BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

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.

Objective This study aims to monitor the mRNA ratio of podocin to nephrin (PNR) in glomerular podocytes of early diabetic kidney disease (DKD) rat models. The feasibility of using PNR as an early diagnostic indicator for DKD was evaluated by comparing it with the urinary albumin-to-creatinine ratio (U-ACR). Additionally, the early intervention effects of valsartan and fosinopril sodium on DKD were compared. Methods The DKD rat model was established by caudal intravenous injection of streptozotocin (STZ) at a dosage of 60 mg/kg. The early changes in PNR and U-ACR were monitored and compared, followed by timely intervention with valsartan and fosinopril sodium. Hematoxylin and eosin staining (HE) was used to observe glomerular structure, while transmission electron microscopy examined the ultrastructure of glomerular podocytes. ResultsPNR reached the critical value(≥1) on day 9 after modeling, earlier than U-ACR, which reached the critical value(≥30 mg/g) on day 15. Intervention with valsartan and fosinopril sodium on day 9 after modeling significantly reduced U-ACR (P < 0.05), with low-dose valsartan showing better results than high-dose (P>0.05), while high-dose fosinopril sodium outperformed low-dose (P>0.05). Both low doses of valsartan and fosinopril sodium significantly reduced PNR (P<0.05), with no significant effect observed for high doses. The interventions with valsartan and fosinopril sodium improved and maintained glomerular structure and podocyte arrangement. ConclusionPNR changes earlier than U-ACR, indicating its potential as an early diagnostic marker for DKD in rats. Early intervention with valsartan and fosinopril sodium demonstrates a therapeutic effect on DKD in rats.

Objective The potential mechanism of hepatotoxicity induced by rhubarb was preliminarily explored by network pharmacology and verified by cell experiments.Methods Based on network pharmacology,component collection and target prediction are carried out through multiple databases.PPI network construction,GO enrichment analysis and KEGG pathway analysis were combined with software to systematically predict the mechanism of hepatotoxicity induced by rhubarb.The pathway information predicted by network pharmacology was verified by primary hepatocyte experiments and Western blot experiments.Results The results of network pharmacology showed that RH was the main component of hepatotoxicity induced by rhubarb.Seventeen core targets of hepatotoxicity induced by rhubarb were obtained.KEGG results suggested that DNA damage and apoptosis were one of the key mechanisms of hepatotoxicity induced by rhubarb.The results of primary hepatocytes and Western blot showed that RH could inhibit the viability of primary hepatocytes in a time-dose dependent manner.ABT and SFP can significantly reduce the toxicity of RH on primary liver cells in mice,and RFP can increase the toxicity of RH to mouse primary liver cells.Upregulation of γ-H2AX and PARP-1 protein in primary liver cells of mice after treatment with different concentrations of RH.Conclusion RH in rhubarb can significantly inhibit the viability of mouse primary hepatocytes,and its toxicity to mouse primary hepatocytes is mainly caused by the metabolic activation of RH by CYP 2C9.RH can activate PARP-1 protein,phosphorylate H2AX,induce DNA damage and apoptosis in mouse primary hepatocytes.

Objective:To investigate the association between hyperuricemia and the risk for stroke occurrence, as well as the mediating effect of hypertension on this association.Methods:In this study, the China Chronic Diseases and Nutrition Surveillance system in 2015 was used as baseline data. We identified hospital admissions for stroke using the electronic homepage of inpatient medical records from 2013-2020, and death data were obtained from the 2015-2020 National Mortality Surveillance System. A retrospective cohort was established after matching and linking the database. The Cox proportional hazard regression model was used to analyze the relationship between hyperuricemia and the risk of stroke and its subtypes. Restricted cubic spline analysis was conducted to examine the dose-response relationship between serum uric acid levels and the risk for stroke. Mediation analysis was performed to investigate the mediating effect of hypertension on the association between hyperuricemia and the risk for stroke and its subtypes. Subgroup analyses were conducted based on gender and age groups.Results:A total of 124 352 study subjects were included, with an accumulative follow-up time of 612 911.36 person-years. During the follow-up period, 4 638 cases of stroke were found, including 3 919 cases of ischemic stroke and 689 cases of hemorrhagic stroke. The incidence density of stroke was 756.72 per 100 000 person-years, 641.37 per 100 000 person-years for ischemic stroke, and 114.60 per 100 000 person-years for hemorrhagic stroke. Multivariable Cox proportional hazards regression models showed that after adjusting for covariates, compared to those without hyperuricemia, individuals with hyperuricemia had a 16% higher risk for stroke [hazard ratio ( HR)=1.16, 95% CI: 1.06-1.27], a 12% higher risk of ischemic stroke ( HR=1.12, 95% CI: 1.01-1.24), and a 39% higher risk of hemorrhagic stroke ( HR=1.39, 95% CI: 1.11-1.75). Mediation analysis showed that hypertension partially mediated the associations between hyperuricemia and the risk for stroke, ischemic stroke, and hemorrhagic stroke, with mediation proportions of 36.07%, 39.98%, and 25.34%, respectively. The mediating effect is pronounced in the male population and individuals below 65. Conclusion:Hyperuricemia is a risk factor for stroke, and hypertension partially mediates the effect of hyperuricemia on stroke.

Objective:To investigate the perinatal outcomes and risk factors of perinatal complications in preg-nant women with hypertrophic cardiomyopathy(HCM).Methods:A retrospective analysis was carried out on clini-cal data of 100 pregnant women with HCM who delivered in Obstetrical Cardiology Intensive Care Center of Shanghai Renji Hospital between Jan.2000 and Dec.2022.Analyze the incidence of perinatal complications inclu-ding miscarriage,premature birth,small for gestational age infants,neonatal asphyxia,neonatal cardiac malforma-tions and perinatal mortality.Independent risk factors of perinatal complications in pregnant women with HCM were identified using univariate and multivariate Logistic regression.Results:①The mean age was 29.21±4.41 years old,the average gestational age upon admission is 34.46±6.43 weeks.There were 16 patients with a fam-ily history of cardiomyopathy(16％),21 cases with obstructive HCM(21％)and 79 cases of non-obstructive HCM(79％),91 cases with abnormal ECG(91％),mainly with ST-T changes(77 cases,77％).The average in-terventricular septum was 19.39±6.13mm by echocardiography.②Among the 100 pregnancies of 100 HCM pa-tients,6 cases(6％)were miscarriages,94 newborns survived(94％),including 91 cases of cesarean section(91％)and 3 cases of vaginal delivery(3％).The predominant perinatal complications were preterm delivery(39 cases,39％),small for gestational age(5 cases,5％),neonatal asphyxia(3 cases,3％)and neonatal cardiac malformation(2 cases,2％).There were no perinatal deaths.③Univariate Logistic regression analysis showed that pre pregnancy heart function ≥ Grade Ⅱ,increased left atrial diameter,and concomitant pulmonary hyperten-sion were risk factors for perinatal complications in pregnant women with HCM(OR＞1,P＜0.05).Multivariate Lo-gistic regression analysis found that pre pregnancy heart function ≥ Grade Ⅱ was an independent risk factor for predicting the occurrence of perinatal complications in pregnant women with HCM(OR 6.270,P＜0.05).Conclu-sions:HCM during pregnancy can induce poor perinatal outcome.More attention should be paid to risk assess-ment and pregnancy management.Early detection of risk factors can reduce the incidence of perinatal complica-tions.

【Objective】 To analyze the independent influencing factors of repeated extracorporeal shock wave lithotripsy (ESWL) in the treatment of upper urinary calculi (UUC), based on which a nomogram model was established to predict the efficacy. 【Methods】 Clinical and imaging data of 203 patients receiving repeated ESWL during Jan.2020 and Dec.2022 were collected, including 117 cases in the successful group and 86 cases in the unsuccessful group.The patients’ age and sex, stone volume (SV), surface area (SA), skin-to-site distance (SSD), maximum CT value, mean stone density (MSD), and stone heterogeneity index (SHI) were compared between the two groups.The independent predictors were analyzed with logistic regression and the meaningful variables (P<0.05) were used to establish a nomogram.The efficacy of the model was evaluated using receiver operating characteristic (ROC) curve and decreasing curve analysis (DCA).Internal validation was also performed. 【Results】 Stepwise regression showed that SV, SSD, MSD and SHI were independent influencing factors (P<0.05).The area under the ROC curve (AUC), optimal threshold, sensitivity and specificity were 0.793 (95%CI: 0.674-0.911), 0.619, 77.1% and 74.0%, respectively.The DCA curve was above two extreme curves.Hosmer-Lemeshow test and calibration curve showed that the nomogram had a good fitting degree (χ²=5.526, P=0.489), and the correction C-index was 0.746. 【Conclusion】 SV, SSD, MSD and SHI are independent predictors of the efficacy of repeated ESWL in the treatment of UUC.The nomogram established based on the above indicators has good predictive efficiency and clinical applicability.

Objective:To explore the predictive value of the prognostic nutritional index (PNI) in concurrently infected patients with acute-on-chronic liver failure (ACLF).Methods:220 cases with ACLF diagnosed and treated at the First Affiliated Hospital of Xi'an Jiaotong University from January 2011 to December 2016 were selected. Patients were divided into an infection and non-infection group according to whether they had co-infections during the course of the disease. Clinical data differences were compared between the two groups of patients. Binary logistic regression analysis was used to screen out influencing factors related to co-infection. The receiver operating characteristic curve was used to evaluate the predictive value of PNI for ACLF co-infection. The measurement data between groups were compared using the independent sample t-test and the Mann-Whitney U rank sum test. The enumeration data were analyzed using the Fisher exact probability test or the Pearson χ2 test. The Pearson method was performed for correlation analysis. The independent risk factors for liver failure associated with co-infection were analyzed by multivariate logistic analysis. Results:There were statistically significant differences in ascites, hepatorenal syndrome, PNI score, and albumin between the infection and the non-infection group ( P ?

Objective:To investigate the perinatal outcomes and risk factors of perinatal complications in preg-nant women with hypertrophic cardiomyopathy(HCM).Methods:A retrospective analysis was carried out on clini-cal data of 100 pregnant women with HCM who delivered in Obstetrical Cardiology Intensive Care Center of Shanghai Renji Hospital between Jan.2000 and Dec.2022.Analyze the incidence of perinatal complications inclu-ding miscarriage,premature birth,small for gestational age infants,neonatal asphyxia,neonatal cardiac malforma-tions and perinatal mortality.Independent risk factors of perinatal complications in pregnant women with HCM were identified using univariate and multivariate Logistic regression.Results:①The mean age was 29.21±4.41 years old,the average gestational age upon admission is 34.46±6.43 weeks.There were 16 patients with a fam-ily history of cardiomyopathy(16％),21 cases with obstructive HCM(21％)and 79 cases of non-obstructive HCM(79％),91 cases with abnormal ECG(91％),mainly with ST-T changes(77 cases,77％).The average in-terventricular septum was 19.39±6.13mm by echocardiography.②Among the 100 pregnancies of 100 HCM pa-tients,6 cases(6％)were miscarriages,94 newborns survived(94％),including 91 cases of cesarean section(91％)and 3 cases of vaginal delivery(3％).The predominant perinatal complications were preterm delivery(39 cases,39％),small for gestational age(5 cases,5％),neonatal asphyxia(3 cases,3％)and neonatal cardiac malformation(2 cases,2％).There were no perinatal deaths.③Univariate Logistic regression analysis showed that pre pregnancy heart function ≥ Grade Ⅱ,increased left atrial diameter,and concomitant pulmonary hyperten-sion were risk factors for perinatal complications in pregnant women with HCM(OR＞1,P＜0.05).Multivariate Lo-gistic regression analysis found that pre pregnancy heart function ≥ Grade Ⅱ was an independent risk factor for predicting the occurrence of perinatal complications in pregnant women with HCM(OR 6.270,P＜0.05).Conclu-sions:HCM during pregnancy can induce poor perinatal outcome.More attention should be paid to risk assess-ment and pregnancy management.Early detection of risk factors can reduce the incidence of perinatal complica-tions.

Objective:To investigate the perinatal outcomes and risk factors of perinatal complications in preg-nant women with hypertrophic cardiomyopathy(HCM).Methods:A retrospective analysis was carried out on clini-cal data of 100 pregnant women with HCM who delivered in Obstetrical Cardiology Intensive Care Center of Shanghai Renji Hospital between Jan.2000 and Dec.2022.Analyze the incidence of perinatal complications inclu-ding miscarriage,premature birth,small for gestational age infants,neonatal asphyxia,neonatal cardiac malforma-tions and perinatal mortality.Independent risk factors of perinatal complications in pregnant women with HCM were identified using univariate and multivariate Logistic regression.Results:①The mean age was 29.21±4.41 years old,the average gestational age upon admission is 34.46±6.43 weeks.There were 16 patients with a fam-ily history of cardiomyopathy(16％),21 cases with obstructive HCM(21％)and 79 cases of non-obstructive HCM(79％),91 cases with abnormal ECG(91％),mainly with ST-T changes(77 cases,77％).The average in-terventricular septum was 19.39±6.13mm by echocardiography.②Among the 100 pregnancies of 100 HCM pa-tients,6 cases(6％)were miscarriages,94 newborns survived(94％),including 91 cases of cesarean section(91％)and 3 cases of vaginal delivery(3％).The predominant perinatal complications were preterm delivery(39 cases,39％),small for gestational age(5 cases,5％),neonatal asphyxia(3 cases,3％)and neonatal cardiac malformation(2 cases,2％).There were no perinatal deaths.③Univariate Logistic regression analysis showed that pre pregnancy heart function ≥ Grade Ⅱ,increased left atrial diameter,and concomitant pulmonary hyperten-sion were risk factors for perinatal complications in pregnant women with HCM(OR＞1,P＜0.05).Multivariate Lo-gistic regression analysis found that pre pregnancy heart function ≥ Grade Ⅱ was an independent risk factor for predicting the occurrence of perinatal complications in pregnant women with HCM(OR 6.270,P＜0.05).Conclu-sions:HCM during pregnancy can induce poor perinatal outcome.More attention should be paid to risk assess-ment and pregnancy management.Early detection of risk factors can reduce the incidence of perinatal complica-tions.