HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

OBJECTIVES: To investigate the synergistic mechanism of the traditional Chinese medicine Rosa laevigata Michx. (RLM) for treatment of pulmonary arterial hypertension (PAH). METHODS: Network pharmacological analysis was carried out to screen the active ingredients of RLM and PAH disease targets and construct the "component-target-disease" interaction network, followed by gene enrichment analysis and molecular docking studies. In the cell experiments, primary cultures of rat pulmonary arterial smooth muscle cells were exposed to hypoxia for 24 h and treated with solvent or 100, 200 and 300 mg/mL RLM, and the changes in cell proliferation were detected using Western blotting for PCNA and immunofluorescence staining. In the animal experiment, male SD rats were randomized into 5 control group, monocrotaline (MCT) solvent group, and MCT with RLM (100, 200 and 300 mg/mL) treatment groups. HE staining and immunofluorescence staining were used to observe histopathological changes in the pulmonary blood vessels of the rats. RESULTS: Seven core active ingredients (including β-sitosterol and kaempferol) in RLM and 39 key disease targets were identified, and molecular docking showed that SRC was a high-affinity target. KEGG enrichment analysis showed that the differential genes were significantly enriched in calcium signaling and PI3K-AKT pathways. In rat pulmonary arterial smooth muscle cells, hypoxic exposure significantly up-regulated cellular expression of PCNA and phosphorylation levels of Src and AKT1, which were obviously lowered by RLM treatment. In RLM-treated rat models, the mean pulmonary artery pressure and right ventricular hypertrophy index (Fulton index) were significantly reduced, the tricuspid annular plane systolic excursion (TAPSE) was improved, and pulmonary vascular wall thickening and fibrosis were obviously ameliorated. CONCLUSIONS RLM inhibits pulmonary arterial smooth muscle cell proliferation in rat models of hypertension possibly by regulating the Src-AKT1 axis, suggesting the potential of RLM as a new natural drug for treatment of pulmonary hypertension.
Animals ; Cell Proliferation/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Rats, Sprague-Dawley ; Pulmonary Artery/cytology* ; Male ; Rats ; Myocytes, Smooth Muscle/cytology* ; Hypertension, Pulmonary/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Signal Transduction/drug effects* ; Muscle, Smooth, Vascular/cytology* ; src-Family Kinases/metabolism* ; Cells, Cultured

Objective To analyze the influencing factors for poor prognosis in elderly patients with CHD and left ventricular dysfunction(LVD)treated by CABG,and to construct a logistic predic-tion model.Methods A total of 199 elderly CHD patients with LVD undergoing CABG in Zhu-jiang Hospital from April 2020 to April 2023 were retrospectively enrolled.After 1 year of follow-up,according to whether MACCE occurred after surgery,they were divided into MACCE group(24 cases)and non-MACCE group(175 cases).The clinical data were compared between the two groups.Multivariate logistic regression analysis was used to analyze the influencing factors for poor prognosis,and a logistic prediction model was constructed.Results The MACCE group had significantly larger proportions of hypertension,diabetes,chronic kidney disease,NYHA gradeⅢand multi-vessel disease,and smaller proportion of non-cardiopulmonary bypass than the non-MACCE group(P＜0.05,P＜0.01).Multivariate logistic regression analysis showed that diabetes(OR=2.328,95％CI:1.469-3.690,P=0.000),NYH A grade(OR=2.181,95％CI:1.184-4.021,P=0.013),multi-vessel disease(OR=1.996,95％CI:1.187-3.355,P=0.009),and non-cardiopulmonary bypass(OR=0.660,95％CI:0.541-0.806,P=0.000)were independent influen-cing factors for poor prognosis in the patients after CABG.The AUC value of the constructed pre-diction model in predicting poor prognosis was 0.822(95％CI:0.721-0.923),with a sensitivity of 66.70％and a specificity of 80.60％.Conclusion Diabetes,NYHA grade,multi-vessel disease and non-cardiopulmonary bypass are independent influencing factors for poor prognosis in elderly CHD patients complicated with LVD after CABG.The constructed logistic prediction model has certain predictive value for poor prognosis in these elderly patients.

Objective To predict the quality markers of Alismatis Rhizoma and salted Alismatis Rhizoma based on fingerprints and multivariate statistical analysis combined with network pharmacology.Methods HPLC-DAD method was used to establish fingerprints of Alismatis Rhizoma and salted Alismatis Rhizoma.Based on the peak area data of the fingerprints,clustering analysis,principal component analysis and orthogonal partial least squares-discriminant analysis were employed to evaluate the quality of 10 batches of Alismatis Rhizoma and 12 batches of salted Alismatis Rhizoma.The main components with quality differences were screened.Network pharmacology was used to analyze the targets and related pathways of the screened components,A component-target-pathway network was constructed,and molecular docking was used to verify.Quality markers of Alismatis Rhizoma and salted Alismatis Rhizoma were predicted.Results The HPLC fingerprints of Alismatis Rhizoma and salted Alismatis Rhizoma were established.The similarity evaluation showed that the similarity of 10 batches of Alismatis Rhizoma and 12 batches of salted Alismatis Rhizoma ranges from 0.991 to 0.998,0.992 to 1.000,respectively.Nine components with quality differences were identified through multivariate statistical analysis,and five of them were identified as alismoxide,alisol C,alismol,alisol B,23-acetate alisol B.Network pharmacological analysis suggested 278 targets of action associated with the five components.The main signaling pathways of KEGG pathway enrichment analysis were closely related to the main efficacy and modern pharmacological effects of Alismatis Rhizoma and salted Alismatis Rhizoma.These 5 components were preliminary predicted as quality markers for Alismatis Rhizoma and salted Alismatis Rhizoma.Conclusion This study predicted 5 quality markers for Alismatis Rhizoma and salted Alismatis Rhizoma,which can provide reference for their quality control and further research.

Objective:To systematically evaluate the predictive value of the reverse shock index multiplied by the Glasgow coma scale score (rSIG) for mortality of trauma patients.Methods:A comprehensive literature search was conducted to identify studies on the predictive value of rSIG for mortality of trauma patients in the following databases from inception to April 2025, including CNKI, Wanfang Data, SinoMed, PubMed, Cochrane Library, Web of Science, and Embase. Two investigators independently screened the literature, extracted data, and assessed study quality according to predefined inclusion and exclusion criteria. The Quality assessment of diagnostic accuracy studies-2 (QUADAS-2) tool was used to evaluate the risk of bias in the included studies. Meta analysis was performed using Stata 17.0 software with a bivariate mixed-effects model. The following metrics were used to assess the predictive value of rSIG for mortality in trauma patients, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic (SROC) curve (AUC). The influence of various factors on the predictive performance of rSIG was examined, including injury type, study design, region, sample size, cut-off value, rSIG measurement time, and outcome measures. Additionally, sensitivity analysis, Fagan′s nomogram, and Deeks′ funnel plot were employed to assess the robustness of the findings, clinical applicability, and publication bias.Results:A total of 15 studies involving 710 612 trauma patients were included, 26 105 of whom were deceased. Meta analysis results showed that rSIG had a pooled sensitivity of 0.78(95% CI 0.71, 0.84), a pooled specificity of 0.78(95% CI 0.68, 0.86), a pooled PLR of 3.60(95% CI 2.46, 5.27), a pooled NLR of 0.28(95% CI 0.22, 0.36), a pooled DOR of 12.70(95% CI 8.10, 19.91), and an AUC of 0.85(95% CI 0.81, 0.87) for predicting mortality of trauma patients. Subgroup analysis identified injury type as one of the major sources of heterogeneity, and the predictive specificity of rSIG was significantly higher in patients with multiple trauma (0.82) than in those with isolated traumatic brain injury (0.65) ( P<0.05). Sensitivity analysis indicated that the findings were robust and stable. Fagan′s nomogram showed that when the pre-test probability was 7%, the post-test probability of death increased to 21% in patients with low rSIG and decreased to 2% in those with high rSIG. Deeks′ funnel plots suggested no significant publication bias among the included studies ( P>0.05). Conclusion:Low rSIG has good predictive performance for mortality of trauma patients and can serve as an effective tool for early and rapid prognosis assessment with superior predictive performance in patients with multiple trauma compared to those with traumatic brain injury.

Objective:To investigate the differences in acute intestinal injury and regulatory mechanisms in mice following carbon ion FLASH radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT).Methods:Healthy C57BL/6J mice were randomly divided into three groups: control group, FLASH-RT group (100 Gy/s), and CONV-RT group (0.1 Gy/s), with 9 mice in each group. All mice received carbon ion whole abdominal radiotherapy. DNA double-strand breaks (DSB) and cell proliferation were evaluated by measuring the expression of phosphorylated histone H2AX (γ-H2AX) and nuclear-associated antigen 67 (Ki67) using immunohistochemistry; apoptosis was analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL); transcriptome sequencing was used to analyze the differences in molecular pathways between FLASH-RT and CONV-RT.Results:Compared with the CONV-RT group, the FLASH-RT group showed significantly reduced intestinal γ-H2AX signal at 3 h after radiotherapy ( t=3.80, P<0.01), significantly increased expression of Ki67 at the base of intestinal crypts at 6 h after radiotherapy ( t=4.30, P<0.001), and a significantly decreased number of TUNEL-positive cells at 12 h after radiotherapy ( t=3.08, P<0.01). Transcriptome sequencing analysis showed that FLASH-RT specifically activated the insulin-like growth factor (IGF) pathway, avoiding the excessive activation of CONV-RT-induced nuclear factor-κB and B cell receptor inflammatory pathways as well as the inhibition of energy metabolism. Conclusions:Compared with CONV-RT, carbon ion FLASH-RT can reduce DSB damage, preserve the proliferative activity of intestinal stem cells, activate the IGF pathway, and regulate inflammatory, immune, and metabolic pathways, thereby significantly alleviating acute intestinal epithelial injury. Specifically, the regulation of repair pathways mediated by reduced DSB and the inhibition of inflammatory pathways are potential protective mechanisms for normal tissues.

Objective:To investigate the characteristics of the endometrial microbiota in patients with varying degrees of intrauterine adhesion (IUA).Methods:This single-center cross-sectional observational study enrolled 115 patients with IUA who were treated at the Hysteroscopic Center of Fuxing Hospital, Capital Medical University, from May 2022 to October 2023. After quality control and data preprocessing, 81 samples met the inclusion criteria for analysis. Patients were grouped according to an established IUA scoring and grading system into mild IUA ( n=38) and moderate-to-severe IUA ( n=43). Endometrial tissue was collected under sterile conditions. Bacterial genomic DNA was extracted, the 16S rRNA V3-V4 region was amplified, and sequencing was performed on an Illumina platform. Differences in endometrial microbiota diversity and composition were compared between the two groups. Results:Patients with varying degrees of IUA exhibited comparable species richness, evenness and diversity of endometrial microbiota. At the phylum level, the endometrial microbiota across all subjects was predominantly composed of Proteobacteria, Firmicutes, Cyanobacteriota, Bacteroidota, and Actinobacteriota, with Proteobacteria (32.29%) and Firmicutes (23.82%) showing the highest mean relative abundances. At the genus level, Ralstonia (16.67%), Lactobacillus (13.45%), and Streptococcus (7.07%) were the most abundant genera. Group comparisons showed that the abundance of Ralstonia was higher in the mild IUA group, whereas Lactobacillus, Vibrio and Pseudoalteromonas were more abundant in the moderate-to-severe IUA group; however, these differences did not reach statistical significance (all P>0.05). LEfSe analysis further indicated that Lactobacillus, Vibrio, Pseudoalteromonas, Aeromonas, Ureaplasma and Acetobacterium were relatively enriched in the moderate-to-severe IUA group, while Geobacillus, Stomatobaculum and Fusicatenibacter were more abundant in the mild IUA group. Conclusion:The composition of the endometrial microbiota differs among patients with varying IUA severity. IUA progression may be associated with alterations in the endometrial microbiota; however, causal relationships and underlying mechanisms require further investigation.

Objective:To investigate the characteristics of the endometrial microbiota in patients with varying degrees of intrauterine adhesion (IUA).Methods:This single-center cross-sectional observational study enrolled 115 patients with IUA who were treated at the Hysteroscopic Center of Fuxing Hospital, Capital Medical University, from May 2022 to October 2023. After quality control and data preprocessing, 81 samples met the inclusion criteria for analysis. Patients were grouped according to an established IUA scoring and grading system into mild IUA ( n=38) and moderate-to-severe IUA ( n=43). Endometrial tissue was collected under sterile conditions. Bacterial genomic DNA was extracted, the 16S rRNA V3-V4 region was amplified, and sequencing was performed on an Illumina platform. Differences in endometrial microbiota diversity and composition were compared between the two groups. Results:Patients with varying degrees of IUA exhibited comparable species richness, evenness and diversity of endometrial microbiota. At the phylum level, the endometrial microbiota across all subjects was predominantly composed of Proteobacteria, Firmicutes, Cyanobacteriota, Bacteroidota, and Actinobacteriota, with Proteobacteria (32.29%) and Firmicutes (23.82%) showing the highest mean relative abundances. At the genus level, Ralstonia (16.67%), Lactobacillus (13.45%), and Streptococcus (7.07%) were the most abundant genera. Group comparisons showed that the abundance of Ralstonia was higher in the mild IUA group, whereas Lactobacillus, Vibrio and Pseudoalteromonas were more abundant in the moderate-to-severe IUA group; however, these differences did not reach statistical significance (all P>0.05). LEfSe analysis further indicated that Lactobacillus, Vibrio, Pseudoalteromonas, Aeromonas, Ureaplasma and Acetobacterium were relatively enriched in the moderate-to-severe IUA group, while Geobacillus, Stomatobaculum and Fusicatenibacter were more abundant in the mild IUA group. Conclusion:The composition of the endometrial microbiota differs among patients with varying IUA severity. IUA progression may be associated with alterations in the endometrial microbiota; however, causal relationships and underlying mechanisms require further investigation.