Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

AIM: To investigate the correlation between fundus blood flow parameters and carotid artery ultrasound blood flow parameters in patients with hypertensive retinopathy(HRP).METHODS: A total of 50 patients(22 left eyes and 28 right eyes)with HRP admitted to our hospital from June 2021 to June 2023 were retrospectively included as the experimental group, and 50 healthy physical examination subjects(22 left eyes and 28 right eyes)during the same period were included as the healthy group. Pearson correlation was used to analyze the correlation between fundus blood flow parameters and carotid artery ultrasound blood flow parameters.RESULTS: The AUC values of fundus blood flow parameters and carotid artery ultrasound blood flow parameters and their combined diagnosis of HRP were 0.853, 0.844 and 0.935, respectively. Pearson correlation analysis showed that carotid systolic peak blood flow velocity was negatively correlated with foveal avascular zone(FAZ)area, FAZ circumference and non-circularity index, and positively correlated with macular vascular density(all P<0.05). The end-diastolic blood flow velocity was positively correlated with FAZ area and macular vascular density(all P<0.05). The internal carotid artery resistance index was positively correlated with FAZ area(P<0.05).CONCLUSION: The combination of fundus blood flow parameters and carotid artery ultrasound blood flow parameters in the diagnosis of HRP has good application value in the diagnosis of HRP.

BACKGROUND:Studies have shown that metformin has anti-inflammatory,anti-tumor,anti-aging and vasoprotective effects,and can inhibit the progression of osteoarthritis,but its specific mechanism of action remains unclear. OBJECTIVE:To investigate the mechanism of metformin on cartilage protection in a rat model of osteoarthritis. METHODS:Forty male Sprague-Dawley rats were randomly divided into four groups(n=10 per group):blank,control,sham-operated,and metformin groups.The blank group did not undergo any surgery.In the sham-operated group,the joint cavity was exposed.In the model group and the metformin group,the modified Hulth method was used to establish the osteoarthritis model.At 1 day after modeling,the rats in the metformin group were given 200 mg/kg/d metformin by gavage,and the model,blank,and sham-operated groups were given normal saline by gavage.Administration in each group was given for 4 weeks consecutively.Hematoxylin-eosin staining,toluidine blue staining,and safranin O-fast green staining were used to observe the morphological structure of rat knee joints.Immunohistochemical staining and western blot were used to detect the protein expression of SOX9,type Ⅱ collagen,a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5),Beclin1,P62,phosphatidylinositol 3-kinase(PI3K),p-PI3K,protein kinase B(AKT),p-AKT,mammalian target of rapamycin(Mtor),and p-Mtor in rat cartilage tissue. RESULTS AND CONCLUSION:The results of hematoxylin-eosin,toluidine blue and safranin O-fast green staining showed smooth cartilage surface of the knee joints and normal histomorphology in the blank group and the sham-operated group,while in the model group,there was irregular cartilage surface of the knee joint and cartilage damage,with a decrease in the number of chondrocytes and the content of proteoglycans in the cartilage matrix.In the metformin group,there was a significant improvement in the damage to the structure of the cartilage in the knee joints of the rats,and the cartilage surface tended to be smooth,with an increase in the number of chondrocytes and the content of proteoglycans in the cartilage matrix.Immunohistochemistry staining and western blot results showed that compared with the control and sham-operated groups,the expression of SOX9,type Ⅱ collagen,and Beclin1 proteins in the cartilage tissue of rats in the model group was significantly decreased(P<0.05).Conversely,the expression of ADAMTS5,P62,as well as p-PI3K,p-AKT,and p-Mtor proteins was significantly increased(P<0.05).Furthermore,compared with the model group,the expression of SOX9,type Ⅱ collagen,and Beclin1 proteins in the cartilage tissue of rats in the metformin group was significantly increased(P<0.05),while the expression of ADAMTS5,P62,as well as p-PI3K,p-AKT,and p-Mtor proteins was significantly decreased(P<0.05).To conclude,Metformin can improve the autophagy activity of chondrocytes and reduce the degradation of cartilage matrix in osteoarthritis rats by inhibiting the activation of PI3K/AKT/Mtor signaling pathway,thus exerting a protective effect on articular cartilage.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

BACKGROUND: Generalized pustular psoriasis (GPP), a rare and recurrent autoinflammatory disease, imposes a substantial burden on patients and society. Awareness of GPP in China remains limited. METHODS: This cross-sectional survey, conducted between September 2021 and May 2023 across 14 hospitals in China, included GPP patients of all ages and disease phases. Data collected encompassed demographics, clinical characteristics, economic impact, disease severity, quality of life, and treatment-related complications. Risk factors for GPP recurrence were analyzed. RESULTS: Among 127 patients (female/male ratio = 1.35:1), the mean age of disease onset was 25 years (1st quartile [Q1]-3rd quartile [Q3]: 11-44 years); 29.2% had experienced GPP for more than 10 years. Recurrence occurred in 75.6% of patients, and nearly half reported no identifiable triggers. Younger age at disease onset ( P  = 0.021) and transitioning to plaque psoriasis ( P  = 0.022) were associated with higher recurrence rates. The median diagnostic delay was 8 months (Q1-Q3: 2-41 months), and 32.3% of patients reported misdiagnoses. Comorbidities were present in 53.5% of patients, whereas 51.1% experienced systemic complications during treatment. Depression and anxiety affected 84.5% and 95.6% of patients, respectively. During GPP flares, the median Dermatology Life Quality Index score was 19.0 (Q1-Q3: 13.0-23.5). This score showed significant differences between patients with and without systemic symptoms; it demonstrated correlations with both depression and anxiety scores. Treatment costs caused financial hardship in 55.9% of patients, underscoring the burden associated with GPP. CONCLUSIONS The substantial disease and economic burdens among Chinese GPP patients warrant increased attention. Patients with early onset disease and those transitioning to plaque psoriasis require targeted interventions to mitigate the high recurrence risk.
Humans ; Male ; Female ; Psoriasis/pathology* ; Adult ; Cross-Sectional Studies ; Adolescent ; Child ; Young Adult ; Quality of Life ; Middle Aged ; China/epidemiology* ; Recurrence ; Risk Factors ; Surveys and Questionnaires ; East Asian People

BACKGROUND: Alpha-glucosidase inhibitors or dipeptidyl peptidase-4 inhibitors are both hypoglycemia agents that specifically impact on postprandial hyperglycemia. We compared the effects of acarbose and sitagliptin add on to metformin on time in range (TIR) and glycemic variability (GV) in Chinese patients with type 2 diabetes mellitus through continuous glucose monitoring (CGM). METHODS: This study was a randomized, open-label, active-con-trolled, parallel-group trial conducted at 15 centers in China from January 2020 to August 2022. We recruited patients with type 2 diabetes aged 18-65 years with body mass index (BMI) within 19-40 kg/m 2 and hemoglobin A1c (HbA1c) between 6.5% and 9.0%. Eligible patients were randomized to receive either metformin combined with acarbose 100 mg three times daily or metformin combined with sitagliptin 100 mg once daily for 28 days. After the first 14-day treatment period, patients wore CGM and entered another 14-day treatment period. The primary outcome was the level of TIR after treatment between groups. We also performed time series decomposition, dimensionality reduction, and clustering using the CGM data. RESULTS: A total of 701 participants received either acarbose or sitagliptin treatment in combination with metformin. There was no statistically significant difference in TIR between the two groups. Time below range (TBR) and coefficient of variation (CV) levels in acarbose users were significantly lower than those in sitagliptin users. Median (25th percentile, 75th percentile) of TBR below target level <3.9 mmol/L (TBR 3.9 ): Acarbose: 0.45% (0, 2.13%) vs . Sitagliptin: 0.78% (0, 3.12%), P = 0.042; Median (25th percentile, 75th percentile) of TBR below target level <3.0 mmol/L (TBR 3.0 ): Acarbose: 0 (0, 0.22%) vs . Sitagliptin: 0 (0, 0.63%), P = 0.033; CV: Acarbose: 22.44 ± 5.08% vs . Sitagliptin: 23.96 ± 5.19%, P <0.001. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV (group with small wave, moderate wave and big wave). No significant difference was found in the complexity of glucose time series index (CGI) between acarbose users and sitagliptin users. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV. CONCLUSIONS: Acarbose had slight advantages over sitagliptin in improving GV and reducing the risk of hypoglycemia. Time series analysis of CGM data may predict GV and the risk of hypoglycemia. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR2000039424.
Humans ; Metformin/therapeutic use* ; Sitagliptin Phosphate/therapeutic use* ; Acarbose/therapeutic use* ; Diabetes Mellitus, Type 2/blood* ; Middle Aged ; Male ; Female ; Adult ; Blood Glucose/drug effects* ; Hypoglycemic Agents/therapeutic use* ; Aged ; Glycated Hemoglobin/metabolism* ; Adolescent ; Young Adult ; China ; East Asian People

Objective To investigate the expression profile of cell adhesion molecular 3(CADM3)on pulmonary endothelial cells,analyze its role in mediating specific adhesion to monocyte,and explore a new mechanism of hypoxia inducing peripheral monocyte infiltration in pulmonary vessels.Methods Human umbilical vein endothelial cells(HUVEC),rat pulmonary vascular endothelial cells(rPEC),and rat aortic endothelial cells(rAEC)were subjected,and divided into normoxic(21%O2)control group and hypoxic(1%O2 or 5%O2)treatment group.Analyzing the transcriptome data of HUVEC exposure to hypoxia for 8 h screened a differentially expressed molecule,CADM3.Cell adhesion experiments,siRNA interference,immunohistochemical assay,Western blotting,and flow cytometry were used to study the role of CADM3 in hypoxia specific high adhesion of HUVEC monocytes.Iron chelator deferoxamine(DFX)and shRNA interference were employed to enhance the expression of HIF-1α,and the effect of HIF-1 transcriptional activity on CADM3 expression was analyzed.Results Hypoxic treatment resulted in enhanced expression of CADM3 in HUVEC,and the expression level reached the peak at 6-8 h after hypoxia,and then decreased.Transfection with siRNA targeting CADM3 decreased the expression of CADM3,and significantly reduced the adhesion rate of hypoxic HUVEC-U937 cells when compared with the negative control group(P<0.05).Compared with the solvent control group,the protein levels of HIF-1α and its target protein STC2 in HUVEC treated with DFX(100 μmol/L)were increased.Transfection with shRNA targeting HIF-1α led the protein levels of HIF-1α and its target protein STC2 decreased,but had no effect on the protein expression of CADM3 in comparison to the negative control group.The protein level and distribution of CADM3 on the cell membrane were increased in hypoxic rPEC.No expression of CADM3 protein was found in the rAEC when compared with rPEC.After treatment with 5 μg/mL LPS,there were no significant changes in HIF-1α,STC2 and CADM3 in rPEC cultured under normoxia or hypoxia.The adhesion rate between hypoxia rPEC with CD11b+cells was the highest,with statistical significance(P<0.01).After incubation with anti-CADM3 antibody,the adhesion of hypoxic rPEC-U937 was significantly decreased compared with the solvent control group(P<0.05).Conclusion Hypoxia specifically induces the expression of CADM3 in pulmonary vascular endothelial cells in a HIF-1-independent manner,and promotes the specific adhesion of pulmonary vascular endothelial cells and monocytes induced by hypoxia.

Objective To investigate the expression of serum microRNA(miR)-494 and miR-155 in chil-dren with Enterovirus type 71 hand-foot-mouth disease(EV71-HFMD),and to analyze the clinical significance of serum miR-494 and miR-155 in EV71-HFMD.Methods A total of 145 children with EV71-HFMD treated in this hospital from May 2021 to May 2023 were selected.According to the severity of the disease,they were divided into mild group(n=81)and severe group(n=64).In addition,73 healthy and disease-free children in the hospital were included in the health group.Serum expression levels of miR-494 and miR-155 as well as helper T cell 17(Th17),regulatory T cell(Treg)and Th17/Treg in the three groups were detected and com-pared.Pearson correlation analysis was used to analyze the correlation between the expression levels of serum miR-494,miR-155,Th17 and Treg,as well as Th17/Treg.The clinical data of children with EV71-HFMD were collected,and the factors influencing the severity of EV71-HFMD were analyzed by multivariate Logistic regression model.Results Compared with healthy group,serum miR-494,miR-155,Th17 and Th17/Treg in mild and severe groups were increased,and Treg were decreased(P＜0.05).Compared with mild group,ser-um miR-494,miR-155,Th17 and Th17/Treg in severe group were increased,and Treg was decreased(P＜0.05).Pearson correlation analysis showed that Th17 and Th17/Treg were positively correlated with the ex-pression levels of serum miR-494 and miR-155,while Treg was negatively correlated with the expression lev-els of serum miR-494 and miR-155(P＜0.05).The peak temperature,duration of fever ≥3 d proportion and eruption of isthmus in severe group were higher than those in mild group(P＜0.05).Multivariate Logistic re-gression results showed that the duration of fever ≥3 d,eruption in the isthmus,the high expression level of miR-494 and the high expression level of miR-155 were risk factors for severe EV71-HFMD(P＜0.05).Conclusion Se-rum miR-494 and miR-155 are abnormally elevated in children with EV71-HFMD,and the changes in their levels are closely related to Th17/Treg imbalance.Increased expression levels of serum miR-494 and miR-155 are risk factors for severe EV71-HFMD.

Objective:To systematically elucidate the molecular mechanism of hesperetin in the treatment of heart failure by network pharmacology, molecular docking, and molecular dynamics, and to clarify its key targets and pathway regulatory networks.Methods:Potential targets of hesperetin were retrieved from the PubChem, Pharmmapper, SwissTargetPrediction, and Similarity ensemble approach databases. Heart failure-related targets were obtained from the OMIM, GeneCards, and TTD databases. Intersection targets were identified using Venny 2.1. A protein-protein interaction (PPI) network of potential targets was constructed using the STRING database and Cytoscape 3.9.0 software. Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses of key targets were performed using the Metascape database. Molecular docking was carried out using Autodock vina1.1.2. GROMACS (2024.03) was employed to conduct a 100 ns molecular dynamics simulation on the optimal affinity complex. The thermodynamic stability of the candidate complex during simulation was evaluated by analyzing the root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and binding free energy. Data were analyzed by an independent sample t test or one-way analysis of variance. Results:A total of 356 related targets of hesperetin and 2 923 related targets of heart failure were screened, with 152 intersection targets identified as potential targets for hesperetin intervention in heart failure. PPI network topological analysis revealed key targets for hesperetin intervention in heart failure, including insulin-like growth factor 1, estrogen receptor 1 (ER1), cysteine aspartic acid specific protease-3, sarcoma proto-oncogene, matrix metalloproteinase 9 (MMP9), MMP2, Janus kinase 2 (JAK2), albumin, heat shock protein 90 alpha family class A member 1, epidermal growth factor receptor, and B-cell lymphoma-2 (Bcl-2). GO functional enrichment analysis indicated that biological processes were mainly enriched in response to hormone stimulation, positive regulation of cell migration, gland development, response to nutritional levels, regulation of system processes, and response to trauma. Molecular functions were primarily enriched in phosphotransferase activity, nuclear receptor activity, endopeptidase activity, kinase binding, heme binding, hormone binding and protease binding. Cellular components were mainly enriched in membrane-related structures such as vesicle cavity, membrane raft, vacuole cavity, receptor complex and extracellular matrix containing collagen. KEGG pathway enrichment analysis showed that these key targets were significantly enriched in lipid and atherosclerosis, diabetic cardiomyopathy, and the hypoxia-inducible factor-1 signaling pathway. Molecular docking results indicated that the binding energy of hesperetin to MMP9 (?46.442 kJ/mol) was significantly lower than that to other key targets. Molecular dynamics simulations revealed that the hesperetin-MMP9 complex maintained structural stability, with an average RMSD of 1.60 ?. The average RMSF values of MMP9 residues (0.83 ?) and ligand atoms (0.68 ?) indicated stable protein conformation and ligand-binding states. The Rg values of MMP9 [(15.04±0.60) ?] and hesperetin [(4.19±0.35) ?] showed minimal fluctuations, further supporting structural compactness. The total binding free energy of the hesperetin-MMP9 complex during the 100 ns simulation was (?142.3±6.3) kJ/mol, with minimal energy fluctuations, confirming that the complex remained structurally stable without significant energy transition throughout the simulation.Conclusions:Hesperetin may bind effectively to targets such as MMP9, JAK2, Bcl-2, and ER1, and form a stable complex with MMP9. It is suggested to influence biological processes related to lipids and signaling pathways such as atherosclerosis, diabetic cardiomyopathy, and hypoxia-inducible factor-1, thereby playing a role in heart failure intervention.