Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.

［摘要］ 目的：探讨穿膜蛋白125（transmembrane protein125，TMEM125）在肺腺癌组织与A549 细胞中的表达，以及影响细胞 的增殖和侵袭能力的分子机制。方法：从癌症基因组图谱（the cancer genome atlas，TCGA）数据库收集肺腺癌数据包，下载临床 信息及基因表达谱数据。分析TMEM125 在肺腺癌组织中的表达及其与患者总生存期的相关性。构建TMEM125 过表达A549 细胞株，以CCK-8 法、细胞划痕实验检测TMEM125 过表达对肿瘤细胞的增殖和迁移能力的影响；流式细胞术检测TMEM125 过 表达对A549 细胞的细胞周期和凋亡的影响。WB检测TMEM125 过表达对下游NF-κB信号通路、凋亡蛋白的影响；免疫共沉淀 法（co-immunoprecipitation，Co-IP）检测TMEM125 与NF- κB 抑制因子结合Ras 样2（NF- κB inhibitor interacting Ras-like 2， NKIRAS2）的相互作用。利用TNFα（10 ng/ml）处理TMEM125 过表达A549 细胞，CKK-8、流式细胞术及WB检测其对细胞增殖、 凋亡以及NF-κB信号通路相关蛋白表达的影响。去甲基化试剂地西他滨处理A549 细胞，qPCR和WB检测TMEM125 基因和蛋 白的表达。结果：TMEM125 mRNA在肺腺癌组织中表达水平显著低于正常组织（P<0.001），启动子甲基化水平显著高于正常组 织（P<0.001），并且低、中表达患者总生存期显著低于高表达患者（P<0.001）。过表达TMEM125 抑制了A549 细胞的增殖和迁移 （P<0.01），增加细胞G2/M 期，促进细胞凋亡（P<0.01）；过表达TMEM125 与NKIRAS2 相互作用，显著抑制NF- κB 的活性 （P<0.01）；地西他滨处理A549 细胞可促进TMEM125 表达并且抑制细胞增殖（P<0.01）。结论：启动子高甲基化水平降低了 TMEM125 基因表达，导致其抑制NF-κB活性功能和抑制细胞增殖的作用下降，并且降低了细胞对地西他滨的敏感性。

Objective To investigate the clinical efficacy of carotid endarterectomy in treatment of patients with suba-cute cerebral infarction. Methods Sixty patients diagnosed and treated in our hospital were analyzed and randomly di-vided into two groups. The control group was given conservative treatment and the experimental group was given carotid endarterectomy treatment. The treatment effects of the two groups were compared. Results The treatment effects were ideal for 93.3% of the experimental group, which was higher than that of the control group (80.0%) (P<0.05); After the treatment, two groups were not significantly different in indicators such as PT, TT and FIB (P>0.05); After treatment, APTT of the experimental group was (27.9±2.4) seconds, which was lower than that of the control group(30.4±6.8) sec-onds(P<0.05); The incidence of surgical adverse reactions of the experimental group was 20.0%, which was lower than that of the control group (53.3%)(P<0.05). Conclusion The incidence of subacute cerebral infarction is relatively high. The clinical application of carotid endarterectomy shows good treatment effects, can improve clinical treatment effects and reduce the incidence of complications, thereby worthy of promotion and application.

AIM: To obverse the expression and localization of urocortin on ultrathin cryosections of syncytiotrophoblast of human term placenta with immunocytochemistry technique under transmission electron microscope. METHODS: The human term placenta tissue from Cesarean delivery and normal labor were fixed in 4% paraformaldehyde, and then divided into two parts. One part was for regular immunocytochemistry under microscope, and the other part was used to prepare ultrathin cryosections for immunocytochemistry under transmission electron microscope. RESULTS: 1.Uroncortin mainly distributed in cytoplasm of syncytiotrophoblast of human term placenta under microscope. Urocortin also appeared in cytoplasm in some stromal cells. 2. Under transmission electron microscope, the anti-urocortin gold particles were observed in cytoplasm of syncytioptrophoblast ultrathin cryosections and sited on rough-surfaced endoplasmic reticulum. The anti-urocortin gold particles also appeared on nucleus and nuclear membrane of syncytiotrophoblast. CONCLUSION: Syncytiotrophoblast of human term placenta synthesized and secreted urocortin. The internalization of urocortin within syncytiotrophoblast nuclear indicates that urocortin may act as intracrine.