Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025070
Schisandrin A (SchA), a bioactive lignan that was isolated from the dried fruit of Schisandra chinensis, has attracted much attention because of its diverse spectrum of pharmacological effects. The aim of this study is to clarify the function of SchA in diabetes-related fear memory impairment and its molecular mechanisms. Rats are randomly assigned to 4 groups: the control group (Con group), the DM group, the DM + SchA group, and the Con + SchA group. The results demonstrate that SchA treatment improves insulin sensitivity, reduces blood glucose, and significantly reduces memory impairment. SchA treatment also prevents histological damage, enhances synaptic protein production, and significantly decreases Aβ42 formation in the diabetic prefrontal cortex. Further research reveals that SchA therapy decreases microglial activation and the expression levels of variables linked to inflammation while increasing the phosphorylation of proteins implicated in the insulin resistance signaling pathway. Furthermore, in the prefrontal cortex of diabetic rats, SchA decreases ferroptosis by increasing the protein expressions of GPX4, SLC7A11, Nrf2, HO-1, and SIRT1. Overall, our findings suggest that SchA may lessen diabetes-associated fear memory impairment symptoms by, most likely, lowering ferroptosis and inflammatory responses in the prefrontal brain of diabetic rats. SchA may be a useful therapy for diabetes, including memory impairment.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024168
Uncoupling protein-2 (UCP2) controls the antioxidant response and redox homeostasis in cancer and is considered a potent molecular target for cancer treatment. However, the specific mechanism of UCP2 inhibition and its role in glioblastoma (GBM) have not yet been elucidated. Here, we attempt to identify a UCP2 inhibitor and study the underlying molecular mechanism in GBM. Bioinformatics analysis and immunohistochemistry are used to validate the high expression of UCP2 in GBM and its prognostic significance. Drug intervention and tumor xenograft experiments are conducted to determine the inhibitory effect of genipin, a UCP2 inhibitor, on UCP2. The mitochondrial membrane potential and key ferroptosis genes are examined to determine the occurrence of ferroptosis. High expression of UCP2 in GBM is associated with poor prognosis, and inhibiting UCP2 can alleviate the malignant behavior of GBM tumors. Genipin can downregulate the expression of GPX4 and upregulate the expression of ACSL4 by inhibiting UCP2, leading to ferroptosis and alleviating the malignant behavior of tumors. In summary, UCP2 is a potential therapeutic target for GBM. Genipin, which targets UCP2, effectively inhibits GBM development by inducing ferroptosis in vivo and in vitro. These findings indicate that genipin treatment based on UCP2 targeting has potential therapeutic applications with a clinical perspective for the treatment of GBM patients.
Chinese Traditional and Herbal Drugs•2026•DOI: 10.7501/j.issn.0253-2670.2026.16.20261603
The inflorescences of Inula japonica Thunb. (Asteraceae) are a traditional Chinese medicine used for treating cough, phlegm, and vomiting. Sesquiterpenoid dimers, formed via Diels-Alder, hetero-Diels-Alder, [2+2] cycloaddition, or radical coupling, exhibit potent anti-inflammatory, neuroprotective, and antitumor activities. However, their low natural abundance and structural complexity hinder isolation and development. This study isolated six sesquiterpenoid dimers from the ethyl acetate fraction of a 90% ethanol extract of I. japonica using multiple chromatographic techniques. Their structures were elucidated by HRESIMS, NMR, IR, UV, and calculated NMR/ECD. Compounds 1 (inujaponolide T) and 3 (inujaponolide U) are new: a eudesmane-guaiane dimer and a 1,10-seco-eudesmane-guaiane dimer, respectively. The other four were identified as inujaponolide E (2), inujaponolide D (4), inujaponolide I (5), and japonicone X (6). In vitro anti-hepatocellular carcinoma activity was evaluated against HepG2 cells using MTT and colony formation assays. All compounds exhibited potent cytotoxicity with IC50 values of 2.61–13.94 μmol/L; compound 6 was most active (IC50 = 2.61 μmol/L). A preliminary structure-activity relationship indicated a positive correlation between the number of acetoxy substituents and antitumor activity. Compounds 1 and 3 inhibited cell viability and reduced colony formation in a dose-dependent manner. These findings expand the chemical diversity of I. japonica and provide a basis for developing these dimers as anti-hepatocellular carcinoma lead compounds.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026036
Forkhead box protein M1 (FOXM1) is a key transcription factor that regulates cell cycle progression and is frequently overexpressed in human cancers, driving tumor proliferation and therapy resistance. FOXM1 recognizes the canonical forkhead response element (FKH motif, RYAAAYA) through its conserved DNA-binding domain (DBD). Here, we report the high-resolution crystal structure of the FOXM1-DBD in complex with a double-stranded DNA substrate containing two FKH motifs. The structure reveals that FOXM1-DBD adopts the canonical winged-helix fold, with the third α-helix (α3) inserted into the DNA major groove to mediate sequence-specific recognition. Within this helix, Asn283, Arg286, and His287 form an essential triad that engages DNA bases through specific hydrogen bonds and hydrophobic interactions. Using structure-guided mutagenesis of key DNA-interacting residues combined with biophysical validation by isothermal titration calorimetry (ITC) and DNA binding assessment via electrophoretic mobility shift assay (EMSA), we confirm the functional importance of these residues and uncover position-dependent tolerance to base substitutions within the FKH motif. Furthermore, we demonstrate that FOXM1 overexpression promotes cell proliferation and upregulates the transcription of target genes in a DBD-dependent manner. Our findings provide a structural basis for understanding the DNA recognition mechanism of FOXM1 and offer mechanistic insights into how FOXM1 selectively binds to its genomic targets to regulate transcription.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025070
Diabetes mellitus (DM) is a metabolic and endocrine disorder with a projected global prevalence of 783 million by 2045. Individuals with type 2 diabetes face a 20–60% elevated risk of cognitive dysfunction, yet therapeutic options remain limited. This study investigates the efficacy of Schisandrin A (SchA), a bioactive lignan from Schisandra chinensis, in a streptozotocin-induced diabetic rat model. Rats were randomized into control, DM, DM+SchA, and Con+SchA groups. SchA treatment improved insulin sensitivity, reduced blood glucose, and significantly attenuated fear memory impairment. Histological analysis revealed decreased prefrontal cortex damage, enhanced synaptic protein expression, and reduced Aβ42 formation. Mechanistically, SchA suppressed microglial activation and inflammatory markers while increasing phosphorylation of insulin resistance pathway proteins. Furthermore, SchA mitigated ferroptosis by upregulating GPX4, SLC7A11, Nrf2, HO-1, and SIRT1 in the diabetic prefrontal cortex. These findings suggest that SchA alleviates diabetes-associated memory impairment by concurrently reducing neuroinflammation and ferroptosis, positioning SchA as a potential therapeutic agent for diabetes-related cognitive decline.