MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis, atopic dermatitis, and chronic urticaria. Previously, we identified a class of diaryl urea (DPU) MRGPRX2 antagonists with sub-micromolar IC₅₀ values in vitro. However, the structure-activity relationship remains unclear. Herein, we adopted a "relative symmetry with electronegativity of different key-groups" strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety. Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023, that possess relatively symmetric electron-withdrawing substituents, remarkable inhibited mast cell degranulation at a sub-micromolar IC₅₀ in vitro and alleviated anaphylactic symptoms. Furthermore, B-1023, mitigated antigen-induced pulmonary inflammation (AIPI) in mice and competitively bonded to MRGPRX2. In summary, the "relative symmetry with electronegativity of different key-groups" strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.

Traditional Chinese medicine(TCM)is extensively utilized for clinical disease prevention and treatment.However,due to the intricate nature of its material basis and the multiple factors involved in the preparation process,ensuring comprehensive quality control of TCM proves to be challenging.By instilling a clear understanding of its effective and harmful substances and implementing control over the content and limit of TCM during the preparation process,the controllability and repeatability of its quality can be guaranteed.Currently,China is facing a dearth of innovative technology for drug development,necessitating an increase in research and development efficiency,especially in the realm of high-throughput precision analytical equipment.The country has long relied on imported pharmaceutical analysis equipment with a particular efficiency in high-end intelligent analysis equipment.This is especially concerning considering the urgent requirement to establish a"pharmaceutical intelligent analysis system."This project,supported by the Major Instrument Development Project of the National Science and Technology Funds,employs cell membrane chromatography technology,complemented by biotechnology and artificial intelligence technology,to devise a two-dimensional cell membrane chromatography(2D/CMC)analyzer.The project has successfully conducted a demonstration application of the"2D/CMC-Traditional Chinese Medicine Pharmacodynamic Substance Analyzer"and the"2D/CMC-Traditional Chinese Medicine Injection Allergen Analyzer".These tools have enhanced the screening and discovery efficiency of TCM's effective substances and allergen components.Moreover,the equipment amalgamates qualitative and quantitative analysis,thereby serving as an effective analytical tool to enhance the quality and efficacy of traditional Chinese medicine.

Hepatocellular carcinoma(HCC)is one of the most common tumor types and remains a major clinical challenge.Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC.However,few mitophagy inhibitors have been approved for clinical use in humans.Pyrimethamine(Pyr)is used to treat infections caused by protozoan parasites.Recent studies have reported that Pyr may be beneficial in the treatment of various tumors.However,its mechanism of action is still not clearly defined.Here,we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis.Mechanistically,Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells.In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29(SNAP29)-vesicle-associated membrane protein 8(VAMP8)interaction.Moreover,Pyr acted synergistically with sorafenib(Sora)to induce apoptosis and inhibit HCC proliferation in vitro and in vivo.Pyr enhances the sensitivity of HCC cells to Sora,a common chemotherapeutic,by inhibiting mitophagy.Thus,these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor.Notably,Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Angiomyfibroblastoma (AMF)is a kind of rare benign tumour. The clinical and imaging findings of AMF are nonspecific. In October 2019, 1 case of Angiomyfibroblastoma of perineum was admitted to Heze Municipal Hospital for surgical treatment. Final pathological diagnosis was AMF. So far, neither recurrence nor metastasis has been detected for 5 months.