In recent years, harmful algal blooms have led to frequent occurrences of shellfish toxin contamination, posing a significant threat to the safety of aquatic products and public health. As a potent neurotoxin, domoic acid (DA) can accumulate in shellfish, highlighting the urgent need for rapid and highly sensitive detection methods. In this study, we developed a fluorescent aptasensor based on a dual-signal amplification system by combining G-quadruplex (G4) dimers with multi-walled carbon nanotubes (CNTs). The sensor is designed with a hairpin-structured aptamer as the recognition probe, where short multi-walled CNTs serve as both a fluorescence quencher and platform, and G4 dimers are incorporated into the sensing interface to enhance signal output. In the absence of the target, the hairpin-structured aptamer remains closed, keeping the fluorescence signal “off”. Upon binding to DA, the aptamer undergoes a specific conformational change that exposes the G4-dimer sequence. The exposed sequence then binds to thioflavin T (ThT), which in turn generates a greatly enhanced fluorescence signal, leading to a substantial fluorescence enhancement and completing the second stage of the cascade amplification. Under optimal conditions, the constructed sensor achieves rapid detection of DA within 5 min, with a low detection limit of 1.1 ng/mL. This work presents a valuable tool for the rapid and sensitive detection of DA in shellfish, with promising applications in marine environmental monitoring and food safety regulation.

Lung cancer remains to be the leading cause of cancer-related mortality worldwide, with non-small cell lung carcinoma (NSCLC) accounting for approximately 85% and the five-year survival rate below 20%. Microcolin A (Mic A), a lipopeptide derived from marine cyanobacteria, exhibits significant antitumor activity, however, its underlying mechanism is unclear. Hsp90 is highly expressed in various cancer tissues and positively correlated with tumor progression and aggressiveness. Existing studies have shown that most Hsp90 inhibitors target the N-terminal ATP-binding pockets, however, the clinical trials of the relevant candidate drugs have been halted or postponed for insufficient stratification and side effects. In contrast, targeting the C-terminal domain of Hsp90 may be a more promising route to develop the anti-cancer drug. In this study, we find that Hsp90α is a potential target for Mic A, which could target the C-terminal of Hsp90α and suppress its expression in NSCLC cells. Mic A could also induce the apoptosis of NSCLC cells through reactive oxygen species (ROS) and ERK phosphorylation pathways, and the autophagy process may also be involved in the mechanism. In the NSCLC xenograft tumor model, Mic A could significantly reduce the growth of xenograft tumors by reducing Hsp90 and upregulating ERK phosphorylation. Overall, our research provides a broader perspective for a deeper understanding of the development of anti-tumor drugs targeting Hsp90, and the mechanism of intracellular downstream signaling pathways. And the Mic A, a tool molecule derived from the ocean, could provide significant references for the future development of anti-NSCLC.

ETHNOPHARMACOLOGICAL RELEVANCE:Jiu-Wei-Yong-An (JWYA) decoction is a clinical traditional Chinese medicine prescription for atopic dermatitis (AD). Its anti-inflammatory and anti-pruritic activities have been previously confirmed, yet the underlying molecular mechanism remains unclear. AIM OF STUDY:This work aimed to identify JWYA's bioactive compounds and clarify its therapeutic mechanisms against AD. MATERIALS AND METHODS:We established MC903-induced AD mouse models and TNF-α/IFN-γ-stimulated HaCaT keratinocytes to assess JWYA's efficacy. LC-MS/MS combined with bioinformatics, public microarray datasets, and compound-target prediction was used to screen active components and core pathways. In vivo dermatitis severity and epidermal thickness were quantified after 14-day JWYA oral administration. Western blotting detected pathway protein expression in vitro and in vivo. TLR4 inhibitor TAK-242 rescue assays verified TLR4-dependent regulation. Molecular docking, molecular dynamics (MD) simulations, DARTS and CETSA assays further validated the direct binding of candidate compounds to TLR4/MyD88/NF-κB. RESULTS:Thirteen absorbable ingredients of JWYA were identified, with the TLR4/MyD88/NF-κB cascade screened as the core anti-AD pathway. JWYA alleviated AD-like lesions, reduced IgE and proinflammatory cytokines, and suppressed TLR4/MyD88/NF-κB overactivation in mice and keratinocytes; TAK-242 assays confirmed JWYA's effects rely on intact TLR4 signaling. Phylliroside and Suspenoidside B exhibited high affinity toward core targets, with direct physical binding validated by MD, DARTS and CETSA. CONCLUSIONS:JWYA ameliorates AD through multi-component, multi-target modulation of the TLR4/MyD88/NF-κB inflammatory axis. Phylliroside and Suspenoidside B are key bioactive substances that directly bind TLR4/MyD88/NF-κB to inhibit NF-κB hyperactivation, relieving AD-related inflammation. This study provides experimental basis for JWYA's clinical application and subsequent monomer drug development.

Seawater immersion wounds carry high health risks owing to seawater's high-salt, hypertonicity and diverse bacteria, and current therapies are limited and nonspecific, posing clinical challenges. In this study, high-viscosity chitosan (HVCS, viscosity >1000 mPa & centerdot;s) from Antarctic krill shells was used as the matrix, glutamate as a molecular bridge linked dopamine and HVCS; high-viscosity dopamine-glutamate-chitosan (DGCS) was synthesized via amide bond-based covalent networks. DGCS inherits the rapid gel-forming ability of HVCS while showing its excellent favorable adaptability to seawater immersion wound surfaces. The introduction of dopamine and glutamic acid endows DGCS with more prominent mechanical properties and biological activities, including cell proliferation-promoting, antibacterial, and anti-inflammatory effects, and particularly inhibits the growth of specific Gram-negative pathogenic bacteria such as Vibrio vulnificus and Vibrio parahaemolyticus in vitro. More importantly, in seawater immersion wound rat models, DGCS hydrogel outperforms commercial chitosan dressings and silvadene in regulating wound inflammation, promoting collagen deposition, angiogenesis and healing. In conclusion, DGCS integrates antibacterial, anti-inflammatory and pro-healing functions, offering an effective multifunctional strategy for seawater immersion wound treatment, realizing the high-value-added valorization of shrimp shell waste and expanding HVCS's application in wound dressings.

Marine fungi hold immense research significance, acting as a treasure trove capable of generating complex chemical architectures and a diverse array of biologically active secondary metabolites. Talaromyces sp.6B3 was isolated from marine, and six compounds were extracted from its fermentation broth. Structural characterization of these compounds was accomplished using NMR spectroscopy, mass spectrometry, and circular dichroism spectroscopic analyses. Compounds 1-5 are novel entities within this series, whereas compounds 1, 2, and 6 are classified as furanone derivatives. Compounds 1 and 4 demonstrated inhibitory activity against Staphylococcus aureus, with a MIC of 25 mu g/mL. Compound 1 exhibited a modest inhibitory effect against both A549 and H460 cancer cell, whereas compound 4 demonstrated a modest inhibitory effect against the H460 cell.

First-in-class (FIC) drugs are considered the main drivers of new drug discovery and have novel targets and mechanisms. The proportion of FIC drugs among new drugs provides fundamental guidance for both academic and pharmaceutical research. From a global perspective, 81 FIC drugs were approved in 2023 and 2024. Among them, small-molecule drugs account for a greater percentage (51.9%), illustrating the discovery of new chemical entities. Macromolecule drugs (48.1%), which mainly consist of antibody analogs, represent a growing trend as new biotechnology techniques have emerged. In terms of FIC drug indications, cancer remained the top priority (22.0%), with 18 FIC therapies, revealing the high patient need in this context. As for innovations regarding mechanism-based therapies, diverse enzymes were the most common FIC drugs (32.1%), with 26 novel targets identified. In this review, the performance and characteristics of FIC drug approvals in 2023 and 2024 will be presented, providing information on breakthroughs and insights for global drug discovery.

Two new sesquiterpene phenols, dactyltone A (1) and dactyltone B (2), were isolated from the marine sponge Dactylospongia elegans collected from the South China Sea. Their structures were elucidated by comprehensive spectroscopic analysis (including NMR and HRESIMS) combined with experimental and calculated electronic circular dichroism (ECD) data. Notably, the carbonylation at C-2 observed in ring A of marine sponge-derived sesquiterpene phenols represents an uncommon structural feature. Biological evaluation revealed that both compounds showed selective immunosuppressive activity, specifically inhibiting ConA-induced T-cell proliferation with IC50 values of 6.53 μM and 9.85 μM for 1 and 2, respectively, while demonstrating no significant antibacterial or cytotoxic effects at tested concentrations.

Worldwide, lung cancer is the most common cause of cancer-related death, which is made worse by the development of drug resistance during treatment. It is urgent to develop new therapeutic methods and small molecule drugs for tumor resistance. Chaetocin, extracted from Chaetomium minutum, is a natural compound with good antitumor activity. However, there are few studies on its tumor resistance. In this paper, firstly, chaetotocin significantly inhibited the viability and migration of cisplatin-resistant non-small cell lung cancer (NSCLC) cells and inhibited the xenograft growth of nude mice. Chaetocin at 4 mg/kg significantly inhibited A549/DDP xenograft growth with an inhibition rate of 70.43%. Subsequently, the underlying mechanism behind the actions of chaetocin was explored. It was discovered that chaetocin can inhibit transketolase (TKT), thereby inhibiting the growth of NSCLC cells and inducing cell death. Compared with cisplatin-sensitive cells, a lower concentration of chaetocin can inhibit cisplatin-resistance cell viability and migration. Mechanistically, TKT was identified as a potential target for chaetocin. The KD value of the interaction between chaetocin and TKT was 63.2 μM. An amount of 0.2 μM chaetocin may suppress the enzyme activity and expression level of TKT. We found the TKT expression is higher in cisplatin-resistant cells, which further explains why these cells were more vulnerable to chaetocin in terms of cell phenotype. Additionally, the muti-omics analysis and RNA interference suggested that chaetocin can inhibit the PI3K/Akt signaling pathway through TKT. In conclusion, chaetocin could directly bind to TKT, inhibiting its enzyme activity and expression, which interfered with intracellular metabolism and oxidation-reduction balance, and then regulated the PI3K/Akt signaling pathway to inhibit the growth of NSCLC and induce apoptosis.

Two uncommon epoxyquinols, pyrrolocytosporin A (1) and cytosporin E2 (2), along with the known cytosporin Y1 (3), were isolated from the solid defined medium of the Arctic-derived fungus Eutypella sp. D-1. Their structures were established through comprehensive analyses of spectroscopic and electronic circular dichroism data. Structurally, compound 1 represented the first nitrogen-containing epoxyquinol characterized by a pyrrole fused cytosporin framework, while compound 2 contained an uncommon cyclic carbonate functionality. The antibacterial, immunosuppressive, anti-inflammatory, and cytotoxic activities of all compounds were evaluated. Among the three metabolites, only compound 1 exhibited inhibitory effects on nitric oxide production induced by lipopolysaccharide with an IC50 value of 6.55 μM. Additionally, only compound 2 displayed inhibitory activity against ConA-induced T-cell proliferation with an IC50 value of 9.85 μM.

Two new compounds, macrolactin XY (1) and (5R, 9S, 10S)-5-(hydroxymethyl)-1,3,7-decatriene-9,10-diol (2), together with nine known compounds (3–11) were isolated from the marine Bacillus subtilis sp. 18 by the OSMAC strategy. These compounds were evaluated for antibacterial activity against six tested microorganisms. Compounds 1–5 and 7–10 showed varied antibacterial activity, with the minimum inhibitory concentration (MIC) ranging from 3 to 12 μg/mL. Macrolactin XY (1) was found to possess superior antibacterial activity, especially exhibiting significant effectiveness against Enterococcus faecalis. The antibacterial activity mechanism against E. faecalis was investigated. The mechanism may disrupt bacterial cell membrane integrity and permeability, and also inhibit the expression of genes associated with bacterial energy metabolism, as established by the experiments concerning cell membrane potential, SDS-PAGE electrophoresis, cell membrane integrity, and key gene expressions. This study offers valuable insights and serves as a theoretical foundation for the future development of macrolactins as antibacterial precursors.

With the advancement of bioinformatics, the integration of genome mining with efficient separation technology enables the discovery of a greater number of novel bioactive compounds. The deletion of the key gene responsible for triterpene cyclase biosynthesis in the polar strain Eutypella sp. D-1 instigated metabolic shunting, resulting in the activation of dormant genes and the subsequent production of detectable, new compounds. Fifteen sesquiterpenes were isolated from the mutant strain, with eight being new compounds. The structural elucidation of these compounds was obtained through a combination of HRESIMS, NMR spectroscopy, and ECD calculations, revealing six distinct skeleton types. Compound 7 possessed a unique skeleton of 5/10 macrocyclic ether structure. Based on the gene functions and newly acquired secondary metabolites, the metabolic shunting pathway in the mutant strain was inferred. Compounds 6, 8, 11, 14, and 15 exhibited anti-inflammatory effects without cytotoxicity through the release of nitric oxide from lipopolysaccharide-stimulated RAW264.7 cells. Notably, acorane-type sesquiterpene 8 inhibited nitric oxide production and modulated the MAPK and NLRP3/caspase-1 signaling pathways. Compound 8 also alleviated the CuSO4-induced systemic neurological inflammation symptoms in a transgenic fluorescent zebrafish model.

Brevetoxins (PbTxs) are very potent marine neurotoxins that can cause an illness clinically described as neurologic shellfish poisoning (NSP). These toxins are cyclic polyether in chemistry and have increased their geographical distribution in the past 2 decades. However, the ethical problems as well as technical difficulties associated with currently employed analysis methods for marine toxins have spurred the quest for suitable alternatives to be applied in a regulatory monitoring regime. In this work, we reported the first instance of concurrent aptamer selection of Brevetoxin-1 (PbTx-1) and Brevetoxin-2 (PbTx-2) and constructed a biolayer interferometry (BLI) biosensor utilizing PbTx-1 aptamer as a specific recognition element. Through an in vitro selection process, we have, for the first time, successfully selected DNA aptamers with high affinity and specificity to PbTx-1 and PbTx-2 from a vast pool of random sequences. Among the selected aptamers, aptamer A5 exhibited the strongest binding affinity to PbTx-1, with an equilibrium dissociation constant (KD) of 2.56 μM. Subsequently, we optimized aptamer A5 by truncation to obtain the core sequence (A5-S3). Further refinement was achieved through mutations based on the predictions of a QGRS mapper, resulting in aptamer A5-S3G, which showed a significant increase in the KD value by approximately 100-fold. Utilizing aptamer A5-S3G, we fabricated a label-free, real-time optical BLI aptasensor for the detection of PbTx-1. This aptasensor displayed a broad detection range from 100 nM to 4000 nM PbTx-1, with a linear range between 100 nM and 2000 nM, and a limit of detection (LOD) as low as 4.5 nM. Importantly, the aptasensor showed no cross-reactivity to PbTx-2 or other marine toxins, indicating a high level of specificity for PbTx-1. Moreover, the aptasensor exhibited excellent reproducibility and stability when applied for the detection of PbTx-1 in spiked shellfish samples. We strongly believe that this innovative aptasensor offers a promising alternative to traditional immunological methods for the specific and reliable detection of PbTx-1.

Polar fungi play a vital role as prolific sources of unique chemical structures and diverse bioactive compounds. Eutypella sp. D-1 is a fungus isolated from the Arctic, and six compounds were extracted from the fermentation broth. Their structures are elucidated from HRESIMS, NMR spectroscopy, and ECD calculations. Compounds 1-5 are newly discovered compounds, with compound 1 possessing a rare peroxide-bridge structure. Compounds 1-4 are categorized as pimarane-type diterpenes, while compounds 5 and 6 belong to the eudesmanolide sesquiterpenes. Compound 4 demonstrates anti-inflammatory activity by inhibiting lipopolysaccharide-induced nitric oxide release in RAW264.7 cells. Compounds 4 and 5 show antibacterial activity against Escherichia coli and Staphylococcus aureus.

Eight new 12,8-eudesmanolide sesquiterpenes, eutypellaolides A–H (1–8), and two new eudesmane-type sesquiterpenes, eutypellaolides I–J (9–10), along with four known 12,8-eudesmanolide compounds 11–14, were isolated from the culture extract of the polar fungus Eutypella sp. D-1 by one strain many compounds (OSMAC) approach. The structures of these compounds were determined through comprehensive spectroscopic data and experimental and calculated ECD analysis. Antibacterial, immunosuppressive, and PTP1B inhibition activities of these compounds were evaluated. Compounds 1 and 11 exhibited strong inhibitory activities against Bacillus subtilis and Staphylococcus aureus, with each showing an MIC value of 2 μg/mL. Compound 9 displayed weak immunosuppressive activity against ConA-induced T-cell proliferation with an inhibitory rate of 61.7% at a concentration of 19.8 μM. Compounds 5, 11, and 14 exhibited weak PTP1B inhibition activities with IC50 values of 44.8, 43.2, and 49.5 μM, respectively.

A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1–3 and 11–12) from rice medium and eight cytosporins (compounds 2 and 4–11) from solid defined medium. The structures of the seven new compounds, eutypelleudesmane A (1), cytosporin Y (2), cytosporin Z (3), cytosporin Y1 (4), cytosporin Y2 (5), cytosporin Y3 (6), and cytosporin E1 (7), were elucidated by analyzing their detailed spectroscopic data. Structurally, cytosporin Y1 (4) may be a key intermediate in the biosynthesis of the isolated cytosporins, rather than an end product. Compound 1 contained a unique skeleton formed by the ester linkage of two moieties, cytosporin F (12) and the eudesmane-type sesquiterpene dihydroalanto glycol. Additionally, the occurrence of cyclic carbonate moieties in compounds 6 and 7 was found to be rare in nature. The antibacterial, immunosuppressive, and cytotoxic activities of all compounds derived from Eutypella sp. D-1 were evaluated. Unfortunately, only compounds 3, 6, 8, and 10–11 displayed immunosuppressive activity, with inhibitory rates of 62.9%, 59.5%, 67.8%, 55.8%, and 68.7%, respectively, at a concentration of 5 μg/mL.

) and truncated RXRα (tRXRα). Meanwhile, RXR-modulating drugs began to attract more interest from oncologists because of their potential in interfering with cancer cell proliferation, differentiation, and apoptosis according to the important and comprehensive regulation effects of RXR in tumorigenesis. Herein, we will review the comprehensive role of RXR between RXR signaling and oncogenesis, with a highlighted focus on the undervalued rexinoid-related cancer therapy, and discuss and propose its great potential in future clinics.

The ocean is the largest biological resource in the world. The special characteristics of marine ecological environment（high pressure, high salt, and low oxygen） make the competition for survival among marine organisms very fierce, resulting in many marine organisms producing a large number of secondary metabolites with special structures and biological activities during their life activities. In this paper, we summarized 93 natural antifungal active substances isolated from microorganisms, animals, and plants of marine sources from 2016 to 2021,and provided an outlook on their application prospects. In addition, the antifungal effects of marine natural products are reviewed.

现代生物工程综合实验课程是以分子生物学技术为主要教学内容的综合性理论实践课程.当前,军队院校许多课程缺乏"为战育人"的导向性.文章首先从聚焦于战场、贴合海军岗位实际需求的基本要求出发,围绕现代生物工程综合实验课程的自身特点,阐述了新课程体系构建的基本构想;然后,从课程教学内容本身出发,阐述理论教学和实验教学内容的具体设计;最后,围绕"为战育人"的导向,从塑造浓厚的实战化教学氛围、注重知识元素和思政元素的有机统一以及注重多元化教学手段的充分运用这三个方面阐述新课程体系建设和实施的要点.

The Arctic-derived fungus Eutypella sp. D-1 can produce numerous secondary metabolites, and some compounds exhibit excellent biological activity. Seven pimarane-type diterpenes, including three new compounds eutypellenone F (1), libertellenone Y (2), and libertellenone Z (3), and four known compounds (4–7), were isolated from fermentation broth of Eutypella sp. D-1 by the OSMAC strategy of adding ethanol as a promoter in the culture medium. Compound 2 has a rare tetrahydrofuran-fused pimarane diterpene skeleton. The anti-inflammatory activity of all compounds was evaluated. Compounds 3–6 showed a significant inhibitory effect on cell NO release at 10 μmol/L by in vitro experiments, of which 3–5 had inhibitory rates over 60% on nitric oxide (NO) release. Subsequently, the anti-inflammatory activity of 3–5 was evaluated based on a zebrafish model, and the results showed that 3 had a significant inhibitory effect on inflammatory cells migration at 40 μmol/L, while 4 and 5 had a significant inhibitory effect at 20 μmol/L. Moreover, compounds 3–5 have the same conjugated double bond structure, which may be an important group for these compounds to exert anti-inflammatory activity.