OBJECTIVES: To investigate the role of the calcium/calmodulin (CaM)-mediated activation of calcineurin (CN)-nuclear factor of activated T cells (NFAT) signaling pathway in mediating the regulatory effect of hyperforin (HY) on stress-induced depression-like disorder (DP) in mice. METHODS: C57BL/6J mice were randomly divided into control group, DP model group, and hyperforin treatment group (n=15). Behavioral changes of the mice were assessed using open field test (OFT), sucrose preference test (SPT), tail suspension test (TST), light/dark box test (LDB), and novel object suppression test (NSFT). Immunohistochemistry was used to detect tyrosine hydroxylase (TH) expression in the CA1 region of the hippocampus, and serum serotonin (5-HT) and norepinephrine (NA) levels were detected with ELISA. Western blotting was used to analyze the expressions of TNF-α, IL-1β, IL-2, and CN-NFAT pathway proteins. In cultured BV-2 microglial cells with lipopolysaccharide (LPS) stimulation, the effects of hyperforin and CN inhibitor (CNIS) on expressions of ionized calcium-binding adapter molecule 1 (IBA-1), 5-HT, NA, inflammatory cytokines and CN-NFAT pathway proteins were examined using immunofluorescence assay, ELISA or Western blotting. RESULTS: Compared with the control mice, the mice in DP group showed significantly reduced activity in OFT, decreased sucrose consumption in SPT, reduced shuttle crossing in LDB, and lowered food intake in NSFT with significantly increased immobility in TST. The mice with DP showed significantly decreased TH-positive neurons, lowered 5-HT and NA levels, and increased expressions of TNF-α, IL-1β, IL-2 and CaM-CN-NFAT pathway proteins. In cultured BV-2 cells, LPS stimulation strongly increased cellular IBA-1 expression, decreased the levels of neurotransmitters (5-HT and NA), and increased the levels of inflammatory cytokines and CN-NFAT signaling, and these changes were effectively reversed by treatment with hyperforin or CNIS. CONCLUSIONS Hyperforin improves stress-induced depression-like behaviors in mice and activated BV-2 cells by targeting the CN-NFAT signaling pathway.
Animals ; Mice, Inbred C57BL ; Mice ; Microglia/drug effects* ; Depression/etiology* ; Perylene/pharmacology* ; Calcineurin/metabolism* ; NFATC Transcription Factors/metabolism* ; Calcium Signaling/drug effects* ; Stress, Psychological ; Phloroglucinol/pharmacology* ; Signal Transduction ; Male ; Behavior, Animal/drug effects* ; Terpenes

Jasmonic acid (JA), a plant endogenously synthesized lipid hormone, plays an important role in response to stress. This manuscript summarized the biosynthesis and metabolism of JA and its related regulatory mechanisms, as well as the signal transduction of JA. The mechanism and regulatory network of JA in plant response to biotic and abiotic stresses were systematically reviewed, with the latest advances highlighted. In addition, this review summarized the signal crosstalk between JA and other hormones in regulating plant resistance to various stresses. Finally, the problems to be solved in the study of plant stress resistance mediated by JA were discussed, and the application of new molecular biological technologies in regulating JA signaling to enhance crop resistance was prospected, with the aim to facilitate future research and application of plant stress resistance.
Signal Transduction ; Cyclopentanes ; Oxylipins ; Plant Growth Regulators

Objective:To screen and verify the key radioresistance genes regulated by m6A methylation in nasopharyngeal carcinoma (NPC) based on the chip data and cell experiments.Methods:The microarray data of NPC radioresistance genes, m6A regulated genes and mRNA expression profiles of NPC genes were downloaded from Gene Expression Omnibus (GEO) database. The differential genes were screened and statistically analyzed by R software. The biological processes, signal pathways and interaction networks of these genes were analyzed by bioinformatics. The m6A regulatory factors were knocked down and the radioresistant strains were constructed. The above m6A differential radioresistant genes of NPC were screened and verified by real-time reverse transcription PCR (qRT-PCR) and Western blot. The m6A modification of screened genes and their direct binding ability with methyltransferase 3 (METTL3) were verified by methylated RNA immunoprecipitation qPCR (MeRIP-qPCR). The siRNA of selected genes was transfected into NPC cells, and after treatment with ionizing radiation, cell proliferation was detected by CCK-8 assay and EdU, apoptosis and cell cycle were detected by flow cytometry, and radiosensitivity was detected by clone formation assay. The trend of differences in the abundance of Fe 2+ and lipid peroxidation between the control and EGLN3 knockdown groups after ionizing radiation treatment was compared by paired t-test. Results:Chip data GSE48501 intersected with GSE200792 and GSE53819 to obtain 6 differential genes, including EGLN3, FOSL2, ADM, JUN, VEGFA and PRDM1. The target genes of EGLN3 and FOSL2 were further screened by TNMplot and KMplot, etc. The mRNA of the target genes directly bound to METTL3 and were subjected to its mediated modification of m6A. The target genes were up-regulated in the parental cells after irradiation in a dose and time gradient manner, which were also significantly up-regulated in radioresistant cells. After EGLN3 and FOSL2 were down regulated, the proliferation activity of NPC cells was more significantly decreased after irradiation, and the radiosensitization ratio was statistically significant compared with that of NPC cells without EGLN3 and FOSL2 down-regulation. After irradiation, EGLN3 down-regulated NPC cells significantly down-regulated glutathione peroxidase 4 (GPX4) expression, increased the abundance of Fe 2+ and lipid peroxidation, which played a role in radiosensitization by inducing ferroptosis. Conclusions:EGLN3 and FOSL2 play a role in radioresistance in NPC through METTL3 mediated m6A methylation. Down-regulation of EGLN3 combined with ionizing radiation can increase the intracellular Fe 2+ abundance and lipid peroxidation and down-reuglate the expression of GPX4 in NPC cells, which can enhance radiosensitization for NPC radiotherapy by the ferroptosis pathway.

Background::Long non-coding RNAs (lncRNAs) plays an important role in the progression of gastric cancer (GC). Their involvement ranges from genetic regulation to cancer progression. However, the mechanistic roles of RP11-789C1.1 in GC are not fully understood.Methods::We identified the expression of lncRNA RP11-789C1.1 in GC tissues and cell lines by real-time fluorescent quantitative polymerase chain reaction. A series of functional experiments revealed the effect of RP11-789C1.1 on the proliferation of GC cells. In vivo experiments verified the effect of RP11-789C1.1 on the biological behavior of a GC cell line. RNA pull-down unveiled RP11-789C1.1 interacting proteins. Western blot analysis indicated the downstream pathway changes of RP11-789C1.1, and an oxaliplatin dosing experiment disclosed the influence of RP11-789C1.1 on the drug sensitivity of oxaliplatin. Results::Our results demonstrated that RP11-789C1.1 inhibited the proliferation of GC cells and promoted the apoptosis of GC cells. Mechanistically, RP11-789C1.1 inhibited checkpoint kinase 1 (CHK1) phosphorylation by binding ataxiatelangiectasia mutated and Rad3 related (ATR), a serine/threonine-specific protein kinase, promoted GC apoptosis, and mediated oxaliplatin sensitivity.Conclusion::In general, we discovered a tumor suppressor molecule RP11-789C1.1 and confirmed its mechanism of action, providing a theoretical basis for targeted GC therapy.

Antimicrobial resistance (AMR), is regarded as one of the top 10 global public health threats. Addressing AMR through the One Health strategy has become a global consensus. AMR monitoring plays a crucial role as the cornerstone of AMR response strategies. This study thoroughly analyzed current situation and progress of AMR monitoring based on the One Health concept in China, the United Kingdom, the United States, and the European Union, and comprehensively compared the similarities and differences of AMR monitoring systems across these countries and regions. The research found that cross-national, cross-regional, and cross-sectoral cooperation in AMR monitoring is increasingly strengthening. However, notable discrepancies still exist among different countries and regions. Notably, most AMR monitoring systems prioritize human and animal health, with relatively insufficient monitoring in the environmental sector. Given the current landscape, China still needs to continue to promote standardized AMR monitoring data sharing and integration across the human, animal, food, and environmental fields, striving to construct a comprehensive and systematic "whole-chain" AMR monitoring system to better tackle this global public health challenge effectively.

Objective:To analyze and evaluate the safety and efficacy of a Chinese domestically manufactured Heart Con-type implantable third-generation magnetic and hydrodynamic levitation left ventricular assist device(LVAD) for the treatment of end-stage heart failure(ESHF), by reporting the results of eleven-center clinical trial on 50 cases.Methods:This study was a multicenter clinical trial, designed by means of prospective, multicenter and single-group target value. 50 subjects with ESHF were competitively enrolled and treated with HeartCon as the LVAD in eleven centers. The primary efficacy measure was survival, defined as either the subjects experiencing the transition to heart transplantation(HT) or myocardial recovery assisted by the device within 90 days, or as successfully assisted by the LVAD for full 90 days after implantation. The target survival rate was 60%, other observations included implantation success rate, mortality, pump failure needing replacement or emergency heart transplantation.Results:All enrolled 50 patients received LVAD implantation successfully, 46 survived with the pump for 90 days, 1 patient transitioned to heart transplantation, and 3 patients experienced pump thrombosis, within which 2 patients underwent pump replacement and continued to live with the pump for 90 days, and the other one received emergency heart transplantation. There were no dropout subjects. The survival rate at full 90 days after HeartCon implantation was 100%. The survival rates with pump in the full set analysis and the protocol set analysis were 96.00% and 95.92% respectively, which were higher than the target value of 60%. The differences were both statistically significant( P<0.05). Conclusion:The results of the multicenter clinical trial with the largest sample size in China using domestically manufactured third-generation LVAD has demonstrated that, HeartCon is a safe and effective LVAD to treat ESHF patients.

Objective To investigate the mechanism and the effect of miR-524-5p regulating HEG1 expression on the proliferation and epithelial-mesenchymal transition of esophageal cancer cells. Methods The expression levels of miR-524-5p and HEG1 mRNA in esophageal cancer cells and normal esophageal epithelial cells were detected by qRT-PCR. KYSE30 cells were divided into miR-524-5p mimic group, miR-524-5p NC group, miR-524-5p mimic+pcDNA3.1 group, and miR-524-5p mimic+pcDNA3.1-HEG1 group. Non-transfected cells were set as the normal control group (group Control). CCK-8 method was applied to detect the proliferation ability of KYSE30 cells. Western blot analysis was conducted to detect the expression of proteins related to EMT, invasion, and migration and the HEG1 protein. Scratch and Transwell assays were applied to detect the migration and invasion abilities of KYSE30 cells. A dual-luciferase reporter gene was used to examine the targeting relationship between miR-524-5p and HEG1. Results miR-524-5p was lowly expressed in four esophageal cancer cell lines, namely, TE-1, KYSE30, KYSE150, and NEC (P < 0.05). KYSE30 cells with the lowest expression level were selected for subsequent experiments. HEG1 mRNA was highly expressed in four esophageal cancer cell lines (P < 0.05). The GEPIA database showed that HEG1 was highly expressed in esophageal cancer tumor tissues (P < 0.05). KYSE30 cells in the miR-524-5p mimic group had lower proliferation ability, colony formation number, mesenchymal marker protein expression, and migration and invasion abilities and upregulated epithelial marker protein E-cadherin level than cells in the miR-524-5p NC group (P < 0.05). The miR-524-5p mimic+pcDNA3.1-HEG1 group significantly reversed the inhibitory effect of overexpression of miR-524-5p on the proliferation, epithelial–mesenchymal transformation, invasion, and metastasis of KYSE30 cells (P < 0.05). The luciferase activity of cells in the miR-524-5p mimic and WT-HEG1 co-transfection groups was lower than that in the miR-524-5p NC and WT-HEG1 co-transfection groups (P < 0.05). Conclusion miR-524-5p is lowly expressed in EC cells and tissues. The overexpression of miR-524-5p can negatively regulate the expression of HEG1 in esophageal cancer cell line (KYSE30 cells) and reduce the proliferation, EMT process, and invasion and migration abilities of KYSE30 cells.

【Objective】 To investigate the clinical characteristics and prognostic factors of small cell carcinoma of bladder (SCCB), and to explore the efficacy of neoadjuvant therapy. 【Methods】 Clinical information of 47 SCCB patients were retrospectively collected, and the clinical and pathological features were compared with those of urothelial carcinoma (UBC). The prognostic factors and efficacy of neoadjuvant therapy were also investigated. 【Results】 SCCB had higher baseline tumor staging, and was more likely to invade the muscle (100%) and metastasize distantly (21.3%). The overall survival was poor (median: 13.1 months, 1-year survival rate: 53.7%, 5-year overall survival rate: 15.4%). Tumor T staging was a risk factor for SCCB, while neoadjuvant therapy was an independent protective factor that significantly reduced the risk of recurrence and metastasis (HR: 0.189, 95%CI: 0.051-0.697, P=0.012) and death (HR: 0.177, 95%CI: 0.045-0.698, P=0.013), and significantly improved disease-free survival and overall survival. In addition, compared with neoadjuvant chemotherapy alone, neoadjuvant chemotherapy combined with immunotherapy could improve the pathological complete response rate. 【Conclusion】 SCCB is highly malignant and prone to metastasis, and has a poor prognosis. Neoadjuvant therapy combined with radical cystectomy is recommended as the first-line treatment.

Arthroplasty, Replacement, Hip ; Female ; Femoral Neck Fractures/surgery* ; Humans ; Osteoporosis/surgery* ; Pregnancy

Non-alcoholic steatohepatitis (NASH) is an important link for the progression of metabolic-related fatty liver disease to end-stage liver disease such as cirrhosis and hepatocellular carcinoma, which seriously endangers human health. NASH pathogenesis is complex, and involves the interaction between hepatic parenchymal and non-parenchymal cells (NPCs), sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and so on. Herein, the relevant research progress of NPCs in the pathogenesis of NASH is reviewed in order to further understand the role of NPCs in NASH.