Based on the theory of "disease of both blood and water" in Essentials from the Golden Cabinet （《金匮要略》）， and in combination with the dynamic syndrome evolution of heart failure with preserved ejection fraction （HFpEF）， this paper systematically clarifies the pathomechanism of HFpEF， characterized by yang deficiency as the root， blood stasis as the pivotal factor and water retention as the manifestation. Accordingly， the therapeutic principles have been proposed， which are warming yang and banking up original qi to consolidate the root， activating blood and unblocking collaterals to smooth the mechanism， and promoting urination and regulating pivot to remove the branch. On this basis， a compound formula structure of "one monarch， one minister and one assistant" is established， forming an integrated intervention strategy that synergistically combines the three methods of warming yang， activating blood， and promoting urination through combined classical formulas. Zhenwu Decoction （真武汤）， which warms yang and dissolves rheum， is used to consolidate the root and directly target the source of yang deficiency， serving as the monarch； Guizhi Fuling Pills （桂枝茯苓丸）， which activates blood， promotes urination and unblocks the pivot， assists in interrupting the binding of blood stasis and water retention， serving as the minister； Tingli Dazao Xiefei Decoction （葶苈大枣泻肺汤）， which regulates qi， disperses retained fluids， and eliminates the manifestation， alleviates acute water-retention symptoms， serving as the assistant. This compound formula is warming without being drying， diuretic without being drastic， and dispels stasis without consuming blood， thereby achieving the therapeutic effects of warming yang， activating blood， and promoting urination.

Histone lactylation is a recently identified post-translational modification, wherein lactate mediates the enzymatic addition of lactyl groups to lysine residues on histones. Since its discovery, extensive research has demonstrated that histone lactylation is widely present in human tissues and plays a pivotal role in regulating the transcription of specific genes. Subsequent studies have further established this modification as a widespread epigenetic mark with significant physiological implications. With advancing research, accumulating evidence confirms that lactylation at distinct histone sites elicits diverse biological effects—such as promoting cell proliferation, driving inflammatory responses, and enhancing fibrosis—all of which profoundly influence disease progression and serve as key drivers of disease onset and development. Conversely, inhibiting histone lactylation can alter disease outcomes, positioning histone lactylation as a promising therapeutic target. Moreover, studies have revealed crosstalk between histone lactylation and other post-translational modifications, such as acetylation and methylation, which collectively regulate disease progression. Notably, lactylation occurs not only on histones but also on non-histone proteins. Histone lactylation activates specific gene transcription and reshapes metabolic epigenetics, while non-histone lactylation directly modulates enzyme activity, signal transduction, and protein stability. These two facets form a synergistic network through shared lactate pools, common modifying enzyme systems, and pathway crosstalk, thereby constructing a multi-dimensional regulatory framework—namely, the “histone lactylation-metabolism hub-non-histone lactylation” axis. This architecture bridges metabolism and epigenetics, and deciphering its topological structure may provide novel targets for precise intervention in diseases driven by lactate-mediated signaling hijacking. Traditional Chinese medicine (TCM), grounded in clinical practice, has been shown to regulate histone lactylation by modulating lactate metabolism and lactylation-related enzymes, thereby influencing disease progression. Moreover, certain TCM formulations exhibit potential as alternative therapies for drug-resistant diseases, underscoring the significance of further exploring TCM-mediated regulation of histone lactylation in future therapeutic strategies. This review aims to elucidate the mechanisms underlying histone lactylation, systematically delineate the associations between site-specific histone lactylation and various diseases, present a comprehensive landscape of the “lactate-histone lactylation and functional protein lactylation” axis, and summarize the mechanistic basis and research advances in TCM-mediated regulation of histone lactylation for disease treatment. Additionally, we discuss current challenges in histone lactylation research and propose future directions, ultimately aiming to deepen understanding and broaden perspectives on the roles and therapeutic potential of histone lactylation in disease.

Colorectal cancer (CRC) is characterized by persistently high incidence and mortality. Current therapies are limited by drug resistance and modest patient benefit, underscoring the urgent need for new perspectives rooted in tumor biology. The unique metabolic landscape of CRC makes it an ideal model in which to dissect the pathological roles of lactylation regulatory networks: microsatellite-stable (MSS) CRC, which accounts for approximately 85% of cases, concurrently upregulates glycolysis and oxidative phosphorylation, engaging in intense metabolic competition with immune cells; the intratumoral lactate pool exhibits a distinctive “dual-source supply” feature—in addition to tumor-intrinsic glycolysis, substantial exogenous lactate is provided by gut microbiota dysbiosis and by colonizing bacteria within liver metastases; high-frequency oncogenic mutations and lactylation modifications establish a feed-forward circuit of “oncogene-driven lactate accumulation-lactylation-facilitated tumor progression”. Moreover, MSS CRC displays near-complete unresponsiveness to immune checkpoint inhibitors, a phenomenon underpinned by multiple immune evasion mechanisms mediated by lactate and lactylation. Lactate metabolism is a hallmark of metabolic reprogramming in cancer. Lactate homeostasis provides tumor cells with metabolic substrates, modulates redox status, and regulates fatty acid metabolism to promote malignant progression. Notably, lactate can drive lactylation—an emerging post-translational modification (PTM) in which lactyl groups are attached to lysine residues, dynamically governing gene transcription and protein function and thereby establishing a bridge between metabolism and epigenetics. Lactate and lactylation form a multidimensional, coordinated network: lactylation of key metabolic enzymes such as LDHA reinforces a positive feedback loop that sustains lactate production; lactylation of upstream transcription factors such as HIF-1α drives metabolic reprogramming; furthermore, lactylation engages in crosstalk with m6A and m5C RNA modifications as well as with other PTMs such as acetylation, profoundly reshaping cellular behavior. In CRC, histone lactylation drives malignant phenotypes by activating immunosuppressive programs, inhibiting ferroptosis, and promoting invasion and migration; non-histone lactylation accelerates translation elongation, stabilizes β‑catenin, maintains redox homeostasis, and prevents PD-L1 degradation, thereby facilitating tumor progression. Lactylation-related gene signatures have demonstrated potential for prognostic stratification. Therapeutic strategies targeting the lactylation network range from upstream metabolic intervention to modulation of the modifying enzymes and direct blockade of lactylation modifications, forming a hierarchical interventional framework. However, current evidence derives predominantly from cell lines and xenograft models, and a causal relationship between lactylation and malignant progression in CRC has yet to be rigorously established. Whether inhibition of lactylation can alter CRC phenotypes independently of metabolic alterations and acetylation fluctuations remains a central unanswered question in the field. This review systematically examines the research progress and translational challenges surrounding lactylation regulatory networks, aiming to provide a circumspect assessment to inform the development of novel therapeutic strategies for CRC.

ObjectiveColorectal cancer (CRC) is a highly heterogeneous malignancy, and traditional Chinese medicine (TCM) syndrome differentiation is widely used in its clinical management. However, the biological basis underlying different TCM syndromes remains insufficiently understood. This study aimed to investigate the proteomic differences between qi-blood deficiency syndrome (QBDS) and damp-heat syndrome (DHS) in CRC patients and to establish a “syndrome-differential protein-herbal component” network for exploring potential molecular mechanisms and therapeutic targets associated with syndrome-specific treatment strategies. MethodsTumor tissue samples were collected from 10 patients with pathologically confirmed CRC, including 5 patients diagnosed with QBDS and 5 with DHS according to standardized TCM syndrome differentiation criteria. Tandem mass tag (TMT)-based quantitative proteomics was employed to identify differentially expressed proteins (DEPs) between the two syndrome groups. Functional enrichment analyses, including Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, were performed to characterize the biological functions and signaling pathways associated with the identified DEPs. Least absolute shrinkage and selection operator (LASSO) regression analysis was further applied to screen key syndrome-related proteins and construct a core protein prediction model. Subsequently, molecular docking was conducted to evaluate the binding affinities between representative herbal compounds, astragaloside IV and berberine, and the identified core proteins. Finally, cell counting kit-8 (CCK-8) assays were performed in HCT 116 and HT-29 colorectal cancer cell lines to validate the anti-proliferative activities of these compounds in vitro. ResultsA total of 44 DEPs were identified between QBDS and DHS tissues, including 21 upregulated and 23 downregulated proteins in the QBDS group relative to the DHS group. Functional enrichment analyses revealed that these proteins were primarily associated with antiviral immune responses, regulation of inflammatory signaling, NF‑κB signaling pathways, cholesterol metabolism, and other biological processes relevant to tumor progression and host immune regulation. LASSO regression analysis identified eight core proteins with potential syndrome-specific significance. Among them, ST7, GPCPD1, and PODXL were closely associated with QBDS, whereas FAT1, GRB7, KRT7, MAFF, and MMP8 were associated with DHS. Molecular docking demonstrated favorable interactions between astragaloside IV and QBDS-related proteins, with binding energies lower than -5 kcal/mol, indicating stable binding activity. Berberine exhibited even lower binding energies and stronger binding specificity toward DHS-related core proteins. In vitro experiments further confirmed that both compounds inhibited CRC cell proliferation, while berberine displayed significantly greater anti-proliferative efficacy. The lowest 48 h IC₅₀ value of berberine reached 15.21 mg/L in CRC cells, indicating a stronger growth-inhibitory effect than astragaloside IV. ConclusionCRC patients with QBDS and DHS exhibit distinct proteomic characteristics, suggesting that different TCM syndromes possess unique molecular signatures. The identified core proteins may serve as potential biomarkers for syndrome differentiation, while astragaloside IV and berberine may exert therapeutic effects through targeting syndrome-specific molecular networks. These findings provide preliminary proteomic evidence supporting syndrome-guided precision integrative medicine in CRC and offer new insights into the biological basis of TCM syndrome differentiation and individualized therapeutic strategies.

ObjectiveTo explore the potential mechanism of Xiezhuo Jiedu prescription in regulating autophagy in the treatment of ulcerative colitis （UC） by bioinformatics and animal experiments. MethodsThe differentially expressed genes （DEGs） in the colonic mucosal tissue of UC patients was obtained from the Gene Expression Omnibus （GEO）， and those overlapped with autophagy genes were obtained as the differentially expressed autophagy-related genes （DEARGs）. DEARGs were imported into Metascape and STRING， respectively， for gene ontology/Kyoto Encyclopedia of Genes and Genomics （GO/KEGG） enrichment analysis and protein-protein interaction （PPI） analysis. Finally， 15 key DEARGs were obtained. The core DEARGs were obtained by least absolute shrinkage and selection operator （LASSO） regression and receiver operating characteristic curve （ROC） analysis. The CIBERSORT deconvolution algorithm was used to analyze the immunoinfiltration of UC patients and the correlations between core DEARGs and immune cells. C57BL/6J mice were assigned into a normal group and a modeling group. The mouse model of UC was established by free drinking of 2.5% dextran sulfate sodium. The modeled mice were assigned into low-， medium-， and high-dose Xiezhuo Jiedu prescription and mesalazine groups according to the random number table method and administrated with corresponding agents by gavage for 7 days. The colonic mucosal morphology was observed by hematoxylin-eosin staining. The protein and mRNA levels of cysteinyl aspartate-specific proteinase 1 （Caspase-1）， cathepsin B （CTSB）， C-C motif chemokine-2 （CCL2）， CXC motif receptor 4 （CXCR4）， and hypoxia-inducing factor-1α （HIF-1α） in the colon tissue were determined by Western blot and real-time fluorescence quantitative polymerase chain reaction， respectively. ResultsThe dataset GSE87466 was screened from GEO and interlaced with autophagy genes. After PPI analysis， LASSO regression， and ROC analysis， the core DEARGs （Caspase-1， CCL2， CTSB， and CXCR4） were obtained. The results of immunoinfiltration analysis showed that the counts of NK cells， M0 macrophages， M1 macrophages， and dendritic cells in the colonic mucosal tissue of UC patients had significant differences， and core DEARGs had significant correlations with these immune cells. This result， combined with the prediction results of network pharmacology， suggested that the HIF-1α signaling pathway may play a key role in the regulation of UC by Xiezhuo Jiedu prescription. The animal experiments showed that Xiezhuo Jiedu prescription significantly alleviated colonic mucosal inflammation in UC mice. Compared with the normal group， the model group showed up-regulated protein and mRNA levels of caspase-1， CCL2， CTSB， CXCR4， and HIF-1α， which were down-regulated after treatment with Xiezhuo Jiedu prescription or mesalazine. ConclusionCaspase-1， CCL2， CTSB， and CXCR4 are autophagy genes that are closely related to the onset of UC. Xiezhuo Jiedu prescription can down-regulate the expression of core autophagy genes to alleviate the inflammation in the colonic mucosa of mice.

Objective·To investigate the therapeutic effects of neferine(Nef)on intervertebral disc degeneration(IDD)and the underlying regulatory pathways.Methods·The effects of Nef on the viability and proliferation of nucleus pulposus cells were assessed using the cell counting kit-8(CCK-8)assay.Molecular docking software was employed to analyze the potential binding sites of Nef within the Kelch domain of kelch-like ECH-associated protein 1(KEAP1).Tumor necrosis factor-α(TNF-α)was used to induce ferroptosis and inflammation in nucleus pulposus cells.Western blotting was performed to detect the expression levels of nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4(NRF2/GPX4)pathway-and nuclear factor-KB(NF-κB)pathway-related proteins under TNF-α stimulation with or without Nef.The effect of Nef on the metabolism of extracellular matrix in nucleus pulposus cells was evaluated using high-density cell culture.A needle puncture-induced IDD rat model was established,and 5 μL of 1.5 μmol/L Nef was injected twice into the intervertebral disc at the Co3/4 level(IDD+Nef group),while an equivalent volume of PBS was injected into the Co2/3 disc(IDD group).After 4 weeks,the intervertebral space height was detected by X-ray,disc degeneration was detected by magnetic resonance imaging,and disc structure was evaluated by histological staining.Results·The CCK-8 assay revealed that Nef at concentrations of 1.5 μmol/L and below did not inhibit the viability and proliferation of nucleus pulposus cells.Molecular docking results suggested that Nef might activate NRF2 by directly binding to the KEAP1 Kelch domain,thereby reducing the interaction between KEAP1 and NRF2.Western blotting indicated that Nef significantly increased the expression of the key ferroptosis-inhibiting proteins NRF2 and GPX4,while decreasing the expression of the phospho-P65 protein in the NF-κB pathway(all P＜0.05).The high-density culture of nucleus pulposus cells demonstrated that Nef mitigated the TNF-α-induced degradation of the extracellular matrix(P＜0.05).Animal study results showed that compared to the IDD group,the IDD+Nef group exhibited a greater intervertebral disc space height,a lower Pfirrmann grade(both P＜0.05),and a reduced degree of histological degeneration.Conclusion·Nef may inhibit TNF-α-induced ferroptosis in nucleus pulposus cells by activating the KEAP1/NRF2/GPX4 pathway and reduce TNF-α-induced inflammation and extracellular matrix degradation by suppressing the NF-κB pathway,thereby alleviating IDD in rats.

Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 ? by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Ⅰa-loop-helix Ⅰβ motif which cor-responds to helix Ⅰ of other P450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,the γ-domain.The structure reveals a homodimer in which the γ-domain of one molecule interacts with the β-domain of another.The plane of heme group makes an angle of ap-proximately 40° with the helix Ⅰa-loop-helix Ⅰβ motif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recogni-tion.Phe-301,Ser-303 and Gly-305 from the helix Ⅰa-loop-helix Ⅰβ motif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.

Objective: To explore the association between serum nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), NIMA-related kinase 7 (NEK7) and pulmonary fibrosis among patients with coal workers' pneumoconiosis, so as to provide a basis for the assessment of the degree of pulmonary fibrosis. Methods: Coal workers with pneumoconiosis hospitalized in the Second Affiliated Hospital of Xuzhou Medical University from July 2022 to July 2023 were selected by simple random sampling. Data such as age, stage of pneumoconiosis, and dust-exposure duration were collected through the hospital's electronic medical record management system. Venous blood was collected to detect the levels of serum NLRP3 and NEK7. High-resolution computed tomography (HRCT) image data of the chest were obtained through the hospital's imaging reporting system. The left and right lungs were divided into 6 pulmonary regions according to the upper, middle, and lower parts. The pulmonary fibrosis score was quantified according to the proportion of the pulmonary area occupied by HRCT manifestations of pulmonary fibrosis, including reticular shadows, pleural and interlobular septal thickening, traction bronchiectasis, and honeycombing. The association between the levels of serum NLRP3, NEK7, and pulmonary fibrosis was analyzed using a multiple linear regression model. Results: A total of 81 patients with coal workers' pneumoconiosis were included, all of whom were male, with a mean age of (71.46±11.69) years. There were 48, 28, and 5 cases in stage Ⅰ, stage Ⅱ, and stage Ⅲ of pneumoconiosis pathological staging, accounting for 59.26%, 34.57%, and 6.17%, respectively. There were 45 cases of tunneling and coal mining, accounting for 55.56%. There were 41 cases with dust exposure years of ≥30 years, accounting for 50.62%. The median serum NLRP3 and NEK7 in patients with coal workers' pneumoconiosis were 2.01 (interquartile range, 2.33) ng/mL and 0.98 (interquartile range, 0.83) ng/mL. The median score of pulmonary fibrosis was 5.00 (interquartile range, 5.50) points. After adjusting for age, stage of pneumoconiosis, type of work and dust-exposure duration, multiple linear regression analysis showed that serum NLRP3 (β'=0.649) and NEK7 (β'=0.346) were positively correlated with the pulmonary fibrosis score. Conclusion The increase in the levels of serum NLRP3 and NEK7 in patients with coal workers' pneumoconiosis is related to the increase in the degree of pulmonary fibrosis.

Recent advances in large models demonstrate significant prospects for transforming the field of medical imaging. These models, including large language models, large visual models, and multimodal large models, offer unprecedented capabilities in processing and interpreting complex medical data across various imaging modalities. By leveraging self-supervised pretraining on vast unlabeled datasets, cross-modal representation learning, and domain-specific medical knowledge adaptation through fine-tuning, large models can achieve higher diagnostic accuracy and more efficient workflows for key clinical tasks. This review summarizes the concepts, methods, and progress of large models in medical imaging, highlighting their potential in precision medicine. The article first outlines the integration of multimodal data under large model technologies, approaches for training large models with medical datasets, and the need for robust evaluation metrics. It then explores how large models can revolutionize applications in critical tasks such as image segmentation, disease diagnosis, personalized treatment strategies, and real-time interactive systems, thus pushing the boundaries of traditional imaging analysis. Despite their potential, the practical implementation of large models in medical imaging faces notable challenges, including the scarcity of high-quality medical data, the need for optimized perception of imaging phenotypes, safety considerations, and seamless integration with existing clinical workflows and equipment. As research progresses, the development of more efficient, interpretable, and generalizable models will be critical to ensuring their reliable deployment across diverse clinical environments. This review aims to provide insights into the current state of the field and provide directions for future research to facilitate the broader adoption of large models in clinical practice.
Humans ; Diagnostic Imaging/methods* ; Precision Medicine/methods* ; Image Processing, Computer-Assisted/methods*

This study aims to comprehensively analyze the material basis of toad visceral oil(hereafter referred to as toad oil), and explore the pharmacological effect of toad oil on atopic dermatitis(AD). Ultra-high performance liquid chromatography-linear ion trap/orbitrap high-resolution mass spectrometry(UHPLC-LTQ-Orbitrap-MS) and gas chromatography-mass spectrometry(GC-MS) were employed to comprehensively identify the chemical components in toad oil. The animal model of AD was prepared by the hapten stimulation method. The modeled animals were respectively administrated with positive drug(0.1% hydrocortisone butyrate cream) and low-and high-doses(1%, 10%) of toad oil by gavage. The effect of toad oil on AD was evaluated with the AD score, ear swelling rate, spleen index, and pathological section results as indicators. A total of 99 components were identified by UHPLC-LTQ-Orbitrap-MS, including 14 bufadienolides, 7 fatty acids, 6 alkaloids, 10 ketones, 18 amides, and other compounds. After methylation of toad oil samples, a total of 20 compounds were identified by GC-MS. Compared with the model group, the low-and high-dose toad oil groups showed declined AD score, ear swelling rate, and spleen index, alleviated skin lesions, and reduced infiltrating mast cells. This study comprehensively analyzes the chemical composition and clarifies the material basis of toad oil. Meanwhile, this study proves that toad oil has a good therapeutic effect on AD and is a reserve resource of traditional Chinese medicine for external use in the treatment of AD.
Animals ; Dermatitis, Atopic/immunology* ; Disease Models, Animal ; Mice ; Male ; Gas Chromatography-Mass Spectrometry ; Humans ; Bufonidae ; Oils/administration & dosage* ; Chromatography, High Pressure Liquid ; Female ; Mice, Inbred BALB C