ObjectiveTo investigate the effect of Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma on ferroptosis in the rat model of myocardial infarction and further elucidate its role in myocardial remodeling. MethodsThe rat model of myocardial infarction was established by ligation of the left anterior descending coronary artery. The 50 successfully modeled rats were randomly divided into model group， ferroptosis inhibitor group （2 mg·kg^-1）， enalapril group （2.1 mg·kg^-1）， and low- and high-dose （4 g·kg^-1 and 8 g·kg^-1， respectively） Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma， with 10 rats in each group. The rat model of myocardial infarction was established by ligation of the left anterior descending coronary artery. After 4 weeks of treatment， echocardiography was used to assess the cardiac structure and function. Hematoxylin-eosin （HE） staining and Masson staining were employed to observe pathological morphology and fibrosis of the myocardial tissue. Serum levels of N-terminal pro-B-type natriuretic peptide （NT-proBNP）， transforming growth factor-β （TGF-β）， and myosin heavy chain-β （MHC-β） were measured by enzyme-linked immunosorbent assay （ELISA）. Prussian blue staining was performed to detect myocardial iron deposition. The myocardial mitochondrial structure was observed by transmission electron microscopy. Levels of malondialdehyde （MDA） and glutathione （GSH） in the myocardial tissue were determined by lipid peroxidation assay kits. Immunofluorescence assay was conducted to observe the fluorescence intensity of nuclear factor E₂-related factor 2 （Nrf2） in the myocardial tissue. Western blot analysis was performed to evaluate the expression levels of proteins in the Nrf2/solute carrier family 7 member 11 （SLC7A11）/glutathione peroxidase 4 （GPX4） pathway. ResultsCompared with the sham group， the model group showed increased left ventricular end-diastolic diameter （LVEDD）， left ventricular end-systolic diameter （LVESD）， and serum levels of NT-proBNP， TGF-β， and MHC-β （P<0.01）， decreased left ventricular ejection fraction （LVEF） and left ventricular fractional shortening （LVFS） （P<0.01）， disarrangement of myocardial cells， inflammatory cell infiltration， severe myocardial fibrosis， increased myocardial iron deposition， and irregular mitochondrial morphology with vacuolation. Furthermore， the modeling led to increased MDA （P<0.01）， decreased GSH （P<0.01）， diminished Nrf2 fluorescence intensity in the myocardial tissue， and downregulated expression levels of Nrf2， SLC7A11， and GPX4 （P<0.01）. Compared with the model group， Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma reduced the LVEDD， LVESD， and serum levels of NT-proBNP， TGF-β， and MHC-β （P<0.05， P<0.01）， increased the LVEF and LVFS （P<0.05， P<0.01）， alleviated pathological changes such as myocardial cell disarrangement， inflammatory cell infiltration， myocardial fibrosis， and iron deposition， lowered the level of MDA （P<0.05， P<0.01）， raised the level of GSH （P<0.05， P<0.01）， improved the mitochondrial morphology and reduced vacuolation in the myocardial tissue， enhanced Nrf2 fluorescence intensity， and upregulated the expression levels of Nrf2， SLC7A11， and GPX4 （P<0.05， P<0.01） in the rat model of myocardial infarction. ConclusionGardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma alleviates pathological damage and myocardial remodeling in the rat model of myocardial infarction by inhibiting ferroptosis， the mechanism of which is related to the activation of Nrf2/SLC7A11/GPX4 signaling pathway.

ObjectiveTo investigate the effect of Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma on ferroptosis in the rat model of myocardial infarction and further elucidate its role in myocardial remodeling. MethodsThe rat model of myocardial infarction was established by ligation of the left anterior descending coronary artery. The 50 successfully modeled rats were randomly divided into model group， ferroptosis inhibitor group （2 mg·kg^-1）， enalapril group （2.1 mg·kg^-1）， and low- and high-dose （4 g·kg^-1 and 8 g·kg^-1， respectively） Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma， with 10 rats in each group. The rat model of myocardial infarction was established by ligation of the left anterior descending coronary artery. After 4 weeks of treatment， echocardiography was used to assess the cardiac structure and function. Hematoxylin-eosin （HE） staining and Masson staining were employed to observe pathological morphology and fibrosis of the myocardial tissue. Serum levels of N-terminal pro-B-type natriuretic peptide （NT-proBNP）， transforming growth factor-β （TGF-β）， and myosin heavy chain-β （MHC-β） were measured by enzyme-linked immunosorbent assay （ELISA）. Prussian blue staining was performed to detect myocardial iron deposition. The myocardial mitochondrial structure was observed by transmission electron microscopy. Levels of malondialdehyde （MDA） and glutathione （GSH） in the myocardial tissue were determined by lipid peroxidation assay kits. Immunofluorescence assay was conducted to observe the fluorescence intensity of nuclear factor E₂-related factor 2 （Nrf2） in the myocardial tissue. Western blot analysis was performed to evaluate the expression levels of proteins in the Nrf2/solute carrier family 7 member 11 （SLC7A11）/glutathione peroxidase 4 （GPX4） pathway. ResultsCompared with the sham group， the model group showed increased left ventricular end-diastolic diameter （LVEDD）， left ventricular end-systolic diameter （LVESD）， and serum levels of NT-proBNP， TGF-β， and MHC-β （P<0.01）， decreased left ventricular ejection fraction （LVEF） and left ventricular fractional shortening （LVFS） （P<0.01）， disarrangement of myocardial cells， inflammatory cell infiltration， severe myocardial fibrosis， increased myocardial iron deposition， and irregular mitochondrial morphology with vacuolation. Furthermore， the modeling led to increased MDA （P<0.01）， decreased GSH （P<0.01）， diminished Nrf2 fluorescence intensity in the myocardial tissue， and downregulated expression levels of Nrf2， SLC7A11， and GPX4 （P<0.01）. Compared with the model group， Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma reduced the LVEDD， LVESD， and serum levels of NT-proBNP， TGF-β， and MHC-β （P<0.05， P<0.01）， increased the LVEF and LVFS （P<0.05， P<0.01）， alleviated pathological changes such as myocardial cell disarrangement， inflammatory cell infiltration， myocardial fibrosis， and iron deposition， lowered the level of MDA （P<0.05， P<0.01）， raised the level of GSH （P<0.05， P<0.01）， improved the mitochondrial morphology and reduced vacuolation in the myocardial tissue， enhanced Nrf2 fluorescence intensity， and upregulated the expression levels of Nrf2， SLC7A11， and GPX4 （P<0.05， P<0.01） in the rat model of myocardial infarction. ConclusionGardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma alleviates pathological damage and myocardial remodeling in the rat model of myocardial infarction by inhibiting ferroptosis， the mechanism of which is related to the activation of Nrf2/SLC7A11/GPX4 signaling pathway.

Objective To investigate the factors influencing hyperdynamic circulation-related indicators in patients with liver cirrhosis and ascites.Methods A retrospective analysis was conducted on the clinical data of 377 patients diagnosed with cirrhosis-associated ascites at the Third People's Hospital of Kunming between October 2022 and October 2024.Patients were categorized into grade 1,grade 2,and grade 3 ascites groups according to ascites severity grading.The general demographic characteristics and clinical parameters of the three groups were compared.Potential positive predictors were initially identified through univariate analyses,including Spearman correlation and non-parametric tests.Binary logistic regression and multiple linear regression models were subsequently employed to investigate the factors influencing high dynamic circulation-related indicators(heart rate[HR],E/A ratio,and left ventricular diastolic function[LVDF])in patients with cirrhosis-related ascites.Results Significant differences in the incidence of HR,the ratio of early to late diastolic filling velocities(E/A),and LVDF were observed among different ascites groups(P<0.05).Age,ascites depth,serum chloride(Cl-),CO2,red cell distribution width coefficient of variation(RDW-CV),and etiology were identified as independent determinants of HR in patients with liver cirrhosis and ascites.Age,white blood cell count(WBC),albumin(ALB),and etiology were independent determinants of E/A in patients with liver cirrhosis and ascites.Age(OR=1.088,95%CI 1.062-1.114,P<0.001)and serum potassium(K+)(OR=1.919,95%CI 1.218-3.025,P=0.005)were independent risk factors for LVDF in patients with cirrhotic ascites,whereas RDW-CV(OR=0.902,95%CI 0.883-0.961,P=0.023)and ALB(OR=0.921,95%CI 0.883-0.961,P<0.001)were identified as protective factors.Conclusions Serum ALB is an independent influencing factor for E/A ratio and LVDF in cirrhotic patients with ascites and hyperdynamic circulation.K+and RDW-CV are also independent predictors of LVDF,whereas Cl-independently influences heart rate.Clinical monitoring and targeted intervention for these parameters should be emphasized.

Objective To explore the relationship between corrected QT interval(QTc)and short-term mortality rate in patients with cirrhotic ascites and the predictive value of QTc combined with Child-Pugh class for short-term death.Methods Patients hospitalized with cirrhotic ascites from October 2022 to March 2024 were selected as study subjects(training set,n=245),and similar patients from April to October 2024 were included for external validation(validation set,n=88).Patients'demographic data,basic clinical data,and first electrocardiography related indicators on admission were collected.Patients were divided into a death group and a survival group according to the 30-day follow-up result.The influencing factors for prognosis were explored by Lasso regression and univariate and multivariate binary logistic regression.A death risk nomogram model was constructed and evaluated by receiver operating characteristic curve(ROC curve),calibration curve,and decision curve.Data were analyzed for normality using Shapiro-Wilk test.Pairwise comparison for continuous data that were normally distributed was conducted by the independent-samples t test.Pairwise comparison for continuous data that were not normally distributed was conducted by the Mann-Whitney U test.Pairwise comparison for categorical data was performed using the chi-square test.Results The mortality rates were 35.1%(86/245)in the training set and 30.7%(27/88)in the validation set.Lasso regression showed that combined tumor,QTc,hematocrit,total bilirubin(TBil),direct bilirubin,alkaline phosphatase,albumin,cholinesterase,high-density lipoprotein cholesterol,carcinoembryonic antigen,international normalized ratio,model for end-stage liver disease(MELD),and Child-Pugh class were potential influencing factors for 30-day death in patients with cirrhotic ascites.Univariate and multivariate logistic regression showed that QTc(odds ratio[OR]=1.010,95%confidence interval[CI]:1.001-1.020,P=0.039),presence of tumor(OR=6.904,95%CI:2.997-12.391,P<0.001),TBil(OR=1.009,95%CI:1.004-1.014,P=0.001),and Child-Pugh class(OR=2.532,95%CI:1.256-5.105,P=0.009)were independent risk factors for 30-day death in patients with cirrhotic ascites.For the nomogram model constructed based on the results of the multivariate logistic analysis,the area under the ROC curve in the training set was 0.824;the sensitivity and specificity were 81.1%and 74.4%,respectively;the Hosmer-Lemeshow goodness-of-fit test showed P=0.673;the mean absolute error of the calibration curve was 0.020.The area under the ROC curve in the validation set was 0.886;the sensitivity and specificity were 91.8%and 70.4%,respectively;the Hosmer-Lemeshow goodness-of-fit test showed P=0.965;the mean absolute error of the calibration curve was 0.032.With the threshold probability of 0.15 to 0.85,the decision curve suggested a good benefit.The area under the ROC curve of the predictive model(0.824)was greater than conventional MELD score(0.700),MELD-Na score(0.698),and Child-Pugh score(0.674)(all P<0.05).Conclusion QTc is an independent predictor of short-term death in patients with cirrhotic ascites,and the prognostic model including QTc and Child-Pugh class has a good predictive value for short-term mortality rate.

Objective To investigate the factors influencing hyperdynamic circulation-related indicators in patients with liver cirrhosis and ascites.Methods A retrospective analysis was conducted on the clinical data of 377 patients diagnosed with cirrhosis-associated ascites at the Third People's Hospital of Kunming between October 2022 and October 2024.Patients were categorized into grade 1,grade 2,and grade 3 ascites groups according to ascites severity grading.The general demographic characteristics and clinical parameters of the three groups were compared.Potential positive predictors were initially identified through univariate analyses,including Spearman correlation and non-parametric tests.Binary logistic regression and multiple linear regression models were subsequently employed to investigate the factors influencing high dynamic circulation-related indicators(heart rate[HR],E/A ratio,and left ventricular diastolic function[LVDF])in patients with cirrhosis-related ascites.Results Significant differences in the incidence of HR,the ratio of early to late diastolic filling velocities(E/A),and LVDF were observed among different ascites groups(P<0.05).Age,ascites depth,serum chloride(Cl-),CO2,red cell distribution width coefficient of variation(RDW-CV),and etiology were identified as independent determinants of HR in patients with liver cirrhosis and ascites.Age,white blood cell count(WBC),albumin(ALB),and etiology were independent determinants of E/A in patients with liver cirrhosis and ascites.Age(OR=1.088,95%CI 1.062-1.114,P<0.001)and serum potassium(K+)(OR=1.919,95%CI 1.218-3.025,P=0.005)were independent risk factors for LVDF in patients with cirrhotic ascites,whereas RDW-CV(OR=0.902,95%CI 0.883-0.961,P=0.023)and ALB(OR=0.921,95%CI 0.883-0.961,P<0.001)were identified as protective factors.Conclusions Serum ALB is an independent influencing factor for E/A ratio and LVDF in cirrhotic patients with ascites and hyperdynamic circulation.K+and RDW-CV are also independent predictors of LVDF,whereas Cl-independently influences heart rate.Clinical monitoring and targeted intervention for these parameters should be emphasized.

Objective To explore the relationship between corrected QT interval(QTc)and short-term mortality rate in patients with cirrhotic ascites and the predictive value of QTc combined with Child-Pugh class for short-term death.Methods Patients hospitalized with cirrhotic ascites from October 2022 to March 2024 were selected as study subjects(training set,n=245),and similar patients from April to October 2024 were included for external validation(validation set,n=88).Patients'demographic data,basic clinical data,and first electrocardiography related indicators on admission were collected.Patients were divided into a death group and a survival group according to the 30-day follow-up result.The influencing factors for prognosis were explored by Lasso regression and univariate and multivariate binary logistic regression.A death risk nomogram model was constructed and evaluated by receiver operating characteristic curve(ROC curve),calibration curve,and decision curve.Data were analyzed for normality using Shapiro-Wilk test.Pairwise comparison for continuous data that were normally distributed was conducted by the independent-samples t test.Pairwise comparison for continuous data that were not normally distributed was conducted by the Mann-Whitney U test.Pairwise comparison for categorical data was performed using the chi-square test.Results The mortality rates were 35.1%(86/245)in the training set and 30.7%(27/88)in the validation set.Lasso regression showed that combined tumor,QTc,hematocrit,total bilirubin(TBil),direct bilirubin,alkaline phosphatase,albumin,cholinesterase,high-density lipoprotein cholesterol,carcinoembryonic antigen,international normalized ratio,model for end-stage liver disease(MELD),and Child-Pugh class were potential influencing factors for 30-day death in patients with cirrhotic ascites.Univariate and multivariate logistic regression showed that QTc(odds ratio[OR]=1.010,95%confidence interval[CI]:1.001-1.020,P=0.039),presence of tumor(OR=6.904,95%CI:2.997-12.391,P<0.001),TBil(OR=1.009,95%CI:1.004-1.014,P=0.001),and Child-Pugh class(OR=2.532,95%CI:1.256-5.105,P=0.009)were independent risk factors for 30-day death in patients with cirrhotic ascites.For the nomogram model constructed based on the results of the multivariate logistic analysis,the area under the ROC curve in the training set was 0.824;the sensitivity and specificity were 81.1%and 74.4%,respectively;the Hosmer-Lemeshow goodness-of-fit test showed P=0.673;the mean absolute error of the calibration curve was 0.020.The area under the ROC curve in the validation set was 0.886;the sensitivity and specificity were 91.8%and 70.4%,respectively;the Hosmer-Lemeshow goodness-of-fit test showed P=0.965;the mean absolute error of the calibration curve was 0.032.With the threshold probability of 0.15 to 0.85,the decision curve suggested a good benefit.The area under the ROC curve of the predictive model(0.824)was greater than conventional MELD score(0.700),MELD-Na score(0.698),and Child-Pugh score(0.674)(all P<0.05).Conclusion QTc is an independent predictor of short-term death in patients with cirrhotic ascites,and the prognostic model including QTc and Child-Pugh class has a good predictive value for short-term mortality rate.

Objective To analyze the hepatitis B virus infection with extreme reduction of cholinesterase(CHE)not caused by liver synthesis dysfunction,and to explore its clinical significance.Methods The clinical data of 2 rare cases hospitalized in the 3rd people's hospital of Kunming in July 2021 and February 2022,including liver function,coagulation function,hepatitis B markers,hepatitis B virus volume,and whole exon sequencing,were collected and analyzed,and literature was reviewed.Results CHE was extremely reduced in 2 patients with HBV infection,liver synthesis function was good,and whole exon sequencing showed the presence of butyrylcholinesterase(BCHE)gene mutation.Conclusion The extremely low CHE in this case is not due to liver function disorder.Exon sequencing detected mutations in the BCHE gene in two patients.Screening for BCHE mutations may be necessary in patients with extremely low cholinesterase levels not due to liver dysfunction.

Objective To explore the improvements of high-fat intake on lung injury induced by Paragonimus proliferus infection in rats, and to preliminarily explore the mechanisms underlying the role of cytochrome P450 4A1 (CYP 4A1) in the improve ments. Methods SD rats were randomly assigned into three groups, including the normal control group (n = 10), the infection and normal diet group (n = 12) and the infection and high-fat diet group (n = 12). Rats in the normal control group were fed with normal diet and without any other treatments, and animals in the infection and normal diet group were subcutaneously injected with 8 excysted metacercariae of P. proliferus via the abdominal wall, followed by feeding with normal diet, while rats in the infection and high-fat diet group were subcutaneously injected with 8 excysted metacercariae of P. proliferus via the abdominal wall, followed by feeding with high-fat diet. All rats were sacrificed 28 weeks post-infection, and serum samples and lung specimens were collected. Following hematoxylin-eosin (HE) staining of rat lung specimens, the rat lung injury was observed under an optical microscope, and alveolitis was evaluated using semi-quantitative scoring. Serum interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assay (ELISA), and the cytochrome P450 4A1 (CYP 4A1) expression was quantified in rat lung specimens at transcriptional and translational levels using quantitative real-time PCR (qPCR) and Western blotting assays. Results Alveolar wall thickening, edema and inflammatory cell infiltration were alleviated 28 weeks post-infection with P. proliferus in rats in the infection and high-fat diet group relative to the infection and normal diet group, and no alveolar consolidation was seen in the infection and high-fat diet group. The semi-quantitative score of alveolitis was significantly higher in the infection and normal diet group [(2.200 ± 0.289) points] than in the normal control group [(0.300 ± 0.083) points] and the infection and high-fat diet group [(1.300 ± 0.475) points] (both P values < 0.05), and higher serum IL-1β [(151.586 ± 20.492)] pg/mL and TNF-α levels [(180.207 ± 23.379) pg/mL] were detected in the infection and normal diet group than in the normal control group [IL-1β: (103.226 ± 3.366) pg/mL; TNF-α: (144.807 ± 1.348) pg/mL] and the infection and high-fat diet group [IL-1β: (110.131 ± 12.946) pg/mL; TNF-α: (131.764 ± 27.831) pg/mL] (all P values < 0.05). In addition, lower CYP 4A1 mRNA (3.00 ± 0.81) and protein expression (0.40 ± 0.02) was quantified in lung specimens in the infection and normal diet group than in the normal control group [(5.03 ± 2.05) and (0.84 ± 0.14)] and the infection and high-fat diet group [(11.19 ± 3.51) and (0.68 ± 0.18)] (all P values < 0.05). Conclusion High-fat intake may alleviate lung injuries caused by P. proliferus infection in rats through up-regulating CYP 4A1 expression in lung tissues at both translational and transcriptional levels.

Objective: To assess the effectiveness of online and offline myopia prevention and control health education interventions using wearable behavior monitoring tools for non myopic elementary school students,so as to provide evidence based medical support for public health practices. Methods: From May to June in 2021, two schools were selected within the same county in Jiangsu Province. School 1 conducted online and offline parental health education ( n =111), while school 2 exclusively conducted offline health education activities, representing the traditional intervention group ( n =122). Students from both schools underwent monitoring through wearable behavior tracking tools, with feedback reports provided (eye distance, eye duration, ambient light, and outdoor exposure time). Both schools relied on activities to carry out health education interventions, and organized the distribution of promotional materials and display boards. The intervention group also established WeChat groups to conduct online "Healthy Parents Action" (answering and providing feedback on health knowledge related to myopia prevention and control, myopia prevention and control, science popularization, etc. raised by parents). Evaluation criteria included myopia rates, post dilation refractive error, and axial length, with a tracking period of two years (from 2021 to 2023). Additionally, the study collected refractive parameters from non myopic students who did not participate in wearable tool monitoring in the 12 classes across the two schools. Results: The baseline results indicated that there were no significant differences between the two groups in terms of refractive parameters and wearable tool monitoring results (including screen time, viewing distance, outdoor exposure time, and homework light exposure)( t/Z/χ 2=1.94,1.17,0.58,0.40,0.80,0.69,0.32, P >0.05). After a two-year follow up, in the first and second year, the myopia rate of the online Healthy Parents Action group (11.4%, 29.7%) were lower than that of the traditional group (26.2%, 50.9%), and the degree of refractive change in the intervention group [0.63(0.38,1.19)D] was lower than that of the traditional group [0.91(0.40,1.50)D], and all the differences were statistically significant( χ 2/ Z =4.93，10.37，2.29， P <0.05). However, there were no significant differences ( P >0.05) in axial length changes between the two groups over the twoyear intervention period. Nevertheless, in the second year, the axial length change in the traditional group [0.35(0.20,0.65)mm] was lower than that in the natural observation group [0.55(0.30,0.75)mm], and this difference was statistically significant ( Z =1.92, P <0.05). Conclusions Online and offline myopia prevention and control health education can effectively reduce myopia rates. The intervention mode combining wearable behavior monitoring tools with online health education may have better effects, but further large sample and multi center studies are needed to provide additional evidence and confirmation.

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
Anilides/pharmacology* ; Animals ; Carcinoma, Hepatocellular/drug therapy* ; Cell Line, Tumor ; Cell Proliferation ; Endothelial Cells/metabolism* ; Humans ; Liver Neoplasms/drug therapy* ; Pyridines/pharmacology* ; Sirolimus/pharmacology* ; Xenograft Model Antitumor Assays