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 investigate the role of preoperative 3D printing simulation technology in the interventional endovascular exclusion of Stanford B aortic dissection.Methods A retrospective study protocol was used to select 76 patients with Stanford B-type aortic dissection who underwent endovascular isolation surgery in our hospital from January 2019 to January 2021 in the study.Among them,40 patients underwent simulated surgery with preoperative 3D printing simulation technology(simulation group)and another 36 patients received conventional endovascular isolation surgery(control group).The two groups were compared in terms of the.cardiac ultrasound indicators,the true and false lumen diameters,and the complication rates of the proximal aortic rupture plane,stent end plane,and abdominal trunk artery plane at different times before and after surgery.Results As com-pared to the control group,the simulation group showed significantly longer surgical time,extracorporeal circulation time,aortic occlusion time,and ICU stay time(all P<0.05).After the operation,the true lumen diameter of the proximal aortic rupture plane,stent end plane,and abdominal trunk artery plane were significantly increased in two groups at months 1,3,and 6(P<0.05),but the false lumen diameter of the proximal aortic rupture plane,stent end plane,and abdominal trunk artery plane were significantly decreased(P<0.05)compared to preoperative levels.The LVEF and FS of the two groups were significantly increased 6 months after surgery(P<0.05).Conclusion The preoperative 3D printing simulation technology in the interventional endovascular isolation of Stanford B aortic dissection can ensure the surgical effect.It can achieve the same surgical effect as the traditional procedures and importantly it can reduce the difficulty of operation and shorten the operation time.

With the rapid development of artificial intelligence technology,small molecule generation models have emerged as a significant research direction in the field of drug discovery.These models,including Generative Adversarial Networks(GANs),Variational Autoencoders(VAEs),and diffusion models,have proven to possess remarkable capabilities in optimizing drug properties and generating complex molecular structures.This article comprehensively analyzes the application of the aforementioned advanced technologies in the drug discovery process,demonstrating how they supplement and enhance traditional drug design methods.At the same time,it addresses the challenges facing current methods in terms of data quality,model complexity,computational cost,and generalization ability,with a prospect of future research directions.

While neuroblastoma accounts for 15% of childhood tumor-related deaths, treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs. Currently, maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical, especially high-risk patients. However, differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy, unclear mechanism, and few drug options. Through compound library screening, we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691. The protein kinase B (AKT) pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation, yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear. Here, we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines. Further evidence including neurites outgrowth, cell cycle arrest, and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691. Meanwhile, with the introduction of other AKT inhibitors, it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation. Furthermore, silencing AKT was found to have the effect of inducing neuroblastoma differentiation. Finally, confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo, suggesting that Hu7691 is a potential molecule against neuroblastoma. Through this study, we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.

The incidence of valvular heart disease (VHD) increases with age, and its principal therapy is valve replacement. However, in recent years, the emergence of transcatheter interventions has changed the traditional therapy, making high-risk patients of surgery see dawn of hope. 3D printing technology has developed rapidly since it was applied to the medical field in 1990. Moreover, it has been widely applied in many surgical majors via refined reduction technology. However, the application of 3D printing technology in cardiovascular surgery is still in the preliminary stage, especially in the field of VHD. This article aims to review basic principles of 3D printing technology, its advantages in the therapy of VHD, and its current status of clinical application. Furthermore, this article elaborates current problems and looks forward to the future development direction.

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation

Objective    To evaluate the clinical value of three-dimensional (3D) printing model in accurate and minimally invasive treatment of double outlet right ventricle (DORV). Methods    From August 2018 to August 2019, 35 patients (22 males and 13 females) with DORV aged from 5 months to 17 years were included in the study. Their mean weight was 21.35±8.48 kg. Ten patients who received operations guided by 3D printing model were allocated to a 3D printing model group, and the other 25 patients who received operations without guidance by 3D printing model were allocated to a non-3D printing model group. Preoperative transthoracic echocardiography and CT angiography were performed to observe the location and diameter of ventricular septal defect (VSD), and to confirm the relationship between VSD and double arteries. Results    The McGoon index of patients in the 3D printing model group was 1.91±0.70. There was no statistical difference in the size of VSD (13.20±4.57 mm vs. 13.40±5.04 mm, t=−0.612, P=0.555), diameter of the ascending aorta (17.10±2.92 mm vs. 16.90±3.51 mm, t=0.514, P=0.619) or diameter of pulmonary trunk (12.50± 5.23 mm vs. 12.90±4.63 mm, t=−1.246, P=0.244) between CT and 3D printing model measurements. The Pearson correlation coefficients were 0.982, 0.943 and 0.975, respectively. The operation time, endotracheal intubation time, ICU stay time and hospital stay time in the 3D printing model group were all shorter than those in the non-3D printing model group (P<0.05). Conclusion    The relationship between VSD and aorta and pulmonary artery can be observed from a 3D perspective by 3D printing technology, which can guide the preoperative surgical plans, assist physicians to make reasonable and effective decisions, shorten intraoperative exploration time and operation time, and decrease the surgery-related risks.