, mADSCs with Hmga2-knockdown were transplanted into the defect, and bone repair was evaluated 6 weeks later using micro-CT scanning and histological staining. Results GEO database analysis showed that HMGA2 expression was upregulated during adipogenic differentiation of ADSCs. Protein-protein interaction network analysis suggested that the potential HMGA2 targets in osteogenic differentiation of ADSCs included SMAD7, CDH1, CDH2, SNAI1, SMAD9, IGF2BP3, and ALDH1A1. In mADSCs, Hmga2 knockdown significantly upregulated the expressions of RUNX2, OPN, and OCN and increased cellular alkaline phosphatase activity and calcium deposition. In a critical-sized calvarial defect model, transplantation of mADSCswith Hmga2 knockdown significantly promoted new bone formation. Conclusion HMGA2 is a crucial regulator of osteogenic differentiation in ADSCs, and Hmga2 knockdown significantly promotes osteogenic differentiation of ADSCs and accelerates ADSCs-mediated bone defect repair in mice. Table and Figures | Reference | Related Articles | Metrics | Comments（0）

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Therapeutic mechanism of Guizhi Gancao Decoction for heart failure: a network pharmacology-based analysis ZHAO Yuxi, ZHAO Xu, ZHU Qingnan, ZHU Bingrui, ZHANG Zhenbin, CHEN Jing Journal of Southern Medical University    2023, 43 (5): 772-782.   DOI: 10.12122/j.issn.1673-4254.2023.05.13 Abstract （517）   HTML （24）    PDF（pc） （6144KB）（2205）       Knowledge map    Save Objective To predict the targets and pathways in the therapeutic mechanism of Guizhi Gancao Decoction (GZGCD) against heart failure (HF) based on network pharmacology. Methods The chemical components of GZGCD were analyzed using the databases including TCMSP, TCMID and TCM@Taiwan, and the potential targets of GZGCD were predicted using the SwissTargetPrediction database. The targets of HF were obtained using the databases including DisGeNET, Drugbank and TTD. The intersection targets of GZGCD and HF were identified using VENNY. Uniport database was used to convert the information, and the components- targets-disease network was constructed using Cytoscape software. The Bisogene plug-in, Merge plug-in, and CytoNCA plug-in in Cytoscape software were used for protein-protein interaction (PPI) analysis to acquire the core targets. Metascape database was used for GO and KEGG analysis. The results of network pharmacology analysis were verified with Western blot analysis. Three factors (PKCα, ERK1/2 and BCL2) were screened according to the degree value of network pharmacology results and the degree of correlation with heart failure process. The pentobarbtal sodium was dissolvein H9C2 cells treated with serum- free high glucose medium to simulate the ischemic anoxic environment of heart failure. The total proteins of myocardial cells were extracted. The protein contents of PKCα, ERK1/2 and BCL2 were determined. Results We identified a total of 190 intersection targets between GZGCD and HF using Venny database, involving mainly the circulatory system process, cellular response to nitrogen compounds, cation homeostasis, and regulation of the MAPK cascade. These potential targets were also involved in 38 pathways, including the regulatory pathways in cancer, calcium signal pathway, cGMP-PKG signal pathway, and cAMP signal pathway. Western blot analysis showed that in an in vitro H9C2 cell model of HF, treatment with GZGCD downregulated PKCα and ERK1/2 expressions and upregulated BCL2 expression. Conclusion The therapeutic mechanism of GZGCD for HF involves multiple targets including PRKCA, PRKCB, MAPK1, MAPK3, and MAPK8 and multiple pathways including the regulatory pathway in cancer and the calcium signaling pathway Related Articles | Metrics | Comments（0）

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Hsa-miR-148a-3p promotes malignant behavior of breast cancer cells by downregulating DUSP1 XU Jiaming, LIN Long, CHEN Qionghui, LI Lan Journal of Southern Medical University    2023, 43 (9): 1515-1524.   DOI: 10.12122/j.issn.1673-4254.2023.09.09 Abstract （199）   HTML （23）    PDF（pc） （5214KB）（1660）       Knowledge map    Save Objective To investigate the role of Hsa-miR-148a-3p in regulating biological behaviors of breast cancer cells and explore the mechanism. Methods TCGA database was used to identify the differential miRNAs and mRNAs in breast cancer, and the protein-protein interaction (PPI) network was constructed using String and Cytoscape to screen the top 10 hub genes and construct the miRNA-TOP10hub network. RT-qPCR was used to detect the expressions of Hsa-miR-148a-3p and DUSP1 in breast cancer tissues and cell lines. The effects of Hsa-miR-148a-3p mimic and inhibitor on proliferation, migration, invasion and apoptosis of MCF-7 cells were analyzed, and luciferase reporter gene experiment was performed to verify the binding of Hsa-miR-148a-3p to DUSP1. The effect of Hsa-miR-148a-3p overexpression on breast cancer cell xenograft growth was evaluated in nude mice. Kaplan-Meier survival curve analysis was used to analyze the survival of the tumor-bearing mice, and the expression level of DUSP1 in the xenografts was detected using immunohistochemistry. Results A total of 54 differential miRNAs and 799 differential mRNAs were identified in breast cancer; 3716 target genes were intersected with the differential mRNA, resulting in 150 intersected genes. The top 10 hub genes were downregulated in breast cancer tissues in the PPI network. Double luciferase reporter gene experiment confirmed that Hsa-miR-148a-3p was capable of binding to DUSP1. Hsa-miR-148a-3p was up-regulated and DUSP1 was down-regulated significantly in breast cancer tissues and cells (P<0.01). In breast cancer cells, Hsa-miR-148a- 3p mimic strongly promoted cell proliferation, migration and invasion and inhibited cell apoptosis (P<0.01). Hsa-miR-148a-3p overexpression obviously promoted xenograft growth in nude mice (P<0.01), shortened survival time of the mice (P<0.01), and reduced the expression of DUSP1 in the xenografts (P<0.01). Conclusion Hsa-miR-148a-3p promotes malignant behavior of breast cancer cells by inhibiting the expression of DUSP1. Related Articles | Metrics | Comments（0）

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Erchen Decoction improves iron homeostasis in mice with non-alcoholic fatty liver disease by regulating iron transport capacity in the spleen DENG Guanghui, JIA Hui, LI Yunjia, LI Junjie, WU Chaofeng, SHI Hao, QIN Mengchen, ZHAO Jiamin, LIU Chang, LIAO Yuxin, GAO Lei Journal of Southern Medical University    2023, 43 (8): 1287-1296.   DOI: 10.12122/j.issn.1673-4254.2023.08.04 Abstract （592）   HTML （23）    PDF（pc） （3455KB）（1603）       Knowledge map    Save Objective To investigate the effect of Erchen Decoction on iron homeostasis in mice with nonalcoholic fatty liver disease (NAFLD) and its mechanism for regulating iron transport in spleen cells. Methods Thirty male C57BL/6J mice were given a high-fat diet for 12 weeks and randomized (n=6) at the 7th week for gavage (3 times a week) of drinking water (NAFLD model group), Erchen Decoction at low, medium and high doses (7.5, 15, and 30g/kg, respectively), or polyene phosphatidyl choline (PPC; 9.12 mg/kg), with another 6 mice with low-fat and low-sugar feeding as the control group. The active components of Erchen Decoction were determined by HPLC-MS. Lipid accumulation in the liver was evaluated by HE staining and Nile red staining. Prussian blue staining was used to observe iron content in the spleen. The iron ion content in the liver tissue was detected using a detection kit. The expressions of ferroportin1 (Fpn1), transferrin receptor (TfR), Steap3, HO-1, Ter-119, CD163 and CD68 were detected using Western blotting, immunohistochemistry and immunofluorescence staining. Results Medium- and high-dose Erchen Decoction partially reversed the increase of lipid accumulation in the liver of NAFLD mice and showed better lipid-lowering effect than PPC. The NAFLD mice showed significantly decreased iron ion content in the spleen with increased hepatic and serum iron contents (P<0.05), decreased TfR protein expression (P<0.05), and increased Fpn1 and Steap3 protein expressions (P<0.05), and these changes were significantly improved by the drug interventions. Erchen Decoction also improved the function of CD163 macrophages in the spleen of NAFLD mice by up-regulating the expression of HO-1 (P<0.05). Conclusion Erchen Decoction can alleviate high- fat diet-induced iron metabolism disorder by improving the iron ion transport ability of the spleen cells to delay the progression of NAFLD. Related Articles | Metrics | Comments（0）

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Exploring the therapeutic mechanism of Liuwei Suanzao decoction for perimenopausal insomnia based on network pharmacology and animal experiments ZHANG Qian, ZHANG Meikui, LIU Yinglu, WANG Yan, LV Feifei, WANG Yuguo Journal of Southern Medical University    2023, 43 (9): 1536-1547.   DOI: 10.12122/j.issn.1673-4254.2023.09.11 Abstract （342）   HTML （38）    PDF（pc） （3884KB）（1526）       Knowledge map    Save Objective To explore the therapeutic mechanism of Liuwei Suanzao decoction (LWSZD) for perimenopausal insomnia (PI) based on network pharmacology. Methods TCMSP and Batman-TCM databases were searched for the active ingredients and targets of LWSZD and a herb- active ingredient-target network was constructed, and the disease targets were obtained from the OMIM, Genecards and Gene databases. The common targets were imported into STRING database and Cytoscape software to screen the core therapeutic targets, and GO enrichment and KEGG pathway analyses were performed using DAVID database. Molecular docking of the main active ingredients of LWSZD and the core targets was conducted using AutoDock, and the results were verified by observing the therapeutic effects of LWSZD and zolpidem in a rat model of PI induced by bilateral ovariectomy and intraperitoneal p-chlorophenylalanine injection. Results A total of 99 active ingredients, 389 drug targets, 187 PI-related targets, and 15 drug-PI common targets were screened. The core active ingredients were armepavine, sanjoinenine and mairin, and the core targets included ESR1, SIRT1, SERPINE1, COMT and CCL2, which were involved in the positive regulation of transcription from RNA polymerase II promoter, signal transduction, response to drug and positive regulation of transcription and in the pathways of dopaminergic synapses, tyrosine metabolism and tryptophan metabolism. Molecular docking results showed that LWSZD had a strong binding with ESR1, SIRT1 and SERPINE1 and was comparable to zolpidem. In the rat models of PI, treatment with LWSZD effectively alleviated the symptoms of insomnia (P<0.01), improved the levels of estrogen and other HPO axis-related hormones (P<0.05), and promoted the mRNA and protein expressions of ESR1 and SIRT1 in the hypothalamus tissues (P<0.01). Conclusion The active ingredients armepavine, sanjoinenine and mairin in LWSZD may synergistically regulate the expressions of ESR1, SIRT1 and SERPINE1 to improve PI in rats. Related Articles | Metrics | Comments（0）

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METTL3 inhibitor STM2457 improves metabolic dysfunction-associated fatty liver disease by regulating mitochondrial function in mice GAO Yinan, WANG Peijun, LU Sumei, MA Wanshan Journal of Southern Medical University    2023, 43 (10): 1689-1696.   DOI: 10.12122/j.issn.1673-4254.2023.10.06 Abstract （521）   HTML （23）    PDF（pc） （4948KB）（1442）       Knowledge map    Save Objective To investigate the effect of methyltransferase-like 3 (METTL3) inhibitor STM2457 in metabolic dysfunction-associated fatty liver disease (MAFLD). Methods C57BL/6J mouse models of MAFLD induced by high-fat diet feeding for 16 weeks were treated with intraperitoneal injections of STM2457 (50 mg/kg) for 2 weeks. The changes in m6A modification level in the liver tissue of the mice were determined with dot-blot hybridization, and the hepatic levels of triglyceride (TG), alanine aminotransferase (ALT) and glutathione aminotransferase (AST) were detected. The histological changes of the liver and changes in insulin resistance and metabolic profile of the mice were evaluated using HE staining, insulin tolerance tests and metabolic cages; transmission electron microscopy (TEM) was employed to examine the changes in mitochondrial morphology. In a HepG2 cell model of steatosis induced by treatment with sodium oleate/sodium palmitate for 48 h, the protective effect of STM2457 (1 μmol/L) on mitochondrial function was assessed by measuring mitochondrial membrane potential using a fluorescence probe (JC-1). Results The mouse models of MAFLD showed significant elevation of m6A modification level in the liver tissues and obviously upregulated mRNA expression of METT3 (P<0.05). Treatment with STM2457 significantly reduced body weight and liver lipid deposition and m6A modification levels, increased glucose tolerance and insulin sensitivity, lowered hepatic TG and serum ALT and AST levels, and increased respiratory entropy (RQ) in the mouse models (all P<0.05). HepG2 cells with steatosis exhibited obvious mitochondrial swelling with decreased mitochondrial membrane potential, but the STM2457-treated cells maintained a normal mitochondrial morphology with a higher membrane potential (P<0.05). Conclusion The METTL3 inhibitor STM2457 improves MAFLD by reducing high-fat diet-induced mitochondrial damage in mice. Related Articles | Metrics | Comments（0）

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Therapeutic mechanism of Shenbing Decoction III for renal fibrosis in chronic kidney disease: a study with network pharmacology, molecular docking and validation in rats LUO Guanfeng, LIU Huaxi, XIE Bei, DENG Yijian, XIE Penghui, ZHAO Xiaoshan, SUN Xiaomin Journal of Southern Medical University    2023, 43 (6): 924-934.   DOI: 10.12122/j.issn.1673-4254.2023.06.07 Abstract （1291）   HTML （18）    PDF（pc） （4146KB）（1441）       Knowledge map    Save Objective To observe the effect of Shenbing Decoction III for improving renal function and pathology in rats with 5/6 nephrectomy and analyze its therapeutic mechanism for renal fibrosis in chronic kidney disease using network pharmacology combined with molecular docking. Methods Forty male SD rats were randomized into two groups to receive two-staged 5/6 nephrectomy (n=30) or sham operation (n=10), and 2 weeks after the final operation, serum creatinine level of the rats was measured. The rats with nephrectomy were further randomized into Shenbing Decoction III group, losartan group and model group for daily treatment with the corresponding drugs via gavage starting at 1 week after 5/6 nephrectomy. After 16 weeks of treatment, serum creatinine and urea nitrogen levels of the rats were measured, and HE staining and Western blotting were used to examine the changes in renal pathology and fibrosis-related factors. Network pharmacology combined with molecular docking study was performed to explore the therapeutic mechanism Shenbing Decoction III against renal fibrosis in chronic kidney disease, and Western blotting was used to verify the expressions of the core targets. Results Compared with those in the model group, the rats receiving 5/6 nephrectomy and Shenbing Decoction III treatment showed significantly reduced serum creatinine and urea nitrogen levels, lessened renal pathologies, and improvement of the changes in epithelial mesenchymal transition-related proteins. Network pharmacological analysis showed that the main active ingredients of Shenbing Decoction III were acacetin, apigenin, eupatilin, quercetin, kaempferol and luteolin, and the key targets included STAT3, SRC, CTNNB1, PIK3R1 and AKT1. Molecular docking study revealed that the active ingredients of Shenbing Decoction III had good binding activity to the key targets. Western blotting showed that in rats with 5/6 nephrectomy, treatment with Shenbing Decoction III obviously restored the protein expression of STAT3, PI3K, and AKT in renal tissue. Conclusion Shenbing Decoction III can reduce renal injury induced by 5/6 nephrectomy in rats, and its therapeutic effects are mediated possibly by its main pharmacologically active ingredients that alleviate renal fibrosis via modulating multiple targets including STAT3, PIK3R1, and AKT1. Related Articles | Metrics | Comments（0）

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JAG1 affects monocytes-macrophages to reshape the pre-metastatic niche of triple-negative breast cancer through LncRNA MALAT1 in exosomes XU Mengqi, SHI Yutong, LIU Junping, WU Minmin, ZHANG Fengmei, HE Zhiqiang, TANG Min Journal of Southern Medical University    2023, 43 (9): 1525-1535.   DOI: 10.12122/j.issn.1673-4254.2023.09.10 Abstract （226）   HTML （14）    PDF（pc） （2356KB）（1409）       Knowledge map    Save Objective To investigate the effect of JAG1 on the activities of monocytes-macrophages in pre-metastatic niche (PMN) of triple-negative breast cancer (TNBC) and explore the possible regulatory mechanism. Methods JAG1 expression in human TNBC MDA-MB-231 and MDA-MB-231B cells was detected using quantitative real-time PCR (qRT-PCR). Ten female nude mice were inoculated with MDA-MB-231 cells (n=5) or MDA-MB-231B cells (n=5) in the mammary fat pad, and 6 weeks later, the tumor tissues were collected for immunohistochemistry. Human monocytes THP-1 cells were treated with rhJAG1 or conditioned media (CM) of TNBC MDA-MB-231 and MDA-MB-231B cells to assess the direct effect of JAG1 on monocytes and its effect on monocytes in the PMN using monocyte-endothelial adhesion, Transwell assay, qRT- PCR and Western blotting. Transmission electron microscopy and nanoparticle tracking analyses were used to identify the effect of JAG1 on exosome release from the TNBC cells. MiRNAs interacting with lncRNA MALAT1 were identified by bioinformatics and validated using qRT- PCR. Results Compared with MDA-MB-231 cells, the invasive strain MDA-MB- 231B cells showed significantly higher JAG1 expression and greater liver metastasis potential (P<0.01). Both direct treatment with rhJAG1 and treatment with the conditioned media promoted adhesion and migration and affected differentiation of the monocytes (P<0.05). Transmission electron microscopy and nanoparticle tracking analysis showed that JAG1 strongly enhanced exosome secretion from MDA-MB-231 cells (P<0.01) and increased MALAT1 content in the exosomes (P<0.0001). Five candidate miRNAs related to MALAT1 and JAG1 were identified by bioinformatics analysis, and miR-26a-5p was identified as a potential target of MALAT1 in monocytes-macrophages in TMN (P<0.0001). Conclusion JAG1 can promote exocrine secretion of TNBC and increase the expression of MALAT1 to cause targeted downregulation of miR- 26a- 5p in monocytes-macrophages in the PMN, which in turn increases JAG1 expression in monocytes-macrophages to affect their adhesion, migration and osteoclast differentiation in the PMN. Related Articles | Metrics | Comments（0）

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Comparison of clinical effects and safety of remidazolam and esketamine for preoperative sedation in children WU Meichao, YANG Fangfang, MA Xingjun, CAI Ning Journal of Southern Medical University    2023, 43 (12): 2126-2131.   DOI: 10.12122/j.issn.1673-4254.2023.12.18 Abstract （498）   HTML （19）    PDF（pc） （836KB）（1362）       Knowledge map    Save Objective To compare the clinical effects and safety of remiazolam and esketamine in preoperative sedation in children. Methods This study was conducted among 61 children (1-4 years old) undergoing elective bilateral tonsillectomy with or without adenoidectomy under general anesthesia from January 2022 to March 2023. The children were randomized into two groups to receive preoperative sedation with intravenous administration of 0.2 mg/kg remidazolam (R group, 30 cases) or 0.5 mg/kg esketamine (S group, 31 cases). The two groups were compared for PSAS score, vital signs (MAP, SpO2, and HR), sedation score, mask acceptance score at induction, sedation onset time, postoperative recovery time, MAP and HR after induction, Ramsay sedation score after awakening, doses of propofol and remifentanil during anesthesia, emergence agitation (EA), postoperative adverse effects and negative postoperative behavioral changes (NPOBCs) on the 7th and 14th days after operation. Results The PSAS score, sedation score, mask acceptance score at induction, MAP and HR after induction, Ramsay sedation score after awakening, propofol dose during anesthesia induction, and the incidence of EA and NPOBCs after operation were all similar between the two groups (P>0.05). Compared with those in S group, the sedation onset time was slightly longer, the recovery time was shorter, and the doses of propofol and remifentanil for anesthesia maintenance was higher (P<0.05) in R group. Sedation with remidazolam did not cause significant changes in MAP, SpO2 or HR (P>0.05), while administration of esketamine significantly increased MAP and HR (P<0.05) without obviously affecting SpO2 (P>0.05). Conclusion In children aged 1-4 years, compared with 0.5 mg/kg esketamine, intravenous injection of 0.2 mg/kg remidazolam for preoperative sedation has a slightly longer onset time and is associated with a shorter recovery time and more stable hemodynamics, suggesting its good feasibility and safety. 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 （263）   HTML （22）    PDF（pc） （8437KB）（1324）       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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VDAC1 participates in house dust mite- induced asthmatic airway inflammation in mice by inducing ferroptosis of airway epithelial cells HUANG Yi, Lin Lishan, HUANG Haohua, DONG Hangming Journal of Southern Medical University    2023, 43 (8): 1333-1338.   DOI: 10.12122/j.issn.1673-4254.2023.08.09 Abstract （598）   HTML （20）    PDF（pc） （1615KB）（1294）       Knowledge map    Save Objective To investigate the role of voltage-dependent anion-selective channel protein 1 (VDAC1) in house dust mite (HDM)-induced asthmatic airway inflammation and its mechanism for regulating ferroptosis in airway epithelial cells. Methods Human airway epithelial (HBE) cells were exposed to a concentration gradient (200, 400 and 800 U) of HDM alone or in combination with treatment with 10 μmol/L VBIT-4 (a VDAC1 inhibitor) for 24 h, and the expressions of VDAC1 and ferroptosis-associated proteins in the cells were examined. Adult male BALB/c mice were treated with intranasal instillation of VBIT-4, HDM, or both, and the level of airway inflammation and the expressions of ferroptosis-associated proteins were detected with immunohistochemistry. Results In HBE cells, HDM exposure caused a significant increase of mitochondrial ROS (mtROS) production and obviously decreased the mitochondrial membrane potential. The exposed cells showed obviously increased protein expressions of VDAC1 (P=0.005) and FTH1 (P=0.030) but decreased protein expression of GPX4 (P=0.015) and FTH1 (P=0.037), while the treatment with VBIT-4 repressed the expression of GPX4 (P=0.001) and inhibited the expression of VDAC1. In BALB/c mice, treatment with VBIT-4 significantly improved HDM-induced airway inflammation by reducing the number of inflammatory cells (P=0.029) in the airway and the number of eosinophils in the alveolar lavage fluid. Immunohistochemical staining showed that GPX4 expression in the airway epithelial cells was significantly increased after treatment with VBIT-4. Conclusions VDAC1 participates in HDM-induced chronic airway inflammation in bronchial asthma by causing ferroptosis of the airway epithelial cells. Related Articles | Metrics | Comments（0）

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Associations of circulating leptin levels with colorectal adenoma and colorectal cancer: a case-control and Mendelian randomization study ZHAO Huanling, LING Yuxiao, MI Shuai, ZHU Jiahao, FAN Jiayao, YANG Ye, WANG Jing, LI Yingjun Journal of Southern Medical University    2023, 43 (12): 1989-1997.   DOI: 10.12122/j.issn.1673-4254.2023.12.01 Abstract （410）   HTML （81）    PDF（pc） （988KB）（1206）       Knowledge map    Save Objective To explore the causal association between circulating leptin levels and the risk of colorectal adenoma and colorectal cancer. Methods We collected demographic and clinical data and serum samples from 497 patients with colorectal adenoma, 955 patients with colorectal cancer, and 911 healthy individuals from the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Zhuji People's Hospital, and Lin'an District First People's Hospital. Instrumental variables of leptin were selected and genotyping tests were performed. A logistic regression model and stratified analysis were used to evaluate the association of serum leptin levels with colorectal adenoma, colorectal cancer, and the progression of colorectal adenoma to colorectal cancer. Genetic risk score (GRS) and single nucleotide polymorphisms (SNPs) were further used as instrumental variables in one-sample and two-sample Mendelian randomization analyses leveraging two-stage least squares and inverse-variance weighted methods to estimate the causal association of leptin levels with the risk of colorectal adenoma, colorectal cancer, and progression of colorectal adenoma to colorectal cancer. Results High levels of leptin, compared with its lowest quartile, were positively correlated with colorectal adenoma (P=0.005) and negatively with colorectal cancer (P<0.001) and the risk of progression of colorectal adenoma to colorectal cancer (P<0.001). Mendelian randomization analysis showed that GRS of leptin, either weighted or not, was not significantly correlated with the risk of colorectal adenoma, colorectal cancer, or the progression of colorectal adenoma to colorectal cancer, nor did the two-sample Mendelian randomization study support an association between leptin and the risk of colorectal cancer (P>0.05). Conclusion Although the case-control study suggests probable correlations of leptin with the risk of colorectal adenoma, colorectal cancer, and colorectal adenoma progression to colorectal cancer, Mendelian randomization studies did not support a causal association of leptin with the risks of colorectal adenoma, colorectal cancer, or colorectal adenoma progression to colorectal cancer. Related Articles | Metrics | Comments（0）

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Jianpi Zishen granule inhibits podocyte autophagy in systemic lupus erythematosus: a network pharmacology and clinical study CHEN Junjie, HUANG Chuanbing, LI Ming Journal of Southern Medical University    2024, 44 (3): 465-473.   DOI: 10.12122/j.issn.1673-4254.2024.03.07 Abstract （188）   HTML （20）    PDF（pc） （2111KB）（1203）       Knowledge map    Save Objective To explore the therapeutic mechanism of Jianpi Zishen (JPZS) granules for systemic lupus erythematosus (SLE) in light of podocyte autophagy regulation. Methods TCMSP, GeneCards, OMIM, and TTD databases were used to obtain the targets of JPZS granules, SLE, and podocyte autophagy. The protein-protein interaction network was constructed using Cytoscape, and the key active ingredients and targets were screened for molecular docking. In the clinical study, 46 patients with SLE were randomized into two groups to receive baseline treatment with prednisone acetate and mycophenolate mofetil (control group) and additional treatment with JPZS granules (observation group) for 12 weeks, with 10 healthy volunteers as the healthy control group. Urinary levels of nephrin and synaptopodin of the patients were detected with ELISA. Western blotting was performed to determine peripheral blood levels of p- JAK1/JAK1, p-STAT1/STAT1, LC3II/LC3I, and p62 proteins of the participants. Results Four key active ingredients and 5 core target genes (STAT1, PIK3CG, MAPK1, PRKCA, and CJA1) were obtained, and enrichment analysis identified the potentially involved signaling pathways including AGE-RAGE, JAK/STAT, EGFR, and PI3K/Akt. Molecular docking analysis showed that STAT1 was the most promising target protein with the highest binding activity, suggesting its role as an important mediator for signal transduction after JPZS granule treatment. In the 43 SLE patients available for analysis, treatment with JPZS granule significantly reduced serum levels of p- JAK1/JAK1, p- STAT1/STAT1, and LC3II/LC3I (P<0.05 or 0.01), increased the protein level of P62 (P<0.05), and reduced urinary levels of nephrin and synaptopodin (P<0.05). Conclusion The therapeutic effect of JPZS granules on SLE is mediated probably by coordinated actions of quercetin, kaempferol, β-sitosterol, and isorhamnetin on their target gene STAT1 to inhibit the JAK/STAT pathway, thus suppressing autophagy and alleviating podocyte injuries in SLE. Related Articles | Metrics | Comments（0）

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Analysis of therapeutic mechanism of Liushen Wan against colitis-associated colorectal cancer based on network pharmacology and validation in mice ZHANG Xuefang, CHEN Yanhua, LI Zongheng, SHANG Jing, YUAN Zeting, DENG Wanli, LUO Ying, HAN Na, YIN Peihao, YIN Jun Journal of Southern Medical University    2023, 43 (7): 1051-1062.   DOI: 10.12122/j.issn.1673-4254.2023.07.01 Abstract （692）   HTML （73）    PDF（pc） （3383KB）（1181）       Knowledge map    Save Objective To explore the therapeutic mechanism of Liushen Wan (LSW) against colitis-associated colorectal cancer (CAC) by network pharmacology. Methods TCMSP, BATMAN-TCM, CNKI, PubMed, Genecards, OMIM, and TTD databases were used to obtain the related targets of LSW and CAC. The common targets of LSW and CAC were obtained using Venny online website. The PPI network was constructed using Cytoscape 3.8.2 to screen the core targets of LSW in the treatment of CAC. GO and KEGG enrichment analysis were conducted using DAVID database. The therapeutic effect of LSW on CAC was evaluated in a C57BL/6J mouse model of AOM/DSS-induced CAC by observing the changes in body weight, disease activity index, colon length, and size and number of the tumor. HE staining and RT-qPCR were used to analyze the effect of LSW on inflammatory mediators. Immunohistochemistry and TUNEL staining were used to evaluate the effect of LSW on the proliferation and apoptosis of AOM/DSS-treated colon tumor cells. Immunohistochemistry and Western blotting were used to detect the effects of LSW on the expression of TLR4 proteins in CAC mice. Results Network pharmacology analysis identified 69 common targets of LSW and CAC, and 33 hub targets were screened in the PPI network. KEGG pathway enrichment analysis suggested that the effect of LSW on CAC was mediated by the Toll-like receptor signaling pathway. In the mouse model of AOM/DSS-induced CAC, LSW significantly inhibited colitis-associated tumorigenesis, reduced tumor number and tumor load (P<0.05), obviously improved histopathological changes in the colon, downregulated the mRNA levels of pro-inflammatory cytokines, and inhibited the proliferation (P<0.01) and promoted apoptosis of colon tumor cells (P<0.001). LSW also significantly decreased TLR4 protein expression in the colon tissue (P<0.05). Conclusion LSW can inhibit CAC in mice possibly by regulating the expression of TLR4 to reduce intestinal inflammation, inhibit colon tumor cell proliferation and promote their apoptosis. Related Articles | Metrics | Comments（0）

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UPLC-Q-TOF-MS/MS combined with network pharmacology for exploring anti-inflammatory mechanism of Eurycoma longifolia LIU Fang, ZHANG Yuanfang, LIU Peng, LIU Jiamin, LIU Siyu, WANG Junjie Journal of Southern Medical University    2023, 43 (6): 879-888.   DOI: 10.12122/j.issn.1673-4254.2023.06.02 Abstract （1154）   HTML （23）    PDF（pc） （2673KB）（1132）       Knowledge map    Save Objective To explore the mechanisms that mediate the anti-inflammatory activity of Eurycoma longifolia. Methods Kunming mouse models of xylene-induced ear swelling and lipopolysaccharide (LPS)-induced acute pneumonia were used to compare the anti- inflammatory activities of aqueous and ethanol extracts of Eurycoma longifolia. UPLC-Q-TOF-MS/MS was used to identify the chemical composition in the ethanol extract of Eurycoma longifolia, based on which the potential anti-inflammatory targets of Eurycoma longifolia were screened using the databases including SwissADME, SwissTargetPrediction, and Genecards. The String database was used to generate the protein-protein interaction (PPI) network, and Cytoscape was used for network topology analysis and screening the core targets. The enrichment of the core targets was analyzed using Metascape database, the core components and targets were docked with Autodock software, and the docking results were visualized using Pymol software. In a RAW264.7 cell model of LPS-induced inflammation, the Griess reagent was used to measure NO level, and Western blotting was performed to detect the expression levels of MAPK1, JAK2, and STAT3 proteins to verify the anti- inflammatory mechanism of Eurycoma longifolia. Results The ethanol extract (75% ) of Eurycoma longifolia (ELE) was the active site, which contained a total of 37 chemical components. These chemical compounds and diseases had 541 targets, involving the JAK/STAT3, cAMP and other signaling pathways. Twelve indicator components were identified, which all showed good results of molecular docking with two core targets involved in the signaling pathways. In the cell validation experiment, treatment of the cells with low-, medium-, and high-dose ELE significantly reduced NO release in the cells, and ELE at the medium dose significantly decreased the cellular expressions of JAK2 and STAT3. Conclusion The anti-inflammatory activity of Eurycoma longifolia is attributed primarily to its active ingredients bitter lignin and alkaloids, which may regulate the JAK/STAT3 signaling pathway by targeting JAK2 and STAT3. Related Articles | Metrics | Comments（0）

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Liuwei Dihuang Pills alleviates postmenopausal osteoporosis and fatigue in rats by inhibiting the epigenetic regulatory molecule BRD4 pathway RUAN Hongliang, SHE Dongmei, SUN Shaoqiu Journal of Southern Medical University    2023, 43 (12): 1998-2005.   DOI: 10.12122/j.issn.1673-4254.2023.12.02 Abstract （291）   HTML （41）    PDF（pc） （2497KB）（1103）       Knowledge map    Save Objective To explore the role of epigenetic signal molecule bromodomain protein 4 (BRD4) in mediating the therapeutic effect of Liuwei Dihuang (LWDH) Pills on postmenopausal osteoporosis (PMOP) and fatigue. Methods Thirty rat models of PMOP induced by bilateral ovariectomy were randomized equally into two groups for treatment with normal saline (model group) or LWDH Pills (385.7 mg/kg), with another 15 sham-operated rats as the sham operation group. After 12 weeks of treatment, femoral samples were taken to determine the bone density and BRD4 protein expression. The weight- bearing exhaustive swimming time of the rat models was recorded, and serum levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were measured using enzyme-linked immunosorbent assay. In cultured primary osteoblasts the changes in the expressions of BRD4, MAPK and NF-κB proteins were detected by immunofluorescence staining following treatment with LWDH Pills. Results The rat models of PMOP showed significantly up-regulated expression of BRD4 protein in the femoral tissue (P<0.05), which was obviously lowered by treatment with LWDH Pills. The rats treated with LWDH Pills also showed significant improvement of fatigue. Immunofluorescent staining of the osteoblasts showed that treatment with LWDH Pills significantly decreased the protein expressions of BRD4, MAPK and NF-κB. Analysis of the GSE56116 dataset revealed that that patients with kidney-yin deficiency had significantly higher BRD4 expression than those in the kidney-yang-deficiency group and non-kidney-deficiency group (P<0.05). The upregulation of BRD4 expression involved multiple signaling pathways including neural ligand receptor response, cytoskeleton rearrangement, cytokine interaction, and granulocyte colony-stimulating factor chemotaxis pathways. Conclusion LWDH can alleviate PMOP and fatigue by decreasing BRD4 signaling pathway, suggesting that potential of BRD4 as a promising therapeutic target for PMOP. Related Articles | Metrics | Comments（0）

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Colorectal cancer cells induce the formation of cancer-associated fibroblasts by activating the ERK signaling pathway in fibroblasts DENG Ting, DU Boyu, XI Xueyan Journal of Southern Medical University    2023, 43 (6): 943-951.   DOI: 10.12122/j.issn.1673-4254.2023.06.09 Abstract （1010）   HTML （14）    PDF（pc） （2225KB）（1071）       Knowledge map    Save Objective To investigate the mechanism by which conditioned medium of colorectal cancer cells promotes the formation of cancer-associated fibroblasts (CAFs). Methods Normal human colorectal fibroblasts (CCD-18Co cells) in logarithmic growth phase were treated with the conditioned media of colorectal cancer HCT116 cells (HCT116-CM) or Caco-2 cells (Caco-2-CM) alone or in combination with 300 nmol/L ERK inhibitor SCH772984. The expression levels of CAFs-related molecular markers were detected in the treated cells with real-time quantitative PCR (RT- qPCR) and immunofluorescence assay, and the changes in cell proliferation, colony formation and migration were assessed with RTCA, colony formation and wound healing assays; Western blotting was performed to detect the activated signaling pathways in the fibroblasts and the changes in CAFs formation after blocking of the signaling pathway. Results HCT116-CM and Caco-2-CM significantly up-regulated mRNA expression levels of CAFs markers (including α-SMA, FAP, FN and TGF-β) in CCD-18Co cells, and strongly promoted fibroblast transformation into CAFs (P<0.05). The two conditioned media also promoted the proliferation, colony formation and migration of CCD-18Co cells (P<0.05) and significantly increased the levels of α-SMA protein and ERK phosphorylation in the cells (P<0.05). The ERK inhibitor SCH772984 obviously inhibited the expression of α-SMA and the transformation of CCD-18Co cells into CAFs induced by the conditioned medium of colorectal cancer cells (P<0.05). Conclusion Colorectal cancer cells may induce the formation of colorectal CAFs by activating the ERK pathway in the fibroblasts. Related Articles | Metrics | Comments（0）

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Zuogui Jiangtang Jieyu Decoction promotes neural stem cell self-renewal and activates Shh signaling in the hippocampal dentate gyrus of diabetic rats with depression YANG Hui, WANG Hua, LI Chenglong, HE Xiong, LEI Shihui, LI Wei, MENG Pan, WANG Jinxi, LIU Jian, WANG Yuhong Journal of Southern Medical University    2023, 43 (5): 694-701.   DOI: 10.12122/j.issn.1673-4254.2023.05.03 Abstract （328）   HTML （24）    PDF（pc） （1992KB）（1071）       Knowledge map    Save Objective To investigate the effect of Zuogui Jiangtang Jieyu Decoction (ZJJ) on Shh signaling and self-renewal of neural stem cells in the hippocampal dentate gyrus of diabetic rats with depression. Methods Diabetic rat models with depression were randomly divided into model group, positive drug (metformin+ fluoxetine) group, and low-, medium-, and high-dose ZJJ groups (n=16), with normal SD rats as the control group. The positive drugs and ZJJ were administered by gavage, and the rats in the control and model groups were given distilled water. After the treatment, blood glucose level was detected using test strips, and behavioral changes of the rats were assessed by forced swimming test and water maze test. ELISA was used to examine the serum level of leptin; The expressions of nestin and Brdu proteins in the dentate gyrus of the rats were detected using immunofluorescence assay, and the expressions of self-renewal marker proteins and Shh signaling proteins were detected using Western blotting. Results The diabetic rats with depression showed significantly increased levels of blood glucose and leptin (P<0.01) and prolonged immobility time in forced swimming test (P<0.01) and increased stage climbing time with reduced stage seeking time and stage crossings in water maze test (P<0.01). The expressions of nestin and Brdu in the dentate gyrus, the expressions of cyclin D1, SOX2, Shh, Ptch1, Smo in the hippocampus and the nuclear expression of Gli-1 were decreased (P<0.01) while hippocampal Gli-3 expression was increased significantly (P<0.01) in the rat models. Treatment of rat models with high-dose ZJJ significantly reduced the blood glucose (P<0.01) and leptin level (P<0.05) and improved their performance in behavioral tests (P<0.01). The treatment also obviously increased the expressions of nestin, Brdu, cyclin D1, SOX2, Shh, Ptch1, and Smo and the nuclear expression of Gli-1 in the dentate gyrus (P<0.01) and reduced hippocampal expression of Gli-3 (P<0.05) in the rat models. Conclusion ZJJ can significantly improve the self-renewal ability of neural stem cells and activate Shh signaling in dentate gyrus of diabetic rats with depression. Related Articles | Metrics | Comments（0）