Background/Aims: Cholangiocarcinoma (CCA) is a primary malignant neoplasm with an extremely poor prognosis. While combined chemoradiotherapy has been demonstrated to delay CCA progression to a certain extent, the absence of specific molecular biomarkers or targets significantly hinders the diagnosis and treatment of CCA. Methods: Through cross-analysis of proteomics and ADMA modificationomics, we identified DDX1 overexpressed in CCA with elevated R602-ADMA modifications. HPLC-MS/MS identified PRMT1 as the methyltransferase and USP10 as the deubiquitinating enzyme for DDX1. Immunofluorescence and nuclear-cytoplasmic partitioning experiments confirmed DDX1’s nuclear localization. GO and KEGG analyses clarify the biological functions of DDX1 in response to hypoxia. RNA-seq transcriptomics analyzed key pathways influenced by DDX1. A hydrodynamic in situ CCA mouse model was established to validate the chemopreventive effects of the PRMT1-specific inhibitor GSK715 on CCA development. Results: DDX1 promotes CCA progression both in vivo and in vitro and can be inhibited by GSK715. Mechanistically, PRMT1 mediates ADMA modification at position R602 of DDX1. This modification promotes DDX1 nuclear localization by recruiting USP10 to deubiquitinate DDX1, while simultaneously inhibiting PRMT1 degradation. DDX1 promotes the transcription of PRMT1 and USP10 by binding to the mRNA 3’UTR region, establishing a positive feedback regulatory pathway. This mechanism promotes the occurrence and development of CCA and can serve as a target for the inhibitor GSK715 to suppress CCA progression. Conclusions Our study identified DDX1-R602-ADMA modification as a novel ADMA modification in CCA. It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA.

Objective To explore the protective effect and mechanism of Xinkang Granules-containing serum in adriamycin-induced injury of cardiomyocytes H9C2 based on cGAS-STING signaling axis.Methods Adriamycin was used to induce the H9C2 cells injury model.The cells were divided into normal group,model group,Xinkang Granules group and inhibitor group.After 24 hours of intervention,the CCK-8 method was used to detect cell survival rate,the DCFH-DA fluorescent probe was used to detect the content of cell reactive oxygen species(ROS),cell apoptosis rate was detected by flow cytometry,ELISA was used to detect the content of tumor necrosis factor-α(TNF-α)in cell supernatant,colorimetry was used to detect lactate dehydrogenase(LDH)in cells,RT-qPCR was used to detect the expression of mitochondrial transcription factor A(TFAM),cyclic guanosine-adenylate synthetase(cGAS),stimulator of interferon genes(STING)and TNF-α mRNA,Western blot and immunofluorescence were used to detect the protein expressions of cGAS and STING.Results Compared with the normal group,cell survival rate in the model group was significantly reduced(P<0.01),the ROS content was significantly increased(P<0.01),the apoptosis rate significantly increased(P<0.01),the content of TNF-α in the supernatant significantly increased(P<0.01),the activity of LDH significantly increased(P<0.01),the expression of TFAM mRNA significantly decreased(P<0.01),and the expressions of TNF-α,cGAS,STING mRNA and the protein expression of cGAS and STING significantly increased(P<0.01).Compared with the model group,cell survival rate in Xinkang Granules group and inhibitor group significantly increased(P<0.01),the ROS content significantly decreased(P<0.01),the apoptosis rate significantly decreased(P<0.01),the content of TNF-α in supernatant significantly decreased(P<0.01),the activity of LDH significantly decreased(P<0.01),the expression of TFAM mRNA significantly increased(P<0.01),and the expressions of TNF-α,cGAS,STING mRNA and the protein expressions of cGAS and STING significantly decreased(P<0.05,P<0.01).Conclusion Xinkang Granules have a protective effect on adriamycin-induced H9C2 cardiomyocytes,which may be related to the inhibition of cGAS/STING axis activation and the secretion of inflammatory factors.

Objective:To establish a mouse model of spinal cord injury(SCI),and to investigate the effect of electroacupuncture(EA)intervention on cell apoptosis after acute SCI and its mechanism.Methods:Female C57BL/6 mice were used to establish a model of SCI,and after successful modeling,the mice were randomly divided into SCI group,EA group,and Rosiglitazone group(R group);a sham-operation group(Sham group)was also established.After successful modeling,the mice in the EA group were given EA at bilat-eral Jiaji points and Zusanli once a day for 14 days,those in the R ture,and the number of surviving cells.The EA group and the R group had a significant reduction in the expression of caspase-3 and significant increases in the expression of PPARγ and CD36,and the EA group had significant reductions in the expression of Hba-a1 and Hbb-bt.In addition,RNA-Seq and TMT/iTRAQ techniques,significant analysis,Venn analysis,and dual-omics analysis identi-fied Hba-a1 and Hbb-bt as the target genes of EA.The KEGG pathway enrichment analysis showed that EA had a significant effect on the PPAR signaling pathway.Conclusion:By regulating the PPARγ-CD36 signaling pathway,EA can promote the clearance of Hba-a1 and Hbb-bt after SCI,reduce the expression level of caspase-3,alleviate cell apoptosis,and facilitate the recovery of spinal cord nerve function.

Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

Pain is one of the common non-motor symptoms in patients with Parkinson disease and is characterized by early onset， a high incidence rate， and diverse types of discomfort， which seriously affects the quality of life of patients. Based on the related concepts of pain in Parkinson disease and the current status of research in China， this article reviews the commonly used non-pharmaceutical interventions for alleviating pain in patients and their mechanisms， in order to provide a basis for developing pain management regimens.
Parkinson Disease ; Pain

Objective To explore the protective effect and mechanism of Xinkang Granules-containing serum in adriamycin-induced injury of cardiomyocytes H9C2 based on cGAS-STING signaling axis.Methods Adriamycin was used to induce the H9C2 cells injury model.The cells were divided into normal group,model group,Xinkang Granules group and inhibitor group.After 24 hours of intervention,the CCK-8 method was used to detect cell survival rate,the DCFH-DA fluorescent probe was used to detect the content of cell reactive oxygen species(ROS),cell apoptosis rate was detected by flow cytometry,ELISA was used to detect the content of tumor necrosis factor-α(TNF-α)in cell supernatant,colorimetry was used to detect lactate dehydrogenase(LDH)in cells,RT-qPCR was used to detect the expression of mitochondrial transcription factor A(TFAM),cyclic guanosine-adenylate synthetase(cGAS),stimulator of interferon genes(STING)and TNF-α mRNA,Western blot and immunofluorescence were used to detect the protein expressions of cGAS and STING.Results Compared with the normal group,cell survival rate in the model group was significantly reduced(P<0.01),the ROS content was significantly increased(P<0.01),the apoptosis rate significantly increased(P<0.01),the content of TNF-α in the supernatant significantly increased(P<0.01),the activity of LDH significantly increased(P<0.01),the expression of TFAM mRNA significantly decreased(P<0.01),and the expressions of TNF-α,cGAS,STING mRNA and the protein expression of cGAS and STING significantly increased(P<0.01).Compared with the model group,cell survival rate in Xinkang Granules group and inhibitor group significantly increased(P<0.01),the ROS content significantly decreased(P<0.01),the apoptosis rate significantly decreased(P<0.01),the content of TNF-α in supernatant significantly decreased(P<0.01),the activity of LDH significantly decreased(P<0.01),the expression of TFAM mRNA significantly increased(P<0.01),and the expressions of TNF-α,cGAS,STING mRNA and the protein expressions of cGAS and STING significantly decreased(P<0.05,P<0.01).Conclusion Xinkang Granules have a protective effect on adriamycin-induced H9C2 cardiomyocytes,which may be related to the inhibition of cGAS/STING axis activation and the secretion of inflammatory factors.

Chronic heart failure （CHF） is a clinical syndrome resulting from damage to the myocardium， leading to changes in the function or structure of the heart and causing reduced pumping and/or filling capacity. Its pathogenesis is complex， potentially involving myocardial fibrosis， apoptosis and autophagy of cardiomyocytes， inflammatory responses， oxidative stress， and myocardial remodeling. Our team believes that the fundamental pathogenesis of CHF is heart-Qi deficiency， with the disease location in the heart， which is closely related to other organs. Due to heart-Qi deficiency， blood circulation weakens， leading to blood stasis， which in turn generates water-dampness and phlegm turbidity that accumulate over time and become toxic. The interaction between water stasis， Qi stagnation， blood stasis， and phlegm toxicity further weakens the body， creating a vicious cycle （deficiency， stasis， water retention， and toxicity） that is difficult to resolve. Under physiological conditions， the nuclear factor-κB （NF-κB） signaling pathway functions normally， maintaining vital activities and immune responses. However， in pathological states， the NF-κB signaling pathway becomes imbalanced， triggering inflammatory responses and other issues. Research has shown that traditional Chinese medicine （TCM） can regulate the NF-κB signaling pathway through multiple pathways， targets， and effects， effectively improving the progression of CHF. As a result， this has become a research hotspot for the prevention and treatment of the disease. Guided by TCM theory， this research group reviewed the literature to summarize the activation pathways of the NF-κB pathway and its interactions with other pathways. Additionally， the group summarized the research progress on the regulation of the NF-κB pathway in the treatment of CHF using Chinese medicines， their active ingredients， Chinese medicine compounds， and Chinese patent medicines. This study is expected to clarify the mechanisms and targets by which TCM treats CHF by regulating the NF-κB pathway， thereby guiding clinical treatment and drug development for CHF.

BACKGROUND:In recent years,with the development of biological scaffold materials and bioprinting technology,tissue-engineered bone has become a research hotspot in bone defect repair. OBJECTIVE:To summarize the current treatment methods for bone defects,summarize the biomaterials and bioprinting technology for preparing tissue-engineered bone scaffolds,and explore the application of biomaterials and printing technology in tissue engineering and the current challenges. METHODS:Search terms were"bone defect,tissue engineering,biomaterials,3D printing technology,4D printing technology,bioprinting,biological scaffold,bone repair"in Chinese and English.Relevant documents published from January 1,2009 to December 1,2022 were retrieved on CNKI,PubMed and Web of Science databases.After being screened by the first author,high-quality references were added.A total of 93 articles were included for review. RESULTS AND CONCLUSION:The main treatment methods for bone defects include bone transplantation,membrane-guided regeneration,gene therapy,bone tissue engineering,etc.The best treatment method is still uncertain.Bone tissue engineering technology is a new technology for the treatment of bone defects.It has become the focus of current research by constructing three-dimensional structures that can promote the proliferation and differentiation of osteoblasts and enhance the ability of bone formation.Biological scaffold materials are diverse,with their characteristics,advantages and disadvantages.A single biological material cannot meet the demand for tissue-engineered bone for the scaffold.Usually,multiple materials are combined to complement each other,which is to meet the demand for mechanical properties while taking into account the biological properties of the scaffold.Bioprinting technology can adjust the pore of the scaffold,build a complex spatial structure,and is more conducive to cell adhesion,proliferation and differentiation.The emerging 4D printing technology introduces"time"as the fourth dimension to make the prepared scaffold dynamic.With the synchronous development of smart materials,4D printing technology provides the possibility of efficient repair of bone defects in the future.

Objective To investigate the efficacy and safety of Yushi Huayu Zhixue prescription (Huayu prescription) combined with levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis (AM). Methods A prospective,randomized,double-blind,placebo-controlled trial was designed and 102 patients with AM admitted to the outpatient department of International Peace Maternal & Child Health Hospital and The First Affiliated Hospital of Naval Medical University (Second Military Medical University) from Dec. 2019 to Dec. 2022 were enrolled. The patients were randomly divided into Huayu prescription group and placebo group for double-blind clinical trial. The Huayu prescription group was treated with Huayu prescription 1 month after LNG-IUS placement,while the placebo group was treated with placebo 1 month after LNG-IUS placement,and both Huayu prescription and placebo were taken for 3 months. A total of 95 patients completed the follow-up,including 47 in the Huayu prescription group and 48 in the placebo group;and 7 were shed,with a shedding rate of 6.86％. The pictorial blood loss assessment chart (PBAC) score,uterine spotting days,visual analogue scale (VAS) score,uterine volume,serum carbohydrate antigen 125 (CA125) level and traditional Chinese medicine (TCM) syndrome quantitative score were compared between the 2 groups,and the safety was evaluated. Results After 3 months of treatment,compared with the placebo group,the PBAC score,spotting days,uterine volume,serum CA125 level and TCM syndrome quantitative score of patients in the Huayu prescription group were all decreased (all P<0.05),but there was no significant difference in the VAS score of dysmenorrhea (P>0.05). During the follow-up,no patients in the Huayu prescription group but 2 patients in the placebo group received surgical treatment (including 1 case of laparoscopic hysterectomy and 1 case of laparoscopic adenomyomectomy),and there was no significant difference in the surgical rate between the 2 groups (P>0.05). Meanwhile,no obvious adverse reactions were found in both groups. Conclusion Huayu prescription can significantly improve the spotting of patients with AM,promote uterine volume reduction,reduce serum CA125 level,and significantly improve the TCM syndrome of AM. It is suggest that AM patients should take Huayu prescription after placing LNG-IUS,so as to reduce the adverse reactions of LNG-IUS.

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8⁺ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.