Current Issues in Molecular Biology最新文献

Cervical cancer (CC) remains a common malignant tumor that seriously threatens women's health globally. Gramine (GR), a natural alkaloid derived from plants such as Arundo donax L., exhibits anti-tumor activities, yet its mechanistic actions in CC are still unclear. Here, we integrated cell-based assays, network pharmacology, and multi-omics analysis to systematically investigate the molecular mechanisms underlying GR's anti-CC effects. In vitro experiments showed that GR significantly inhibited proliferation and migration, induced apoptosis, and triggered G₀/G₁ phase cell cycle arrest in HeLa cells. Integrated multi-omics analysis identified CDK2 as a critical target of GR, with both mRNA and protein levels markedly reduced following treatment. Mechanistically, GR likely suppresses CC progression by modulating the "CYP4A22-AS1/LINC00958-hsa-miR-133b-CDK2" competitive endogenous RNA (ceRNA) axis. Immune analysis indicated positive correlations of CDK2, CYP4A22-AS1, and LINC00958 with the immune checkpoint molecule CD47. Collectively, our findings demonstrate that GR inhibits CC through a ncRNA-mediated suppression of CDK2, leading to reduced HeLa cell proliferation and migration and enhanced apoptosis. These results provide a mechanistic rationale for developing GR as a candidate agent for targeted therapy and immuno-combination strategies in CC.

Oral drugs classified under Class III of the Biopharmaceutics Classification System (BCS) are defined by high aqueous solubility yet low intestinal permeability. Their restricted oral bioavailability arises not from inadequate dissolution, but is primarily governed by the intestinal permeability barrier, coupled with substantial inter-individual variability in absorption. This review adopts the intestinal permeability barrier as its core analytical framework to dissect the key determinants of oral absorption for BCS III drugs, while presenting a comparative and critical evaluation of prevailing bioavailability enhancement strategies. From perspectives including mechanism of action, achievable magnitude of enhancement, applicable physicochemical and physiological conditions, and translational feasibility, the intrinsic mechanistic limitations and applicable boundaries of distinct strategies are delineated. Finally, this paper concludes that the absorption barriers of BCS III drugs cannot be universally surmounted by a single strategy, emphasizing the significance of mechanism-guided strategy selection for the rational design of oral drug delivery systems. In doing so, it provides a foundational basis for the rational development of oral delivery systems tailored to BCS III drugs.

Cardiomyopathies represent a heterogeneous group of myocardial diseases that share overlapping clinical and genetic profiles but distinct morphological and molecular signatures. Advances in molecular genetics and next-generation sequencing have revolutionized the diagnostic landscape, revealing that up to 60% of cardiomyopathies have an identifiable genetic basis. From a pathologist's perspective, integrating histopathological findings with molecular data is crucial for understanding genotype-phenotype correlations and for guiding precision medicine. This review provides an updated overview of the molecular pathology of major cardiomyopathy subtypes, including dilated, hypertrophic, restrictive, arrhythmogenic, and non-compaction forms. For each entity, we discuss morphologic hallmarks, genetic mechanisms, and their impact on disease progression and sudden cardiac death. Special emphasis is placed on the role of desmosomal, sarcomeric, and cytoskeletal proteins in myocardial structure and function, and on how their mutations disrupt cardiomyocyte integrity and signaling pathways. Furthermore, we address the emerging role of molecular autopsy in unexplained sudden cardiac death, underscoring the importance of multidisciplinary collaboration among pathologists, geneticists, and clinicians. Finally, we highlight future directions in molecular diagnostics and targeted therapies, which are reshaping the classification and management of cardiomyopathies.

Activation of the stimulator of interferon genes (STING) pathway has emerged as a promising strategy for cancer immunotherapy. However, the initial cyclic dinucleotide (CDN) analogs developed as STING agonists have shown limited efficacy in clinical trials, prompting interest in non-CDN small-molecule alternatives. In this study, we identified a novel series of bromophenol derivatives as effective STING agonists. Among these derivatives, OSBP63 robustly activated the STING signaling pathway, resulting in enhanced phosphorylation of interferon regulatory factor 3 (p-IRF3) and increased secretion of interferon-β (IFN-β). Co-administration of Marine Bromophenol Derivative (OSBP63) with paclitaxel (PTX), a conventional anticancer drug, significantly suppressed B-cell lymphoma-2 (BCL-2) expression and protein kinase B (AKT) phosphorylation, thereby demonstrating pronounced anti-tumor activity in a mouse model of breast cancer. These findings suggest that OSBP63 represents a promising non-CDN small-molecule STING agonist candidate, offering a valuable lead for future anticancer therapeutic development.

This review aims to systematically synthesize recent research advances on the antimicrobial peptides (AMPs) derived from the black soldier fly (Hermetia illucens). Against the backdrop of the escalating global crisis of antimicrobial resistance (AMR), AMPs have emerged as pivotal candidates to replace conventional antibiotics. As a unique saprophagous insect, H. illucens has evolved a robust and efficient innate immune system to thrive in its pathogen-rich environment. The AMPs it produces demonstrate remarkable broad-spectrum activity, high stability, and a low propensity for inducing resistance. Based on cutting-edge research available up to 2025, this article will provide an in-depth exploration of the astounding molecular diversity of H. illucens AMPs, their key structure-function relationships, and their multifaceted mechanisms of action, ranging from membrane disruption to immunomodulation. It will also highlight engineering strategies driven by artificial intelligence (AI). Finally, the review will assess the significant translational potential of these AMPs in combating multidrug-resistant bacteria, analyzing the current status of research in animal models, the challenges for industrial production, and viable future development pathways. The goal is to provide a solid theoretical foundation and forward-looking perspective to facilitate the translation of this valuable biological resource from basic research to clinical and agricultural applications.

Pulmonary involvement in cystic fibrosis (CF) is characterised by respiratory infections caused by bacteria, viruses, and fungi, as well as by dysregulated inflammatory and immune responses. Although essential for the host's initial defence against these microorganisms, the innate immune response is altered in its main cellular (airway epithelial cells (AECs), monocytes, macrophages, and neutrophils) and molecular (cytokines, chemokines, signal transduction pathways, and transcription factors) components. MicroRNAs (miRNAs) form a regulatory network at the level of inflammatory and immune responses, and their dysregulation has been observed in immortalised and primary CF AECs as well as in monocytes, macrophages, and neutrophils from CF patients. Although the study of individual miRNAs is helping to dissect the specific altered events in CF lung disease (CFLD), large-scale genomic and transcriptomic studies are more likely to capture its full complexity. The studies we identified suggest that miRNAs are involved in various processes related to CFLD, including impaired pathogen response, compensation for hyperinflammation, altered antigen presentation, and wound healing in AECs and macrophages. However, clinical studies involving large cohorts of patients are needed to obtain meaningful results and identify new therapeutic targets. Equally important will be the study of the miRNome as circulating biomarkers for the purposes of diagnostic and prognostic precision medicine.

Lipid profiling is a key element of modern biology and medicine, providing information on the structure, function, and dynamics of lipid metabolism in health and disease. This review presents the latest state of the art in the application of matrix-assisted laser ionization mass spectrometry (MALDI-MS) in lipidomics, with a particular focus on the analysis of cholesterol, triglycerides (TAGs), and the main classes of phospholipids and sphingolipids. The theoretical basis of the technique is discussed, including ionization mechanisms, matrix selection and mass analyzer configurations, and the influence of experimental parameters on spectral quality. The specificity of sterol and TAG ionization, challenges associated with ion suppression, and strategies for improving detection sensitivity and selectivity are discussed. Particular attention is paid to molecular imaging (MALDI-MSI), which enables spatial mapping of lipids in tissues and is of increasing importance in neurobiological, oncological, and metabolic research. The review highlights the advantages of MALDI for rapid lipid profiling and tissue analysis, while also pointing out technical limitations (e.g., difficulties in detecting sterols, matrix interference, limited quantification) and the need for method standardization. MALDI-MS appears to be a complementary technique to LC-MS/ESI-MS and DESI-MS, with great translational potential, particularly in the context of diagnostics, biomarker studies, and in situ lipid imaging.

Cancer therapies frequently induce hepatotoxicity, complicating treatment courses and outcomes. Natural products, including polyphenol-rich extracts, have shown hepatoprotective activity via anti-oxidative and anti-inflammatory mechanisms, often linked to NF-κB and PI3K-Akt pathways. Apple-derived polyphenols (e.g., phlorizin/phloretin) also demonstrate liver-protective effects in experimental settings. In this study, we examined whether ASE mitigates cancer-related liver damage by rebalancing the apoptosis-survival axis and maintaining PI3K-Akt signaling in an endometrial cancer mouse model. Female Institute of Cancer Research mice with induced endometrial cancer received ASE (0-200 mg) over 13 days; liver tissues were analyzed for Caspase-3, p53, LC3, and SQSTM1 using histology stains, Western blot (e.g., Caspase-3/9, Bcl-xL, PI3K, Akt, PCNA, IGF-IR), ELISA, and qRT-PCR (GAPDH). ImageJ (version 1.54f; RRID: SCR_003070) quantification statistical analysis followed (mean ± SD; post-hoc tests). ASE exhibited dose-dependent modulation of apoptosis and survival readouts in liver tissue of cancer-bearing mice: (i) Caspase-9/3 and Bcl-xL showed differential regulation across doses; (ii) PI3K-Akt and IL-2 signals were preserved or restored toward baseline at specific doses; and (iii) histology indicated partial structural recovery. Thus, ASE may mitigate liver injury by re-balancing apoptosis-survival signaling and promoting structural recovery. Our interpretation emphasizes that dose, route, and formulation are critical for translational potential.

Schiff bases are widely studied for their biological activities, yet structure-activity relationships governing their anticancer potential remain insufficiently understood. In this work, eight structurally diverse imine derivatives (A-H) were evaluated for their cytotoxic, biochemical, and biomolecular interactions in human cancer cells. Their antiproliferative effects were assessed in HeLa, A549, and LS174T cell lines, with MRC-5 fibroblasts used as a non-malignant control. Cytotoxicity screening identified three compounds (A, B, and F) with the highest potency, prompting further mechanistic investigation. Cell cycle analysis revealed G1 arrest and accumulation of sub-G1 populations for all three derivatives, with compound B additionally increasing S-phase content and compound F inducing G2/M arrest. All compounds reduced intracellular ROS levels and caused significant DNA damage at subtoxic concentrations. Western blot analysis demonstrated downregulation of HIF-1α and PDK3, suggesting disruption of hypoxia-associated metabolic signaling. Fluorescence quenching experiments showed strong binding of the active compounds to bovine serum albumin (K_a ≈ 10⁶ M^-1), and molecular docking supported stable interactions near tryptophan-adjacent binding regions. Collectively, these findings indicate that selected Schiff bases exert multi-target anticancer activity by modulating oxidative stress, DNA integrity, cell-cycle progression, and metabolic adaptation pathways, warranting further investigation of their therapeutic potential.

AflatoxinB1 (AFB1) is a hepatotoxic mycotoxin whose bioactivation by cytochrome P450 (CYP450) enzymes generates reactive metabolites that drive oxidative stress, inflammation, and apoptosis. Propolis is a bee-derived product with antioxidant and immunomodulatory properties. To investigate whether propolis supplementation attenuates AFB1-induced hepatic injury by modulating inflammatory mediators, Nrf2-HO-1 signaling, mitochondrial apoptosis, and CYP450 expression in rats, twenty-four male Sprague-Dawley rats were randomly allocated to four groups (n = 6): control, AFB1 (25 µg/kg/day), propolis (250 mg/kg/day), and AFB1 + propolis. Treatments were given by oral gavage for 28 days. Hepatic IL-1β, IL-6, TNF-α, Nrf2 and HO-1 levels were measured by ELISA. Histopathology was assessed on H&E-stained sections. Bax, Bcl-2, caspase-3, CYP1A2, CYP3A4, CYP2C19 and cytochrome P450 reductase expressions were evaluated immunohistochemically and quantified by ImageJ. Data were analyzed using one-way ANOVA with Tukey's post hoc test. AFB1 significantly increased hepatic IL-1β and IL-6 and reduced Nrf2 levels, while propolis supplementation restored Nrf2, elevated HO-1 and significantly lowered IL-6 compared with AFB1 alone (p < 0.05). AFB1 induced marked hydropic degeneration, sinusoidal congestion, and mononuclear infiltration, alongside increased Bax and caspase-3 and decreased Bcl-2 expression; these changes were largely reversed in propolis-treated groups. AFB1 upregulated CYP1A2, CYP3A4 and cytochrome P450 reductase, whereas propolis co-treatment significantly suppressed their expression without affecting CYP2C19. Propolis supplementation attenuated AFB1-induced liver injury through coordinated anti-inflammatory, antioxidant, anti-apoptotic and metabolic regulatory effects, notably via restoration of Nrf2-HO-1 signaling and down-regulation of key CYP450 isoenzymes. Propolis may represent a promising natural dietary strategy against AFB1-associated hepatotoxicity, warranting further translational research.