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.

Iron overload is strongly associated with heart disease. Ferroptosis is a new form of regulated cell death indicated in cardiac ischemia-reperfusion (I/R) injury. However, the specific molecular mechanism of myocardial injury caused by iron overload in the heart is still unclear, and the involvement of ferroptosis in iron overload-induced myocardial injury is not fully understood. In this study, we observed that ferroptosis participated in developing of iron overload and I/R-induced cardiomyopathy. Mechanistically, we discovered that Parkin inhibited iron overload-induced ferroptosis in cardiomyocytes by promoting the ubiquitination of long-chain acyl-CoA synthetase 4 (ACSL4), a crucial protein involved in ferroptosis-related lipid metabolism pathways. Additionally, we identified p53 as a transcription factor that transcriptionally suppressed Parkin expression in iron-overloaded cardiomyocytes, thereby regulating iron overload-induced ferroptosis. In animal studies, cardiac-specific Parkin knockout mice (Myh6-CreER ^T2 /Parkin ^fl/fl ) fed a high-iron diet presented more severe myocardial damage, and the high iron levels exacerbated myocardial I/R injury. However, the ferroptosis inhibitor Fer-1 significantly suppressed iron overload-induced ferroptosis and myocardial I/R injury. Moreover, Parkin effectively protected against impaired mitochondrial function and prevented iron overload-induced mitochondrial lipid peroxidation. These findings unveil a novel regulatory pathway involving p53-Parkin-ACSL4 in heart disease by inhibiting of ferroptosis.

Objective:To compare the lung shunt fraction (LSF) of 90Y imaging after 90Y-selective internal radiation therapy (SIRT) and preoperative 99Tc m-macroaggregated albumin (MAA) imaging in patients with liver malignant tumors, and compare the volume and visual score of intrahepatic distribution of both nucleins on SPECT/CT images. Methods:A total of 91 patients with liver malignant tumors (78 males, 13 females; age (56.7±13.7)years; 99 cases) who underwent 90Y-SIRT in the Second Affiliated Hospital of Guangzhou Medical University from November 2022 to June 2024 were retrospectively collected. All patients underwent preoperative 99Tc m-MAA simulation and postoperative 90Y distribution verification by whole-body planar scintigraphy and hepatic SPECT/CT imaging. ROIs of the liver and lungs under the anterior-posterior position were delineated on the planar scintigraphy and LSF of 99Tc m-MAA and 90Y were calculated. The volume of interest (VOI) was drawn on the SPECT/CT images to calculate the nuclide distribution volume of both 99Tc m-MAA and 90Y within the liver. Wilcoxon signed rank test was used to compare the difference between two groups. In addition, the liver was divided into five lobes, namely left lateral lobe, left medial lobe, caudate lobe, right anterior lobe and right posterior lobe. Visual assessment of 90Y and 99Tc m-MAA radioactive distribution was performed ( 90Y and 99Tc m-MAA uptakes were graded on a scale of 0-3, where 0 indicated no nuclide accumulation and 3 indicated heavy accumulation). Kappa consistency test was used to analyze the scores of the corresponding lobes between two groups. Results:LSF for 99Tc m-MAA was 11.60%(4.27%, 15.03%), and LSF for 90Y was 11.80%(9.70%, 13.30%), without significant difference ( Z=-1.50, P=0.134). The distribution volume of 99Tc m-MAA within the liver was 542.63(204.00, 818.00)ml, which was significantly different from that of 90Y (688.69(287.00, 954.00)ml; Z=-7.37, P<0.001). Kappa values of the score of each lobe between 99Tc m-MAA imaging and 90Y imaging were 0.469-0.740 (all P<0.001). Conclusions:99Tc m-MAA simulation is reliable for assessing LSF for 90Y-SIRT. The distribution volume of 99Tc m-MAA is generally smaller than that of 90Y, but the consistency of the visual score of radioactive distribution is high. Overall, 99Tc m-MAA may well simulate the distribution pattern of 90Y-SIRT.

AKT,also known as Protein Kinase B(PKB),plays a critical role in cell proliferation and metabolism.There are three isoforms of AKT:AKT1,AKT2,and AKT3.The effects of these isoforms on the pluripotency and differentiation of mouse embryonic stem cells(mESCs)remain unclear.This study aims to explore the impact of three AKT isoform-specific knockouts on the self-renewal and differen-tiation of mouse embryonic stem cells.Using CRISPR/Cas9 gene-editing technology,AKT isoform-spe-cific knockout cell lines were established.The phenotypic and molecular changes were analyzed through Western blotting,flow cytometry,qRT-PCR,CCK-8 assays,Alkaline Phosphatase(AP)staining,and RNA-seq.The construction of AKT isoform-specific knockout cell lines was successful.The loss of AKT1 and AKT2 inhibited the proliferation of mESCs.The knockout of any single AKT isoform did not affect the expression of pluripotency genes at both mRNA or protein levels.However,during embryoid body forma-tion,the deletion of any of the three AKT isoforms affected the mRNA expression levels of genes in all three germ layers.Transcriptome analysis showed that compared to wild-type mESCs,995,547,and 429 differentially expressed genes(|log2FC|≧1,P＜0.05)were identified inAKT1,AKT2,and AKT3 isoform-specific knockout cells,respectively.There was some overlap in the differentially expressed genes regulated by these three isoforms.In conclusion,the independent knockout of AKT isoforms does not af-fect the maintenance of pluripotency in mouse embryonic stem cells,but they are crucial for differentia-tion.The three AKT isoforms can collectively regulate gene expression while retaining their own regulato-ry specificity.This study provides a foundation for understanding the unique and overlapping roles of AKT isoforms in stem cell biology,highlighting their importance in maintaining stem cell function and differen-tiation.

AKT,also known as Protein Kinase B(PKB),plays a critical role in cell proliferation and metabolism.There are three isoforms of AKT:AKT1,AKT2,and AKT3.The effects of these isoforms on the pluripotency and differentiation of mouse embryonic stem cells(mESCs)remain unclear.This study aims to explore the impact of three AKT isoform-specific knockouts on the self-renewal and differen-tiation of mouse embryonic stem cells.Using CRISPR/Cas9 gene-editing technology,AKT isoform-spe-cific knockout cell lines were established.The phenotypic and molecular changes were analyzed through Western blotting,flow cytometry,qRT-PCR,CCK-8 assays,Alkaline Phosphatase(AP)staining,and RNA-seq.The construction of AKT isoform-specific knockout cell lines was successful.The loss of AKT1 and AKT2 inhibited the proliferation of mESCs.The knockout of any single AKT isoform did not affect the expression of pluripotency genes at both mRNA or protein levels.However,during embryoid body forma-tion,the deletion of any of the three AKT isoforms affected the mRNA expression levels of genes in all three germ layers.Transcriptome analysis showed that compared to wild-type mESCs,995,547,and 429 differentially expressed genes(|log2FC|≧1,P＜0.05)were identified inAKT1,AKT2,and AKT3 isoform-specific knockout cells,respectively.There was some overlap in the differentially expressed genes regulated by these three isoforms.In conclusion,the independent knockout of AKT isoforms does not af-fect the maintenance of pluripotency in mouse embryonic stem cells,but they are crucial for differentia-tion.The three AKT isoforms can collectively regulate gene expression while retaining their own regulato-ry specificity.This study provides a foundation for understanding the unique and overlapping roles of AKT isoforms in stem cell biology,highlighting their importance in maintaining stem cell function and differen-tiation.

Objective:To compare the lung shunt fraction (LSF) of 90Y imaging after 90Y-selective internal radiation therapy (SIRT) and preoperative 99Tc m-macroaggregated albumin (MAA) imaging in patients with liver malignant tumors, and compare the volume and visual score of intrahepatic distribution of both nucleins on SPECT/CT images. Methods:A total of 91 patients with liver malignant tumors (78 males, 13 females; age (56.7±13.7)years; 99 cases) who underwent 90Y-SIRT in the Second Affiliated Hospital of Guangzhou Medical University from November 2022 to June 2024 were retrospectively collected. All patients underwent preoperative 99Tc m-MAA simulation and postoperative 90Y distribution verification by whole-body planar scintigraphy and hepatic SPECT/CT imaging. ROIs of the liver and lungs under the anterior-posterior position were delineated on the planar scintigraphy and LSF of 99Tc m-MAA and 90Y were calculated. The volume of interest (VOI) was drawn on the SPECT/CT images to calculate the nuclide distribution volume of both 99Tc m-MAA and 90Y within the liver. Wilcoxon signed rank test was used to compare the difference between two groups. In addition, the liver was divided into five lobes, namely left lateral lobe, left medial lobe, caudate lobe, right anterior lobe and right posterior lobe. Visual assessment of 90Y and 99Tc m-MAA radioactive distribution was performed ( 90Y and 99Tc m-MAA uptakes were graded on a scale of 0-3, where 0 indicated no nuclide accumulation and 3 indicated heavy accumulation). Kappa consistency test was used to analyze the scores of the corresponding lobes between two groups. Results:LSF for 99Tc m-MAA was 11.60%(4.27%, 15.03%), and LSF for 90Y was 11.80%(9.70%, 13.30%), without significant difference ( Z=-1.50, P=0.134). The distribution volume of 99Tc m-MAA within the liver was 542.63(204.00, 818.00)ml, which was significantly different from that of 90Y (688.69(287.00, 954.00)ml; Z=-7.37, P<0.001). Kappa values of the score of each lobe between 99Tc m-MAA imaging and 90Y imaging were 0.469-0.740 (all P<0.001). Conclusions:99Tc m-MAA simulation is reliable for assessing LSF for 90Y-SIRT. The distribution volume of 99Tc m-MAA is generally smaller than that of 90Y, but the consistency of the visual score of radioactive distribution is high. Overall, 99Tc m-MAA may well simulate the distribution pattern of 90Y-SIRT.

The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.

As a novel iron-dependent form of cell death, ferroptosis is characterized by the excessive accumulation of phospholipids containing polyunsaturated fatty acids (PUFA) on the cell membrane and peroxidation. Lipid droplets are always in the dynamic transition of generation and decomposition, play a central role in regulating lipid metabolism, and are always in the dynamic transition of generation and decomposition. Lipid droplet metabolism is closely related to the occurrence of ferroptosis and plays an important role in the disease caused by ferroptosis. This review firstly focuses on the lipid droplet metabolism process and its effects on the storage and release of PUFA, and further elucidates the regulatory mechanism and key regulatory proteins of lipid drop metabolism on ferroptosis, in order to reveal the intrinsic relationship between lipid droplets and ferroptosis, and provide a new strategy for disease prevention and treatment.

In the process of achieving the"Healthy China 2030"goal,the importance of health knowledge popularization behavior is increasingly prominent.Medical communication has emerged to meet the growing demand for medical popularization and improve the shortage of professional medical staff in medical knowledge popularization.At present,literature is relatively scarce on the development process of medical communication in the academic community.By analyzing the development process of this discipline,this paper divided the development process of the knowledge system of medical communication into three stages,including the"initial stage",the"practical exploration stage",and the"rapid development stage".After summarizing the different characteristics exhibited in the three stages,it can be concluded that the number of colleges and universities offering medical communication courses is gradually increasing,and social organizations such as the Society of Medical Communication have been established one after another,expanding the influence of the discipline.The development of medical communication not only helps to enhance the popularization and communication abilities of medical students,but also accelerates the development of China's health industry through its extensive influence at the practical level.

Objective:To study the feasibility of magnetic resonance imaging(MRI)technique with amide proton transfer(APT)in predicting the prognosis of cerebral stroke.Methods:A total of 71 patients with acute cerebral stroke who admitted to the Nanjing First Hospital,Nanjing Medical University from September 2022 to May 2023 were selected.All of them underwent the test of National Institute of Health Stroke Scale(NIHSS),and received the MRI examination with chemical exchange saturation transfer(CEST).According to the modified Rankin scale(mRS)values of 1-month follow-up,they were divided into favorable recovery group(mRS<2,44 cases)and poor group(mRS≥2,27 cases).The asymmetric magnetization transfer ratio(MTRasym)image(APT)was obtained by analyzing data with special software.And then,the difference(△APTw)of APT values between ischemic zone and contralateral normal tissue was further calculated.The △APTw values of two groups were compared and analyzed,and the Pearson correlation analysis was adopted to analyze the correlation among △APTw,NIHSS and mRS.The receiver operating characteristics(ROC)curve was drawn,and the area under curve(AUC)of ROC curve was calculated.Results:There were significant positive correlations among △APTw,NIHSS and mRS scores(R2=0.659,0.522,P<0.001),and the differences of △APTW,NIHSS and mRS scores between the favorable recovery group and poor group were significant(t=5.73,6.36,13.92,P<0.05),respectively.The AUC value was 0.886,and the sensitivity and specificity of prediction were respectively 77.8%and 95.5%.The positive and negative predictive values were respectively 91.3%and 87.5%.Conclusion:APT imaging technique has feasibility in predicting the prognosis of acute cerebral ischemic stroke.