2025年 · 第08卷第04期

线粒体是真核细胞中主要的产生能量的细胞器，通过氧化磷酸化为必需的生物合成过程提供动力[1].这些细胞器是高度动态的，并不断经历融合和裂变的循环，以支持需要能量的细胞活动，如胃酸分泌的质子泵[2].这些膜重塑事件受来自动力蛋白超家族的进化保守的鸟苷三磷酸酶（GTPase）调节，外膜和内膜的融合分别由MFN1/2和OPA1介导，裂变由Drp1发生[3].然而，关于Drp1如何锚定到线粒体外膜上知之甚少。在这里，我们报道了一种以前未表征的蛋白质C3orf33，作为Drp1的新型衔接子，并根据其控制线粒体裂变的功能将其命名为Mitofissin（MiSN）。我们的初步筛选表明MiSN定位于线粒体。为了可视化动态和精细的MiSN定位，我们瞬时转染U2OS细胞以表达绿色荧光蛋白（GFP）-MiSN，然后使用晶格结构照明显微镜（Lattice SIM）进行实时成像。如中所示图1AMiSN与线粒体染料MitoTracker共定位。仔细检查放大的图像显示，MiSN信号在有丝分裂追踪器的外部（图1A，箭头）。对细胞级分的进一步表征显示，MiSN富集在线粒体级分中（图1B).因此，我们得出结论，MiSN是一种新的线粒体外膜蛋白。

The active ingredients of ginger (Zingiber officinale) are 6-gingerol, 8-gingerol, and 10-gingerol. Ginger is reported to be an antioxidant, anticancer, and anti-inflammatory agent because of its bioactive metabolites. The 3 gingerols share a standard ring structure with different side chains. The maintenance of telomeric length by telomerase is a major issue in almost all cancers. Targeting TERRA G4 could provide a method to inhibit telomerase activity. Molecular docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area, principal component analysis, and free energy landscape analysis were performed to evaluate gingerol-TERRA G4 interactions, the extent and stability of these interactions, and the binding free energy and stability of the complexes of the 3 gingerols with TERRA G4. The results revealed that 10-gingerol has superior binding and stabilizing potential for TERRA G4 structures. These findings suggest that TERRA G4 could be a promising therapeutic target for cancer and that 10-gingerol may serve as a potential anticancer lead compound. Further in vitro and in vivo studies to determine the effective dose and toxicity are necessary to evaluate its safety and efficacy.

This study aimed to design novel 1,8-naphthyridine derivatives as potential anticancer agents that target topoisomerase II via a ligand-based drug design strategy. We developed a robust quantitative structure-activity relationship model via multiple linear regression, achieving a coefficient of determination (R²) of 0.6991. External validation demonstrated high predictive ability, with Q² (F1) and Q² (F2) scores of 0.8683 and 0.8670, respectively, indicating substantial reliability in predicting the biological activity of new compounds. Our dataset includes 23 analogs of 1,8-naphthyridine derivatives. The 2-dimensional structures of these compounds were drawn via ChemDraw 15.0 and optimized via density functional theory with the B3LYP hybrid functional approach via Spartan 14.1. Molecular descriptors were calculated via PaDEL software and further processed via Data Pretreatment Software V.WPS 1.2. The Kennard-Stone algorithm in the dataset division graphical user interface 1.2 split the dataset into training and test sets. Docking studies against the DNA topoisomerase II receptor (Protein Data Bank ID: 1ZXM) revealed substantial interactions, with all the newly designed ligands (L1 to L5) exhibiting superior binding affinities (-9.3 to -8.9 kcal/mol) compared with the existing datasets and the standard drug bevacizumab (-6.0 kcal/mol). The pharmacokinetic evaluation revealed zero violations of Lipinski’s rule of five. Hence, further in-depth in vitro and in vivo investigations are recommended to validate these theoretical findings.

Sepsis-induced acute lung injury (SALI) increases morbidity and mortality among patients in the intensive care unit, often progressing to acute respiratory distress syndrome (ARDS) in patients and resulting in death. Exploring the proteomic associations related to SALI can further elucidate its molecular mechanisms and provide novel targets for underlying treatment.

We conducted 2-sample Mendelian randomization (MR) to analyze the relationship between plasma proteins and sepsis. Additionally, differentially expressed genes (DEGs) between the SALI and sepsis groups were identified using the GSE65682 dataset from the Gene Expression Omnibus (GEO) database. By intersecting the plasma proteins analyzed by MR with DEGs related to SALI, we identified and validated the marked plasma proteins, which were accurate and robust according to multiple sensitivity analyses.

A total of 541 plasma proteins were significantly associated with sepsis according to 2-sample MR analysis by the inverse-variance-weighted method. Moreover, 206 DEGs between the SALI and sepsis groups from the GSE65682 dataset in the GEO database were identified. By intersecting the 541 plasma proteins with the 206 DEGs, we identified plasma proteins (CD74, CDKN2C, CLU, HBQ1, IL7R, and OLFM4) that were negatively associated with SALI risk. According to inverse-variance-weighted analysis, their odds ratios ranged from 0.676 (95% confidence interval [CI] 0.498 to 0.919) for CD74 to 0.889 (95% CI 0.813 to 0.973) for CDKN2C. Enrichment analysis indicated that these proteins were involved primarily in immune responses. From the enriched network, we established the relationships between the above genes and immune receptor activity and the luminal side of the membrane or endoplasmic reticulum membrane.

This study revealed that plasma proteins (CD74, CDKN2C, CLU, HBQ1, IL7R, and OLFM4) are causally protective against SALI, which contributes to the early identification and accurate treatment of SALI and could decrease the incidence of ARDS or even the risk of death.

Concomitant exotropia is a common chronic eye disease characterized by abnormal movement of the extraocular muscles caused by a functional imbalance of the nerves related to the movement of the extraocular muscles. This study revealed that the expression levels of S-100β and the muscle area decreased in the extraocular muscles of patients with concomitant exotropia, whereas the expression of calcitonin gene-related peptide (CGRP) increased. In CGRP-KO rats, low expression of CGRP was positively correlated with muscle atrophy. Moreover, the expression level of muscle cells, which are fast myosin heavy chain positive and slow myosin positive in CGRP-KO rats, was lower than that in the control group. Drug intervention experiments further confirmed the inhibitory effect of CGRP on muscle atrophy. The level of apoptosis in the extraocular muscles of CGRP-KO rats was significantly greater than that in the control group (P < 0.05), and the phosphorylation level of AKT/CREB in the extraocular muscles of patients with concomitant exotropia was greater than that in the control group. The increased expression of CGRP in the extraocular muscles of patients with concomitant exotropia may inhibit the apoptosis of extraocular muscle cells through the AKT/CREB signaling pathway and participate in the protective effect of the extraocular muscles in concomitant exotropia.

The primary aim of this research was to address the significant challenge of low and unpredictable drug absorption following oral administration, which often occurs due to poor water solubility. Niosomes, which are lipid-based vesicles, have been explored as potential solutions to increase the solubility of water-insoluble drugs.

Niosomal suspensions were prepared with the thin-film hydration method. Various concentrations of Span 20, Span 40, Tween 60, and cholesterol were used to optimize the formulation. The resulting formulations were characterized, and their properties were assessed.

The optimal formulation, namely, NS6, which was composed of Span 40 (200 mg) and cholesterol (40 mg), had a size of 206.1 nm and a zeta potential of -36.5 mV. Adjusting the surfactant concentration resulted in a maximum drug entrapment efficiency of 88.89%. Statistical analysis confirmed that NS6 was the optimal formulation.

This study demonstrates that niosomal suspensions are promising drug delivery systems with potential for use in treating type 2 diabetes. Niosomes facilitate the sustained release and enhanced solubility of drugs, rendering them convenient and effective tools for enhancing drug delivery to target sites.

Monoamine oxidase (MAO) is an enzyme that plays a crucial role in breaking down monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, thereby regulating their levels in the brain and other tissues. A decrease in MAO enzymes leads to a nonfatal neurological condition that can lead to Parkinson’s disease. In this study, compounds from Tecomella undulata that mimic the structure of MAO-A can be used as substitutes for the blood-brain barrier, which was confirmed via in silico approaches. To study protein-ligand interactions, the target protein, MAO-A (Protein Data Bank ID: 2Z5Y), was subjected to molecular docking and dynamics studies with high-affinity compounds extracted from T. undulata. Among the 30 phytochemicals that were subjected to molecular docking simulation to examine the behavior of the dynamic protein complex, the compounds with the highest binding affinities were squalene, benzoic acid, 4-methyl-[4-(methoxycarbonyl)phenyl] methyl ester, and stigmasterol. In terms of the root mean square deviation (RMSD), root mean square fluctuation, ligand RMSD, radius of gyration, solvent accessible surface area, and H bond, ligand binding demonstrated sustained stability throughout the simulation period. The results suggest that substances derived from T. undulata show important potential for treating Parkinson’s disease, justifying additional research through both in vitro and in vivo experiments.

Gene therapy, a revolutionary approach to treating genetic disorders, aims to introduce functional genes into cells to correct genetic defects. Liposomes, artificial lipid vesicles, have emerged as promising nonviral vectors for gene delivery. Owing to their biocompatibility, versatility, and ability to encapsulate various therapeutic molecules, liposomes are ideal candidates for gene therapy. This review explores the principles of liposome-based gene therapy, including composition, mechanisms of action, and applications. We discuss the challenges and limitations of liposome-mediated gene delivery and ongoing research efforts to improve their efficacy and safety. In conclusion, liposomes offer a promising avenue for developing effective and safe gene therapies for various genetic diseases.

Cofilin is a pivotal actin-binding protein that plays a central role in regulating cytoskeletal dynamics, contributing to essential cellular processes such as migration, invasion, intracellular trafficking, and apoptosis. Dysregulation of cofilin is increasingly recognized to play a role in the pathogenesis and progression of various cancers, including gliomas and colorectal, breast, and bladder cancers. Cofilin facilitates cancer cell motility and metastasis by severing actin filaments, promoting invadopodia formation, and inducing epithelial-to-mesenchymal transition. Cofilin also modulates oncogenic signaling pathways, such as the phosphoinositide 3-kinase/protein kinase B and Rho guanosine triphosphatase pathways, and influences mitochondrial dynamics, thereby contributing to apoptosis resistance, metabolic reprogramming, and immune evasion. Recent advances in high-resolution imaging and multiomics analyses have revealed the spatiotemporal regulation of cofilin in the tumor microenvironment and its potential for use as a diagnostic and prognostic biomarker. Elevated cofilin expression is correlated with poor clinical outcomes and resistance to therapies, making cofilin an attractive target for cancer treatment. Preclinical models have demonstrated that targeting cofilin or its upstream regulators can improve therapeutic responses and suppress metastasis. This review explores the structural, functional, and regulatory roles of cofilin in cancer biology and highlights its emerging therapeutic potential. Future research should focus on the development of selective inhibitors and personalized treatment strategies to leverage cofilin as a target in precision oncology.

Dendritic cells (DCs) are critical for initiating and regulating immune responses, including responses in allergic asthma; they are traditionally divided into subgroups based on surface markings, function, and origin. In allergic asthma, DCs stimulate and activate T helper 2 cells during the generation of cytokines such as interleukin-4 (IL-4), IL-5, and IL-13, which promote allergic inflammation with airway hyperresponsiveness. However, recent research has highlighted the existence of DC subsets with immune regulatory properties that can counteract allergic reactions and promote tolerance. These regulatory DCs induce regulatory T-cell reactions and suppress effector T-cell reactions, thereby maintaining immune homeostasis and preventing excessive inflammation. The recognition and description of these immunoregulatory DC subsets are essential for the improvement of new therapeutic strategies for allergic asthma. Targeting specific signaling pathways involved in DC-mediated immune regulation could open new avenues for therapeutic interventions. Additional research is necessary to elucidate the particular mechanisms underlying the function and potential of DC subsets as therapeutic targets.

One of the latest and most promising AKT inhibitors for use in cancer treatment appears to have promising potential, particularly when the underlying issue is the dysregulation of the PI3K/AKT1/mTOR pathway. The PI3K/AKT/mTOR pathway is essential for various cellular functions, such as growth, metabolism, survival, and proliferation, and it has been found to be disrupted in numerous cancers, particularly breast cancer. Preclinical studies have highlighted the anticancer properties of capivasertib, leading to further investigations in clinical trials. This phase 3 CAPItello-291 trial demonstrated the effectiveness of capivasertib when combined with fulvestrant for patients with hormone receptor-positive (HR⁺) and human epidermal growth factor receptor 2-negative (HER2^-) advanced breast cancer. This combination therapy enhanced progression-free survival in patients, especially those with alterations in the PI3K/AKT1 pathway. Data are also available on the combination with paclitaxel, indicating tolerability and clinical benefits. General pharmacokinetic assessments suggest favorable absorption and distribution profiles of capivasertib, enabling flexible dosing schedules. However, significant concerns remain regarding side effects, particularly diarrhea, hyperglycemia, and rash. Nevertheless, current clinical trials are optimizing the administration of capivasertib for intermittent dosing while exploring its overall effectiveness against various cancers, including BRCA-mutated cancers, due to its interaction with PARP inhibitors. The use of capivasertib is a crucial advancement in targeted cancer therapy, offering renewed optimism for patients facing challenging malignancies. Future research should focus on refining treatment protocols, minimizing toxic effects, and identifying predictive biomarkers to improve patient outcomes.

Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid peroxidation and distinct morphological changes. This process is driven by key mechanisms, including polyunsaturated fatty acid synthesis, lipid peroxidation, iron metabolism, and the glutathione peroxidase 4 antioxidant system. Owing to their altered redox balance and metabolic states, cancer cells are particularly susceptible to ferroptosis. Oncogenic signaling pathways such as those involving rat sarcoma viral oncogene homolog (RAS), nuclear factor erythroid 2-related factor 2 (NRF2), mechanistic target of rapamycin (mTOR), hypoxia, and tumor protein p53 (TP53) play critical roles in regulating ferroptosis sensitivity in cancer cells. Inducing ferroptosis has emerged as a promising therapeutic strategy to target therapy-resistant cancer cells, especially those exhibiting mesenchymal and dedifferentiated phenotypes. Various ferroptosis-inducing drugs, including sorafenib, cisplatin, and statins, have shown potential in cancer treatment. To enhance the efficacy and specificity of these agents, innovative drug delivery systems such as nanoparticles, hydrogels, and liposomes have been developed. These advanced delivery methods aim to improve drug stability, target specificity, and therapeutic outcomes. For instance, the suppression of ferroptosis could help prevent tumor initiation, minimize treatment-related side effects, and preserve immune cell function. This dual role of ferroptosis in cancer underscores the complexity of its interplay with cancer biology. Understanding the molecular mechanisms and context-dependent functions of ferroptosis is crucial for the development of effective therapeutic strategies. Targeting ferroptosis has marked potential for overcoming treatment resistance and improving therapeutic outcomes in oral cancer patients. A deeper understanding of the molecular pathways governing ferroptosis will enable the development of more precise and effective cancer treatments, ultimately enhancing patient outcomes.

Multidrug-resistant prostate cancer, particularly castration-resistant prostate cancer, remains a marked therapeutic challenge because of poor drug bioavailability, systemic toxicity, and resistance mechanisms. Nanoparticle-based codelivery systems improve targeted drug accumulation, stability, and controlled release within the tumor microenvironment. The complementary mechanisms of action of these agents include paclitaxel-induced mitotic arrest and apoptosis, and chrysin increases cytotoxicity by modulating oxidative stress, suppressing survival pathways, and overcoming drug resistance. Preclinical studies have demonstrated superior efficacy and reduced toxicity compared with those of monotherapies. Despite promising results, formulation challenges, regulatory barriers, and scalability issues must be addressed to translate this dual-drug strategy into clinical applications. Overall, the codelivery of paclitaxel-chrysin via nanocarriers represents a promising advance in the personalized treatment of resistant prostate cancer.