ObjectiveChemotherapy is one of the important therapeutic approaches for cancer treatment. However, the emergence of multidrug resistance and side effects significantly limit its application. To address these challenges, chemotherapy is often combined with other drugs or therapies. Among the 13 human fucosyltransferases (FUTs) identified, FUT8 (alpha-(1,6)-fucosyltransferase) is the only enzyme responsible for core fucosylation. Core fucosylation plays an important role in cancer occurrence, metastasis and chemotherapy resistance, making the suppression of FUT8 a potential strategy for reversing multidrug resistance. This study aims to evaluate the feasibility of combining the small molecule FUT8 inhibitor 2FF (2-deoxy-2-fluoro-L-fucose) with the clinical chemotherapeutic drug doxorubicin (DOX) for treating malignant tumors. MethodsThe human hepatocellular carcinoma cell line HepG2 and mouse colon cancer cell line CT26 cells were treated with 2FF, DOX or their combination and core fucosylation levels were assessed using Lectin blot. HepG2 and CT26 cells were exposed to 50 μmol/L 2FF for 72 h, followed by treatment with a gradient concentration of DOX for 24 h. Cell viability and IC₅₀ values were determined via the CCK-8 assay. Transwell invasion assays were conducted to evaluate the combined effect of 2FF and DOX on the invasion ability of HepG2 cells. Flow cytometry was performed to analyze the impact of 2FF, DOX and their combination on membrane PD-L1 expression of HepG2 cells. To assess the in vivo effect, 6- to 8-week-old female BALB/c mice (20-25 g), were subcutaneously injected with 1×10⁶ CT26 cells into the right axilla (four groups, six mice in each group). After the average tumor volume reached 100 mm³, mice were treated with DOX, 2FF, their combination, or saline (mock group) every other day. DOX was administrated intraperitoneally (2 mg/kg), 2FF intravenously (5 mg/kg), and the combination group, received the both treatment. Tumor size was measured every other day using a vernier caliper. ResultsThis study demonstrated that DOX upregulates the core fucosylation levels in HepG2 and CT26 cells,while 2FF effectively inhibits this DOX-induced effect. Furthermone, 2FF enhanced the sensitivity of HepG2 and CT26 cells to DOX. The combination of 2FF and DOX synergistically inhibited the invasion ability of HepG2 cells, and enhanced the anti-tumor efficacy of CT26 subcutaneous tumor model in BALB/c mice. However the combination treatment led to weight loss in mice. In addition, DOX increased the cell surface PD-L1 expression in HepG2 cells, which was effectively suppressed by 2FF. ConclusionThe FUT8 inhibitor 2FF effectively suppresses DOX-induced upregulation of core fucosylation and PD-L1 levels in tumor cells, and 2FF synergistically enhances the anticancer efficacy of DOX.

With the increasing incidence of diabetes mellitus in recent years， cardiomyopathy caused by diabetes mellitus has aroused wide concern and this disease is characterized by high insidiousness and high mortality. The early pathological changes of diabetic cardiomyopathy （DCM） are mitochondrial structural disorders and loss of myocardial metabolic flexibility. The turbulence of mitochondrial quality control （MQC） is a key mechanism leading to the accumulation of damaged mitochondria and loss of myocardial metabolic flexibility， which， together with elevated levels of oxidative stress and inflammation， trigger changes in myocardial structure and function. Qi deficiency and stagnation is caused by the loss of healthy Qi， and the dysfunction of Qi transformation results in the accumulation of pathogenic Qi， which further triggers injuries. According to the theory of traditional Chinese medicine （TCM）， DCM is rooted in Qi deficiency of the heart， spleen， and kidney. The dysfunction of Qi transformation leads to the generation and lingering of turbidity， stasis， and toxin in the nutrient-blood and vessels， ultimately damaging the heart. Therefore， Qi deficiency and stagnation is the basic pathologic mechanism of DCM. Mitochondria， similar to Qi in substance and function， are one of the microscopic manifestations of Qi. The role of MQC is consistent with the defense function of Qi. In the case of MQC turbulence， mitochondrial structure and function are impaired. As a result， Qi deficiency gradually emerges and triggers pathological changes， which make it difficult to remove the stagnant pathogenic factor and aggravates the MQC turbulence. Ultimately， DCM occurs. Targeting MQC to treat DCM has become the focus of current research， and TCM has the advantages of acting on multiple targets and pathways. According to the pathogenesis of Qi deficiency and stagnation in DCM and the modern medical understanding of MQC， the treatment should follow the principles of invigorating healthy Qi， tonifying deficiency， and regulating Qi movement. This paper aims to provide ideas for formulating prescriptions and clinical references for the TCM treatment of DCM by targeting MQC.

AIM:To identify transcriptional differences between the ocular surface ectoderm(OSE)and surface ectoderm(SE)using RNA-seq, and elucidate the OSE transcriptome landscape and the regulatory networks involved in its development.METHODS:OSE and SE cells were differentiated from human embryonic stem(hES)cells. Differentially expressed genes(DEGs)between OSE and SE were analyzed using RNA-seq. Based on the DEGs, we performed gene ontology(GO)analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis, and protein-protein interaction(PPI)network analysis. Transcription factors(TFs)and hub genes were screened. Subsequently, TF-gene and TF-miRNA regulatory networks were constructed using the NetworkAnalyst platform.RESULTS:A total of 4 182 DEGs were detected between OSE and SE cells, with 2 771 up-regulated and 1 411 down-regulated genes in OSE cells. GO-BP analysis revealed that up-regulated genes in OSE were enriched in the regulation of ion transmembrane transport, axon development, and modulation of chemical synaptic transmission. Down-regulated genes were primarily involved in nuclear division, chromosome segregation, and regulation of cell cycle phase transition. KEGG analysis indicated that up-regulated genes in OSE cells were enriched in signaling pathways such as cocaine addiction, axon guidance, and amphetamine addiction, while down-regulated genes were enriched in proteoglycans in cancer, ECM-receptor interaction, protein digestion and absorption, and cytokine-cytokine receptor interaction. Additionally, compared with SE, 204 TFs(including FOS, EGR1, POU5F1, SOX2, and PAX6)were up-regulated, and 80 TFs(including HAND2, HOXB6, HOXB5, HOXA5, and HOXB8)were down-regulated in OSE cells. Furthermore, we identified 6 up-regulated and 9 down-regulated hub genes in OSE cells, and constructed TF-gene and TF-miRNA regulatory networks based on these hub genes.CONCLUSIONS:The transcriptome characteristics of OSE and SE cells were elucidated through RNA-seq analysis. These findings may provide a novel insight for studies on the development and in vitro directed induction of OSE and corneal epithelial cells.

Objective To investigate the mechanism of naringenin resisting lower extremity deep venous thrombosis(LEDVT)in rats.Methods Sixty rats were randomly divided into 6 groups,i.e.,sham-operation group,model group,naringenin low-,medium-,and high-dose groups,and naringenin high-dose + STING agonist 2.5 hexamethylene cacodylate(DMXAA)group,with 10 rats in each group.The coagulation indexes[D-dimer,thrombin time(TT),activated partial thromboplastin time(APTT),prothrombin time(PT)],inflammation indexes[interleukin 1β(IL-1β),interleukin 6(IL-6),tumor necrosis factor α(TNF-α)]and oxidative stress indexes[malondialdehyde(MDA),glutathione peroxidase(GSH-Px),superoxide dismutase(SOD)];Hematoxylin-eosin(HE)staining to detect thrombus formation in venous tissues;wet and dry mass of thrombus were detected;ultrastructure of venous thrombus was detected by transmission electron microscope(TEM);protein expressions of cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)in venous thrombus tissue were detected by Western Blot.Results(1)Compared with the sham-operation group,rats in the model group showed an increase in D-dimer levels,IL-1β,IL-6,TNF-α levels,MDA content,thrombus wet and dry mass,and a decrease in TT,APTT,PT,SOD activity,and GSH-Px activity(all P＜0.05);and compared with the model group,rats in naringen's low-,medium-,and high-dose groups showed a decrease in D-dimer levels,IL-1β,IL-6,TNF-α levels,MDA content,thrombus wet and dry mass,TT,APTT and PT,SOD activity and GSH-Px activity were increased(P＜0.05)in a dose-dependent manner compared with the model group;compared with the naringenin high-dose group,rats in the naringenin high-dose + DMXAA group,D-dimer levels,IL-1β,IL-6,TNF-α levels,MDA content,thrombus wet and dry mass were elevated,TT,APTT and PT,SOD activity and GSH-Px activity were decreased(P＜0.05).(2)Compared with the sham-operation group,the expression levels of cGAS and STING proteins in the venous thrombus tissues of rats in the model group were elevated(P＜0.05);compared with the model group,the expression levels of cGAS and STING proteins in the venous thrombus tissues of rats in the naringeno low-,medium-and high-dose groups were significantly reduced(P＜0.05);cGAS and STING protein expression levels in the naringenin high-dose + DMXAA group were significantly higher than those in the naringenin high-dose group(P＜0.05).Conclusion Naringenin can inhibit the activation of cGAS/STING signalling pathway,thereby inhibiting the inflammatory response and resisting oxidative stress,and thus alleviating the LEDVT.

Objective To investigate the molecular mechanism of Shema Zhichuan Liquid in the treatment of neutrophilic asthma(NA)based on network pharmacology and in vivo experiments.Methods(1)The TCMSP,literature search and Swiss ADME and Swiss Target Prediction databases were used to search and screen the active components and their targets of Shema Zhichuan Liquid.OMIM,GeneCards,DisGeNET and DrugBank databases were used to search and screen NA disease-related targets.The intersection of the active components and NA disease-related targets of Shema Zhichuan Liquid was obtained through the microbiology platform to obtain the potential targets of Shema Zhichuan Liquid for the treatment of NA(common targets).Cytoscape 3.8 software was used to construct the network of"Chinese medicinals-active components-potential targets".The PPI network of potential targets was established by STRING database,and the core targets were obtained by analysing the built-in Mcode plug-in.The Metascape platform was used to enrich the gene ontology(GO),Kyoto Encyclopaedia of Genes and Genomes(KEGG)pathways for the potential targets.(2)BALB/C mice were acclimatised and fed for 1 week and randomly divided into a blank group,NA model group,low-dose group(2.5 g·kg-1)and high-dose group of Shema Zhichuan Liquid(10 g·kg-1),and control group of Dexamethasone(1 mg·kg-1);the NA mouse model was replicated by intraperitoneal injection of sensitizer(OVA+CFA)and nebulized inhalation excitation.OVA/CFA(20 μg OVA+75 μg CFA,0.3 mL)was injected intraperitoneally to sensitize on days 0,7 and 14 respectively,and 5%OVA suspension was nebulized on days 21-30(8 mL each time,40 minutes each time,once a day);1 hour before nebulisation,each group was administered by gastric gavage,and the Dexamethasone control group was administered by intraperitoneal injection once a day.The pathological changes of mouse lung tissue were observed by HE staining;IL-8 content in alveolar lavage fluid was detected by ELISA;mRNA expression levels of NLRP3 and CXCR2 were detected by RT-qPCR;and p-mTOR protein expression levels was detected by immunohistochemistry.Results(1)A total of 826 active component targets and 154 NA disease-related targets were obtained,and 51 potential targets(common targets)for the treatment of NA were obtained from the intersection of the active component and the NA disease-related targets of Shema Zhichuan Liquid.Through the network analysis of"Chinese medicinals-active components-potential targets",quercetin,lignocerotoxin,kaempferol,stigmasterol,naringenin and other key active components were obtained.The PPI network analysis of potential targets yielded 29 core targets,including AKT1,IL6,TNF,EGFR,NLRP3,RELA,MIF,CXCR2,VEGFA,etc..The GO functional enrichment analysis yielded 882 biological process entries,33 cellular component entries,and 61 molecular function entries;KEGG analysis yielded 142 signaling pathways,mainly involving TNF signaling pathway,influenza A signaling pathway,Toll-like receptor pathway,MAPK signaling pathway,mTOR signaling pathway and so on.(2)Results of animal experiments:compared with the blank group,mice in the NA model group showed obvious damage to the airway mucosa,structural disorders,a large number of inflammatory cells infiltration,mucosal congestion,oedema,obvious thickening of the alveolar wall,and narrowing of the alveolar lumen;the level of the inflammatory factor IL-8 in the alveolar lavage fluid was significantly elevated(P＜0.05);the mRNA expressions of NLRP3 and CXCR2 in the lung tissues of the mice were significantly up-regulated(P＜0.01),and the protein expression of p-mTOR was significantly increased.Compared with the NA model group,the structural arrangement of bronchial epithelial cells in the mice in the low-and high-dose groups of Shema Zhichuan Liquid was slightly disordered,with a small amount of inflammatory cell infiltration around the airways and blood vessels,and the congestion and edema of the bronchial mucosa were significantly reduced;the mRNA expression of CXCR2 in the lung tissues of the mice was significantly down-regulated(P＜0.01),and the level of expression of p-mTOR protein was significantly reduced.The IL-8 level in the vesicular lavage fluid of mice in the high-dose group was significantly reduced(P＜0.05);the mRNA expression of NLRP3 in the lung tissue of mice in the low-dose group was significantly down-regulated(P＜0.05).Conclusion The therapeutic effect of Shema Zhichuan Liquid on NA may be achieved through the key active components,such as quercetin,lignocerol and kaempferol,acting on the core targets,such as NLRP3 and CXCR2,and regulating the key signaling pathways,such as the TNF signaling pathway,the MAPK signaling pathway,the Toll-like signaling pathway,and the mTOR pathway.

Objective To investigate the effect of E2 signaling in myofibers on muscular macrophage efferocytosis in mice with cardiotoxin-induced acute skeletal muscle injury.Methods Female wild-type C57BL/6 mice with and without ovariectomy and male C57BL/6 mice were given a CTX injection into the anterior tibial muscle to induce acute muscle injury,followed by intramuscular injection of β-estradiol(E2)or 4-hydroxytamoxifen(4-OHT).The changes in serum E2 of the mice were detected using ELISA,and the number,phenotypes,and efferocytosis of the macrophages in the inflammatory exudates and myofiber regeneration and repair were evaluated using immunofluorescence staining and flow cytometry.C2C12 cells were induced to differentiate into mature myotubes,which were treated with IFN-γ for 24 before treatment with β-Estradiol or 4-OHT.The treated myotubes were co-cultured with mouse peritoneal macrophages in a 1:2 ratio,followed by addition of PKH67-labeled apoptotic mouse mononuclear spleen cells induced by UV irradiation,and macrophage efferocytosis was observed using immunofluorescence staining and flow cytometry.Results Compared with the control mice,the female mice with ovariectomy showed significantly increased mononuclear macrophages in the inflammatory exudates,with increased M1 cell percentage,reduced M2 cell percentage and macrophage efferocytosis in the injured muscle,and obviously delayed myofiber regeneration and repair.In the cell co-culture systems,treatment of the myotubes with β-estradiol significantly increased the number and proportion of M2 macrophages and macrophage efferocytosis,while 4-OHT treatment resulted in the opposite changes.Conclusion In injured mouse skeletal muscles,myofiber E2 signaling promotes M1 to M2 transition to increase macrophage efferocytosis,thereby relieving inflammation and promoting muscle regeneration and repair.

italic>Lamiophlomis rotata is an important medicinal plant species endemic to the Tibetan Plateau, which is prone to strong climate change impacts on its habitable range due to the high sensitivity of the Tibetan Plateau to climate change. Accurate quantification of species vulnerability to climate change is essential for assessing species extinction risk and developing effective conservation strategies. Therefore, we carried out the α-shape analysis to determine the habitat of L. rotata. We then carried out the climate-niche factor analysis (CNFA) to assess the vulnerability of L. rotata to climate change based on five climate variables (i.e., mean diurnal range, temperature seasonality, mean temperature of warmest quarter, precipitation of driest month and precipitation of warmest quarter) in the context of two shared socioeconomic pathways (i.e., SSP126 and SSP585) and three global climate models (CMCC-ESM2: Centro Euro-Mediterraneo sui Cambiamenti Climatici-Earth System Model version 2; HadGEM3-GC31-LL: Hadley Global Environment Model version 3-Global Coupled configuration 3.1; IPSL-CM6A-LR: Institut Pierre Simon Laplace-Climate Model version 6) during two different periods (2041-2060 and 2081-2100). The vulnerability of L. rotata to climate change was calculated by integrating the sensitivity and exposure indices of L. rotata to five climate variables. The results showed that L. rotata had the highest vulnerability to the precipitation of warmest quarter. Its vulnerability within its habitat range generally showed a spatial pattern of high value in the southern region and low in the northern region, high in the western region and low in the eastern region. In general, the vulnerability of L. rotata under the SSP585 scenario was higher than that under the SSP126 scenario. The climate data of different global climate models have some influence on the results, while the resulted uncertainty can be reduced by data integration methods. As a result of climate change, the pressure on the survival of L. rotata in the future will be intensified in the low-altitude areas such as the Yarlung Zangbo River, Yigongzangbu River, Zayu River, and Jiaomuzu River, etc., while the highly weathered scree flats or stony alpine meadows in the high-altitude zones, such as the eastern Tanggula Mountain Range, the northern part of Hengduan Mountain Range, and the western part of the Qinling Mountains, may become its refuge. It is necessary to focus on and strengthen the protection and management of L. rotata resources in these vulnerble and critical areas.

Inhibiting the death receptor 3(DR3)signaling pathway in group 3 innate lymphoid cells(ILC3s)pre-sents a promising approach for promoting mucosal repair in individuals with ulcerative colitis(UC).Paeoniflorin,a prominent component of Paeonia lactiflora Pall.,has demonstrated the ability to restore barrier function in UC mice,but the precise mechanism remains unclear.In this study,we aimed to delve into whether paeoniflorin may promote intestinal mucosal repair in chronic colitis by inhibiting DR3 signaling in ILC3s.C57BL/6 mice were subjected to random allocation into 7 distinct groups,namely the control group,the 2％dextran sodium sulfate(DSS)group,the paeoniflorin groups(25,50,and 100 mg/kg),the anti-tumor necrosis factor-like ligand 1A(anti-TL1A)antibody group,and the IgG group.We detected the expression of DR3 signaling pathway proteins and the proportion of ILC3s in the mouse colon using Western blot and flow cytometry,respectively.Meanwhile,DR3-overexpressing MNK-3 cells and 2％ DSS-induced Rag1-/-mice were used for verification.The results showed that paeoniflorin alleviated DSS-induced chronic colitis and repaired the intestinal mucosal barrier.Simultaneously,paeoniflorin inhibited the DR3 signaling pathway in ILC3s and regulated the content of cytokines(interleukin-17A,granulocyte-macrophage colony stimulating factor,and interleukin-22).Alternatively,paeoniflorin directly inhibited the DR3 signaling pathway in ILC3s to repair mucosal damage indepen-dently of the adaptive immune system.We additionally confirmed that paeoniflorin-conditioned me-dium(CM)restored the expression of tight junctions in Caco-2 cells via coculture.In conclusion,paeoniflorin ameliorates chronic colitis by enhancing the intestinal barrier in an ILC3-dependent manner,and its mechanism is associated with the inhibition of the DR3 signaling pathway.

Purpose/Significance To quantitatively analyze and evaluate 26 health informatization construction policies issued at the national level,so as to provide basis for improving related policies.Method/Process Based on the policy modeling consistency(PMC)index model,a health informatization construction policy evaluation index system is constructed,which includes 9 first-level indicators and 36 second-level indicators.Appling it to the evaluation of various policy texts,and the health informatization construction policies are analyzed in a holistic and concrete way.Result/Conclusion The overall score of the health informatization construction policies is ex-cellent.2 policies are at the perfect level,80.6％of policies are at the excellent level,and there are no bad level policy texts.However,the driving force of the policy and the balance of policy recipients need to be further improved.

Objective:To discuss the effect of the force feedback perceptual rehabilitation training on finger motor function of the patients with finger motor dysfunction after stroke,and to provide the basis for the clinical application and promotion of the force feedback perceptual rehabilitation training.Methods:A total of 86 patients with hand dysfunction after stroke were randomly divided into experimental group(n=43)and control group(n=43),and 3 cases in each group fell off from the experiment,and 80 cases were ultimately completed.On this basis,the patients in two groups received the conventional rehabilitation training for 40 min.The patients in control group received the conventional hand function training for 20 min,while the patients in experimental group received the force feedback perception rehabilitation training for 20 min,once per day,5 days per week,for a total of 6 weeks.The hand function recovery of the patients were evaluated before and after treatment by Action Research Arm Test(ARAT),grip strength,modified Ashworth scale(MAS),total active motion(TAM),Fugl-Meyer motor function assessment-upper limb(FMA-UL)finger motor part score,and Barthel index(BI).Results:Before treatment,there were no statistically significant differences in ARAT total score,grip strength,MAS grade,TAM,FMA-UL finger motor part score,and BI score of the patients between two groups(P＞0.05).After treated for 6 weeks,the ARAT scores,grip strengths,TAM,FMA-UL finger motor part scores,and BI scores of the patients in two groups were all increased than those before treatment(P＜0.05),while the MAS grades of the patients had no significant differences(P＞0.05).After treated for 6 weeks,compared with control group,the grasp score and grip score in ARAT score,and the difference of total ARAT score of the patients in experimental group were increased(P＜0.05),the TAM after treatment and the differences of grip strength,TAM,and FMA-UL finger motor part score of the patients before and after treatment were increased(P＜0.05),while the pinch scores and gross movement scores in ARAT score,MAS grades,and the differences of BI score before and after treatment had no significant differences(P＞0.05).Conclusion:Force feedback perceptual rehabilitation training is helpful in improving the finger motor function of the patients with finger motor dysfunction after stroke.