Ginsenoside Rg_2(GRg2) is a triterpenoid compound found in Panax notoginseng. This study explored its effects and mechanisms on diabetic retinopathy and angiogenesis. The study employed endothelial cell models induced by glucose or vascular endothelial growth factor(VEGF), the chorioallantoic membrane(CAM) model, the oxygen-induced retinopathy(OIR) mouse model, and the db/db mouse model to evaluate the therapeutic effects of GRg2 on diabetic retinopathy and angiogenesis. Transwell assays and endothelial tube formation experiments were conducted to assess cell migration and tube formation, while vascular area measurements were applied to detect angiogenesis. The impact of GRg2 on the retinal structure and function of db/db mice was evaluated through retinal thickness and electroretinogram(ERG) analyses. The study investigated the mechanisms of GRg2 by analyzing the activation of Yes-associated protein(YAP) and Toll-like receptors(TLRs) pathways. The results indicated that GRg2 significantly reduced cell migration numbers and tube formation lengths in vitro. In the CAM model, GRg2 exhibited a dose-dependent decrease in the vascular area ratio. In the OIR model, GRg2 notably decreased the avascular and neovascular areas, ameliorating retinal structural disarray. In the db/db mouse model, GRg2 increased the total retinal thickness and enhanced the amplitudes of the a-wave, b-wave, and oscillatory potentials(OPs) in the ERG, improving retinal structural disarray. Transcriptomic analysis revealed that the TLR signaling pathway was significantly down-regulated following YAP knockdown, with PCR results consistent with the transcriptome sequencing findings. Concurrently, GRg2 downregulated the expression of Toll-like receptor 4(TLR4), TNF receptor-associated factor 6(TRAF6), and nuclear factor-kappaB(NF-κB) proteins in high-glucose-induced endothelial cells. Collectively, GRg2 inhibits cell migration and tube formation and significantly reduces angiogenesis in CAM and OIR models, improving retinal structure and function in db/db mice, with its pharmacological mechanism likely involving the down-regulation of YAP expression.
Animals ; Ginsenosides/pharmacology* ; Diabetic Retinopathy/physiopathology* ; Mice ; YAP-Signaling Proteins ; Humans ; Male ; Signal Transduction/drug effects* ; Cell Movement/drug effects* ; Adaptor Proteins, Signal Transducing/genetics* ; Mice, Inbred C57BL ; Neovascularization, Pathologic/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Panax notoginseng/chemistry* ; Endothelial Cells/metabolism* ; Transcription Factors/genetics* ; Angiogenesis

Objective:To investigate the role of the nuclear factor-kappa B (NF-κB) /nuclear factor E2 related factor 2 (Nrf2) pathway in the occurrence of lung tissue in the pulmonary alveolar proteinosis (PAP) model of rats induced by indium tin oxide nanoprticles (Nano-ITO) .Methods:In October 2019, 120 SD rats were divided into 3, 7, 14, 28, 56, and 84 day Nano ITO exposure groups and corresponding time point control groups, with 10 rats in each group; the exposure group was treated with 6 mg/kg·bw Nano-ITO via non exposed tracheal injection, twice a week. Time-course studies were performed to examine the pulmonary toxicity induced by Nano-ITO. At the end of the experiment, cytokines levels and oxidative stress were analyzed in the bronchoalveolar lavaged fluid (BALF). Rat lung tissues were also harvested for staining with HE, PAS, Masson, and Oil Red O. Ultrastructure of lung tissue cells was observed by transmission electron microscope. The localization and expression of NF-κB p65, IκB-α, IKK-β, Nrf2, NQO1, HO-1 were observed by immunohistochemistry, Western blot and real-time fluorescent quantitative PCR. The comparison between the two groups was analyzed by independent sample T test, and the comparison between the multiple groups was analyzed by one-way ANOVA.Results:Nano-ITO intratracheal instillation caused pulmonary toxicity by inducing acute inflammation, granuloma (nodule) formation, and alveolar proteinosis. ELISA analysis showed that, compared with the corresponding time points control groups, the levels of superoxide dismutase (SOD), total antioxidant capacity (T-AOC), malondialdehyde (MDA), interleukin (IL) -1β, IL-6, tumor necrosis factor alpha (TNF-α), IL-10, total protein (TP), and lactate dehydrogenase (LDH) in BALF of rats exposed to Nano ITO were all increased ( P<0.05) ; The protein expression of Nrf2 and NF-κB p65 was upregulated in rat lung tissue, while the protein expression of KK-β was increased ( P<0.01). Nrf2 and its downstream proteins NQO1 and HO-1 were highly expressed in Nano-ITO-induced PAP rat. Conclusion:NF-κB/Nrf2 signal pathway is involved in the process of Nano-ITO induced pulmonary alveolar proteinosis in rats.

Objective:To investigate the correlation between carotid-femoral pulse wave velocity(cfPWV)and carotid artery structural,hemodynamic,and cardiac functional parameters.Methods:A total of 420 healthy volunteers who underwent neck ultrasound,cardiac ultrasound,and cfPWV examination at Kailuan General Hospital from June 2022 to February 2023 were selected,and they were divided into two groups based on the atherosclerosis threshold value of cfPWV>10 m/s,which included high cfPWV group(140 cases,cfPWV>10 m/s)and low cfPWV group(280 cases,cfPWV≤10 m/s).The demographic data(age,sex)of 420 persons were collected,and the common carotid artery diameter(CCAD),common carotid artery intima-media thickness(CIMT),plaque status,peak systolic velocity(PSV),end-diastolic velocity(EDV)and mean flow velocity(MFV)were compared between two groups.Then,the differences of interventricular septal thickness(IVST)of heart,left ventricular posterior wall thickness(LVPWT),the ratio of blood flow velocity at early stage to that at advanced stage in mitral valve(E/A)and stroke volume(SV)were analyzed.Multivariate logistic regression was adopted to analyze the independent influence factors of cfPWV enhancement.Results:The average age of high cfPWV group was(61.31±9.66)years old,which was significantly higher than(51.06±10.47)years old of low cfPWV group,and the difference of that was significant(t=-9.56,P<0.01).In the parameters of common carotid artery,63 persons(45.0%)occurred plaque in 140 persons of high cfPWV group,which was significantly lower than 50 persons(17.86%)in 280 persons of low cfPWV group,and the difference of that between two groups was significant(x2=34.97,P<0.05).The differences of CCAD,CIMT,PSV,EDV and MV of common carotid artery at right side of persons between two groups were significant(t=-2.16,-5.40,4.52,5.59,5.04,P<0.05),respectively.The parameters of heart showed that the LVPWT thickness increased(9.35±1.13)mm,and the ratio of E/A<1 increased 77.86%in high cfPWV group,which were significantly related to the increase of cfPWV(r=0.27,0.38,P<0.01).Multivariate logistic regression analysis indicated that age(OR=1.05,95%CI:1.02-1.08),CCAD(OR=1.63,95%CI:1.22-2.16),plaque presence(OR=1.84,95%CI:1.07-3.17),LVPWT(OR=1.35,95%CI:1.05-1.72),and the ratio of E/A<1(OR=2.37,95%CI:1.32-4.26)were independent predictors of cfPWV enhancement.Conclusion:The enhancement of cfPWV is closely related to high age,the reconstruction of common carotid artery(widening of inside diameter,and plaque formation),left ventricular hypertrophy,and diastolic abnormality,which indicates it is possible that atherosclerosis process accompanies by the change of interaction mechanism of blood vessels-heart.

Objective:To determine if preoperative 68Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/MR could contribute to predicting pathological complete response (pCR) in patients with gastrointestinal cancer undergoing neoadjuvant immunotherapy. Methods:In this retrospective study, 35 patients (23 males, 12 females, age (59.1±7.9) years) with gastrointestinal cancer who underwent 68Ga-FAPI-04 PET/MR after receiving neoadjuvant immunotherapy between February 2021 and January 2024 were enrolled. Clinical data, PET imaging parameters including SUV, peak of SUV normalized by lean body mass (SUL peak), FAPI-positive tumor volume (FTV), and total FAPI-positive lesion burden (TLF), and pathological data were collected and analyzed. Patients were divided into pCR group and non-pCR group, and the independent-sample t test or Mann-Whitney U test was performed to compare those parameters between the 2 groups. ROC curve analysis (Delong test) was performed to evaluate the diagnostic efficiency of each parameter to predict pCR. Results:The overall pCR rate of the neoadjuvant therapy was 40.0%(14/35). In the visual evaluation, 68Ga-FAPI-04 PET was limited in predicting pCR, showing false positivity in 12 patients and false negative in 1 patent. While SUV max( t=2.50, P=0.018), SUL peak( t=3.11, P=0.004), FTV( U=3.00, P=0.030) and TLF( U=2.96, P=0.042) in non-pCR group were all higher than those in pCR group. The predictive efficiency of FTV <1.925cm 3 for pCR was better than the efficiency of PET visual evaluation ( Z=3.61, P<0.001), with the prediction accuracy of 82.86%(29/35). Conclusions:68Ga-FAPI-04 PET/MR may provide an effective clinical tool for guiding further treatment of patients with gastrointestinal cancer undergoing neoadjuvant immunotherapy. The quantitative features derived from 68Ga-FAPI-04 PET appear promising in predicting pCR, which are expected to provide a reference for avoiding surgery.

Objective:To evaluate the efficacy and safety of immunotherapy combined with chemotherapy as conversion therapy for initially unresectable locally advanced esophageal squamous cell carcinoma.Methods:This retrospective case series study analyzed clinical and pathological data of 32 patients with initially unresectable locally advanced esophageal squamous cell carcinoma who received immunotherapy combined with chemotherapy at the Department of Thoracic Surgery, the Fourth Hospital of Hebei Medical University, from June 2020 to December 2024. The cohort included 27 males and 5 females, with an age ( M(IQR)) of 61(9)years (range:46 to 73 years). Five patients were diagnosed with stage Ⅲ, 27 with stage ⅣA. All patients received PD-1 inhibitor sintilimab combined with nedaplatin and albumin-bound paclitaxel. Radiological evaluations were performed every two cycles, the multidisciplinary team evaluation was conducted to determine conversion to resectable status, and patients with successful conversion underwent radical esophagectomy. Follow-up was conducted via telephone or outpatient visits every 3 to 6 months after the last treatment. The primary endpoint was R0 resection rate, secondary endpoints included objective response rate (ORR), pathological complete response (pCR) rate, major pathological response (MPR) rate, event-free survival (EFS), disease-free survival (DFS) in patients with R0 resection, overall survival (OS) and safety. Kaplan-Meier method was used to plot survival curves and estimate median EFS, DFS, OS rates and their 95% CI. The 95% CI for ORR, pCR rate, MPR rate, and downstaging rate were calculated using the Clopper-Pearson method. Results:The median treatment cycle of 2(1) (range:2 to 8). As of June 2025, the median follow-up was 32.5(13.5)months (range:6.4 to 59.1 months). Among the 32 patients, 9 experienced progression or recurrence, including 2 with liver and lymph node metastases, 2 with lung metastases, 2 with thoracic vertebral metastases, and 3 with mediastinal lymph node metastases. After conversion therapy, 29 patients underwent surgery, achieving an R0 resection rate of 84.4% (95% CI:67.2% to 94.7%), a pCR rate of 27.6% (95% CI:12.7% to 47.2%), and an MPR rate of 55.2% (95% CI:35.7% to 73.6%). Grade 3 or higher surgical complications occurred in 6.9%(2/29) of patients, and grade 3 or higher treatment-related adverse events were observed in 15.6%(5/29). Among the 32 patients, the ORR was 56.3% (95% CI:37.7% to 73.6%),the 3-year EFS rate and OS rate was 59.4% (95% CI:40.8% to 86.4%) and 59.7% (95% CI:40.0% to 89.0%) respectively. Conclusion:Immunotherapy combined with chemotherapy demonstrates high conversion rates and favorable safety in the conversion therapy of initially unresectable locally advanced esophageal squamous cell carcinoma, representing a promising treatment strategy.

OBJECTIVE: Cigarette smoking exacerbates the progression of pulmonary tuberculosis (TB). The role of tertiary lymphoid structures (TLS) in chronic lung diseases has gained attention; however, it remains unclear whether smoking-exacerbated lung damage in TB is associated with TLS. This study aimed to analyze the characteristics of pulmonary TLS in smokers with TB and to explore the possible role of TLS in smoking-related lung injury in TB. METHODS: Lung tissues from 36 male patients (18 smokers and 18 non-smokers) who underwent surgical resection for pulmonary TB were included in this study. Pathological and immunohistological analyses were conducted to evaluate the quantity of TLS, and chest computed tomography (CT) was used to assess the severity of lung lesions. The correlation between the TLS quantity and TB lesion severity scores was analyzed. The immune cells and chemokines involved in TLS formation were also evaluated and compared between smokers and non-smokers. RESULTS: Smoker patients with TB had significantly higher TLS than non-smokers ( P < 0.001). The TLS quantity in both the lung parenchyma and peribronchial regions correlated with TB lesion severity on chest CT (parenchyma: r = 0.5767; peribronchial: r = 0.7373; both P < 0.001). Immunohistochemical analysis showed increased B cells, T cells, and C-X-C motif chemokine ligand 13 (CXCL13) expression in smoker patients with TB ( P < 0.001). CONCLUSION Smoker TB patients exhibited increased pulmonary TLS, which was associated with exacerbated lung lesions on chest CT, suggesting that cigarette smoking may exacerbate lung damage by promoting TLS formation.
Humans ; Male ; Tuberculosis, Pulmonary/immunology* ; Middle Aged ; Tertiary Lymphoid Structures/pathology* ; Adult ; Lung/pathology* ; Smoking/adverse effects* ; Smokers ; Aged ; Tomography, X-Ray Computed

We took the surface spike S protein of transmissible gastroenteritis virus(TGEV)as the research object.Based on the Gram-positive enhancer matrix(GEM)-anchor protein(PA)display platform,two kinds of bacteria-like particles(BLPs)with surface-displayed TGEV DA and S1 were prepared using the insect cell-baculovirus expression system.The results showed that the lev-els of IL-4,IFN-γ,IgG,IgA,and sIgA induced by 50 μg BLP-DA were higher than those of the 25μg group.The levels of IL-4,IFN-γ,and sIgA induced by 50 μg BLP-S1 were higher than those of the 25 μg group,while the levels of IgG and IgA were lower than those of the 25 μg group.Under the same dose,when the dose was 25 μg,the levels of IFN-γ,IgG,IgA,and sIgA induced by BLP-S1 were higher than those of BLP-DA,while the level of IL-4 was lower than that of BLP-DA.When the dose was 50 μg,the level of IgG induced by BLP-DA was higher than that of BLP-S1,while the other indicators were lower than those of BLP-S1.Under different immunization routes,the levels of IgA and sIgA in the gavage group were higher than those in the intramuscular injec-tion group,and the levels of some cytokines were significantly higher in the gavage group than in the intramuscular injection group at specific time points,but there was no significant difference in the levels of IgG antibodies.In conclusion,the two types of TGEV BLPs constructed in this study both have good immunogenicity and can induce cellular and humoral immunity in mice.When the immunization doses are the same,the immunogenicity of BLP-S1 is better than that of BLP-DA.

We took the surface spike S protein of transmissible gastroenteritis virus(TGEV)as the research object.Based on the Gram-positive enhancer matrix(GEM)-anchor protein(PA)display platform,two kinds of bacteria-like particles(BLPs)with surface-displayed TGEV DA and S1 were prepared using the insect cell-baculovirus expression system.The results showed that the lev-els of IL-4,IFN-γ,IgG,IgA,and sIgA induced by 50 μg BLP-DA were higher than those of the 25μg group.The levels of IL-4,IFN-γ,and sIgA induced by 50 μg BLP-S1 were higher than those of the 25 μg group,while the levels of IgG and IgA were lower than those of the 25 μg group.Under the same dose,when the dose was 25 μg,the levels of IFN-γ,IgG,IgA,and sIgA induced by BLP-S1 were higher than those of BLP-DA,while the level of IL-4 was lower than that of BLP-DA.When the dose was 50 μg,the level of IgG induced by BLP-DA was higher than that of BLP-S1,while the other indicators were lower than those of BLP-S1.Under different immunization routes,the levels of IgA and sIgA in the gavage group were higher than those in the intramuscular injec-tion group,and the levels of some cytokines were significantly higher in the gavage group than in the intramuscular injection group at specific time points,but there was no significant difference in the levels of IgG antibodies.In conclusion,the two types of TGEV BLPs constructed in this study both have good immunogenicity and can induce cellular and humoral immunity in mice.When the immunization doses are the same,the immunogenicity of BLP-S1 is better than that of BLP-DA.

Objective:To investigate the correlation between carotid-femoral pulse wave velocity(cfPWV)and carotid artery structural,hemodynamic,and cardiac functional parameters.Methods:A total of 420 healthy volunteers who underwent neck ultrasound,cardiac ultrasound,and cfPWV examination at Kailuan General Hospital from June 2022 to February 2023 were selected,and they were divided into two groups based on the atherosclerosis threshold value of cfPWV>10 m/s,which included high cfPWV group(140 cases,cfPWV>10 m/s)and low cfPWV group(280 cases,cfPWV≤10 m/s).The demographic data(age,sex)of 420 persons were collected,and the common carotid artery diameter(CCAD),common carotid artery intima-media thickness(CIMT),plaque status,peak systolic velocity(PSV),end-diastolic velocity(EDV)and mean flow velocity(MFV)were compared between two groups.Then,the differences of interventricular septal thickness(IVST)of heart,left ventricular posterior wall thickness(LVPWT),the ratio of blood flow velocity at early stage to that at advanced stage in mitral valve(E/A)and stroke volume(SV)were analyzed.Multivariate logistic regression was adopted to analyze the independent influence factors of cfPWV enhancement.Results:The average age of high cfPWV group was(61.31±9.66)years old,which was significantly higher than(51.06±10.47)years old of low cfPWV group,and the difference of that was significant(t=-9.56,P<0.01).In the parameters of common carotid artery,63 persons(45.0%)occurred plaque in 140 persons of high cfPWV group,which was significantly lower than 50 persons(17.86%)in 280 persons of low cfPWV group,and the difference of that between two groups was significant(x2=34.97,P<0.05).The differences of CCAD,CIMT,PSV,EDV and MV of common carotid artery at right side of persons between two groups were significant(t=-2.16,-5.40,4.52,5.59,5.04,P<0.05),respectively.The parameters of heart showed that the LVPWT thickness increased(9.35±1.13)mm,and the ratio of E/A<1 increased 77.86%in high cfPWV group,which were significantly related to the increase of cfPWV(r=0.27,0.38,P<0.01).Multivariate logistic regression analysis indicated that age(OR=1.05,95%CI:1.02-1.08),CCAD(OR=1.63,95%CI:1.22-2.16),plaque presence(OR=1.84,95%CI:1.07-3.17),LVPWT(OR=1.35,95%CI:1.05-1.72),and the ratio of E/A<1(OR=2.37,95%CI:1.32-4.26)were independent predictors of cfPWV enhancement.Conclusion:The enhancement of cfPWV is closely related to high age,the reconstruction of common carotid artery(widening of inside diameter,and plaque formation),left ventricular hypertrophy,and diastolic abnormality,which indicates it is possible that atherosclerosis process accompanies by the change of interaction mechanism of blood vessels-heart.

Objective:To determine if preoperative 68Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/MR could contribute to predicting pathological complete response (pCR) in patients with gastrointestinal cancer undergoing neoadjuvant immunotherapy. Methods:In this retrospective study, 35 patients (23 males, 12 females, age (59.1±7.9) years) with gastrointestinal cancer who underwent 68Ga-FAPI-04 PET/MR after receiving neoadjuvant immunotherapy between February 2021 and January 2024 were enrolled. Clinical data, PET imaging parameters including SUV, peak of SUV normalized by lean body mass (SUL peak), FAPI-positive tumor volume (FTV), and total FAPI-positive lesion burden (TLF), and pathological data were collected and analyzed. Patients were divided into pCR group and non-pCR group, and the independent-sample t test or Mann-Whitney U test was performed to compare those parameters between the 2 groups. ROC curve analysis (Delong test) was performed to evaluate the diagnostic efficiency of each parameter to predict pCR. Results:The overall pCR rate of the neoadjuvant therapy was 40.0%(14/35). In the visual evaluation, 68Ga-FAPI-04 PET was limited in predicting pCR, showing false positivity in 12 patients and false negative in 1 patent. While SUV max( t=2.50, P=0.018), SUL peak( t=3.11, P=0.004), FTV( U=3.00, P=0.030) and TLF( U=2.96, P=0.042) in non-pCR group were all higher than those in pCR group. The predictive efficiency of FTV <1.925cm 3 for pCR was better than the efficiency of PET visual evaluation ( Z=3.61, P<0.001), with the prediction accuracy of 82.86%(29/35). Conclusions:68Ga-FAPI-04 PET/MR may provide an effective clinical tool for guiding further treatment of patients with gastrointestinal cancer undergoing neoadjuvant immunotherapy. The quantitative features derived from 68Ga-FAPI-04 PET appear promising in predicting pCR, which are expected to provide a reference for avoiding surgery.