Cyclin-dependent kinase 1 (CDK1) is a key regulator of cell cycle progression and a potential therapeutic target for invasive malignancies. However, developing selective CDK1 inhibitors with manageable toxicity remains a significant challenge. In this study, a novel series of 1,2,4-triazolobenzene sulfonamide derivatives were designed and synthesized based on the structure of JNJ7706621 and its derivative 3n, and subjected to comprehensive bioactivity evaluation and structure-activity relationship discussion. Among them, 11l emerged as a highly promising lead compound, exhibiting nanomolar inhibitory activity against CDK1 (IC50 = 5.5 nM) with high selectivity over CDK2, Aurora A, and CDK4, showing selectivity indices of 4.7-, 14.1-, and 73.2-fold, respectively. In vitro, 11l exhibited broad antiproliferative activity, particularly against HCT116 colon cancer cells. Unlike conventional kinase inhibitors that solely suppress catalytic activity, 11l induced G2/M phase arrest and downregulated CDK1, cyclin B1, and the replication initiation factor CDC45. Further investigation revealed that 11l induces severe DNA replication stress, subsequently activating the p53 signaling pathway to trigger apoptosis. This mechanism was recapitulated in CDC45 knockdown models. In vivo efficacy evaluation demonstrated that 30 mg/kg 11l achieved a tumor growth inhibition (TGI) rate of 56.4%, without inducing significant body weight loss or observable organ toxicity. Collectively, these findings identify 11l as a safe CDK1 inhibitor with a distinct mechanism of action, supporting its potential as a promising therapeutic strategy for cancer treatment.

The structural complexity and potent biological activities of marine natural products continue to attract considerable interest from chemists and biologists due to their unique biochemical mechanisms. In this study, we investigated the protective effects of a marine-sponge derived compound MBL-1 on intestinal inflammation. In vitro assays demonstrated that MBL-1 effectively reduced the production of key pro-inflammatory mediators, including NO, ROS, and cytokines such as IL-1β and IL-18. Mechanistic studies further revealed that these anti-inflammatory effects were mediated through inhibition of the MAPK/NF-κB and NLRP3 signaling pathway. Consistently, in vivo experiments showed that MBL-1 markedly attenuated histological damage and provided strong protection against DSS-induced colitis. Collectively, these findings highlight the potential of MBL-1 as a therapeutic candidate for ulcerative colitis, exerting its anti-inflammatory effects through the systemic modulation of the MAPK/NF-κB and NLRP3 signaling cascade.

Ion channels represent a significant class of drug targets implicated in the development of various diseases. In recent years, there has been a significant increase in research on the structure and function of ion channels, thereby promoting the study of drug targeting mechanisms involving these channels. The ocean serves as a rich reservoir of lead compounds for drug development, undeniably providing a valuable source for ion channel-targeting drugs. However, various factors contribute to the superficial nature of many studies on drug action mechanisms and there is ongoing confusion surrounding related concepts. This review systematically reviews the mechanisms of action of marine natural products and synthetic derivatives studied from 2000 to 2025, with the goal to establish reference standards relevant to this field of study. Additionally, we systematically review the structure-activity relationship studies and summarize drug optimization strategies in subsequent sections. The primary objective of this review is to promote deeper investigations into drug action mechanisms, providing insights for drug development and fostering the emergence of more precise pharmacological terminology to clarify these complex mechanisms.

Edwardsiella tarda is a zoonotic, foodborne intracellular pathogen that causes significant disease in both farmed and wild fish and can also infect humans. By surviving within macrophages, this pathogen evades immune clearance, presenting a challenge for treatment. Compound 5, a marine fungal macrocyclic lactone structurally classified among anti-inflammatory cytochalasins (formerly cytochalasin Z16) and isolated from the marine-derived fungus Aspergillus sp. NBU4698, lacks direct antibacterial activity but markedly enhances macrophage-mediated clearance of E. tarda. This compound exerts multifaceted immunomodulatory effects: it suppresses phagocytosis, pathogen-induced apoptosis, and inflammation while simultaneously promoting bacterial killing. These actions occur through dual regulation of ROS-elevating mitochondrial ROS while reducing total cellular ROS-and via modulation of the lipid droplet-antimicrobial peptide axis, which inhibits E. tarda-stimulated lipid droplet formation and CRAMP expression. Mechanistically, compound 5 targets HSPA5, a protein that appears to coordinate host defense through interactions with alpha-2-macroglobulin (A2M) and siah E3 ubiquitin protein ligase 2 (SIAH2). Our findings identify HSPA5 as a promising target for host-directed therapy and provide the first evidence for cytochalasin-based immunomodulation against intracellular bacterial pathogens.

Triple-negative breast cancer (TNBC) is one of the most prevalent and aggressive subtypes of breast cancer worldwide, contributing significantly to cancer-related mortality in women. Due to the absence of effective targeted therapies, there is an urgent need to identify novel molecular targets and bioactive compounds for TNBC treatment. Eukaryotic elongation factor 1A1 (EEF1A1), a key regulator of protein synthesis through its role in peptide chain elongation, has emerged as a potential therapeutic candidate; however, its functional role in TNBC remains poorly understood. In this study, we isolated a series of Penicillide-like compounds from the mycelium of Penicillium sp. NBU2256, designated as compounds 1-5. Using CCK-8 cytotoxicity assays, compound 2 was identified as the most potent inhibitor of TNBC cell viability. Subsequent mechanistic investigations revealed that compound 2 induced apoptosis, triggered cell cycle arrest, and modulated cancer stem cell properties. To elucidate its molecular target, we employed drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA), which identified EEF1A1 as a direct binding partner of compound 2. Network pharmacology analysis further predicted RPL27A and RPLP0 as downstream effectors of EEF1A1 signaling. Functional validation using actinomycin D and cycloheximide treatments demonstrated that compound 2 suppresses RPL27A and RPLP0 expression at the translational level, thereby inhibiting tumor cell invasion and migration and exerting robust antitumor effects. Collectively, these findings provide novel insights into the anticancer mechanisms of EEF1A1-targeting agents and highlight EEF1A1 as a promising therapeutic target for the treatment of TNBC.

Edwardsiella tarda is an intracellular pathogen capable of surviving within macrophages, evading immune surveillance, and inducing apoptosis and necrosis, leading to systemic infections in both aquatic animals and humans. Unlike traditional ochratoxins-mycotoxins known for nephrotoxic, hepatotoxic, and immunotoxic effects-we identified a novel hydroxy-containing ochratoxin derivative, ochratoxin E (1), along with three known ochratoxins (2-4), from the marine fungus Aspergillus sp. NBU1109. The structure and absolute configuration of compound 1 were elucidated using HRESIMS, NMR, ECD calculations, and single-crystal X-ray diffraction. Crucially, compound 1 showed no cytotoxicity in human LX-2 or murine RAW 264.7 cells, in contrast to the toxic effects of compounds 2-4. Functionally, compound 1 enhanced macrophage phagocytosis and bactericidal activity against E. tarda, and suppressed apoptosis and necrosis. Mechanistically, drug-affinity responsive target stability (DARTS), molecular docking, and cellular thermal shift assays (CETSA) confirmed that compound 1 directly binds AIFM1. This interaction blocked the AIFM1-RIP3 association, reduced RIP3 nuclear translocation, and inhibited apoptotic-necroptotic signaling. These results delineate a unique, non-toxic ochratoxin derivative that targets the AIFM1/RIP3 axis to bolster macrophage defense, highlighting its promise as a lead compound for anti-E. tarda therapy development.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Current treatments, including anti-inflammatory drugs and biologics, often have limited efficacy and significant side effects, highlighting the need for novel therapeutic approaches. Phellodendrine (PHE) is a characteristic ingredient of Phellodendri chinensis, yet its effects and mechanisms on IBD remain elusive. The present study evaluated the potential of PHE for preventing dextran sulfate sodium-induced IBD in zebrafish. PHE effectively reduced inflammatory cell infiltration and modulated polarized macrophages. The qPCR results further confirmed the down-regulation of pro-inflammatory genes and up-regulation of anti-inflammatory factors. Consequently, PHE promoted the resolution of IBD inflammation. PHE also restored intestinal barrier integrity by enhancing MUC2 expression, increasing goblet cell counts, and reducing intestinal permeability of both chemical and physical barriers. In addition, PHE was associated with alterations in the gut microbiome, including a reduction in potentially pathogenic microbes and an increase in beneficial microbial populations. PHE also alleviated oxidative stress. Network pharmacology suggested the potential involvement of the IL-17 signaling pathway, the lipid and atherosclerosis pathway, and the TNF signaling pathway in the preventive effects of PHE against intestinal inflammation in the zebrafish model. In vivo gene expression analysis suggested that JUN, PTGS2, IL1B, DRD2, CALM1, and HSP90AA1 may serve as putative targets of PHE. Collectively, our results indicate that PHE demonstrates potential anti-inflammatory and barrier-protective activities in a zebrafish model of intestinal inflammation. The pharmacological mechanisms by which PHE restores intestinal barriers (microbial, chemical, physical, and immune barriers) include resolving inflammation, decreasing ROS production, and enhancing lipid accumulation in the lumen overlying the intestinal mucus barrier. This study provides novel insights into the preventive effects of PHE against intestinal inflammation in a zebrafish model, suggesting its potential as a candidate for further investigation.

The escalating threat of methicillin-resistant Staphylococcus aureus (MRSA) to global public health necessitates the discovery of antimicrobial agents with novel mechanisms of action. In this study, a DeepSAT-assisted bioactivity-guided fractionation strategy was employed to investigate the marine-derived fungus Aspergillus sp. NBU4698, leading to the isolation of two new macrocyclic gamma-lactams featuring a perhydroisoindolone scaffold, namely Asperlactams A and B (1 and 2). Their structures, including absolute configurations, were unequivocally determined by comprehensive spectroscopic analyses (HRESIMS, NMR, single-crystal X-ray crystallography, and ECD calculations). Compound 1 demonstrated anti-MRSA activity against clinically relevant strain ATCC 43300 with no significant cytotoxicity. Time-kill assays confirmed concentration-dependent bactericidal effects within 24 h treatment. Mechanistic studies of 1 revealed surface topology deformation through cell wall disruption, and compromising membrane integrity via pore formation.

The molecular structure of polyimide (PI) fundamentally influences its various properties. However, the motion characteristics of molecular chain segments, the evolution of internal structures, and the differentiation of system network formation remain issues that require further investigation. Four PI models with representative molecular configurations were established, and the complex attachment mechanism between the PI molecular structure and its final properties was examined using molecular dynamics methods. Specifically, the molecular structure and intermolecular interactions were analyzed through the radial distribution function, reaction barrier, and free volume ratio, while the dynamic behavior of the molecular chains was assessed in terms of mean square displacement, radius of gyration, and torsion angle barrier. The simulated glass transition temperature curve, water molecule migration model, and simulated mechanical property results further demonstrate that the molecular structure is the primary reason for the performance differences observed in PI. Additionally, the validity of the PI models was corroborated by preparing PI materials corresponding to the four molecular structures and comparing the results of model simulations with experimental values. The methodology is invaluable for understanding the dynamic behavior of polyimide molecular segments and for predicting the evolution of polyimide networks.

Improving the power supply resilience under extreme conditions is an important construction goal faced by modern distribution systems (DSs). In this paper, we develop a dynamic restoration framework for renewable DSs with cold-load pickup (CLPU), assisted by the reconfigurable converter-formed multi-terminal soft open point (R-SOP) to minimize the de-energized loads and renewables curtailment under extreme weather events. Traditional SOP often designed as symmetric capacity topology, which may limit the DS restoration quality by the converter capacity of symmetric SOPs. To address this, a dynamic network reconfiguration model of DSs is established that embedded with R-SOP, whose typical feature is the asymmetric converter capacity design while keeping the total port capacity unchanged compared with traditional SOP. On this basis, a multi-period distribution service restoration model is formulated integrating the converter reconfiguration of R-SOP, DS topology changes and coordinated actions of flexible resources to enhance the restoration level and improve the renewable energy utilization. Moreover, restoration strategies that ignore the CLPU phenomenon may face remarkable gap from the realistic system operating conditions. Accordingly, a frequency-constrained dynamic restoration model is proposed in a faster-timescale to respond to the CLPU and restore the DS in a reliable and adaptable manner. Numerical simulations on two modified IEEE test systems and an actual distribution system verify the effectiveness of the developed framework.

Background Neurons are susceptible to oxidative stress due to the elevated reactive oxygen species (ROS) production and the limited antioxidant defense mechanisms. Therefore, it is possible to treat oxidative stress-related neurological disorders via the inhibition of oxidative stress. Chryxanthone A is an extracted substance derived from the endophytic fungal Aspergillus versicolor, with an atypical dihydropyran ring. However, it is unknown whether and how chryxanthone A could produce anti-oxidant protection. Purposes The activity and mechanisms underlying the anti-oxidant protection of chryxanthone A were explored in the study.Study design and methods.HT22 neuronal cells were used to evaluate the anti-oxidant protection of chryxanthone A. Comprehensive bioinformatic methods, including RNA-seq analysis, transcription factor prediction, CMap prediction and molecular docking analysis, were utilized to explore the molecular mechanisms how chryxanthone A prevented oxidative stress, which was confirmed by Western blotting analysis. Results Chryxanthone A concentration-dependently prevented H2O2-induced cell death and increase in intracellular ROS in HT22 cells. Results from RNA-seq and bioinformatic analysis indicated that chryxanthone A might act on mTOR/CREB axis, possibly via binding to the Val2227 site within ATP binding pocket of mTOR. The action of chryxanthone A on H2O2-induced alteration of mTOR/CREB axis were further confirmed in HT22 cells. Conclusion These results suggested that chryxanthone A produced anti-oxidant protection via the action on mTOR/CREB axis, providing a support that chryxanthone A might be developed as a novel drug candidate for the treatment of oxidative stress-related disorders.

The third generation of electronic devices is characterized by integration, high frequency, and high efficiency. These advancements create an urgent demand for multifunctional packaging materials that exhibit crack resistance and effective thermal conductivity. This study proposes a strategy to modulate local interactions in multifunctional nanocomposite by adjusting component composition, ultimately inhibiting crack formation, enhancing heat dissipation, and ensuring uniform electric fields. The results indicate that the incorporation of Ti3C2T x MXene as an interface reinforcement phase leads to a tensile strength of the nanocomposites of sigma = 93.4 MPa, and an in-plane thermal conductivity of Tc = 5.71 Wm-1K-1. Detailed studies on the interfacial bonding between nanocomposite components indicate that crack resistance and thermal conductivity positively correlate with interfacial bonding strength. This finding confirms that the rational design of nanocomposite interfaces is a critical factor in enhancing performance. Additionally, finite element simulation results demonstrate that nanocomposites can reduce the maximum electric field intensity at the junction and improve the electric field distribution within the device. This study establishes a feasible nanocomposite model to enhance the performance of multifunctional nanocomposites by developing dual heterointerfaces at the polymer matrix/inorganic filler interface.

Alternating-voltage control (AVC) is preferred in weak grids to enhance voltage stiffness and active power transfer capability for grid-following voltage source converters (VSCs) with a phase-locked loop. However, asymmetric d-q coupling of control loops is intensified with the AVC due to reactive currents, which leads to undesired interactions and thus risks weak-grid instability. To tackle stability challenge considering the AVC, a parameter tuning approach is first proposed to design the AVC according to the system rating. Based on that, the impact of the AVC on the intensified d-q coupling, stability region, and voltage dynamics are co-investigated. To enhance weak-grid operations, a stability enhancement control is further proposed to reversely compensate for the negative coupling effects induced by the phase-locked loop and AVC. The proposed scheme enables rated power operations of the VSC in ultra-weak grids. Experiments confirm the validity of the proposed method.

The present study reported the discovery of sesterdiaporate (SES), a structurally unique antifungal sesterterpene lactone from Diaporthe sp. HT-79. SES exhibited a pronounced inhibitory effect on spore germination and mycelial growth of Penicillium italicum, with median effective concentrations (EC50) of 0.37 and 0.079 μg/mL, respectively. This inhibitory effect was significantly more pronounced than that observed with prochloraz (0.74 and 6.83 μg/mL, respectively). Treatment with SES resulted in the swelling of both spores and mycelia of P. italicum as well as an increase in cell membrane permeability. Further investigation suggested that SES may disrupt glycosylphosphatidylinositol biosynthesis, ultimately leading to cell death. In vivo tests on navel orange fruit showed that SES was effective in reducing the diameter of lesions caused by P. italicum, with a lesion inhibition percentage of 49.4% at a concentration of 3.7 μg/mL, which was significantly superior to that of prochloraz (14.2% at the same concentration).

Saline lakes are extreme habitats that host unique microbial communities with high biotechnological potential. In this study, a novel strain, designated Q87T, was isolated from Gaxiukule Lake, a high-altitude magnesium sulfate-type saline lake in the Qaidam Basin, China. A polyphasic taxonomic approach, including morphological, physiological, chemotaxonomic, phylogenetic, and genomic analyses, was applied to characterize the isolate. Strain Q87T is a Gram-stain-negative, non-motile, rod-shaped bacterium showing high tolerance to salinity (0-15.0 %, w/v; optimum 5.0 %) and alkalinity (pH 6.0-10.5; optimum pH 7.0), with a temperature range for growth of 10-40 °C (optimum 32 °C). Phylogenetic and genomic analyses confirmed its affiliation with the genus Gracilimonas and revealed it as a distinct species. The genome of strain Q87T (3.3 Mb, G + C 41.5 %) encodes diverse functional genes associated with nitrogen and sulfur metabolism, stress adaptation, and biosynthesis of secondary metabolites, including terpenoids and polyketides. Comparative analyses with reference Gracilimonas strains demonstrated its unique genomic features and ecological adaptability. Structural modeling confirmed functional conservation of key enzymes involved in nitrogen detoxification and sulfide oxidation. Pangenome analysis highlighted the genetic diversity and open nature of the species of the genus Gracilimonas. Biogeographic assessments suggest a wide distribution of the genus in saline environments, especially in sediments. This study expands our understanding of the genus Gracilimonas taxonomy, physiology, and ecological potential, and underscores the importance of extremophilic bacteria as promising resources for environmental and industrial biotechnology.

Gallium nitride (GaN) material emerged as the third-generation semiconductor material due to its superiorities of high critical breakdown electric field, high saturation electron velocity, high electron mobility, and high thermal conductivity. These advantages enable GaN to be suitable for high-density applications such as power factor correction (PFC) circuit. As a typical AC/DC converter, PFC is extensively applied in electric vehicle charging, electronic device power supply etc. However, most GaN devices on the market are enhanced-mode planar high electron mobility transistors (HEMTs). Their high third-quadrant forward voltage leads to large freewheeling conduction loss which significantly increases the power loss of the PFC. To improve the power efficiency, this paper comprehensively analyses the power loss mechanism of a totem-pole PFC converter during the dead time. Based on the analytical results, a dynamic deadtime method for deadtime loss reduction is proposed. The simulation is conducted to validate the analysis and the functionality of the proposed method.

Two Gram-stain-negative, curved-rod-shaped, non-motile and aerobic bacteria W6T and I13T were isolated from marine sediment samples collected from Meishan Island located in the East China Sea. Catalase and oxidase activities and hydrolysis of Tween 40, 60 and 80 were positive for both strains, while nitrate reduction, indole production, methyl red reaction and H2S production were negative. Phylogenetic analyses based on 16S rRNA and genome sequences revealed that strains W6T and I13T formed distinct phylogenetic lineages within the genera Ascidiimonas and Leptobacterium, respectively. Strain W6T showed the closest relatedness to Ascidiimonas aurantiaca N5DA8-2CT with 93.9% 16S rRNA gene sequence similarity, 70.7% average nucleotide identity (ANI), 71.0% average amino acid identity (AAI) and 16.4% digital DNA–DNA hybridization (dDDH) values, while strain I13T was most closely related to Leptobacterium flavescens YM3-301T with 92.1% 16S rRNA gene sequence similarity, 70.5% ANI, 72.1% AAI and 17.2% dDDH values. The two novel strains shared 92.0% 16S rRNA gene sequence similarity to each other and were identified as two distinct species based on 70.7% ANI, 70.4% AAI and 17.1% dDDH values calculated using whole-genome sequences. The genomes of strains W6T and I13T were 4.59 Mbp with a G+C content of 34.5 mol% and 2.38 Mbp with a G+C content of 36.2 mol%, respectively. The only respiratory quinone was menaquinone-6, the major polar lipid was phosphatidylethanolamine and the major cellular fatty acids were iso-C15 : 0, iso-C15 : 1 G and iso-C17 : 0 3-OH. Based on phenotypic, chemotaxonomic and genotypic data, strains W6T and I13T are considered to represent two novel species in the genera Ascidiimonas and Leptobacterium, respectively, in the family Flavobacteriaceae, for which the names Ascidiimonas meishanensis sp. nov. and Leptobacterium meishanense sp. nov. are proposed. The type strains are W6T (=KCTC 102201T=MCCC 1K08928T) and I13T (=KCTC 102202T=MCCC 1K08929T), respectively.

Gouty arthritis, driven by monosodium urate (MSU) crystal deposition and dysregulated inflammation, remains a therapeutic challenge due to the limitations of current treatments. Here, we investigate Herdmanine D (HDD), a marine-derived alkaloid from the ascidian Herdmania momus. It was optimized via structure-activity relationship (SAR) studies and computational modeling to enhance its binding to peroxisome proliferator-activated receptor γ (PPAR-γ), which regulates the PPAR-γ/NF-κB signaling pathway in gout pathogenesis. The optimized HDD derivative 9a demonstrated potent PPAR-γ binding affinity and pharmacokinetic properties, effectively suppressing NF-κB-driven pro-inflammatory cytokines in vitro. In murine MSU-induced gouty arthritis models, 9a alleviated synovial inflammation and tissue damage. Mechanistically, 9a activated PPAR-γ to inhibit NF-κB and attenuate NLRP3 inflammasome assembly. This work highlights HDD as a unique marine scaffold for next-generation antigout therapeutics, merging marine natural product safety with rational design to address unmet clinical needs.

Using together HSQC NMR-guided fractionation and an invivo screening zebrafish model for bioactivity-guided fractionation, four previously undescribed butenolides, perbutanolides A-D (1-4), were isolated from the marine-derived Aspergillus sp. NBU4698. HSQC NMR-based Small Molecule Accurate Recognition Technology (SMART 2.0) was used to simplify the process of discovering and characterizing these structurally related natural products. The structures and absolute configurations were determined by HRESIMS, NMR, polarimetry, and ECD calculations. All the compounds were evaluated for multidrug resistance (MDR) reversing activity in a zebrafish model, and compound 1 induced significant MDR reversal activity by inhibiting PXR-regulated efflux transporters. In addition, compounds 1-3 exhibited a moderate inhibitory effect on pro-inflammatory mediators in RAW264.7 macrophage cells. This is the first report of MDR reversal activity for marine-derived fungal butenolides. These results provide new insights for designing and developing probes and new drugs that can inhibit MDR.