Class III phosphatidylinositol 3-kinase (PtdIns3K) occupies the nexus of autophagy and endomembrane trafficking. Within its core complex, the VPS34 catalytic subunit partners with VPS15, Beclin-1, and ATG14L or UVRAG to convert phosphatidylinositol into PtdIns3P-the lipid cue that seeds phagophore nucleation and endosome-lysosome maturation. By tuning this single signaling node, cells safeguard proteostasis and orchestrate rapid stress responses; when this regulatory network is disrupted, PtdIns3K dysregulation fuels neurodegeneration, tumor progression, immune imbalance, and metabolic disease. This review fuses cutting-edge structural and biochemical insights into PtdIns3K, dissects its multilayered regulation-spanning post-translational modifications, adaptor engagement, and higher-order assembly-and appraises next-generation small-molecule inhibitors designed for precision autophagy control. Decoding and therapeutically exploiting this pathway will open a new chapter in the discovery of innovative therapeutic approaches.

Non-small cell lung cancer (NSCLC) is a malignancy that faces serious resistance challenges in treatment. In this study, we identified Piperlongumine as a promising therapeutic candidate to overcome Osimertinib resistance in NSCLC. We systematically investigated the inhibitory effect of Piperlongumine on NSCLC cells and confirmed that it could effectively inhibit the in vitro kinase activity of wild-type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. We also found that Piperlongumine-induced intrinsic apoptosis by interfering with the EGFR signaling pathway, which was characterized by the down-regulation of the anti-apoptotic protein Mcl-1. Further mechanistic studies revealed that Piperlongumine-induced degradation of Mcl-1 was dependent on the Akt-GSK3β signaling pathway. Additionally, Piperlongumine-promoted interaction between Mcl-1 and β-TRCP, thereby enhancing β-TRCP-mediated ubiquitination and the degradation of Mcl-1. Furthermore, Piperlongumine significantly inhibited tumor growth in both Osimertinib-sensitive and resistant NSCLC xenograft models. These findings highlight the potential of Piperlongumine as an effective agent in overcoming EGFR-targeted therapy resistance and suggest new avenues for its clinical application in NSCLC treatment.

Discoidin domain receptors (DDR) play crucial roles in cell proliferation and differentiation. When DDRs are overexpressed, it has been associated with various diseases such as cancers, fibrotic disorders, and inflammation. This study aimed to expand on previous research by using a structure-based drug design approach to develop a series of new indole-urea derivatives as potent inhibitors of DDR1. Through biochemical analyses, it was found that these compounds effectively inhibited DDR1/2, with compound 7s demonstrating the highest activity against A549 cells (IC50 value of 1.84 μM) while maintaining selectivity for other kinases. In vivo studies showed that compound 7s exhibited stronger antitumor activity compared to dasatinib, without causing significant weight loss at a dose of 30 mg/kg. Further investigation revealed that compound 7s hindered the migration of A549 cells by targeting the ERK, Akt1, and EMT pathways. Additionally, cellular experiments demonstrated that compound 7s suppressed the activation of fibroblasts induced by TGF-β1. In vivo experiments confirmed that compound 7s, at a dose of 30 mg/kg, effectively inhibited DDR1 activation, resulting in a reduction of lung injury and fibrosis induced by bleomycin. Overall, these findings highlight the potential of these novel DDR1 inhibitors as promising therapeutic candidates for the treatment of DDR-related diseases.

Bromodomain protein 4 (BRD4) is an attractive epigenetic target that regulating diverse cellular processes, and the discovery of dual-target inhibitors including BRD4 is an effective approach in cancer treatment to increase potency and reduce drug resistance. Based on the multifunctional drug development strategy, a series of new derivatives of nitrooxy (ONO2) or furoxan (1,2,5-oxadiazole 2-oxide) with BRD4 inhibitor capable of inhibiting BRD4 and simultaneously releasing NO were designed and synthesized. When NO concentrations were measured with Griess reagent under physiological conditions, all compounds released NO at micromolar levels, reaching effective antitumor concentrations. Biological studies showed that the most potent BRD4/NO hybrid 11a exhibited good BRD4 inhibitory activity and selectivity. Further mechanistic studies revealed that 11a significantly decreased the expression of BRD4 and c-Myc, as well as induced cellular apoptosis and autophagic cell death both in vitro and in vivo. In summary, we optimized the chimeric BRD4-inhibitor/NO-donor based on our previous studies, and it should be a lead compound for targeted therapy of OC (ovarian cancer) in the future. This interesting strategy could expand the usage of BRDi in human malignancies and endogenous gastro-transmitters.

Simultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional small-molecule inhibitors were rationally designed and synthesized by incorporating an HDAC pharmacophore into spirooxindole skeletons. These compounds exhibited good inhibitory activities against both targets. In particular, compound 11b was demonstrated to be most potent for MDM2 and HDAC, reaching the enzyme inhibition of 68% and 79%, respectively. Compound 11b also showed efficient antiproliferative activity towards MCF-7 cells with better potency than the reference drug SAHA and Nutlin-3. Furthermore, western blot analysis revealed that compound 11b increased the expression of p53 and Ac-H4 in MCF-7 cells in a dose-dependent manner. Our results indicate that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drug in the future.

Recurrent cardiotoxicity limits the clinical application of doxorubicin (DOX); however the detailed molecular mechanism of DOX cardiotoxicity remains unclear. In the current study, we found that a natural product extracted from Illicium verum, isodunnianol (IDN), mitigates DOX-induced cardiotoxicity by regulating autophagy and apoptosis both in vitro and in vivo. DOX suppressed protective autophagy and induced apoptosis in H9C2 cardiac myoblasts. Additionally, IDN demonstrated up-regulated autophagy and reduced apoptosis through the activation of the AMPK-ULK1 pathway. In addition, the beneficial effects of IDN on DOX which induced myocardial injury were dependent on AMPK and ULK1 phosphorylation. Similar results were also observed in a DOX-induced cardiotoxicity rat model. The combination of IDN and DOX resulted in decreased apoptosis and inflammatory myocardial fibrosis compared to the DOX mono-treatment group. In summary, our findings provide novel insights into the prevention of DOX-related toxicity by isodunnianol, a food source natural product, warranting further investigation.

Bone tumor is a refractory neoplastic growth of tissue in bone. According to the unique environment and phys-chemical characteristics of bone tissues, the chemotherapeutic agents are unlikely to prolong the survival of patients and often associated with systemic side effects. The bone targeting drug delivery via systemic administration may provide both better treatment efficacy and less frequent administration. In this study, we describe the synthesis, in vitro and in vivo evaluation of novel melphalan-bisphosphonate hybrids, with a tumor microenvironment sensitive linkage, which could be enzymatic activation under tumor microenvironment conditions. We have also evaluated the in vitro targeting efficiency of these prodrugs via the affinity of hydroxyapatite (HA) and cellular proliferation. The in vivo distribution suggested the bisphosphonate conjugated prodrugs with high bone selectivity.

目的 探讨患者服用华法林发生出血的原因分析及用药指导.方法 确定引起凝血酶原国际标准化比值异常波动的原因,及时调整用药方案.结果 盐酸地尔硫与华法林联用,可能会增强华法林的抗凝强度,增加出血风险.结论 使用华法林进行抗凝治疗时,应注意药物之间的相互作用,对患者进行详细的用药指导及凝血功能的监测,以减少不良反应的发生.

Idiopathic pulmonary fibrosis (IPF) is a kind of a chronic and fatal lung disease leading to progressive lung function decline. Although several RNA microarray studies on IPF patients have been reported, their results were merely specific to each study with distinct platforms or sample types. In the current study, an integrative transcriptome meta-analysis of IPF was performed to explore regulated pathways, based on four independent expression profiling microarrays of IPF datasets, including 73 samples from IPF tissues or lung fibroblast cells. The results suggested the discoidin domain receptor 1 (DDR1) and downstream c-Jun N-terminal kinases (JNK) pathway may play important roles in the progression of IPF. To our knowledge, discoidin domain receptor 1 (DDR1) is a kind of receptor tyrosine kinase (RTK) with a unique ability to bind both fibrillar and non-fibrillar collagens. Based on the crystallographic structures of DDR1, the combination of molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of PBVS (multicomplex-pharmacophore based virtual screening) and DBVS (docking based virtual screening) methods were used for retrieving novel DDR1 inhibitors from the SPECS database. Twelve hit compounds were selected from the hit compounds and shifted to experimental validations, and the most potent compound was evaluated for its anti-IPF capacity on murine IPF models. Thus, these results may provide valuable information for further discovery of potential lead compounds for IPF therapy.

Since MDM2 is an inhibitor of the p53 tumor suppressor, disrupting the MDM2-p53 interaction is a promising approach for cancer therapy. Here, we used molecular dynamics simulations followed by free energy decomposition analysis to study conformational changes in MDM2 induced by three known spiro-oxindole inhibitors. Analysis of individual energy terms suggests that van der Waals and electrostatic interactions explain much of the binding affinities of these inhibitors. Binding free energies calculated for the three inhibitors using the molecular mechanics-generalized Born surface area model were consistent with experimental data, suggesting the validity of this approach. Based on this structure-function analysis, several novel spiro-oxindole derivatives were selected and evaluated for their ability to block the MDM2-p53 interaction in vitro. These results suggest that combining in silico and experimental techniques can provide insights into the structure-function relationships of MDM2 inhibitors and guide the rational design of anticancer drugs targeting the MDM2-p53 interaction.

OBJECTIVE:To improve the level of pharmaceutical experiment teaching for pharmacy major. METHODS:The ex-periment teaching of pharmacochemistry for pharmacy major in our school was taken as a pilot,and the teaching contents,teach-ing methods and appraisal system were explored. RESULTS:The teaching contents of“designing experiment”of pharmacochemis-try for pharmacy major in our school were added,multimedia teaching mode was introduced and scientific and comprehensive as-sessment mode was established. CONCLUSIONS:The reform of experiment teaching has cultivated the independent thinking and creative ability of students,improved enthusiasm and initiative,achieved good teaching quality and promoted the improvement of professional quality of teaching staff.

The triblock 18β‐glycyrrhetinic acid‐poly(ethylene glycol)‐18β‐glycyrrhetinic acid conjugates (GA‐PEG‐GA) based self‐assembled micelles were synthesized and characterized by FTIR, NMR, transmission electron microscopy, and particle size analysis. The GA‐PEG‐GA conjugates having the critical micelle concentration of 6 × 10−5 M were used to form nanosized micelles, with mean diameters of 159.21 ± 2.2 nm, and then paclitaxel (PTX) was incorporated into GA‐PEG‐GA micelles by self‐assembly method. The physicochemical properties of the PTX loaded GA‐PEG‐GA micelles were evaluated including in vitro cellular uptake, cytotoxicity, drug release profile, and in vivo tissue distribution. The results demonstrate that the GA‐PEG‐GA micelles had low cytotoxicity and good ability of selectively delivering drug to hepatic cells in vitro and in vivo by the targeting moiety glycyrrhetinic acid. In conclusion, the GA‐PEG‐GA conjugates have potential medical applications for targeted delivery of poor soluble drug delivery.

This article introduced the window work of pharmaceutical care in our hospital and the improvements in patients’ satisfaction and reduction of medication errors of clinical professionals after the window establishment.Experiences and deficiency in the work were summarized and improvement measures and recommendations were also proposed.