The global threat of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of novel therapeutic strategies. Our previous work identified A7, a marine-derived aaptamine alkaloid, as a potential anti-MRSA agent. However, its clinical translation is limited by poor membrane permeability and unclear antibacterial mechanism. Targeting antimicrobial agents by liposomes may be a valid strategy in the treatment of infections refractory to conventional routes of antimicrobial treatment. Therefore, this study aimed to develop A7-loaded fusogenic liposomes (A7@FLP) as a targeted drug delivery system. Fusogenic liposomes loaded with A7 were produced and characterized, with the objectives of examining their improved cellular penetration, antibacterial activity, and inhibitory mechanism against MRSA. The results showed that FLP was successfully developed with a size 128.9 ± 2.2 nm. A7@FLP exhibited sustained release and significantly enhanced anti-MRSA activity in a dose-dependent manner. It achieved a minimum inhibitory concentration (MIC) of 1 μg/mL, which showed 2-fold improvement over free A7 (2 μg/mL). Further mechanistic studies revealed that A7@FLP damaged bacterial wall and membrane integrity, thereby disrupting cellular physiological functions and triggering oxidative stress-mediated cell death. The antibacterial effect was found to be multitargeted, involving oxidative stress, lipid peroxidation, membrane damage, and energy metabolism dysfunction. In conclusion, these findings affirm that A7-loaded fusogenic liposomes represent a highly promising therapeutic candidate for combating MRSA infections.

Pepluanol A (1) and pepluacetal (2) belong to a structurally unique class of pepluanol-type Euphorbia diterpenoids, exhibiting immunosuppressive activity via targeting Kv1.3 channels. Herein, we report a divergent synthetic strategy that enables efficient and concise total syntheses of both 1 and 2 from a common advanced intermediate. The synthesis of pepluanol A (1) features an intramolecular Diels-Alder reaction to accomplish the [4 + 2] type cycloaddition for framework construction, whereas the synthesis of pepluacetal (2) is centered on a photoinduced intramolecular [2 + 2] cycloaddition as the key step. Both routes proceed with high stereoselectivity and synthetic efficiency. Further biological evaluation revealed that these diterpenoid natural products and derivatives possess antipulmonary fibrosis activity.

Seven new sesquiterpenes, named penicipenoids A-G (1-7), were isolated from rice-based fermentation cultures of the marine sponge-derived fungus Penicillium sp. 5975, together with ten known analogues (8-17). Their structures were elucidated using high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy, supported by single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD) calculations. Penicipenoid A (1) features an unprecedented sesquiterpene scaffold characterized by a tricyclo[4.4.11,602,7]hendecane core. Penicipenoid D (4) contains an unusual furan substructure within the cadinane-type sesquiterpenoid class, while penicipenoid F (6) represents a rare norsesquiterpene derivative lacking the carbon atom at the C-7 position. The in vivo anti-oxidant and anti-inflammatory effects of these compounds were evaluated using transgenic fluorescent zebrafish models. Penicipenoids A-C (1-3) exhibited anti-oxidant activity in metronidazole (MTZ)-treated transgenic zebrafish embryos, whereas penicipenoid E (5) demonstrated potent anti-inflammatory activity in CuSO4-induced transgenic fluorescent zebrafish embryos.

Two undescribed sesequiterpene hydroquinone meroterpenoids, villosarins A (1) and B (2), together with eight known analogues (3-10), were isolated from the marine sponge Dysidea villosa collected from the South China Sea. The structures of 1 and 2 were elucidated by a combination analysis of HRESIMS, 1D and 2D NMR spectra, and their absolute configurations were determined by electronic circular dichroism (ECD) calculations. Villosarins A and B featured two unusual hydroquinone units modified by furan-2,5-diones. Among the 10 isolates, compounds 1, 2, 7-10 were evaluated for inhibitory activity on the production of inflammatory cytokines, interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in lipopolysaccharide (LPS)-stimulated RAW 264.7 mouse macrophages. Villosarins A (1) and B (2) showed potent inhibitory activity on the production of IL-6, IL-1β, and TNF-α in a dose-dependent manner.

The spirotetronate polyketides are a class of microbial antibiotics structurally featuring a macrocycle core embedded with a cyclohexene ring spiro-linked to tetronic acid and/or a decalin ring. Of them, PA-46101s are characterized with an extra lactone moiety in the macrocycle scaffold. Despite the remarkable antibacterial activities, the biosynthetic pathway of PA-46101s has not been investigated. Herein, the PA-46101s biosynthetic gene cluster was identified from a Streptomyces species. Overexpression of a LuxR transcriptional regulator led to around a 15-fold rise of PA-46101s production. Characterization of an intermediate accumulated upon deletion of the Baeyer-Villiger monooxygenase homologous gene paE1 revealed the first lactone-formation gene from spirotetronate biosynthetic pathways. Characterization of the metabolites of glycosyltransferase gene mutants allowed us to dissect the tailoring glycosylation orders. The obtained PA-46101s analogs exhibited obvious inhibitory activities against the aquatic pathogenic bacteria Edwardsiella piscicida and Vibrio alginolyticus. This study paves the way for the structural diversification of PA-46101s through combinatorial biology.

To evaluate infection risks in rheumatoid arthritis (RA) patients with biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) as monotherapy or combined with conventional synthetic DMARDs (csDMARDs). A comprehensive literature search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from their inception to 31 October 2024 was conducted to identify randomized controlled trials (RCTs) assessing infection risks in RA patients receiving b/tsDMARDs. Primary outcome was serious infection incidence; secondary outcomes included any infection and specific events such as respiratory tract infections, gastroenteritis and herpes zoster. A frequentist network meta-analysis was performed to calculate odds ratios (ORs). A total of 127 RCTs involving 55,749 patients were included. b/tsDMARD monotherapy showed a similar risk of serious infections versus csDMARDs. Combining csDMARDs with adalimumab, infliximab, tofacitinib, or upadacitinib (though not with other b/tsDMARDs) was associated with a significantly increased risk of serious infections (OR 1.51, 95

Polyketide natural products represent a major source of medicinal compounds. The majority of them are biosynthesized by the modular polyketide synthase (PKS) assembly line in Streptomyces spp. Due to the high sequence similarity among the coding regions of PKSs, recombination-mediated gene truncation is prevalent in PKSs. These recombination sites can be the guidelines of reprogramming PKSs for designed biosynthesis. Herein, we have discovered that a PKS module excision naturally occurred between two adjacent enoylreductase (ER) domains in the PKS assembly line of carboxyl polyether ionomycin (INO). The recombination led to significant accumulation of a two-carbon truncated product of INO, neoionomycin A, which exhibited significant anti-inflammatory activities in both zebrafish neuroinflammation and mouse colitis models. Moreover, the natural fusion site of the ER domain was successfully applied to generate the second PKS module excision, yielding another truncated product of INO. The study should represent the first instance of generating the functional hybrid PKS module via a splice junction within the ER domain, thereby adding a new reference site for the rational PKS reconstruction.

Tumor drug resistance remains a major obstacle in cancer therapy, leading to the failure of chemotherapy, targeted therapy, and immunotherapy. This review explores how artificial intelligence (AI), particularly machine and deep learning models, integrates multi-omics data, including genomics, transcriptomics, and proteomics, with large-scale tumor databases such as TCGA and GDSC to enhance the prediction of drug resistance mechanisms. These approaches help identify key biomarkers and molecular pathways underlying resistance, such as DNA repair defects in chemotherapy, secondary mutations in targeted therapy, immunosuppressive microenvironments in immunotherapy, and other complications that alter the tumor-resistance microenvironment, such as thrombosis. Despite challenges like data heterogeneity, model interpretability, and clinical applicability, emerging strategies, such as multimodal data fusion, real-time monitoring via liquid biopsy, and explainable AI (XAI), are paving the way for more accurate and translatable predictive tools. These advances not only facilitate the development of personalized treatment regimens but also hold great potential to substantially improve prognostic outcomes and therapeutic efficacy in precision oncology.

BACKGROUND:Major bleeding (MB) remains a serious complication in atrial fibrillation (AF) patients treated with direct oral anticoagulants (DOACs), but effect estimates for individual factors vary across studies and have not been synthesized in a DOAC-specific framework. OBJECTIVES:To provide a comprehensive DOAC-specific synthesis of risk factors associated with MB in AF patients. METHODS:We systematically searched PubMed, Embase, and the Cochrane Library from their inception to December 2024. We included studies of DOAC-treated AF patients that reported associations between patient characteristics and MB. Random-effects meta-analyses were conducted when at least 2 studies evaluated the same risk factors using comparable definitions. Prespecified subgroup analyses were performed for the MB outcome and for individual DOAC agents. RESULTS:Eighty-three studies involving 970 248 patients were included. Twenty-one variables were associated with MB. We confirmed several well-known risk factors for MB, including a history of bleeding, alcohol use, age ≥65 years, frailty, and high HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), and Drugs/alcohol concomitantly) score. Importantly, this DOAC-focused synthesis also highlighted additional and previously underemphasized risk factors, including cancer, myocardial infarction or peripheral artery disease, heart failure, coronary artery disease, and the use of psychotropic or antiarrhythmic drugs. Overweight status and statin use were associated with a lower MB risk, although these findings should be interpreted with caution. CONCLUSION:This meta-analysis provides an integrated, DOAC-specific, quantitative overview of MB risk factors across multiple clinical and treatment domains. The pooled estimates provide a contemporary evidence base to prioritize variables for refinement, recalibration, and validation of MB risk assessment strategies in DOAC-treated AF populations.

This study established LC-MS-based metabolomics integrated with multivariate statistical analysis (UMMMS) to identify differential metabolites in Actinoalloteichus cyanogriseus under solid versus liquid culture conditions. Using this approach, 48 molecules exhibiting significant abundance differences between solid and liquid media were rapidly screened out. Among these, 8 were preliminarily identified as peptides potentially containing the unique β-Me-Leu residue by targeted MS/MS analysis. Guided by these screening results, 5 previously undiscovered peptides, designated as cyanogristatins A-E (1-5), were isolated. Their structures were elucidated using 1D/2D NMR spectroscopy, HR-MS/MS, and the advanced Marfey's method. Furthermore, 5 effectively reduced the number of migrating inflammatory cell aggregates in a zebrafish model of inflammatory bowel disease at a concentration of 20 μM. In subsequent experiments using an in vitro organoid model, 5 did not exert direct epithelial protective effects; however, ELISA further revealed that it decreased the level of production of TNF-α in intestinal macrophages. This finding suggests that the anti-inflammatory effect of 5 is most likely mediated by the regulation of the cytokine TNF-α. In summary, this study demonstrates the potential of mass spectrometry technology for the comprehensive analysis of natural products, facilitating the rapid discovery of novel compounds and enhancing the exploration of microbial secondary metabolites.

Resistance to single-target therapies has spurred interest in multitarget strategies for acute myeloid leukemia (AML). Heat shock protein 90 (HSP90), a chaperone that stabilizes numerous oncogenic client proteins, represents an attractive therapeutic target for AML; however, the clinical development of early HSP90 inhibitors was limited by dose-limiting toxicities and an excessive heat-shock response (HSR). Through structural optimization of the marine aaptamine scaffold and target identification, ap-a48 was identified as a novel HSP90-targeting anti-AML lead that exhibits potent anti-AML activity and acceptable preliminary tolerability while inducing only a modest HSR. In rats, ap-a48 showed favorable pharmacokinetics with 65.3% oral bioavailability, and in HL-60 xenograft mouse models, it suppressed tumor growth (71.2% inhibition at intraperitoneal 40 mg/kg; 67.3% at oral 60 mg/kg) without significant hepatotoxicity or major organ abnormalities. These findings identify ap-a48 as a promising marine-natural-product-derived HSP90-targeting lead for AML therapy.

Actinoalloteichus caeruleus, the type species of the rare actinomycete genus Actinoalloteichus, was found to produce various classes of bioactive compounds including bipyridine, β-carboline and cyclolipopeptides. Although the chemistry of natural products from A. caeruleus has been well studied over the past two decades, the complete genomes of this talent species along with its secondary metabolic potential was poorly reported. In this work, the complete genome sequence of Actinoalloteichus sp. LHW52806, the only producer of Marinacarboline glucuronic and Cyanogripeptides, was sequenced and the biosynthetic potential was investigated by a genome mining approach. Genomic analyses indicate a circular chromosome consisting of 6,184,314 bp with a G + C content of 72.27

Seven new sesquiterpene hydroquinone/quinone (SQ) meroterpenoids, cinerols L-R (1-7), along with four known analogues (8-11), were identified from a marine sponge, Dysidea cinerea, collected from the shore of the Xisha Islands in the South China Sea. The structures of 1-7 were established by the analysis of NMR, high-resolution MS, and comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Cinerol L (1) is particularly noteworthy, as it features a 5H-pyrrolo[1,2a]-benzimidazole moiety modified by an ethyl sulfonate, while cinerols N (3) and O (4) possess a unique acetyl-substituted hydroquinone moiety. Cinerols L-R (1-7) were evaluated for their inhibitory activity against inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) with IC50 values of 5-20 μM in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages. Furthermore, the potent inhibitory activity on inflammatory cytokines of 4 prompted us to evaluate its effect on the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, a critical pathway that contributes to the inflammatory responses. Cinerol O (4) was unveiled to inhibit cyclooxygenase-2 (COX-2) expression and the production of inflammatory cytokines via suppressing the expression of NF-κB and MAPKs in LPS-induced RAW 264.7 macrophages.

BACKGROUND:Rivaroxaban, a Non-vitamin K oral anticoagulant (NOAC), is extensively employed for patients at heightened risk of thrombosis, including those with non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). However, to date, there is a lack of robust clinical data to explore the efficacy and safety of rivaroxaban in thromboprophylaxis during the early postoperative period (<6 months) in patients following surgical bioprosthetic valve (BPV). METHODS:The REVERSE trial is a prospective, multicenter, non-inferior, randomized controlled trial enrolling a planned 250 patients in China. Patients are randomly assigned 1:1 to receive rivaroxaban (20 mg once daily) or dose-adjusted warfarin (target international normalized ratio 2.0-3.0) for 6 months. The primary outcome is defined as the composite of all-cause death, major cardiovascular events, or major bleeding. The safety outcome is all bleeding events defined by the International Society on Thrombosis and Haemostasis (ISTH). CONCLUSIONS:The REVERSE trial stands as the inaugural multicenter study dedicated to evaluating the efficacy and safety of rivaroxaban for early postoperative anticoagulation in BPV surgery patients. Its findings are anticipated to contribute pivotal evidence regarding the clinical advantages of NOACs. REGISTRATION:URL: https://www. CLINICALTRIALS:gov; Unique identifier: NCT06476301.

Five previously undescribed peptaibiotics, including one 7-mer lipopeptaibol named lipotrichaibol A (1), and four 11-mer peptaibiotics named trichoderpeptides A-D (2–5) were isolated from the rice culture medium of the sponge-derived fungus Trichoderma sp. GXIMD 01001. Their structures and absolute configurations were unambiguously established by extensive spectroscopic data analysis and advanced Marfey’s method. All isolated compounds were evaluated via CCK8 bioassays to investigate their antiproliferative activity. Only compound 1 exerted potent cytotoxicity against HT-29 and DLD-1 cells with IC50 values at 10.3 ± 1.9 and 12.31 ± 1.5 μM, respectively. In further in vitro bioassay, compound 1 exhibited significant inhibition in colony formation assay, induced apoptosis and blocked the cell cycle in the G0/G1 phase. The mechanism may be related to the regulation of the Erk1/2 signaling pathway.

The synthesis of complex natural products bearing fused polycyclic architectures presents formidable synthetic challenges, yet offers significant opportunities for drug discovery. Herein, we report a photoreversible dearomative desymmetrization strategy that enables efficient access to structurally diverse tricyclic frameworks. Employing alkenyl phenol precursors, UV (ultraviolet) light (λ = 310 nm) triggers a stereoselective 6π-desymmetrization, affording four types of skeletons─including scaffolds with vicinal quaternary stereocenters. Additionally, visible light (λ = 450 nm) reverses this process, selectively deconstructing the tricyclic systems back to alkenyl phenol precursors. This methodology's utility is demonstrated through the scalable synthesis of the norzoanthamine alkaloid core, enabling the first total syntheses of 15-hydroxynorzoanthamine, norzoanthamide B, and norzoanthaminone. Subsequent anti-inflammatory profiling of these compounds revealed key structure-activity relationships (SAR) for IL-6 inhibition. Further, 6π-product 2r emerged as a potent TNF-α inhibitor in lipopolysaccharide (LPS)-stimulated THP-1 cells, and norzoanthamine derivative 9 exhibited an antipulmonary fibrosis effect. Mechanistic studies via density functional theory (DFT) calculations elucidated the wavelength-dependent reversibility, correlating excited-state pathways with experimental photochemical control.

Carboxyl polyethers from Actinomycetes have diverse bioactivities, being biosynthesized by type-I polyketide synthetases. Of them, ionomycin, the commercial calcium ionophore, bears a unique enolized 1,3-diketone moiety. Herein, mutagenetic analysis of ionomycin biosynthesis revealed a rare dehydrogenase gene inoJ putatively involved in enol moiety formation. Interruption of the enolized 1,3-diketone formation by inactivating a ketoreductase domain yielded the first natural polyether with an α-pyrone ring, which was demonstrated with significant anti-inflammatory activity in a mouse colitis model.

Four previously undescribed cyclic peptides, reniochpeptins A-D (1-4), were isolated from the marine sponge Reniochalina sp. Their structures were elucidated through comprehensive spectroscopic analyses and a modified advanced Marfey's method. This method utilized ultra-high-performance liquid chromatography coupled with tandem multiple reaction monitoring mass spectrometry, employing a CORTECS T3 column to achieve simultaneous separation of derivatized L-Leu, L-Ile, L-allo-Ile, D-Leu, D-Ile, and D-allo-Ile within 25 min in a single analytical run. Reniochpeptin A displayed moderate inhibitory activity against NCI-H460 cells, with an IC50 value of 4.7 mu M, by inducing cell cycle arrest at the G2/M phase and promoting apoptosis.

Demethyloxyaaptamine, isolated from the marine sponge Aaptos aaptos, features a 1H-benzo[de][1,6]naphthyridine core and exhibits potent antibacterial activity. To systematically investigate its underexplored antibacterial properties and facilitate structural optimization, we constructed a focused library of 28 C-3 alkylamino-substituted derivatives of demethyloxyaaptamine via regioselective functionalization. In vitro evaluation against Staphylococcus aureus revealed that several derivatives possess minimum inhibitory concentrations (MICs) superior to vancomycin. Structure-activity relationship analysis (SAR) demonstrated that the incorporation of moderately hydrophobic alkylamino groups at the C-3 position markedly improved antimicrobial efficacy. Mechanistic investigations demonstrated that these compounds inhibit bacterial growth by targeting bacterial membrane. Together, these findings validate demethyloxyaaptamine as a privileged scaffold for targeting drug-resistant Gram-positive pathogens and deliver critical SAR insights to guide the design of next-generation antibiotics.