Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (dissociation constant (K _D) = 0.39 ± 0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.

Background::The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking.Methods::We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases.Results::We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control.Conclusions::REDH is accessible at http://www.redhdatabase.com/. This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

Objective:To explore the interplay between tumor microenvironment (TME)-associated genes, cuproptosis, and the prognosis of liver cancer through transcriptome sequencing and functional genomics analysis.Methods:Employing a hybrid approach that integrates bioinformatics with fundamental experimental research, we utilized the TCGA database to acquireexpression profiles and clinical-pathological information from 424 liver hepatocellular carcinoma patients. We evaluated ImmuneScore and StromalScore to categorize patients into high and low groups, subsequently identifying differentially expressed genes (DEG) at the intersection of these groups. Core DEG were identified through univariate Cox regression analysis and protein-protein interaction (PPI) network analysis. The association between the expression levels of core genes and the survival time of liver cancer patients was analyzed using the R language and Kaplan-Meier analysis, and verified using the Kaplan-Meier Plotter online database. We established a cuproptosis cell model and performed RNA-seq to examine gene expression alterations during copper-induced cell death, followed by in vitro cell experiments for verification.Results:A total of 1 701 and 2 041 DEG were llinked t ImmuneScore and StromalScore, respectively, encompassing 1 134 commonly upregulated genes and 60 commonly downregulated genes. The top 30 core genes from the PPI network's dominant nodes were cross-referenced with univariate Cox regression results, leading to the identification of the pivotal immune gene CCR7. CCR7 mRNA expression levels were higher in hepatocellular carcinoma tissues than in normal tissues ( P<0.05). Patients with high expression of CCR7 in liver cancer had a longer overall survival compared to those with low expression ( P=0.003). Treatment with elesclomol-CuCl2significantly curtailed the survival of hepatocellular carcinoma cel ( P<0.001). RNA-seq data from the cuproptosis model indicated a downregulation of CCR7 expression during the onset of cuproptosis [|log 2(FC)|=2.27, P<0.001], and downregulation of CCR7 expression enhanced the sensitivity of hepatocellular carcinoma cells to cuproptosis inducers. Conclusion:The TME-related gene CCR7 is implicated in cuproptosis, and its downregulation might facilitate the process in liver cancer.CCR7 holds potential as a biomarker for liver cancer prognosis.

Objective To investigate the expression and role of the Sonic Hedgehog (Shh) signaling pathway in intestinal mucosal barrier injury in rats with severe acute pancreatitis (SAP). Methods A total of 48 Sprague-Dawley rats were divided into sham-operation group (Sham group), SAP model group (SAP group), SAP+Shh signaling pathway-specific agonist purmorphamine group (PUR+SAP group), and SAP+Shh signaling pathway-specific antagonist cyclopamine group (CYC+SAP group) using a random number table, with 12 rats in each group, and each group was further divided into 12-hour and 24-hour subgroups, with 6 rats in each subgroup. Rats were given retrograde injection of 5% sodium taurocholate into the pancreatic and bile ducts to establish a model of SAP, and rats in the intervention groups were given intraperitoneal injection of 0.69 mg/kg purmorphamine and 0.69 mg/kg cyclopamine before modeling. Related samples were collected at 12 and 24 hours after modeling. HE staining was used to observe the pathological changes of the pancreas and the ileum; ELISA was used to measure the serum levels of amylase, lipase, diamine oxidase (DAO), and endotoxin-core antibody (EndoCAb); the TUNEL method was used to observe the apoptosis of intestinal epithelial cells; Western blot was used to measure the expression levels of Shh, Ptch1, and Gli1 in ileal tissue. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups and further comparison between two groups. Results Compared with the Sham group, the SAP group had significant increases in the pathological scores of pancreatic and ileum tissue, the serum levels of lipase, amylase, DAO, and EndoCAb, the apoptosis of intestinal epithelial cells, and the protein expression levels of Shh, Ptch1, and Gli1 in ileal tissue (all P < 0.05). Compared with the SAP group, the PUR+SAP group had significantly alleviated pathological injury and dysfunction of the pancreas and intestine, a significant reduction in the apoptosis of intestinal epithelial cells, and significant increases in the protein expression levels of Shh, Ptch1, and Gli1 in ileal tissue (all P < 0.05). Compared with the SAP group, the CYC+SAP group had significant aggravation of the pathological injury and dysfunction of the pancreas and intestine, a significant increase in the apoptosis of intestinal epithelial cells, and significant reductions in the protein expression levels of Shh, Ptch1, and Gli1 in ileal tissue (all P < 0.05). Conclusion The Shh signaling pathway may be involved in intestinal mucosal barrier injury in SAP and exerts a protective effect.

The C-glycosidic bond that connects the sugar moiety with aglycone is difficult to be broken or made due to its inert nature. The knowledge of C-glycoside breakdown and synthesis is very limited. Recently, the enzyme DgpA/B/C cascade from a human intestinal bacterium PUE was identified to specifically cleave the C-glycosidic bond of puerarin (daidzein-8-C-glucoside). Here we investigated how puerarin is recognized and oxidized by DgpA based on crystal structures of DgpA with or without substrate and biochemical characterization. More strikingly, we found that apart from being a C-glycoside cleaving enzyme, DgpA/B/C is capable of efficiently converting O- to C-glycoside showing the activity as a structure isomerase. A possible mechanistic model was proposed dependently of the simulated complex structure of DgpB/C with 3″-oxo-daidzin and structure-based mutagenesis. Our findings not only shed light on understanding the enzyme-mediated C-glycosidic bond breakage and formation, but also may help to facilitate stereospecific C-glycoside synthesis in pharmaceutical industry.

Schizophrenia (SCZ) is a kind of devastating and common neuropsychiatric disorder, and its etiology remains to be determined. Dizocilpine MK-801 animal models, which can cover the major endophenotypes of SCZ, are widely used in the study of SCZ. In this paper, the research status is reviewed about the pathogenic mechanism, modeling method, behavioral characteristics of MK-801 animal models of SCZ in recent years in order to provide some possible ideas for the study of SCZ.

Objective:To observe the relationship between pulmonary artery systolic pressure (PASP) and acute renal injury (AKI) and prognosis after cardiopulmonary bypass (CPB) heart surgery.Methods:The clinical data of 9 860 patients who underwent CPB heart surgery in Beijing Anzhen Hospital from January 1st, 2015 to December 31st, 2016 were analyzed retrospectively. The patients were divided into two groups according to whether AKI occurred after operation. The clinical data were obtained from hospital information system (HIS) and DoCare including general information, types of operation, preoperative complication, ejection fraction, serum creatinine (SCr), PASP, intraoperative CPB duration, aortic occlusion duration, fluid balance, blood products and drug usage, postoperative mechanical ventilation duration, length of intensive care unit (ICU) and hospital stay, and perioperative central venous pressure (CVP). Multivariate Logistic regression analysis was used to screen the risk factors of AKI after operation. According to the preoperative PASP level, the patients were divided into ≥ 60 mmHg (1 mmHg = 0.133 kPa) group and < 60 mmHg group, and the incidence of AKI and prognosis after operation were compared between the two groups. All patients were followed up by telephone after discharge, and they were divided into survival group and death group according to the follow-up results, and the clinical data were compared between the two groups. Multivariate Cox regression analysis was used to screen the risk factors of long-term prognosis. Kaplan-Meier survival curve was used to analyze the long-term prognosis of two groups with different preoperative PASP levels.Results:6 285 patients were enrolled in the final analysis. ① Among the 6 285 patients, 2 592 patients (41.2%) suffered from AKI after operation, of whom 1 697 (65.5%) were stage 1 according to Kidney Disease: Improving Global Outcomes (KDIGO), which was the main type of AKI. Univariate analysis showed that age, preoperative ejection fraction, SCr, PASP, coronary heart disease, hypertension, diabetes, intraoperative CPB duration, aortic occlusion duration, fluid balance, red blood cell input and norepinephrine, dopamine, epinephrine dosage, postoperative mechanical ventilation duration, the length of ICU and hospital stay, and perioperative CVP might be the risk factors of AKI after operation. Multivariate Logistic regression analysis showed that preoperative PASP was one of independent risk factors for AKI in patients undergoing CPB heart surgery [odds ratio ( OR) = 4.753, 95% confidence interval (95% CI) was 1.328-8.417, P = 0.004]. The incidence of AKI after operation in PASP ≥ 60 mmHg group was significantly higher than that in < 60 mmHg group [73.8% (712/965) vs. 35.3% (1 880/5 320), P < 0.01]. ② After a follow-up of (11±3) months, 237 patients (3.8%) died in 6 285 patients. The mortality of patients in PASP ≥ 60 mmHg group was significantly higher than that in < 60 mmHg group [9.5% (92/965) vs. 2.7% (145/5 320), P < 0.01]. Kaplan-Meier survival curve analysis showed that there was a significant difference between the two groups in cumulative survival rate (Log-Rank test: χ2 = 144.400, P < 0.001). Univariate analysis showed that male, age, preoperative hypertension, ejection fraction, PASP, intraoperative CPB duration, aortic occlusion duration, fluid balance, epinephrine dosage, postoperative mechanical ventilation duration, the length of ICU and hospital stay, and perioperative CVP might be risk factors for long-term death of patients undergoing CPB heart surgery. Multivariate Cox regression analysis showed that for every 1 mmHg increase in preoperative PASP, the long-term mortality increased by 1.126 times [hazard ratio ( HR) = 1.126, 95% CI was 1.003-1.604, P = 0.021]. Conclusion:The increase of PASP is related to AKI after CPB heart surgery, which is an independent risk factor for long-term mortality.

Gegen Qinlian Decoction (GQD), a traditional Chinese medicine (TCM) formula, has long been used for the treatment of common metabolic diseases, including type 2 diabetes mellitus. However, the main limitation of its wider application is ingredient complexity of this formula. Thus, it is critically important to identify the major active ingredients of GQD and to illustrate mecha-nisms underlying its action. Here, we compared the effects of GQD and berberine, a hypothetical key active pharmaceutical ingredient of GQD, on a diabetic rat model by comprehensive analyses of gut microbiota, short-chain fatty acids, proinflammatory cytokines, and ileum transcriptomics. Our results show that berberine and GQD had similar effects on lowering blood glucose levels, modulating gut microbiota, inducing ileal gene expression, as well as relieving systemic and local inflammation. As expected, both berberine and GQD treatment significantly altered the overall gut microbiota structure and enriched many butyrate-producing bacteria, including Faecalibacterium and Roseburia, thereby attenuating intestinal inflammation and lowering glucose. Levels of short-chain fatty acids in rat feces were also significantly elevated after treatment with ber-berine or GQD. Moreover, concentration of serum proinflammatory cytokines and expression of immune-related genes, including Nfkb1, Stat1, and Ifnrg1, in pancreatic islets were significantly reduced after treatment. Our study demonstrates that the main effects of GQD can be attributed to berberine via modulating gut microbiota. The strategy employed would facilitate further stan-dardization and widespread application of TCM in many diseases.

Objective: To explore the clinical value of new rapid pathological diagnosis technology in biliary biopsy by endoscopic retrograde cholangiopancreatography (ERCP). Methods: 7 patients with biliary biopsy by ERCP were selected. In the biliary biopsyoperation, a new type of rapid pathological diagnostic technique is used to perform cytological initial diagnosis of the biopsy tissue. According to the results of rapid pathological diagnosis of biliary biopsy operation, we analyzed the clinical value of new rapid pathological diagnosis technology in the biliary biopsy operation. Results: The new rapid pathological diagnosis technology requires little space and no pollution. The diagnosis takes about 2 to 3 minutes and does not affect the normal biopsy operation. 7 patients with biliary biopsy by ERCP under the assistance of this technique, 5 patients (71.4%) confirmed the requirement of biopsy quality and quantity for the first biopsy with the assistance of this technology and 2 patients (28.6%) met the requirements for biopsy quality and quantity after biopsy again. Conclusions Because of the blindness of biliary biopsy by ERCP, the quality and quantity of biopsy tissue are often not guaranteed. The new rapid pathological diagnosis technology can provide real-time pathological diagnosis during biliary biopsy by ERCP and improve the quality and quantity of biliary biopsy tissue, and the cost of this technology is low, which is suitable for popularization and implementation in hospitals at all levels.

Mediation analysis is mainly used to explore the causal mechanism between independent variable X and dependent variable Y. It determines whether mediator M plays a role and evaluate the role’s degree in the causal path by decomposing the causal path between the independent variable X and the dependent variable Y. However, the classical mediation analysis is generally used for single mediator. This paper introduces a new mediation analysis method for multiple mediators.