Objective To investigate the effects of perampanel on the C-C chemokine receptor 5(CCR5)/cAMP-dependent protein kinase A(PKA)/cyclic-AMP response binding protein(CREB)pathway and hippocampal neuronal damage in epileptic rats.Methods Seventy-two male SPF-grade SD rats were randomly divided into epilepsy group,perampanel group,CCR5 inhibitor(maraviroc)group,recombinant CCL5 protein(rCCL5,CCR5 activator)group,perampanel+rCCL5 group,and a control group,with 12 rats in each group.The duration and frequency of epi-leptic seizures were detected in above groups.HE staining was used to observe the morphology of the hippocampal CA1 region.ELISA was employed to measure the contents of cyclooxygenase-2(COX-2),TNF-α,and IL-18 in the hippocampal CA1 region.Western blotting was conducted to measure the expression levels of CCR5,PKA,and p-CREB in the hippocampal CA1 region.Results Compared with the control group,the epilepsy group demonstrated badly-arranged and swollen neurons in the hippocampal CA1 region,longer duration of epilepsy,higher seizure frequency,increased COX-2,TNF-α and IL-18 contents in the CA1 region,elevated apoptotic rate and CCR5 protein level,and prolonged escape latency,while less number of crossing platforms and reduced protein levels of PKA and p-CREB(P＜0.05).While,both perampanel and maraviroc treatment could reverse above indicators when compared with the levels of the epilepsy group(P＜0.05).In the rCCL5 group,the neural injury was significantly aggravated,the duration of epilepsy and the frequency of epileptic seizures were increased,the contents of COX-2,TNF-α and IL-18 in the hip-pocampal CA1 region were enhanced,the rate of neuronal apoptosis and the expression of CCR5 protein were significantly enhanced,the escape latency was prolonged,and the number of crossed platforms,PKA,and the expression of p-CREb protein were declined(P＜0.05).When compared with the perampanel group,addition of rCCL5 resulted prolonged duration of epilepsy and escape latency,increased frequency of epileptic seizures and protein levels of COX-2,TNF-α,IL-18 and CCR5,more severe neuronal injury in the CA1 region,less platforms crossed,and decreased pro-tein expression of PKA and p-Creb(P＜0.05).The neural apoptotic rate in the hippocampal CA1 region was significantly higher in the perampanel+rCCL5 group than the perampanel group[(10.58±0.43)％vs(6.36±0.31)％,P＜0.05].Conclusion Perampanel may inhibit neuroin-flammation and neuronal apoptosis in epileptic rats by down-regulating CCR5 and then activating the PKA/CREB pathway,and thus attenuate hippocampal neuronal damage.

Objective To explore the risk factors of adverse pregnancy outcomes in the patients with cervical incompetence(CI),and to establish a risk warning model of adverse pregnancy outcomes in CI pa-tients based on decision tree model.Methods The clinical data of 159 patients with CI admitted and treated in this hospital from February 2022 to April 2023 were retrospectively analyzed,and the risk factors for adverse pregnancy outcomes were screened and the decision tree model for postoperative adverse pregnancy outcomes was constructed.The internal verification method was 5-fold cross-validation.Results The incidence rate of adverse pregnancy outcome was 22.64%.The pregnant weeks of cervical cerclage,amniotic cystocele,multiple cervical cerclage,preoperative cervical length and amniotic fluid sediment were all influential factors for ad-verse pregnancy outcome occurrence(P＜0.05).The amniotic fluid sediment was the most important factor affecting the postoperative adverse pregnancy outcome in CI patients,and the preoperative cervical length had little influence on the postoperative adverse pregnancy outcomes in CI patients.The area under the curve(AUC)value of logistic regression model was slightly higher than that of the decision tree model.The accura-cy rate of the 5-fold cross-validation model was 78.3%.Conclusion During clinical treatment,the above two models can be combined to find the influencing factors of postoperative adverse pregnancy outcomes in CI pa-tients from different aspects,and provide references for clinical medical staff to evaluate the disease condition of CI patients and formulate the intervention plans.

Objective:To explore the cardioprotective effects of icariin (ICA) against radiation-induced cardiac disease (RICD) in C57BL/6 mice.Methods:A total of 48 female C57BL/6J mice aged 6-8 weeks were randomly divided into three groups: the control group (CON), the irradiation group (IR), and the irradiation combined with icariin group (IR+ ICA), with 16 mice in each group. The IR and IR+ ICA groups received a single cardiac irradiation at a dose of 30 Gy, while the CON group received no radiation treatment. The IR+ ICA group was treated with ICA (70 mg·kg -1·d -1) two weeks before irradiation until the end of the experiment through intragastric administration. In contrast, the CON and IR groups were treated with an equal volume of vehicle solution (0.5% sodium carboxymethyl cellulose, NaCMC) via intragastric administration. The mice′s mental status, food intake, body weight, and survival rates were monitored during the experiment. At two weeks post-irradiation, the venous blood of the mice was collected and serum was separated for the enzyme-linked immunosorbent assays (ELISA) of creatine kinase MB isoenzyme (CK-MB) and cardiac troponin T (cTnT/TNNT2). At 12 weeks post-irradiation, the cardiac function of the mice was assessed using echocardiography. After the mice were euthanized under anesthesia, the histopathological changes and fibrosis degree of their myocardial tissues were assessed using hematoxylin and eosin (HE) and Masson′s trichrome staining, followed by the calculation of collagen volume fraction (CVF). The differential gene expression of brain natriuretic peptide (BNP), transforming growth factor-β (TGF-β), and interleukin-6 (IL-6) in the cardiac tissues of the mice was detected using real-time reverse transcription-polymerase chain reaction (RT-PCR). Apoptosis-related proteins and proteins associated with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway were determined using Western blotting. The survival curves of the mice were plotted using Kaplan-Meier, and the survival differences of the mice among various groups were compared using the log-rank test. Results:After irradiation, the mice in the IR group showed lethargy, as well as decreased food intake and activity, while these symptoms in the IR+ ICA group were significantly alleviated. At two weeks post-irradiation, the CK-MB and cTnT levels of the IR group were significantly elevated compared with the CON group ( t = 5.28, 8.89, P < 0.01). At 12 weeks post-irradiation, the mice in the IR group exhibited significantly decreased body weight ( t = 2.47, P < 0.05) and decreased survival rates ( HR = 8.25, 95% CI: 1.157-58.770, P < 0.05) compared with the CON group. Echocardiography revealed that the IR group featured decreased left ventricular ejection fraction (EF), decreased fractional shortening (FS), and increased left ventricular end-diastolic diameter (LVDD) compared with the CON group ( t = 7.02, 4.45, P < 0.05). Histopathological examination revealed that the IR group suffered from cardiomyocyte edema, disordered arrangement, and increased fibrosis, with an elevated CVF. The IR group exhibited significantly upregulated gene expression of BNP, TGF-β, and IL-6 in cardiac tissues compared with the CON group ( t = 4.23, 6.39, 4.61, P < 0.05). After-irradiation, the IR group exhibited upregulated apoptosis-related proteins Cleaved Caspase-3 and Bax ( t = 6.29, 9.54, P < 0.05), decreased Bcl-2 expression ( t = 8.20, P < 0.001), and decreased phosphorylation levels of PI3K and Akt ( t = 6.47, 3.42, P < 0.001). The symptoms of the mice were partially ameliorated after treatment with ICA. Specifically, the mice in the IR+ ICA group exhibited higher body weight ( t = 5.13, P < 0.001) and significantly higher survival rates ( HR = 0.121, 95% CI: 0.017-0.864, P < 0.05) than the IR group. Compared to the IR group, the IR+ ICA group showed elevated cardiac function indicators EF and FS( t = 3.23, 3.05, P < 0.05), and reduced LVDD ( t = 3.02, P < 0.05). The histopathological analysis revealed mitigated edema and disordered arrangement of cardiomyocytes in the IR+ ICA group. Furthermore, the IR+ ICA group exhibited significantly lower BNP, TGF-β, and IL-6 expression levels than the IR group ( t = 2.83, 4.15, 2.96, P < 0.05). The expression of apoptosis-related proteins Cleaved Caspase-3 and Bax was lower ( t = 3.23, 3.24, P < 0.05), Bcl-2 expression was higher ( t = 5.92, P < 0.001), and restored phosphorylation levels of PI3K and Akt ( t = 2.89, 8.35, P < 0.001). Conclusions:Icariin has protective effects against the RICD. It alleviates cardiomyocyte apoptosis possibly by upregulating the phosphorylation levels of PI3K and Akt.

Objective:Autoimmune gastritis (AIG) is characterized by the loss of acid-secreting glands, resulting in hypochlorhydria and hypergastrinemia, conditions that significantly increase the risk of developing gastric neuroendocrine tumors (NETs) and gastric adenocarcinoma. In recent years, AIG has garnered increasing attention in both clinical and research settings. However, comprehensive studies on the clinical and endoscopic characteristics of AIG particularly cases complicated by gastric neoplastic lesions remain limited in China. This study aims to comprehensively summarize the clinical and endoscopic features of AIG and its associated gastric neoplastic lesions.Methods:A retrospective analysis was conducted using medical records from patients with AIG diagnosed at Sichuan Provincial People′s Hospital between 2019 and 2024. Data collected included demographic information, medical history, serological test results, imaging findings, and endoscopic observations. The clinical and endoscopic features of AIG patients with gastric NETs or epithelial-derived tumors were compared to those without gastric neoplastic lesions to identify potential risk factors and diagnostic indicators for tumor development in AIG.Results:A total of 72 patients with AIG were included, of whom 62.5% (45/72) were female, with an age range of 30 to 79 years old (mean age: 57±11 years). Parietal cell antibody (PCA) positivity was observed in 93.1% (67/72), intrinsic factor antibody (IFA) positivity in 45.8% (33/72), and Helicobacter pylori ( H. pylori) co-infection in 48.6% (35/72). Endoscopically, 84.7% (61/72) showed prominent corpus-dominant advanced atrophy; 47.2% (34/72) had sticky adherent mucus; and 41.7% (30/72) displayed residual oxyntic mucosa in the gastric body or fundus. Only 23.6% (17/72) had normal antrum mucosa, and just 16.7% (12/72) showed a circular wrinkle-like pattern. Gastric neoplastic lesions were identified in 35 patients (48.6%), including 15 cases (20.8%) with NETs and 20 cases (27.8%) with epithelial-derived tumors (four adenocarcinomas, three adenomas, and 13 cases of intraepithelial neoplasia). No significant differences were found between tumor and non-tumor groups in terms of age, gender, PCA/IFA positivity, gastrin levels, anemia status, folic acid, or serum iron levels. However, patients with NETs had significantly lower vitamin B 12 levels compared to those without tumors (183±111 ng/L vs. 323±159 ng/L, t=2.47, P=0.042). Additionally, AIG patients with NETs were more likely to be H.pylori-negative compared to both the non-tumor group (66.7% vs. 35.1%, χ2=5.26, P=0.072) and the epithelial-derived tumor group (66.7% vs. 30.0%, χ2=5.80, P=0.055). The incidence of reverse atrophy in the epithelial-derived tumor group was significantly lower than that in the non-tumor group (65.0% vs. 91.9%, χ2=6.49, P=0.011) and the NETs group (65.0% vs. 93.3%, χ2=3.90, P=0.048).? Conclusion:In AIG patients with NETs, serum vitamin B 12 levels are significantly reduced, suggesting that vitamin B 12 deficiency may be a key risk factor or clinical indicator for NET development in AIG. Furthermore, NETs are more frequently observed in AIG patients without H.pylori infection, while epithelial-derived tumors are more commonly associated with H.pylori co-infection.

Tumor metastasis is the leading cause of high mortality in most cancers, and numerous studies have demonstrated that the malignant crosstalk of multiple components in the tumor microenvironment (TME) together promotes tumor metastasis. Cancer-associated fibroblasts (CAFs) are the major stromal cells and crosstalk centers in the TME of various kinds of tumors, such as breast cancer, pancreatic cancer, and prostate cancer. Recently, the CAF-induced pro-tumor metastatic TME has gained wide attention, being considered as one of the effective targets for tumor therapy. With in-depth research, CAFs have been found to promote tumor metastasis through multiple mechanisms, such as inducing epithelial-mesenchymal transition in tumor cells, remodeling the extracellular matrix, protecting circulating tumor cells, and facilitating the formation of a pre-metastatic niche. To enhance the anti-tumor metastasis effect, therapeutic strategies designed by combining nano-drug delivery systems with CAF modulation are undoubtedly a desirable choice, as evidenced by the research over the past decades. Herein, we introduce the physiological properties of CAFs, detail the possible mechanisms whereby CAFs promote tumor metastasis, categorize CAFs-based nano-drug delivery strategies according to their anti-metastasis functions and discuss the current challenges, possible solutions, as well as the future directions in order to provide a theoretical basis and reference for the utilization of CAFs-based nano-drug delivery strategies to promote tumor metastasis therapy.

The persistent high prevalence and poor survival outcomes of lung cancer underscore the urgent need for innovative therapeutic modalities. Here, we present a novel multifunctional delivery platform for the synergistic treatment of lung malignancies, combining in situ-triggerable photodynamic therapy (PDT) with radiotherapy. The new platform CLL was developed by loading a new reactive oxygen species (ROS)-triggerable photosensitizer, luminol-conjugated chlorin e6 (Ce6), into liposomes. CLL can be activated through the bioluminescence resonance energy transfer effect under oxidative stress, thereby producing singlet oxygen for targeted tumor treatment without external irradiation. In vitro studies showed significant cytotoxic effects of CLL in both 4T1 and A549 tumor cells. Furthermore, a PDT-radiopharmaceutical combination nanotherapy CLL-¹⁷⁷Lu was engineered by incorporating the radionuclide ¹⁷⁷Lu into CLL. CLL-¹⁷⁷Lu demonstrated synergistic antitumor effects in 4T1 and A549 tumor cells, as well as in mouse models of 4T1 breast cancer lung metastasis or A549 tumor xenografts. Mechanistically, CLL-¹⁷⁷Lu can induce singlet oxygen/ROS generation, enhance tumor cell apoptosis, and promote M1 macrophage-mediated immunotherapy. Preliminary assessments showed a favorable profile for CLL-¹⁷⁷Lu, highlighting its potential as a promising nanotherapy for cancer treatment. Additionally, CLL can serve as a versatile platform for delivering a range of therapies to achieve synergistic antitumor effects.

BACKGROUND: Changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels may not fully translate into patient-reported health status in patients with heart failure (HF). We aimed to evaluate the correlation between NT-proBNP levels and patient-reported health status changes at one month after discharge of patients, and their associations with risk of death and rehospitalization in patients with acute HF. METHODS: We used data from the China Patient-centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study (PEACE 5p-HF Study). Patient-reported health status was measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Patients who were hospitalized for HF and completed the KCCQ-12 and NT-proBNP tests before and one month after discharge were eligible in our study. We stratified patients into different groups based on NT-proBNP levels (i.e., improved, stable, and deteriorated) and KCCQ-12 scores (i.e., not deteriorated and deteriorated). We also examined the associations of the joint NT-proBNP and KCCQ-12 change with the risk of one-year and four-year clinical outcomes. RESULTS: A total of 2461 patients were included in the analysis. The mean age was 64.06 ± 13.51 years, and 36.37% (895/2461) of the study population were female. Among patients with improved NT-proBNP levels, 115 (10.95%) patients had deteriorated KCCQ-12 scores. The correlation between the change in the KCCQ-12 score and NT-proBNP level was weak ( r2 = 0.002, P = 0.013). Stratification by changes in the KCCQ-12 score revealed subgroups with distinctive risks, such that patients with deteriorated KCCQ-12 scores in any of the NT-proBNP change groups exhibited an increased risk of one-year all-cause death than participants with not deteriorated KCCQ-12 scores in any of the NT-proBNP change groups. Patients with improved NT-proBNP levels and deteriorated KCCQ-12 scores presented greater risks of one-year all-cause death (hazard ratio [HR]: 2.45, 95% confidence interval [CI]: 1.34-4.48) than patients with stable NT-proBNP levels and not deteriorated KCCQ-12 scores (HR [95% CI], 1.77 [1.25-2.53]). CONCLUSIONS: A discrepancy between changes in NT-proBNP levels and KCCQ-12 scores was common. The change in NT-proBNP levels was not sufficient to characterize critical aspects related to HF during one month after discharge of patients. Changes in the KCCQ-12 score exhibit complementary information to NT-proBNP levels for the prediction of clinical outcomes in patients with acute HF. REGISTRATION www.clinicaltrials.gov (No. NCT02878811).
Aged ; Female ; Humans ; Male ; Middle Aged ; Health Status ; Heart Failure/metabolism* ; Natriuretic Peptide, Brain/metabolism* ; Peptide Fragments/metabolism* ; Prospective Studies

AIM: To explore the relationship between hyperopia reserve and ocular biometric parameters in 4-14 year-old Uyghur students from Hotan County, Xinjiang, and to provide scientific evidence for myopia prevention.METHODS: From September 1 to October 31, 2023, a stratified random cluster sampling method was used to select 3 264 students(3 264 eyes)from 6 schools in Hotan County. Participants underwent uncorrected distance visual acuity testing, cycloplegic refraction, and ocular biometric measurements. The correlation between spherical equivalent(SE)and ocular biometric parameters was analyzed by multiple linear regression.RESULTS: A total of 1 998 non-myopic students(1 998 eyes)were included in the study, with 1 354 students(67.77%)showing insufficient hyperopia reserve. The detection rate of insufficient hyperopia reserve decreased with age, from 94.12% at age 4 to 18.13% at age 14(P<0.001). Multiple linear regression analysis showed that in the group with sufficient hyperopia reserve, age, gender, uncorrected distance visual acuity, axial length(AL), and keratometry(K)explained 66.5% of the variance in SE; while in the group with insufficient hyperopia reserve, these factors explained only 28.0% of the SE variance.CONCLUSION: In non-myopic Uyghur students aged 4-14 in Hotan County, Xinjiang, the detection rate of insufficient hyperopia reserve was 67.77%. In the group with insufficient hyperopia reserve, age, gender, AL, and K explained only a small portion of the SE variance, suggesting that the refractive status of this population may be influenced by more complex factors.

ObjectiveThis study leverages structural data from antigen-antibody complexes of the influenza A virus neuraminidase (NA) protein to investigate the spatial recognition relationship between the antigenic epitopes and antibody paratopes. MethodsStructural data on NA protein antigen-antibody complexes were comprehensively collected from the SAbDab database, and processed to obtain the amino acid sequences and spatial distribution information on antigenic epitopes and corresponding antibody paratopes. Statistical analysis was conducted on the antibody sequences, frequency of use of genes, amino acid preferences, and the lengths of complementarity determining regions (CDR). Epitope hotspots for antibody binding were analyzed, and the spatial structural similarity of antibody paratopes was calculated and subjected to clustering, which allowed for a comprehensively exploration of the spatial recognition relationship between antigenic epitopes and antibodies. The specificity of antibodies targeting different antigenic epitope clusters was further validated through bio-layer interferometry (BLI) experiments. ResultsThe collected data revealed that the antigen-antibody complex structure data of influenza A virus NA protein in SAbDab database were mainly from H3N2, H7N9 and H1N1 subtypes. The hotspot regions of antigen epitopes were primarily located around the catalytic active site. The antibodies used for structural analysis were primarily derived from human and murine sources. Among murine antibodies, the most frequently used V-J gene combination was IGHV1-12*01/IGHJ2*01, while for human antibodies, the most common combination was IGHV1-69*01/IGHJ6*01. There were significant differences in the lengths and usage preferences of heavy chain CDR amino acids between antibodies that bind within the catalytic active site and those that bind to regions outside the catalytic active site. The results revealed that structurally similar antibodies could recognize the same epitopes, indicating a specific spatial recognition between antibody and antigen epitopes. Structural overlap in the binding regions was observed for antibodies with similar paratope structures, and the competitive binding of these antibodies to the epitope was confirmed through BLI experiments. ConclusionThe antigen epitopes of NA protein mainly ditributed around the catalytic active site and its surrounding loops. Spatial complementarity and electrostatic interactions play crucial roles in the recognition and binding of antibodies to antigenic epitopes in the catalytic region. There existed a spatial recognition relationship between antigens and antibodies that was independent of the uniqueness of antibody sequences, which means that antibodies with different sequences could potentially form similar local spatial structures and recognize the same epitopes.