Objective: To investigate the role and mechanism of the heat-clearing and detoxifying drug Laggerae Herba in regulating the nuclear factor-erythroid 2-related factor-2(Nrf2)/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway to inhibit ferroptosis and improve chronic heart failure induced by transverse aortic arch constriction in mice. Methods: Twenty-four male ICR mice were divided into the sham (n=6) and transverse aortic arch constriction groups (n=18) according to the random number table method. The transverse aortic arch constriction group underwent transverse aortic constriction surgery to establish models. After modeling, the transverse aortic arch constriction group was further divided into the model, captopril, and Laggerae Herba groups according to the random number table method, with six mice per group. The captopril (15 mg/kg) and Laggerae Herba groups (1.95 g/kg) received the corresponding drugs by gavage, whereas the sham operation and model groups were administered the same volume of ultrapure water by gavage once a day for four consecutive weeks. After treatment, the cardiac function indexes of mice in each group were detected using ultrasound. The heart mass and tibia length were measured to calculate the ratio of heart weight to tibia length. Hematoxylin and eosin staining were used to observe the pathological changes in myocardial tissue. Masson staining was used to observe the degree of myocardial fibrosis. Wheat germ agglutinin staining was used to observe the degree of myocardial cell hypertrophy. Prussian blue staining was used to observe the iron deposition in myocardial tissue. An enzyme-linked immunosorbent assay was used to detect the amino-terminal pro-brain natriuretic peptide (NT-proBNP) and glutathione (GSH) contents in mice serum. Colorimetry was used to detect the malondialdehyde (MDA) content in mice serum. Western blotting was used to detect the Nrf2, GPX4, SLC7A11, and ferritin heavy chain 1 (FTH1) protein expressions in mice cardiac tissue. Results: Compared with the sham group, in the model group, the ejection fraction (EF) and fractional shortening (FS) of mice decreased, the left ventricular end-systolic volume (LVESV) and left ventricular end-systolic diameter (LVESD) increased, the left ventricular anterior wall end-systolic thickness (LVAWs) and left ventricular posterior wall end-systolic thickness (LVPWs) decreased, the ratio of heart weight to tibia length increased, the myocardial tissue morphology changed, myocardial fibrosis increased, the cross-sectional area of myocardial cells increased, iron deposition appeared in myocardial tissue, the serum NT-proBNP and MDA levels increased, the GSH level decreased, and Nrf2, GPX4, SLC7A11, and FTH1 protein expressions in cardiac tissue decreased (P<0.05). Compared with the model group, in the captopril and Laggerae Herba groups, the EF, FS, and LVAWs increased, the LVESV and LVESD decreased, the ratio of heart weight to tibia length decreased, the myocardial cells were arranged neatly, the degree of myocardial fibrosis decreased, the cross-sectional area of myocardial cells decreased, the serum NT-proBNP level decreased, and the GSH level increased. Compared with the model group, the LVPWs increased, the iron deposition in myocardial tissue decreased, the serum MDA level decreased, and Nrf2, GPX4, SLC7A11, and FTH1 protein expressions in cardiac tissue increased (P<0.05) in the Laggerae Herba group. Conclusion Laggerae Herba improves the cardiac function of mice with chronic heart failure caused by transverse aortic arch constriction, reduces the pathological remodeling of the heart, and reduces fibrosis. Its mechanism may be related to Nrf2/SLC7A11/GPX4 pathway-mediated ferroptosis.

Objective: This study aimed to construct an animal model of heart failure with preserved ejection fraction (HFpEF) that integrates disease and syndrome based on the "deficiency-blood stasis-toxin" pathogenesis and to evaluate it comprehensively. Methods: The HFpEF mouse model was constructed using a combination of Nω-nitro-L-arginine methyl ester (L-NAME) and a high-fat diet. According to the random number table method, SPF-grade male C57BL/6J mice were randomly assigned to the control, L-NAME, high-fat diet, and model groups, 10 in each group. Comprehensive observations and data collection on macroscopic signs (e.g., fur condition, mental state, stool and urine, oral and nasal condition, paw and body condition, etc.) and cardiac function were performed after 10 and 16 weeks of model induction. Additionally, the syndrome evolution was elucidated based on diagnostic criteria for clinical syndromes of heart failure. Furthermore, pathological and molecular biological examinations of myocardial tissue were performed to assess the stability and reliability of the model. Results: Mice in the model group showed typical characteristics of syndrome of qi deficiency and blood stasis, as well as syndrome of internal heat accumulation, including lethargy, slow response, dull paw color and oral/nasal color, exercise intolerance, abnormal platelet activation, dry feces, and dark yellow urine. The time window for these syndromes was between 10 and 16 weeks post-modeling. Cardiac function assessments revealed severe diastolic dysfunction, concentric myocardial hypertrophy, and myocardial fibrosis in the model group. Pathological examinations showed a significantly increased collagen deposition in the myocardial interstitium, enlarged cross-sectional area of cardiomyocytes, and sparse coronary microvasculature in the model group. Molecular biological analyses indicated marked activation of the inducible nitric oxide synthase/nuclear factor kappa-light-chain-enhancer of activated B cells/NOD-like receptor family pyrin domain containing 3 inflammatory pathway and significantly elevated inflammation levels in the myocardial tissue of the model group. Although mice in the L-NAME and high-fat diet groups also showed certain manifestations of qi deficiency syndrome, the substantial cardiac damage was relatively limited compared to the control group. Conclusion This study has constructed an animal model of HFpEF that integrates disease and syndrome based on the "deficiency-blood stasis-toxin" pathogenesis. The macroscopic and microscopic characteristics of this model are consistent with the manifestations of syndrome of qi deficiency and blood stasis, toxin syndrome, and syndrome of internal heat accumulation. Moreover, it can stably simulate the HFpEF state and reflect phenotypic changes in human disease. This model provides a suitable experimental platform to explore the pathogenesis of HFpEF, evaluate the effectiveness of traditional Chinese medicine (TCM) treatment regimens, and promote in-depth research on TCM syndromes of heart failure.

Aim To explore the mechanism of Guso-ngYigu decoction(GSYG)in the treatment of postm-enopausal osteoporosis(PMOP)based on the gut mi-crobiota.Methods Sixty SPF grade SD rats were ran-domly divided into Control group(Control),Model group(Model),GSYG low-dose group(GSYG-L,1.25 g·kg-1),medium-dose group(GSYG-M,2.5 g·kg-1)and high-dose group(GSYG-H,5 g·kg-1)and alendronate group(Al,0.89 mg·kg-1),with 10 rats in each group.The changes of bone histomorpholo-gy were detected by HE staining and the changes of fe-mur tissue structure were observed by micro-CT.The fecal samples from the colon of Control group,Model group,GSYG-H group were taken to extract the DNA of fecal samples.The Illumina Miseq platform was used to carry out high-throughput sequencing.Results Compared with the Control group,bone trabecula in the Model group was sparse,BV/TV,Tb.Th,Tb.N and BMD decreased(P＜0.01),while SMI and Tb.Sp increased(P＜0.01);compared with the Model group,the number of bone trabeculae in GSYG-L,GSYG-M,GSYG-H group and Al group increased,the bone microstructure was improved,BV/TV,Tb.Th,Tb.N and BMD increased significantly(P＜0.05),and SMI and Tb.Sp increased(P＜0.05).Sequencing results of gut microbiota showed that,compared with the Control group,the gut microbiota diversity of Mod-el group decreased,the flora abundance of Firmicutes decreased,while the Bacteroidetes abundance in-creased.Compared with the Model group,the Firmi-cutes abundance increased and Bacteroidetes abundance decreased in GSYG-H group.Conclusions GSYG can improve bone microstructure and increase bone mineral density,and its mechanism may be related to increasing the diversity of gut microbiota and regulating the structure of gut microbiota.

Objective:To explore the effect of virtual reality (VR) technology in postoperative pain management for surgical patients.Methods:The literature on VR technology for relieving postoperative pain in surgical patients was electronically retrieved from eight databases, including PubMed, Web of Science and so on. The search period was from database establishment to November 19, 2023. Two researchers independently screened literature, extracted data, and conducted literature quality evaluation, using RevMan 5.4 for Meta-analysis.Results:A total of 18 articles were included. Meta-analysis results showed that VR technology could reduce postoperative resting pain scores [ MD=-1.13, 95% CI (-1.29, -0.96), P<0.001], postoperative 12 hour pain scores [ MD=-0.49, 95% CI (-0.73, -0.24), P<0.001], postoperative 24 hour pain scores [ MD=-0.73, 95% CI (-0.92, -0.54), P<0.001], postoperative 48 hour pain scores [ MD=-0.69, 95% CI (-0.84, -0.53), P<0.001], postoperative 72 hour pain scores [ MD=-0.37, 95% CI (-0.59, -0.16), P<0.001], and postoperative pain scores during dressing changes [ MD=-1.11, 95% CI (-2.06, -0.16), P=0.02], and could improve patient postoperative comfort [ MD=8.31, 95% CI (6.57, 10.06), P<0.001] . Conclusions:As a non-pharmacological intervention, VR technology can alleviate postoperative pain and improve patient comfort in surgical patients. In the future, large-scale and high-quality research is still needed to further verify the effectiveness of VR technology.

Objective:To explore the current situation and influencing factors of amputation decision-making dilemma of diabetic foot patients.Methods:From July to December 2023, 200 patients with diabetic foot in the Tianjin Medical University General Hospital and Tianjin Medical University Chu Hsien-I Memorial Hospital were selected as study subjects by convenience sampling. General Information Questionnaire, Decisional Conflict Scale (DCS), Family APGAR Index, and Hospital Anxiety and Depression Scale were used to conduct a cross-sectional survey. Pearson correlation was used to analyze the correlation between diabetic foot patients' amputation decision-making dilemma and family caring, anxiety and depression, and multiple linear regression was used to analyze the influencing factors of diabetic foot patients' amputation decision-making dilemma.Results:A total of 200 questionnaires were distributed, and 180 valid questionnaires were collected, with a valid response rate of 90.0% (180/200). The DCS score of 180 patients with diabetic foot was (30.04±9.77), 76.7% (138/180) patients scored ≥25.0, and they had decision-making dilemma, and 25.0% (45/180) of patients scored ≥37.5, indicating decision-making delay. Multiple linear regression analysis showed that occupational status, diabetes course, family caring, anxiety and depression were the influencing factors of amputation decision-making dilemma of diabetic foot patients ( P<0.05) . Conclusions:Diabetic foot patients face certain dilemmas in the process of amputation decision-making. Clinical medical and nursing staff should reasonably evaluate the patient's occupational status, disease course, family caring, and psychological state, and develop personalized decision support strategies to improve decision quality and prevent changes in the patient's condition caused by delayed decision-making.

Objective:To explore the value of REG3α,sST2 and TNFR1 in peripheral blood for risk stratification and prognostic evaluation of acute graft-versus-host disease(aGVHD)after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in children.Methods:From January 2020 to March 2022,70 children with aGVHD after allo-HSCT in the First Affiliated Hospital of Zhengzhou University were selected as the research objects,of which 50 cases were mild aGVHD(grade Ⅰ-Ⅱ)and 20 cases were severe aGVHD(grade Ⅲ-Ⅳ).30 healthy children who underwent physical examinations in our hospital during the same period were selected as the control group.Luminex platform was used to detect the protein expression levels of REG3α,sST2 and TNFR1 during aGVHD occurrence,and the differences between the three groups were analyzed by one-way ANOVA.According to the outcome of aGVHD treatment within 28 days,the patients were divided into a good prognosis group of 58 cases and a poor prognosis group of 12 cases.The ROC curve was used to analyze the value of REG3α,sST2 and TNFR1 in predicting the prognosis of children with aGVHD.Results:The peripheral blood levels of REG3α,sST2 and TNFR1 in the mild aGVHD and severe aGVHD groups were significantly higher than those in the control group(P＜0.05),and those in the severe aGVHD group were significantly higher than those in the mild aGVHD group(P＜0.05).Compared with the good prognosis group,the peripheral blood levels of REG3α,sST2 and TNFR1 in the poor prognosis group were significantly higher(t=9.27,3.33,2.97;P＜0.01).ROC curve analysis showed that the area under the curve(AUC),sensitivity and specificity of the combined detection of REG3α,sST2 and TNFR1 in predicting the prognosis of children with aGVHD were higher than those of the above indicators detected alone or in pairs.Conclusion:The expression levels of REG3α,sST2 and TNFR1 were related to the severity of aGVHD.The combination of REG3α,sST2 and TNFR1 has a high clinical value in predicting the prognosis of children with aGVHD,which is expected to provide a reliable reference for clinical evaluation of the prognosis of children with aGVHD.

The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer.Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis(YTE-17),attributing these effects to the regu-lation of multiple signaling pathways.However,knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited.In this study,we conducted isobaric tags for relative and absolute quantification(iTRAQ)analysis on intestinal epithelial cells(IECs)exposed YTE-17,both in vitro and in vivo,revealing a significant inhibition of the Wnt family member 5a(Wnt5a)/c-Jun N-terminal kinase(JNK)signaling pathway.Subsequently,we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment(TME),specifically focusing on macrophage-mediated T helper 17(Th17)cell induction in a colitis-associated cancer(CAC)model with Wnt5a deletion.Additionally,we performed the single-cell RNA sequencing(scRNA-seq)on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition,lineage,and functional status of immune mesenchymal cells during different stages of colorectal cancer(CRC)progression.Remarkably,our findings demon-strate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17,leading to the restoration of regulatory T(Treg)/Th17 cell balance in azoxymethane(AOM)/dextran sodium sulfate(DSS)model.Furthermore,we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages.Notably,our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical β-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the TME,involving macrophages and T cells.In summary,our study undergoes the po-tential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment,thereby mitigating the risk of malignancies.

Objective To investigate the early cognitive development characteristics of children with Williams syndrome(WS)at different age stages.Methods From September 2018 to June 2023,106 children diagnosed with WS at the Department of Pediatric Health Care,Children's Hospital,Zhejiang University School of Medicine,aged 1 to<5 years,were prospectively enrolled.All children underwent Gesell developmental diagnostic assessments to analyze the cognitive development characteristics of WS children across different age groups.Results The average age of the 106 WS children was(3.1±1.2)years;58 were male,and 48 were female.There were no significant differences in developmental levels between males and females in the five domains of gross motor skills,fine motor skills,language,personal-social skills,and adaptive behavior(P>0.05).The incidence rates of mild,moderate,severe,and profound developmental disabilities among children of different age groups showed no significant differences(P>0.05).Comparisons of developmental levels in gross motor skills,language,personal-social skills,and adaptive behavior among different age groups were also not statistically significant(P>0.05).With the increase of age,the developmental level of fine motor skills showed a decreasing trend(P<0.05).There were no significant differences in verbal IQ and non-verbal IQ within each age group of WS children(P>0.05).Conclusions The overall developmental level of WS children stabilizes with age,and their early language abilities do not significantly exceed their non-verbal abilities.

Objective To investigate the effects of Yishen Jiangu Pills on the expressions of AMPK/Cyclin Y/CDK16 pathway and autophagy and apoptosis-related proteins in cartilage tissue of rats with knee osteoarthritis(KOA);To discuss its mechanism for the treatment of KOA.Methods Totally 60 2-month-old SD rats were selected and randomly divided into sham-operation group,model group,agonist group,and TCM low-,medium-and high-dosage groups,with 10 rats in each group.Except for the sham-operation group,each group underwent medial meniscectomy and cruciate ligamentotomy to establish the KOA rat model,and the corresponding interventions were given for 14 d.Lequesne MG score was used to evaluate rat behavior,morphology of cartilage tissue was observed by HE and Safranin O-fixed green staining,and Mankin score was performed,Western blot was performed to detect expression of AMPK/Cyclin Y/CDK16 pathway proteins and autophagy proteins such as ULK-1,Beclin-1,LC3B,p62 and apoptotic proteins such as Bcl-2,Bax,Caspase-3,Caspase-9 in cartilage tissue,and autophagosome were observed using transmission electron microscopy.Results Compared with the sham-operation group,Lequesne MG score significantly increased in the model group(P<0.01),there was a significant defect in the surface layer of cartilage,thinning of the cartilage layer,disordered arrangement and irregular morphology of chondrocytes,and a significant increase in Mankin score(P<0.01),the expressions of AMPK,Cyclin Y,CDK16,ULK1,Beclin-1,LC3BⅡ/Ⅰ and Bcl-2 protein in cartilage tissue decreased,while the expressions of p62,Bax,Caspase-3 and Caspase-9 protein increased(P<0.01).Compared with the model group,the Lequesne MG scores of rats in the agonist group and TCM high-dosage group were significantly decreased(P<0.01),the TCM high-dosage group showed smoother cartilage surface,more regular arrangement of chondrocytes,basic integrity of cartilage layer structure,weakened cartilage tissue proliferation,and significantly decreased Mankin score(P<0.01),the expressions of AMPK,Cyclin Y,CDK16,ULK1,Beclin-1,LC3BⅡ/Ⅰ and Bcl-2 protein in cartilage tissue of rats in the agonist group and TCM medium-and high-dosage groups significantly increased(P<0.05,P<0.01),while the expressions of p62,Bax,Caspase-3 and Caspase-9 protein significantly decreased(P<0.05,P<0.01).Conclusion Yishen Jiangu Pills may promote chondrocyte autophagy and inhibit cell apoptosis by activating the AMPK/Cyclin Y/CDK16 pathway in cartilage tissue of KOA model rats,thus reduce cartilage damage.

OBJECTIVE To investigate the intervention effect and potential mechanism of breviscapine on hepatic fibrosis （HF） in rats based on the transforming growth factor-β（1 TGF-β1）/Smad2/extracellular signal-regulated protein kinase 1（ERK1） and Kelch-like epichlorohydrin-associated protein 1（Keap1）/nuclear factor-erythroid 2-related factor 2（Nrf2）/heme oxygenase-1（HO-1） pathways. METHODS Totally 60 rats were randomly divided into normal control group， model group， breviscapine low-dose， medium-dose and high-dose groups （5.4， 10.8， 21.6 mg/kg）， and colchicine group （positive control， 0.45 mg/kg）， with 10 rats in each group， half male and half female. Except for the normal control group， HF model of the other groups was induced by carbon tetrachloride. Subsequently， each drug group was given corresponding medicine by gavage once a day for 28 days. The liver appearance of rats in each group was observed and their liver coefficients were calculated. The levels of alanineaminotransferase （ALT） and aspartate aminotransferase （AST）in serum， those of ALT， AST， superoxide dismutase （SOD），malondialdehyde （MDA） and glutathione peroxidase （GSH- Px） in liver tissue were detected. The liver tissue inflammatory and fibrotic changes were observed. The protein and mRNA expressions of TGF-β1， Smad2， ERK1， Nrf2， Keap1 and HO-in liver tissue were detected. RESULTS Compared with the normal control group， the model group showed large areas of white nodular lesions in the liver， obvious inflammatory cell infiltration and collagen fiber deposition. The body weight， the levels of SOD and GSH-Px in liver tissue， the protein and mRNA expressions of Nrf2 and HO-1 were significantly lowered in the model group （P＜0.05）； the liver coefficient， the percentage of Masson staining positive area， ALT and AST levels of serum and liver tissue， MDA level of liver tissue， the protein and mRNA expressions of TGF-β1， Smad2， ERK1 and Keap1 were significantly increased （P＜0.05）. Compared with the model group， the liver lesions of rats in each drug group were improved， and the above quantitative indexes were generally reversed （P＜0.05）. CONCLUSIONS Breviscapine has a good intervention effect on HF rats， which may be related to inhibiting TGF-β1/Smad2/ERK1 pathway for anti-fibrosis and regulating Keap1/Nrf2/HO-1 pathway to inhibit oxidative stress.