Background/Aims: Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy. Methods: We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues. Results: We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts. Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.

Objective:To explore the relationship between suicide attempts,school bullying,and psychological resilience in children and adolescents with major depressive disorder(MDD)and school bullying and psychological resilience.Methods:A total of 784 patients with MDD aged 10 to 18 years were included.The Chinese version of the Olweus Bullying Victimization Questionnaire,Adolescent Psychological Resilience Scale,and a suicide attempt assessment were utilized to evaluate school bullying,psychological resilience,and suicide attempt.Stepwise logistic regression was applied to identify the associated factors of suicide attempts.Results:The occurrence of suicide at-tempts in children and adolescents with MDD was positively associated with physical bullying(OR=1.85,95％CI:1.14-3.02)and indirect bullying(OR=1.48,95％CI:1.06-2.04),and negatively associated with higher levels of goal focus(OR=0.62,95％CI:0.45-0.85)and positive cognition(OR=0.62,95％CI:0.45-0.85)at higher levels.Conclusion:Bullying significantly increases the risk of suicide attempts in children and adolescents with MDD,while higher psychological resilience could mitigate this risk.

OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

As the brain's resident immune cells, microglia perform crucial functions such as phagocytosis, neuronal network maintenance, and injury restoration by adopting various phenotypes. Dynamic imaging of these phenotypes is essential for accessing brain diseases and therapeutic responses. Although numerous probes are available for imaging pro-inflammatory microglia, no PET tracers have been developed specifically to visualize anti-inflammatory microglia. In this study, we present an ¹⁸F-labeled PET tracer (QTFT) that targets the P2Y₁₂, a receptor highly expressed on anti-inflammatory microglia. [¹⁸F]QTFT exhibited high binding affinity to the P2Y₁₂ (14.43 nmol/L) and superior blood-brain barrier permeability compared to other candidates. Micro-PET imaging in IL-4-induced neuroinflammation models showed higher [¹⁸F]QTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Y₁₂ antagonist. Furthermore, [¹⁸F]QTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Y₁₂ in anti-inflammatory microglia. In a pilot clinical study, [¹⁸F]QTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that [¹⁸F]QTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Y₁₂ overexpressed in anti-inflammatory microglia.

OBJECTIVES: To explore the efficacy of DSA-guided intrathecal drug delivery system combined with Zi Wu Liu Zhu Acupoint Therapy for management of cancer pain and provide reference for its standardized clinical application. Methods and. RESULTS: Recommendations were formulated based on literature review and expert group discussion, and consensus was reached following expert consultation. The consensus recommendations are comprehensive, covering the entire treatment procedures from preoperative assessment and preparation, surgical operation process, postoperative management and traditional Chinese medicine treatment to individualized treatment planning. The study results showed that the treatment plans combining traditional Chinese with Western medicine effectively alleviated cancer pain, reduced the use of opioid drugs, and significantly improved the quality of life and enhanced immune function of the patients. Postoperative follow-up suggested good treatment tolerance among the patients without serious complications. CONCLUSIONS The formulated consensus is comprehensive and can provide reference for clinicians to use DSA-guided intrathecal drug delivery system combined with Zi Wu Liu Zhu Acupoint Therapy. The combined treatment has a high clinical value with a good safety profile for management of cancer pain.
Humans ; Medicine, Chinese Traditional ; Cancer Pain/therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Drug Delivery Systems ; Pain Management/methods* ; China

OBJECTIVE: To investigate the therapeutic effects of Banxia Xiexin Decoction (BXD), a herbal medicine formula, on inflammation and the imbalance of the gut microbiota in a rat model of colorectal cancer (CRC) induced by azoxymethane (AOM) /dextran sulfate sodium (DSS). METHODS: A total of 75 male C57BL/6 mice were randomly divided into five groups: normal control group (NC), model group (MODEL), low-dose BXD treatment group (L-BXD), high-dose BXD treatment (H-BXD) group and MS treatment group (MS). BXD and MS were used in CRC mice at the doses of 3.915 g/kg, 15.66 g/kg, 0.6 g/kg for 3 weeks consecutively. Histopathological changes in the colon were observed using hematoxylin-eosin (HE) staining. The content of inflammatory factors in serum was detected by an enzyme-linked immunosorbent assay (ELISA), and the expression of mRNA and protein of genes related to immunity, apoptosis, inflammation, and inflammatory factors was evaluated. Changes in the intestinal flora of mouse fecal were determined based on high-throughput sequencing of the 16S rRNA microbial gene. RESULTS: Compared to the model group, the low-dose BXD and high-dose BXD groups decreased the number of colon tumors, reversed weight loss, and shortened colon length of mice. The pathological examination showed that BXD alleviated the malignancy of intestinal tumors. It also suppressed signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-9 (MMP-9), and transforming growth factor beta 1 (TGF-β1) expression, while increasing the expression of the tight junction protein ZO-1 in colon tissues. Additionally, the levels of key pathway proteins involved in inflammation (phosphorylated-STAT3, Bcl-2, COX-2) and cell cycle regulatory molecules (c-Myc and PCNA) were reduced. According to 16S rRNA sequence analysis, BXD enhanced the relative abundance of potentially beneficial bacteria, while that of cancer-related bacteria decreased. CONCLUSION BXD plays a preventive role in developing colorectal cancer; its mechanisms are related to the inhibition of inflammation and tumor proliferation, as well as maintenance of intestinal homeostasis.

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [¹⁵N₂]-cystine and [¹³C₅]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Functional dyspepsia (FD), characterized by persistent or recurrent dyspeptic symptoms without identifiable organic, systemic or metabolic causes, is an increasingly recognized global health issue. The objective of this guideline is to equip clinicians and nursing professionals with evidence-based strategies for the management and treatment of adult patients with FD using traditional Chinese medicine (TCM). The Guideline Development Group consulted existing TCM consensus documents on FD and convened a panel of 35 clinicians to generate initial clinical queries. To address these queries, a systematic literature search was conducted across PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, China Biology Medicine (SinoMed) Database, Wanfang Database, Traditional Medicine Research Data Expanded (TMRDE), and the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS). The evidence from the literature was critically appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The strength of the recommendations was ascertained through a consensus-building process involving TCM and allopathic medicine experts, methodologists, pharmacologists, nursing specialists, and health economists, leveraging their collective expertise and empirical knowledge. The guideline comprises a total of 43 evidence-informed recommendations that span a range of clinical aspects, including the pathogenesis according to TCM, diagnostic approaches, therapeutic interventions, efficacy assessments, and prognostic considerations. Please cite this article as: Zhang SS, Zhao LQ, Hou XH, Bian ZX, Zheng JH, Tian HH, Yang GH, Hong WS, He YY, Liu L, Shen H, Li YP, Xie S, Shu J, Zeng BF, Li JX, Liu Z, Xiao ZH, Xiao JD, Zheng PY, Huang SG, Chen SL, Fei GJ. International clinical practice guideline on the use of traditional Chinese medicine for functional dyspepsia (2025). J Integr Med. 2025; 23(5):502-518.
Dyspepsia/drug therapy* ; Humans ; Medicine, Chinese Traditional/methods* ; Practice Guidelines as Topic ; Drugs, Chinese Herbal/therapeutic use*

Objective:To investigate the correlation of epithelial lesions among different biopsy sites in the female lower genital tract and the relationship between age and lesion distribution.Methods:A total of 406 148 patients with cervical biopsy specimens archived at the Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University from January 2010 to December 2021 were analyzed. Among them, 70 309 cases (17.31%) had concurrent vaginal biopsies, and 16 073 cases (3.96%) had concurrent vulvar biopsies. (1) Cases were divided into four 3-year intervals to compare vaginal or vulvar biopsy rates and high-grade squamous intraepithelial lesion (HSIL) or worse (HSIL +) detection rates across time periods. (2) Correlations between cervical lesions and vaginal or vulvar lesions were assessed. (3) Patients were stratified into three age groups (<30, 30-49, and ≥50 years) to compare vaginal or vulvar HSIL + detection rates. Results:Mean ages of patients with cervical, vaginal, and vulvar biopsies were (41.3±11.0), (47.4±12.5), and (41.9±13.2) years, respectively. Patients with vaginal biopsy were significantly older than cervical or vulvar groups (all P<0.001). (1) Vaginal biopsy rates increased markedly from 7.37% (2010—2012) to 22.76% (2019—2021; χ2=9 205.01, P<0.001); vulvar biopsy rates increased slightly from 2.80% to 5.69% ( χ2=1 777.25, P<0.001). Correspondingly, vaginal HSIL + detection rates rose from 0.28% to >0.5% (0.56% in 2013—2015, 0.59% in 2016—2018, 0.51% in 2019—2021; χ2=134.70, P<0.001), while vulvar HSIL + rates increased from 0.03% to 0.33% ( χ2=56.54, P<0.001). (2) Weak correlation existed between cervical and vaginal lesions ( r=0.28; P<0.001; n=70 309), while cervical-vulvar correlation was weaker ( r=0.22, P<0.001; n=16 073). (3) Vaginal HSIL + detection rates were higher in cervical HSIL + patients aged 30-49 years (26.65%) and ≥50 years (26.79%) versus <30 years (14.63%; both P<0.001). Conversely, vulvar HSIL + detection rates were higher in the <30 years group (23.08%) versus 30-49 years (13.83%) and ≥50 years (12.89%; both P<0.05). Conclusions:Vaginal or vulvar lesion detection rates increase with biopsy frequency. Vaginal lesions correlate with cervical abnormalities, whereas vulvar lesions are relatively independent. In cervical HSIL + patients, those <30 years are more prone to have vulvar HSIL +, while those ≥30 years show higher vaginal HSIL + incidence. These age-specific distribution patterns inform optimized biopsy strategies.