Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

Sodium-glucose co-transporter protein 2 inhibitor(SGLT2i)has steadily demonstrated benefits in the treatment of type 2 diabetes complicated with cardiovascular diseases based on evidence-based medicine,but its precise mechanism is yet unknown.We identified type 2 diabetes patients with HFpEF by searching PubMed,Web of Science,China knowledge network(CNKI),and other databases.We then summarized the pathological mechanism of HFpEF caused by type 2 diabetes.At the same time,to link to evidence-based medical,we explored the future of SGLT2i in clinical application.

AIM:Bone morphogenetic protein 7(BMP7)reduces the expression of Yes-related protein 1(YAP1)by down-regulating Ajuba level and decreasing extracellular matrix(ECM)deposition.This study aimed to inves-tigate the influence of these factors on modifying the degree of renal fibrosis in rats with diabetic nephropathy.METH-ODS:Eighteen Sprague-Dawley(SD)rats were randomly divided into three groups:the normal control(NC)group,the diabetes mellitus(DM)group,and the DM group treated with BMP7 overexpressing adeno-associated virus(DM+rAAV-BMP7).Each group consisted of six rats.Diabetic kidney disease(DKD)was established in the DM and DM+rAAV-BMP7 groups by injecting 55 mg/kg streptozotocin(STZ)via the tail vein.NRK-52E cells were divided into three groups:the normal glucose(NG)group,the high glucose(HG)group,and the high glucose group treated with recombinant hu-man BMP7(HG+rhBMP7)group.Pathological changes in renal tissues were observed using hematoxylin and eosin(HE)and Sirius red staining.Immunohistochemical staining was performed to examine the expression sites of Ajuba and YAP1 in the renal cortex.Western blot analysis was conducted to determine the expression levels of BMP7,Ajuba,YAP1,colla-gen type Ⅲ(Col-Ⅲ),and fibronectin(FN)in the rat renal cortex and NRK-52E cells.RT-qPCR was used to measure the mRNA levels of Ajuba and YAP1 in the rat renal cortex.RESULTS:Biochemical indices revealed significantly ele-vated levels of blood glucose,serum creatinine,triglycerides,total cholesterol,and 24-hour urinary protein in the DM group compared to the NC group(P<0.05).In the DM+rAAV-BMP7 group,the levels of serum creatinine,24-hour uri-nary protein,triglycerides,and total cholesterol were lower than those in the DM group(P<0.05).Pathological staining demonstrated that the renal interstitium of the DM group exhibited inflammatory cell infiltration,fibrous tissue,collagen fi-ber deposition,disordered renal tubule arrangement,atrophy,and vacuolar degeneration,which were ameliorated in the DM+rAAV-BMP7 group.Immunohistochemistry revealed that Ajuba and YAP1 were mainly expressed in the cytoplasm and nucleus,with high expression in the cytoplasm of the DM group,which was significantly decreased in the DM+rAAV-BMP7 group.Western blot results indicated that the protein levels of FN,Col-Ⅲ,Ajuba,and YAP1 were up-regulated in the DM and the HG groups(P<0.05),but significantly down-regulated in the DM+rAAV-BMP7 group(P<0.05).RT-qP-CR results demonstrated that the mRNA levels of Ajuba and YAP1 were higher in the DM group and significantly lower in the DM+rAAV-BMP7 group(P<0.05).CONCLUSION:The overexpression of BMP7 can ameliorate renal fibrosis in rats with DKD.This effect is likely mediated by the down-regulation of Ajuba,reduction of YAP1 expression,and subse-quent inhibition of ECM deposition.

Objective To evaluate the efficacy of two kinds of biliary stent placement in the treatment of high bile duct carcinoma.Methods the clinical data of 136 patients with hilar cholangiocarcinoma who underwent biliary stent implantation in Nanyang Central Hospital from January 2021 to September 2023 were analyzed retrospectively.According to the mode of biliary stent placement,the patients were divided into ERCP group(n=86)and transoral cholangiopancreatoscopy group(n=50).In this study,SPSS26.0 was used for analysis.The age,related test indexes,days of hospitalization,postoperative complications,incidence of liver failure,remission rate of jaundice,stent material and patency rate were observed in the two groups.Results all patients completed the operation successfully.The two groups compared the incidence of postoperative liver failure,postoperative remission rate of jaundice,different material stents,postoperative complications and short-term patency rate,there was no significant statistical significance(P＞0.05).There were significant differences in postoperative complications between the two groups(t=12.02,P＜0.05).Compared with postoperative biliary tract infection and postoperative bleeding,the postoperative biliary tract infection and postoperative bleeding in ERCP group were 26.7％and 11.6％respectively,which were significantly higher than those in transoral cholangiopancreatoscopy group 10.0％and 2.0％(x2=5.42,3.94;P＜0.05).Conclusion of the mean hospitalization days between the two patient groups,Transoral cholangioscopy(10.78±2.17)d＜ERCP(12.91±2.96)d.Compared with the 7th day after operation,the liver function of the two groups was significantly improved and the related test indexes decreased significantly.There was no significant difference in postoperative complications and short-term patency rate between plastic stent and metal stent(P＞0.05).When the patency time was more than 6 months,the patency rate of metal stent was significantly higher than that of plastic stent(P＜0.05).Conclusion The placement of bile duct stent by ERCP and Oral choledochoscopy is effective in relieving clinical symptoms of high cholangiocarcinoma and can improve the quality of life of patients.Transoral cholangiopancreatoscopy has low complication rate,faster recovery,greater advantage,but higher cost;plastic stents are beneficial for patients with short expected survival time,and metal stents are more suitable for patients with long expected survival time.

Objective:To investigate the impact of Tumor-Infiltrating Lymphocytes (TILs) density in the tumor stroma on the long-term prognosis of hepatocellular carcinoma (HCC) liver transplant patients meeting the Hangzhou criteria.Methods:This study is a retrospective cohort study. The clinical data of 83 patients with hepatocellular carcinoma who met the Hangzhou criteria and underwent allogeneic liver transplantation from January 2018 to December 2023 in the Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital affiliated to Capital Medical University were collected and analyzed. Hematoxylin and Eosin (HE) staining was used to study the density of TILs in the resected liver grafts. Patients were divided into TILs-negative group (TILs<10%, n=31) and TILs-positive group (TILs≥10%, n=52) based on whether the TILs density exceeded 10%. Clinical and pathological characteristics were analyzed, and the significance of alpha-fetoprotein (AFP), TILs density, and microvascular invasion on the prognosis of HCC patients who met the Hangzhou criteria was studied. Measurement data with normal distribution were expressed as mean±standard deviation ( ± s) and compared between groups using t-test. Measurement data with skewed distribution were expressed as M ( Q1, Q3) and compared using rank-sum tests. Categorical data were compared using chi-square test. Kaplan-Meier method was used to study the relationship between various observation indicators and overall survival, and survival curves were plotted. Log-rank test was used to compare the survival rates between groups, and multivariate Cox regression model was used to adjust for the distribution of risk factors between groups. Results:The preoperative AFP level in the TILs-negative group was (15.69±1.21) U/mL, and in the TILs-positive group was (12.17±0.13) U/mL, with a statistically significant difference between the two groups ( P<0.05). In the TILs-negative group, 8 cases had microvascular invasion, and the number of low, moderate, and high differentiation tumors was 8, 23, and 0, respectively. In the TILs-positive group, 3 cases had microvascular invasion, and the number of low, moderate, and high differentiation tumors was 2, 31, and 19, respectively. The results indicated that patients in the TILs-negative group were more likely to have microvascular invasion and poorer tumor differentiation ( P<0.05). All patients were regularly followed up, and the 1-, 2-, and 3-year survival rates in the TILs-negative group and TILs-positive group were 84.0%, 77.6%, 69.8%, and 94.7%, 91.7%, 86.6%, respectively ( P<0.01). Cox proportional hazards model indicated that microvascular invasion ( RR=4.474, 95% CI: 1.172-17.072, P=0.028) and TILs-negative status ( RR=5.081, 95% CI: 1.420-18.184, P=0.012) were independent risk factors for the long-term prognosis of HCC patients who met the Hangzhou criteria. Conclusions:Among HCC patients meeting the Hangzhou criteria, the density of TILs in the tumor stroma is related to AFP levels, tumor differentiation, and the presence of microvascular invasion. TILs-negative status indicates a poorer prognosis for these patients.

Objective:Osteosarcoma is the most common malignant bone tumor in children and adolescents,characterized by a high potential for proliferation and metastasis.Patients with osteosarcoma who have distant metastases generally have a poor prognosis.Challenges in treatment include incomplete resection of tumor and chemotherapy resistance,with no effective cure currently available.Recent studies suggest that β-1,4-N-acetyl-galactosaminyltransferase 1(B4GALNT1)plays a role in the progression of various malignant tumors.However,the function of B4GALNT1 in osteosarcoma cells has not been reported.This study aims to investigate the expression of B4GALNT1 in osteosarcoma tissues compared to normal tissues and to explore its effects on the proliferation,migration,and invasion of osteosarcoma cells,thereby providing new theoretical foundations and directions for the treatment of osteosarcoma patients. Methods:Tumor tissues and corresponding normal tissue samples were collected from 16 osteosarcoma patients who underwent tumor resection at the Second Xiangya Hospital of Central South University.The patients'ages ranged from 8 to 17 years(median age 12 years).The expression of B4GALNT1 mRNA in osteosarcoma tissues,corresponding normal tissues,3 osteosarcoma cell lines(MG63,Saos-2,and U2OS),and human fetal osteoblastic cells(hFOB)was detected using real-time reverse transcription PCR(real-time RT-PCR).The effects of B4GALNT1 knockdown on the proliferation of osteosarcoma cells Saos-2 and U2OS were analyzed using cell counting kit-8(CCK-8)assays and colony formation assays.The effects of B4GALNT1 knockdown on the migration and invasion abilities of Saos-2 and U2OS cells were evaluated using Transwell migration and invasion assays.Western blotting analysis was performed to assess the impact of B4GALNT1 knockdown on the expression of epithelial-mesenchymal transition(EMT)and invasion-related proteins in Saos-2 and U2OS cells. Results:Real-time RT-PCR results showed that B4GALNT1 mRNA expression levels were significantly higher in osteosarcoma tissues and the 3 osteosarcoma cell lines compared to normal tissues and hFOB cells(all P＜0.0 1).CCK-8 and colony formation assays indicated that B4GALNT1 knockdown significantly reduced the proliferation rate of osteosarcoma cells compared to the control group(all P＜0.05).Transwell migration and invasion assays demonstrated that B4GALNT1 knockdown significantly decreased the number of migrating and invading osteosarcoma cells(all P＜0.01).Western blotting analysis revealed that B4GALNT1 knockdown inhibited the expression of N-cadherin,Snail,Vimentin,and matrix metalloproteinase 9(MMP9)compared to the control group(all P＜0.01). Conclusion:B4GALNT1 is upregulated in osteosarcoma tissues and cell lines,and its knockdown suppresses the malignant phenotype of osteosarcoma cells.B4GALNT1 may function as an oncogene in the proliferation and metastasis of osteosarcoma cells.

Objective To explore root cause of poor prognosis after successful endovascular treatment(EVT)in patients with acute ischemic stroke with large vascular occlusion(AIS-LVO)of anterior circulation.Methods Patients with AIS-LOV of anterior circulation who received successful EVT(postoperative modified thrombolysis incerebral infarction[mTICI]grade≥2b)were retrospectively and continuously collected in the Department of Neurology of Bozhou People's Hospital from January 2022 to March 2024.The baseline and clinical data of the patients were collected,including gender,age,vascular risk factors(hypertension,diabetes,coronary heart disease,hyperlipidemia,valvular heart disease,atrial fibrillation,smoking,and alcohol consumption),prior stroke or transient ischemic attack,baseline blood pressure,baseline National Institutes of Health Stroke scale(NIHSS)score,laboratory test indicators(pre-operative C-reactive protein and D-dimer,post-operative fasting blood glucose,lipid levels,homocysteine,etc).Meanwhile,the data of perioperative indicators was collected,including the time from onset to admission,the time from admission to puncture,the time from puncture to revascularization,the time from onset to puncture,the time from onset to revascularization,remedial measures(balloon dilation,stent placement,arterial thrombolysis)during the surgery or not,using tirofiban or not,postoperative complications(stroke-related pneumonia,stress ulcers,deep vein thrombosis,acute heart failure or renal failure,etc)or not.The patient's medical history and imaging data were collected,and these indicators were defined and collected,including Alberta stroke program early CT score(ASPECTS),location of occlusion(C1 segment of the internal carotid artery,C2 segment to C7 segment of the internal carotid artery,M1 segment of the middle cerebral artery),and the trial of org 10172 in acute stroke treatment(TOAST)classification and a postoperative transformation of cerebral infarction after ischemic stroke and symptomatic intracranial hemorrhage or not.According to the modified Rankin scale(mRS)score at 90 d after surgery,all patients were divided into poor prognosis group(mRS score≥ 3)and good prognosis group(mRS score≤2).The baseline and clinical data of two groups were compared using univariate analysis.Variables with P＜0.1 in the univariate analysis were selected as independent variables,and the poor prognosis was used as the dependent variable.Further,multivariate Logistic regression analysis was performed to identify the influencing factors of poor prognosis after EVT.Results Finally,a total of 192 patients with AIS-LVO of anterior circulation who received successful revascularization were included in this study.There were 101 male patients and 91 female patients.The poor prognosis group had 102 cases and the good prognosis group had 90 cases.Univariate analysis showed that the poor prognosis group had statistically significant differences with the good prognosis group in terms of age(Z=-3.088,P=0.002)and age distribution(x2=13.457,P=0.001),fasting blood glucose(Z=-3.347,P=0.001),baseline NIHSS score(Z=-4.469,P＜0.01),location of occlusion(x2=10.488,P=0.005),transformation of hemorrhage after ischemic stroke(x2=16.943,P＜0.01),and symptomatic intracranial hemorrhage(X2=25.449,P＜0.01),and the baseline ASPECTS of the poor prognosis group was significantly lower than that of the good prognosis group(Z=-4.547,P＜0.01).There were no significant differences in other baseline and clinical data(all P＞0.05).Further multivariate Logistic regression analysis showed that age＞80 years(OR,3.224,95％CI 1.033-10.058,P=0.044),baseline NIHSS score(OR,1.102,95％CI 1.013-1.199,P=0.023),baseline ASPECTS(OR,0.375,95％CI 0.212-0.665,P=0.001),and symptomatic intracranial hemorrhage(OR,7.127,95％CI 1.296-39.203,P=0.024)were independent influencing factors of poor prognosis.Conclusion The independent factors of 90 d poor prognosis after successful EVT in patients with AIS-LVO of anterior circulation are age＞80 years,baseline NIHSS score,baseline ASPECTS,and symptomatic intracranial hemorrhage.

Aim To explore the mechanism and mate-rial basis of Shenkang injection(SKI)in the treatment of renal fibrosis(RF)by bioinformatics and in vitro experiments.Methods The differentially expressed genes of RF were screened by GEO database.With the help of CMAP database,based on the similarity princi-ple of gene expression profile,the drugs that regulated RF were repositioned,and then the components of SKI potential treatment RF were screened by molecular fin-gerprint similarity analysis.At the same time,the core targets and pathways of SKI regulating RF were predic-ted based on network pharmacology.Finally,it was verified by molecular docking and cell experiments.Results Based on the GEO database,two RF-related data sets were screened,and CMAP was relocated to three common RF therapeutic drugs(saracatinib,da-satinib,pp-2).Molecular fingerprint similarity analysis showed that RF therapeutic drugs had high structural similarity with five SKI components such as salvianolic acid B and hydroxysafflor yellow A.Molecular docking results showed that salvianolic acid B,hydroxysafflor yellow A and other components had good binding abili-ty with MMP1 and MMP13,which were the core targets of SKI-regulated potential treatment of RF.Network pharmacology analysis suggested that the core targets of SKI were mainly enriched in signaling pathways such as Relaxin and AGE-RAGE.Cell experiments showed that SKI could significantly reduce the mRNA expres-sion levels of AGER,NFKB1,COL1A1,SERPINE1,VEGFC in AGE-RAGE signaling pathway and MMP1 and MMP13 in Relaxin signaling pathway in RF model cells,and significantly increase the mRNA expression level of RXFP1.Conclusions SKI can play a role in the treatment of RF by regulating Relaxin and AGE-RAGE signaling pathways,and its material basis may be salvianolic acid B,hydroxysafflor yellow A and other components.

Objective To investigate the impact of matrine(Mat)on renal injury in rats with chronic glomerulonephritis by regulating the monocyte chemotactic protein-1(MCP-1)/chemokine C-C-motif receptor 2(CCR2)signaling pathway.Methods The rat model of chronic glomerulonephritis was established by subcutaneous injection of bovine serum albumin,the rats were randomly grouped into control group,model group,low and high dose matrine groups(Mat-L group,Mat-H group),and matrine+CCR2 group(Mat+CCR2 group),with 10 rats in each group.After continuous gavage for 4 weeks,24-hour urine protein excretion was measured;spleen and thymus were removed and organ index was calculated;The levels of blood urea nitrogen(BUN)and serum creatinine(Scr)in the serum of each group were detected,the pathological changes of renal tissue were observed by HE staining;the levels of tumor necrosis factor α(TNF-α)and interleukin(IL)-6 in renal tissue were detected by ELISA;Flow cytometry was applied to detect the proportion of T lymphocyte subsets in peripheral blood of rats in each group;Western blotting was applied to determine the expression of MCP-1 and CCR2 proteins.Results The spleen index and thymus index of rats in the model group rats were obviously reduced,and there were a large number of inflammatory cell infiltration in the renal tissue,the 24-hour urine protein,BUN,Scr,TNF-α,IL-6,and the expression of MCP-1 and CCR2 obviously increased,the peripheral blood T cell subpopulations CD3+,CD4+,and CD4+/CD8+ratio obviously reduced,the proportion of CD8+obviously increased(P＜0.05);The spleen index and thymus index of rats in the Mat-L and Mat-H groups of rats increased,and the phenomenon of renal tissue inflammation and infiltration improved,the 24-hour urine protein,BUN,Scr,TNF-α,IL-6,and the expression of MCP-1 and CCR2 obviously decreased,the peripheral blood T cell subpopulations CD3+,CD4+,and CD4+/CD8+ratio obviously increased,the proportion of CD8+obviously decreased(P＜0.05);CCR2 attenuated the effect of Mat-H on immune function in rats with chronic glomerulonephritis.Conclusion Matrine can alleviate the inflammatory damage and improve the peripheral immune function of rats with chronic glomerulonephritis,and its mechanism may be related to the inhibition of MCP-1/CCR2 signaling pathway.

Objective To evaluate the predictive performance of the Alberta stroke program early computed tomography score(ASPECTS),the Lausanne stroke scale(ASTRAL),DRAGON,START,and the total healthy risks for patients with vascular events calculated(THRIVE-c)score prediction models for the prognosis of patients with acute ischemic stroke(AIS)in Baoding advanced stroke centers,Hebei Province.Methods Clinical data of 909 patients with AIS who were admitted for intravenous thrombolysis in the department of emergency of the advanced stroke center of the Baoding NO.1 Central Hospital from January 2016 to August 2022 were collected and scored using the ASPECTS,ASTRAL,DRAGON,START,and THRIVE-c scales.The 3-month modified Rankin scale(mRS)score was observed for each score,with a score of 0-2 as a good prognosis and 3-6 as a poor prognosis,and multivariate Logistic regression coefficients for the variables in the 5 scores were compared with the original derivation cohort.The predictive efficacy of each scoring model for 3-month poor prognosis of AIS patients was analyzed by using the receiver operator characteristic curve(ROC curve),and area under the curve(AUC)was calculated;the degree of fit of each model to the actual prognostic results was assessed by using the Hosmer-Lemeshow goodness-of-fit test;at the same time,the calibration curves and Brier scores were used as an evaluation of the model's calibration performance indicators.Results A total of 786 patients were enrolled and 340 had a poor prognosis.Comparison of the validation cohort with the original cohort for model construction showed that the mean age in the validation cohort was 65 years old,with a relatively small proportion of 33.84%females,and a median glycemic value of 8.09 mmol/L.The proportion of poor prognosis was lower in the validation cohort compared to the original ASPECTS and THRIVE-c cohort(43.68%vs.51.90%,43.68%vs.50.30%)and higher in the validation cohort compared to the original cohorts of ASTRAL,DRAGON,and START(43.68%vs.34.00%,43.68%vs.35.20%,43.68%vs.39.10%,all P<0.05).ROC curve analysis showed that ASPECTS,ASTRAL,DRAGON,START and THRIVE-c scores all had predictive value for the prognosis of patients with AIS,with AUC and 95%confidence intervals(95%CI)of 0.848(0.820-0.876),0.825(0.795-0.855),0.833(0.805-0.861),0.838(0.811-0.866),and 0.727(0.691-0.762);in the anterior circulation it was 0.852(0.821-0.883),0.817(0.782-0.853),0.815(0.781-0.849),and 0.833(0.800-0.866),0.710(0.668-0.751);and 0.841(0.781-0.902),0.850(0.792-0.908),0.874(0.816-0.931),0.854(0.800-0.908),and 0.775(0.704-0.846)in the posterior loops,respectively.Hosmer-Lemeshow goodness-of-fit test showed that the DRAGON model curve had a smaller gap from the middle diagonal and was better calibrated(χ2=1.483,P=0.993).The Brier score showed that the ASPECTS scoring model had the smallest Brier score was 0.150 and the best performance.Conclusions The ASPECTS,ASTRAL,DRAGON,START,and THRIVE-c scoring models have been shown to be effective in predicting poor prognosis in patients with AIS treated with intravenous thrombolytic therapy at 3 months,with the ASPECTS model showing the most outstanding predictive performance.For anterior infarcts,the ASPECTS score demonstrated the highest predictive efficacy,whereas for posterior infarcts,the DRAGON score had the best predictive performance.The probability of the ASPECTS score in predicting prognosis in the prediction model was in good agreement with the actual probability.