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Advances in metagenomic sequencing have increasingly implicated gut microbiome dysbiosis in numerous complex diseases, yet its application for precise differential diagnosis remains a major challenge. Existing computational approaches often show limited predictive performance and insufficient robustness when applied to large-scale, imbalanced microbiome datasets, and they typically lack mechanisms to effectively capture microbial community-level or functional guild interactions. To address these limitations, we developed AR-CDT Net, a novel deep learning framework that integrates a Multi-Scale Deformable Convolution (MS-DConv) module with a Channel-wise Dynamic Tanh (CD-Tanh) activation function to achieve more accurate and robust classification of host disease states. Evaluated on a large-scale cohort comprising over 8000 samples spanning eight disease phenotypes, AR-CDT Net demonstrated highly competitive within-cohort performance, outperforming nine representative models across the majority of classification tasks. Importantly, in a stringent cross-dataset generalization test, the model was trained on the highly imbalanced primary multi-disease cohort and validated on relatively balanced independent external cohorts. It achieved a statistically significant AUC of 0.7921 on the highly heterogeneous external T2D cohort, confirming that AR-CDT captures transferable biological signals rather than dataset-specific artifacts. Furthermore, by combining dimensionality reduction with SHAP-based interpretation of our One-vs-Rest (OvR) classifiers, AR-CDT disentangles disease-specific pathogenic signatures from the shared dysbiotic background among clinically distinct yet microbially similar diseases.

Melatonin, a phytohormone, has drawn growing interest for its important role in improving plant tolerance to biotic and abiotic stresses. However, its specific function and underlying mechanisms in stomatal immunity remain to be fully elucidated. In this study, we investigated the role of melatonin in mitigating bacterial invasion of Arabidopsis thaliana by modulating stomatal immune responses. To achieve this, melatonin biosynthesis and receptor mutants were employed to monitor guard cell responses to Pseudomonas syringae . Furthermore, single-cell type metabolomics and multi-omics analyses were integrated to dissect the signaling pathways involved. The results demonstrated that melatonin is essential for maintaining stomatal closure during bacterial infection. Single-cell metabolomics revealed that melatonin decreases jasmonic acid (JA) biosynthesis, thereby alleviating the antagonistic interaction with salicylic acid (SA) and positively regulating resistance to bacterial infections. Moreover, multi-omics data support melatonin-mediated crosstalk among JA/coronatine, SA-Non-Pathogenesis-Related 1 (NPR1), and reactive oxygen species/nitric oxide (ROS/NO) in stomatal immunity. This study reveals a sophisticated melatonin-regulated phytohormone crosstalk that orchestrates stomatal immunity against bacterial pathogens. These findings provide novel insights into the integration of melatonin signaling with systemic defense responses in plants.

This study aimed to identify therapeutic targets and signaling pathways of Capilliposide A (LC-A) for diabetic nephropathy (DN) through integrated network pharmacology and experimental validation. Using a DN mouse model induced by high-fat diet (HFD) and streptozotocin (STZ), we investigated the molecular mechanisms of LC-A. The PubChem database provided the two-dimensional structure of LC-A, with subsequent identification of LC-A/DN-associated targets through intersection analysis. Core targets were determined via protein–protein interaction (PPI) network construction, followed by gene ontology enrichment and pathway analyses. Molecular docking simulations evaluated LC-A's binding affinity to DN-related targets. C57BL/6 mice receiving HFD and STZ intraperitoneal injections were treated daily with LC-A or metformin (MET) via oral gavage for 8 weeks. Weekly monitoring included body weight and blood glucose measurements. Post-treatment assessments encompassed serum lipid profiles, renal function biomarkers, inflammatory cytokines, oxidative stress markers, and renal histopathology. Western blotting, immunohistochemistry, and immunofluorescence were performed to analyze inflammatory pathway proteins and apoptosis-related factors. Network pharmacology identified TLR4, NF-κB1, STAT3, EGFR, mTOR, and MAPK as core targets involved in inflammation, oxidative stress, and apoptosis regulation. Pathway enrichment analysis revealed critical inflammatory pathways including IL-17, TNF, and Th17 cell differentiation. Molecular docking confirmed stable binding of LC-A to TLR4, NF-κB1, Bax, and Bcl-2. In vivo experiments demonstrated that LC-A significantly reduced renal injury markers (KI, SCR, BUN), lipid profiles (TG, TC), and oxidative stress (MDA), while enhancing antioxidant enzymes (SOD, GPX, CAT) in DN mice ( P  < 0.05). LC-A effectively suppressed serum inflammatory cytokines (IL-6, TNF-α, IL-1β, MCP-1, iNOS) through NF-κB pathway modulation and apoptosis regulation ( P  < 0.05). Histopathological analysis revealed attenuated renal cortical vacuolization, tubular swelling, glomerular mesangial expansion, sclerosis, and inflammatory infiltration. These findings suggest LC-A as a promising natural nephroprotective agent for DN prevention and treatment.

Background Lonicera japonica Thunb. flower has been used for the treatment of various diseases for a long time and attracted many studies on its potential effects. Transcription factors (TFs) regulate extensive biological processes during plant development. As the restricted reports of L. japonica on TFs, our work was carried out to better understand the TFs’ regulatory roles under different developmental stages in L. japonica . Results In this study, 1316 TFs belonging to 52 families were identified from the transcriptomic data, and corresponding expression profiles during the L. japonica flower development were comprehensively analyzed. 917 (69.68%) TFs were differentially expressed. TFs in bHLH, ERF, MYB, bZIP, and NAC families exhibited obviously altered expression during flower growth. Based on the analysis of differentially expressed TFs (DETFs), TFs in MYB, WRKY, NAC and LSD families that involved in phenylpropanoids biosynthesis, senescence processes and antioxidant activity were detected. The expression of MYB114 exhibited a positive correlation with the contents of luteoloside; Positive correlation was observed among the expression of MYC12 , chalcone synthase (CHS) and flavonol synthase (FLS) , while negative correlation was observed between the expression of MYB44 and the synthases; The expression of LSD1 was highly correlated with the expression of SOD and the total antioxidant capacity, while the expression of LOL1 and LOL2 exhibited a negative correlation with them; Many TFs in NAC and WRKY families may be potentially involved in the senescence process regulated by hormones and reactive oxygen species (ROS). The expression of NAC19 , NAC29 , and NAC53 exhibited a positive correlation with the contents of ABA and H 2 O 2 , while the expression of WRKY53 , WRKY54 , and WRKY70 exhibited a negative correlation with the contents of JA, SA and ABA. Conclusions Our study provided a comprehensive characterization of the expression profiles of TFs during the developmental stages of L. japonica . In addition, we detected the key TFs that may play significant roles in controlling active components biosynthesis, antioxidant activity and flower senescence in L. japonica , thereby providing valuable insights into the molecular networks underlying L. japonica flower development.

Chalocomoracin (CMR), one of the major secondary metabolites found in fungus-infected mulberry leaves, is a potent anticancer agent. However, its anticancer mechanism remains elusive. Here, we demonstrated the potent anti-tumor activity and molecular mechanism of CMR both in vitro and in vivo . We showed for the first time that CMR treatment markedly promoted paraptosis along with extensive cytoplasmic vacuolation derived from the endoplasmic reticulum, rather than apoptosis, in PC-3 and MDA-MB-231cell lines. Additional studies revealed that ectopic expression of Myc-PINK1 (PTEN-induced kinase 1), a key regulator of mitophagy, rendered LNCap cells susceptible to CMR-induced paraptosis, suggesting that the mitophagy-dependent pathway plays a crucial role in inducing paraptosis by activating PINK1. CMR treatment directly upregulated PINK1 and downregulated Alix genes in MDA-MB-231 and PC-3 cell lines. Furthermore, mitophagy signaling and paraptosis with cytoplasmic vacuolation could be blocked by antioxidant N-acetylcysteine (NAC), indicating the novel pathway was triggered by reactive oxygen species (ROS) production. An in vivo MDA-MB-231 xenograft tumor model revealed that CMR suppressed tumor growth by inducing vacuolation production through the same signal changes as those observed in vitro . These data suggest that CMR is a potential therapeutic entity for cancer treatment through a non-apoptotic pathway.

Salt stress impedes plant growth and development, and leads to yield loss. Recently, a halophyte species Mesembryanthemum crystallinum has become a model to study plant photosynthetic responses to salt stress. It has an adaptive mechanism of shifting from C3 photosynthesis to crassulacean acid metabolism (CAM) photosynthesis under stresses, which greatly enhances water usage efficiency and stress tolerance. In this study, we focused on investigating the morphological and physiological changes [e.g., leaf area, stomatal movement behavior, gas exchange, leaf succulence, and relative water content (RWC)] of M. crystallinum during the C3 to CAM photosynthetic transition under salt stress. Our results showed that in M. crystallinum seedlings, CAM photosynthesis was initiated after 6 days of salt treatment, the transition takes place within a 3-day period, and plants became mostly CAM in 2 weeks. This result defined the transition period of a facultative CAM plant, laid a foundation for future studies on identifying the molecular switches responsible for the transition from C3 to CAM, and contributed to the ultimate goal of engineering CAM characteristics into C3 crops.

Key message Metabolomic analysis of flooding-tolerant mutant and abscisic acid-treated soybeans suggests that accumulated fructose might play a role in initial flooding tolerance through regulation of hexokinase and phosphofructokinase. Soybean is sensitive to flooding stress, which markedly reduces plant growth. To explore the mechanism underlying initial-flooding tolerance in soybean, mass spectrometry-based metabolomic analysis was performed using flooding-tolerant mutant and abscisic-acid treated soybeans. Among the commonly-identified metabolites in both flooding-tolerant materials, metabolites involved in carbohydrate and organic acid displayed same profile at initial-flooding stress. Sugar metabolism was highlighted in both flooding-tolerant materials with the decreased and increased accumulation of sucrose and fructose, respectively, compared to flooded soybeans. Gene expression of hexokinase 1 was upregulated in flooded soybean; however, it was downregulated in both flooding-tolerant materials. Metabolites involved in carbohydrate/organic acid and proteins related to glycolysis/tricarboxylic acid cycle were integrated. Increased protein abundance of phosphofructokinase was identified in both flooding-tolerant materials, which was in agreement with its enzyme activity. Furthermore, sugar metabolism was pointed out as the tolerant-responsive process at initial-flooding stress with the integration of metabolomics, proteomics, and transcriptomics. Moreover, application of fructose declined the increased fresh weight of plant induced by flooding stress. These results suggest that fructose might be the critical metabolite through regulation of hexokinase and phosphofructokinase to confer initial-flooding stress in soybean.

Anlotinib is a receptor tyrosine kinase inhibitor with potential anti-neoplastic and anti-angiogenic activities. It has been approved for the treatment of non-small-cell lung cancer. Lysosomes are acidic organelles and have been implicated in various mechanisms of cancer therapeutics. However, the effect of anlotinib on lysosomal function has not been investigated. In the present study, anlotinib induces apoptosis in human colon cancer cells. Through transcriptome sequencing, we found for the first time that anlotinib treatment upregulates ATP6V0E2 (ATPase H + Transporting V0 Subunit E2) and other lysosome-related genes expression in human colon cancer. In human colon cancer, we validated that anlotinib activates lysosomal function and enhances the fusion of autophagosomes and lysosomes. Moreover, anlotinib treatment is shown to inhibit mTOR (mammalian target of rapamycin) signaling and the activation of lysosomal function by anlotinib is mTOR dependent. Furthermore, anlotinib treatment activates TFEB, a key nuclear transcription factor that controls lysosome biogenesis and function. We found that anlotinib treatment promotes TFEB nuclear translocation and enhances its transcriptional activity. When TFEB or ATP6V0E2 are knocked down, the enhanced lysosomal function and autophagy by anlotinib are attenuated. Finally, inhibition of lysosomal function enhances anlotinib-induced cell death and tumor suppression, which may be attributed to high levels of ROS (reactive oxygen species). These findings suggest that the activation of lysosomal function protects against anlotinib-mediated cell apoptosis via regulating the cellular redox status. Taken together, our results provide novel insights into the regulatory mechanisms of anlotinib on lysosomes, and this information could facilitate the development of potential novel cancer therapeutic agents that inhibit lysosomal function.

Eurycomanone (EN) is one of the representative quassinoid diterpenoids from roots of Eurycoma longifolia Jack, a natural medicine that is widely distributed in Southeast Asia. Previous studies showed that EN induces cancer cell apoptosis and exhibits anti-cancer activity, but the molecular mechanism of EN against cancer has still not been elucidated. In this study, we examined the regulatory effect of EN on autophagy to reveal the mechanism of EN-mediated colon cancer growth inhibition. First, we found that EN is able to inhibit colon cancer cell proliferation and colony formation. The angiogenesis level in cancer cells was inhibited as well. Next, the treatment of EN led to the suppression of autophagy, which was characterized by the downregulation of the LC3-II level and the formation of GFP-LC3 puncta under EN treatment in colon cancer. Moreover, we revealed that the mTOR signaling pathway was activated by EN in a time- and concentration-dependent manner. Finally, autophagy induction protected colon cancer cells from EN treatment, suggesting that autophagy improves cell survival. Taken together, our findings revealed the mechanism of EN against colon cancer through inhibiting autophagy and angiogenesis in colon cancer, supporting that the autophagy inhibitor EN could be developed to be a novel anti-cancer agent.

Morus alba is an important medicinal plant that is used to treat human diseases. The leaf, branch, and root of Morus can be applied as antidiabetic, antioxidant, and anti-inflammatory medicines, respectively. To explore the molecular mechanisms underlying the various pharmacological functions within different parts of Morus, organ-specific proteomics were performed. Protein profiles of the Morus leaf, branch, and root were determined using a gel-free/label-free proteomic technique. In the Morus leaf, branch, and root, a total of 492, 414, and 355 proteins were identified, respectively, including 84 common proteins. In leaf, the main function was related to protein degradation, photosynthesis, and redox ascorbate/glutathione metabolism. In branch, the main function was related to protein synthesis/degradation, stress, and redox ascorbate/glutathione metabolism. In root, the main function was related to protein synthesis/degradation, stress, and cell wall. Additionally, organ-specific metabolites and antioxidant activities were analyzed. These results revealed that flavonoids were highly accumulated in Morus root compared with the branch and leaf. Accordingly, two root-specific proteins named chalcone flavanone isomerase and flavonoid 3,5-hydroxylase were accumulated in the flavonoid pathway. Consistent with this finding, the content of the total flavonoids was higher in root compared to those detected in branch and leaf. These results suggest that the flavonoids in Morus root might be responsible for its biological activity and the root is the main part for flavonoid biosynthesis in Morus.