Background/Objectives: As a non-medicinal part resource of Ziziphus jujuba, this study focuses on the total flavonoids from Ziziphus jujuba mesocarp (TFZJM), aiming to optimize the extraction process and explore its sedative and hypnotic effects. Methods: The extraction process of TFZJM was optimized by using single-factor experiments and the Box-Behnken response surface design method. The material basis of TFZJM was analyzed using Ultra-Performance Liquid Chromatography-Quadrupole-Time of Flight-Mass Spectrometry (UPLC-Q-TOF-MS). The mouse insomnia model was induced by intraperitoneal injection of PCPA, and the effects of TFZJM on this model and its potential mechanism were evaluated using multiple methods, such as sleep enhancement induced by pentobarbital sodium, HE staining of tissue sections, ELISA, RT-PCR, WB, and serum metabolomics. Results: The results showed that by optimizing the extraction conditions, a solid-liquid ratio (SLR) of 1:25 g·mL⁻¹, ethanol concentration of 60%, extraction time of 60 min, and extraction rate of 1.98% were achieved. The common chemical basis of the 10 flavonoid components was identified using UPLC-Q-TOF-MS analysis. Compared with the model group, the high-dose TFZJM (TFZJM-H) group had the most significant effect, followed by the medium-dose (TFZJM-M) and low-dose (TFZJM-L) groups. Conclusions: Metabolomic analysis revealed that TFZJM regulates pathways related to the metabolism of phenylalanine, tyrosine, cytochrome P450, and alanine. This lays the foundation for further exploration of the active substances and mechanisms of action of TFZJM in sedation and hypnosis.

Due to the diversity and complexity of the components in traditional Chinese medicine (TCM) extracts, serious membrane fouling has become an obstacle that limits the application of membrane technology in TCM. Pectin, a heteropolysaccharide widely existing in plant cells, is the main membrane-fouling substance in TCM extracts. In this study, a hydrophilic hybrid coating was constructed on the surface of a polyvinylidene fluoride (PVDF) ultrafiltration (UF) membrane co-deposited with polydopamine (pDA) and (3-Aminopropy) triethoxysilane (KH550) for pectin antifouling. Characterization analysis showed that hydrophilic coating containing hydrophilic groups (–NH₃, Si-OH, Si-O-Si) formed on the surface of the modified membrane. Membrane filtration experiments showed that, compared with a matched group (FRR: 28.66%, Rr: 26.87%), both the flux recovery rate (FRR) and reversible pollution rate (Rr) of the pDA and KH550 coated membrane (FRR: 48.07%, Rr: 44.46%) increased, indicating that pectin absorbed on the surface of membranes was more easily removed. Based on the extended Derjaguin–Laudau–Verwey–Overbeek (XDLVO) theory, the fouling mechanism of a PVDF UF membrane caused by pectin was analyzed. It was found that, compared with the pristine membrane (144.21 kT), there was a stronger repulsive energy barrier (3572.58 kT) to confront the mutual adsorption between the coated membrane and pectin molecule. The total interface between the modified membrane and the pectin molecule was significantly greater than the pristine membrane. Therefore, as the repulsion between them was enhanced, pectin molecules were not easily adsorbed on the surface of the coated membrane.

The optimization of membrane permeability is a pivotal approach for mitigating late-stage failures in peptide drug development. By leveraging linker chemical diversity, stapled peptides utilize linker engineering to precisely modulate key physicochemical parameters—such as lipophilicity and conformational constraints—to overcome the desolvation energy penalty. This review systematically evaluates linker-based strategies for enhancing the permeability of stapled peptides, categorized into two primary dimensions: (1) high-throughput screening (HTS) compatibility, focusing on the integration of functionalized linkers into mRNA display, phage display, and DNA-encoded libraries (DELs) to identify lead scaffolds with inherent permeability potential during early discovery; and (2) post-screening structural refinement, covering rational design strategies including intramolecular hydrogen-bond (IMHB) shielding, “chameleonic” adaptations, and stimuli-responsive reversible stapling. Furthermore, we analyze the paradigm shift in assessment methodologies from qualitative imaging to quantitative cytosolic delivery assays, which have deepened our understanding of mechanisms such as the charge/lipophilicity threshold balance and metabolism-driven trapping. Overall, linker engineering provides a robust technical roadmap for developing the next generation of cell-permeable stapled peptide therapeutics.

The c-Jun N-terminal kinase (JNK) pathway is a central driver of fibrosis, inflammation, and neurodegeneration. While direct JNK inhibitors have shown therapeutic promise, achieving high isoform selectivity remains a significant medicinal chemistry challenge. Furthermore, targeting the upstream ‘gatekeepers’ MKK4 and MKK7 offers a distinct mechanism to modulate pathway output with greater precision. Consequently, medicinal chemistry efforts have shifted upstream to the dual-specificity kinases MKK4 and MKK7. This review critically evaluates the structural biology and pharmacological evolution of small-molecule inhibitors targeting these nodes. We contrast the distinct therapeutic landscapes of the two kinases: while MKK4 inhibition has emerged as a breakthrough strategy for unlocking liver regeneration (exemplified by the first-in-class clinical candidate HRX215), MKK7 inhibition is primarily pursued for its anti-fibrotic and anti-inflammatory potential. Special attention is given to structure-based design strategies, including the exploitation of the unique hinge-region cysteine (Cys218) for MKK7-specific covalent targeting and the optimization of scaffold selectivity against off-targets like BRAF. Finally, we discuss emerging modalities, such as PROTACs and dual inhibitors, outlining a roadmap for the next generation of precision therapeutics targeting the MKK–JNK axis.

As the key enzyme catalyzing the final step in heme and chlorophyll biosynthesis, protoporphyrinogen oxidase (PPO) is a crucial target for herbicide development. To date, over 40 PPO inhibitors have been commercialized. They offer high efficacy, environmental safety, low application rates, and broad-spectrum weed control. Recently, significant progress has been made in PPO structural biology, with several crystal structures resolved. Despite decades of use, the emergence of resistant weeds necessitates the continuous innovation of novel PPO inhibitors. This review systematically summarizes PPO three-dimensional structures, enzyme-inhibitor interaction mechanisms, and quantitative structure–activity relationships (QSARs). Finally, we outline rational molecular design strategies for the next generation of PPO inhibitors.

As the key enzyme catalyzing the final step in the biosynthesis of heme and chlorophyll, protoporphyrinogen oxidase (PPO) has become a crucial target for herbicide development. To date, more than 40 PPO-inhibiting herbicides have been developed, exhibiting multiple advantageous characteristics: they combine high efficacy with environmental friendliness, feature low effective concentrations, rapid action, long-lasting effects, and excellent control of both monocotyledonous and dicotyledonous weeds. In recent years, significant progress has been made in the structural biology of PPO—five crystal structures from tobacco, humans, and various bacteria have been resolved, most of which are presented as enzyme-inhibitor complexes. Although the development of such herbicides spans over five decades, novel PPO inhibitors still hold broad potential for innovation due to the resistance of early applied PPOs. This review systematically summarizes the three-dimensional structures of PPO from different sources, the interaction mechanisms between the enzyme and inhibitors, studies on quantitative structure-activity relationships of inhibitors, and outlines molecular design directions for the next generation of PPO inhibitors.