AIM:To explore the mechanism of Salvia miltiorrhiza(Danshen)-derived exosome-like nanoparti-cles(DDN)in attenuating oxidative damage in endothelial cells through the activation of the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB/Akt)/endothelial nitric oxide synthase(eNOS)signaling pathway.METHODS:The DDN were characterized by transmission electron microscopy and dynamic light scattering.Fluorescence microscopy and flow cytometry were used to evaluate the uptake of DDN by human umbilical vein endothelial cells(HUVECs).The viability,migration and invasion of HUVECs were assessed using CCK8 assay,wound-healing assay and Transwell assay,respec-tively.The HUVECs were induced by angiotensin II(Ang II)for oxidative stress and intervened with DDN or LY294002(a PI3K inhibitor).The levels of reactive oxygen species were determined by flow cytometry,and intracellular nitric oxide(NO)content was measured using a biochemical assay kit.Additionally,the protein levels of NADPH oxidase 4(NOX4),NOX2,endothelial nitric oxide syntnase(eNOS),p-eNOS,Akt and p-Akt were examined by Western blot.RESULTS:(1)Transmission electron microscopy and dynamic light scattering analysis revealed that DDN had good bio-compatibility and stability.(2)According to fluorescence images and flow cytometry results,DDN were strongly taken up by HUVECs.(3)Compared with control group,DDN significantly promoted the viability,migration and invasion of HUVECs,showing a dose-dependent effect.(4)Compared with control group,DDN remarkably increased intracellular NO levels,thereby enhancing endothelial cell vasodilation via activating the PI3K/Akt/eNOS signaling pathway.(5)The PI3K/Akt/eNOS pathway played a critical role in mitigating oxidative stress and improving cellular function in response to DDN treat-ment.CONCLUSION:The DDN mediate PI3K/Akt/eNOS signaling pathway activation to significantly alleviate Ang II-induced oxidative damage in endothelial cells,suggesting a potential vascular protective effect of DDN.

Objective To explore the role of nucleolin 6(NOL6)in the occurrence and development of hypertension and its mechanism of regulating ribosome biogenesis.Methods Differentially expressed genes were screened based on the GEO database(chip GSE212338),and intersection analysis was conducted in combination with genes related to ribosome generation to obtain genes related to ribosome biogenesis in hypertension.The rats were divided into control group and model group(L-NAME group).The hypertensive rat model was induced by N-nitro-L-arginine methyl ester(L-NAME),and the thickness and pathological changes of the aortic wall in each group were observed by HE staining.The expression of ribosomal RNA(rRNA)in rat aortic tissues was detected by qPCR to reflect ribosome biogenesis,and the protein expression of NOL6 was detected by Western blotting.Human umbilical vein endothelial cells(HUVECs)were cultured and grouped for treatment(control group,L-NAME group,AngⅡ group,AngⅡ+si-NC group,AngⅡ+si-NOL6 group,and AngⅡ+CX-5461 group).The generation of neocRNA in HUVEC was detected by EU.The protein and mRNA expressions of NOL6 in HUVEC were detected by Western blotting and qPCR,respectively.Western blotting was used to detect the protein expressions of endothelial nitric oxide synthase(eNOS)and p-eNOS.Results By combining the differential expression analysis of the GEO hypertension dataset GSE212338 and the ribosome biogenesis gene set,six core genes with significantly altered expression in hypertension and related to ribosome biogenesis were identified.The difference in NOL6 was the most significant.Compared with the control group,the aortic wall thickness of rats in the L-NAME group increased significantly.Ribosomal RNA expression was significantly upregulated;the protein and mRNA expressions of NOL6 were significantly upregulated,too.Compared with the control group,the generation of neoRNA in the cells of the L-NAME group increased significantly;the levels of NOL6 protein and mRNA,ribosomal RNA and neoRNA in the Ang Ⅱ group were significantly increased compared with the control group but significantly decreased compared with the Ang Ⅱ+si-NC group.Compared with the Ang Ⅱ+si-NOL6 group,the protein and mRNA expressions of NOL6 in the AngⅡ+si-NC group and the AngⅡ+CX-5461 group cells were significantly increased.Compared with the AngⅡ+si-NC group,the levels of ribosomal RNA and neoRNA in the AngⅡ+si-NOL6 group and the AngⅡ+CX-5461 group were significantly decreased;the protein expressions of eNOS and p-eNOS were significantly increased.Conclusion NOL6 is associated with abnormal ribosome biogenesis in hypertension.NOL6 can affect the expression of eNOS by regulating ribosome biogenesis,thereby regulating the occurrence and development of hypertension.

OBJECTIVE To construct a prediction model for the efficacy of serotonin-norepinephrine reuptake inhibitor(SNRI)in inpatients with moderate and severe depression by using a machine learning method.METHODS The case records of inpatients with moderate and severe depression treated with SNRI antidepressants were collected from a third-grade class-A hospital in Xinjiang from January 2022 to October 2024;those patients were divided into effective group and ineffective group based on the Hamilton depression scale-24 score reduction rate.After screening the characteristic variables related to the therapeutic efficacy of SNRI drugs through LASSO regression,five prediction models including support vector machine,k-nearest neighbor,random forest,lightweight gradient boosting machine and extreme gradient boosting were constructed using the training set.Bayesian optimization was used to adjust the hyperparameters of these models.The performance of the models was evaluated in the validation set to select the optimal model.The Shapley additive explanations method was used to perform explainable analysis on the best model.RESULTS The medical records from 355 hospitalized patients with moderate and severe depression were collected,comprising 285 cases in the effective group and 70 cases in the ineffective group,resulting in an overall therapeutic response rate of 80.28%.After feature variable screening,five characteristic variables for therapeutic efficacy were obtained,including Hamilton anxiety scale,blood urea nitrogen,combination of anti-anxiety drugs,drinking history,and first onset of the disease.Compared with other models,the random forest model performed the best.The area under the receiver operating characteristic curve was 0.85,the area under the precision-recall curve was 0.87,the accuracy was 0.74,and the recall rate value was 0.75.CONCLUSIONS The random forest model constructed based on five characteristic variables demonstrates potential for predicting the therapeutic efficacy of SNRI antidepressants in hospitalized patients with moderate and severe depression.

Objective To analyze the clinical characteristics of immune checkpoint inhibitor(ICI)-related hepatotoxicity(ICIH)in cancer patients.Methods A retrospective analysis was conducted on clinical data of cancer patients with ICIH from January 2019 to December 2024.Patients with Grade 1-2 liver injury were defined as the mild group,and those with Grade 3-4 liver injury were defined as the severe group.Results Among 13 patients with ICIH,10(76.92%)were males and 3(23.08%)were females,with a mean age of 67.8±5.2 years.Twelve patients(92.3%)were aged 60 years or above.ICIH first occurred between cycle 1 and cycle 14 after initial treatment,with the highest incidence observed within cycles 1-5.Combination therapy(combination chemotherapy or targeted agents)was used in 10 patients(76.92%).Among the 13 patients,the distribution of liver injury grades was as follows:1 case of Grade 1(7.69%),2 cases of Grade 2(15.38%),5 cases of Grade 3(38.46%),and 5 cases of Grade 4(38.46%).Liver injury types included hepatocellular(38.46%),cholestatic(38.46%),and mixed(23.08%).After drug discontinuation and supportive care,9 patients(69.23%)fully recovered,2(15.38%)improved,and 2(15.38%)showed no improvement.No significant differences were observed between the mild and severe groups in terms of age,body mass index,baseline lymphocyte count,platelet count,neutrophil count,monocyte count,alanine aminotransferase,aspartate aminotransferase,lactate dehydrogenase,alkaline phosphatase,lymphocyte-to-monocyte ratio,neutrophil-to-lymphocyte ratio,and platelet-to-lymphocyte ratio(P>0.05).Conclusion ICIH typically occurs within 1 to 5 cycles after ICI administration,with non-specific clinical manifestations,which lead to a diagnosis of exclusion.Despite a generally favorable prognosis,severe ICIH can be fatal,particularly in patients with primary liver cancer.Prompt discontinuation of ICIs and initiation of Corticosteroid therapy can lead to timely improvement of patient's condition.

Objective:To investigate whether brown adipose tissue-derived exosomes(BAT-exos) could ameliorate endothelial cell injury by activating Pink1-Parkin pathway-mediated mitophagy.Methods:Endothelial cell injury was induced with angiotensin Ⅱ(Ang Ⅱ) to establish a cellular injury model. Exosomes were isolated from both brown adipose tissue and white adipose tissue and characterized by transmission electron microscopy(TEM), nanoparticle tracking analysis(NTA), fluorescence labeling, and Western blot. Cell viability was assessed using the CCK-8 assay, and apoptosis rates were determined by flow cytometry. Levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-6, and IL-8 were measured by ELISA. Mitochondrial autophagy was assessed by immunofluorescence colocalization, and protein expression levels of Pink1, Parkin, and LC3 Ⅱ/I were determined by Western blot.Results:Ang Ⅱ induced endothelial cell apoptosis, activated inflammatory responses, and suppressed mitophagy, as evidenced by decreased expression of mitophagy-related proteins. Following the successful characterization of BAT-exos, we found that BAT-exos activated mitophagy and alleviated endothelial cell injury, whereas white adipose tissue-derived exosomes(WAT-exos) inhibited mitophagy and exacerbated injury. Mechanistically, BAT-exos targeted the Pink1-Parkin signaling pathway to activate mitophagy.Conclusion:BAT-exos markedly improve endothelial cell injury by activating mitophagy through the Pink1-Parkin pathway, providing new insights and potential therapeutic targets for cardiovascular diseases.

Objective To analyze the clinical characteristics of immune checkpoint inhibitor(ICI)-related hepatotoxicity(ICIH)in cancer patients.Methods A retrospective analysis was conducted on clinical data of cancer patients with ICIH from January 2019 to December 2024.Patients with Grade 1-2 liver injury were defined as the mild group,and those with Grade 3-4 liver injury were defined as the severe group.Results Among 13 patients with ICIH,10(76.92%)were males and 3(23.08%)were females,with a mean age of 67.8±5.2 years.Twelve patients(92.3%)were aged 60 years or above.ICIH first occurred between cycle 1 and cycle 14 after initial treatment,with the highest incidence observed within cycles 1-5.Combination therapy(combination chemotherapy or targeted agents)was used in 10 patients(76.92%).Among the 13 patients,the distribution of liver injury grades was as follows:1 case of Grade 1(7.69%),2 cases of Grade 2(15.38%),5 cases of Grade 3(38.46%),and 5 cases of Grade 4(38.46%).Liver injury types included hepatocellular(38.46%),cholestatic(38.46%),and mixed(23.08%).After drug discontinuation and supportive care,9 patients(69.23%)fully recovered,2(15.38%)improved,and 2(15.38%)showed no improvement.No significant differences were observed between the mild and severe groups in terms of age,body mass index,baseline lymphocyte count,platelet count,neutrophil count,monocyte count,alanine aminotransferase,aspartate aminotransferase,lactate dehydrogenase,alkaline phosphatase,lymphocyte-to-monocyte ratio,neutrophil-to-lymphocyte ratio,and platelet-to-lymphocyte ratio(P>0.05).Conclusion ICIH typically occurs within 1 to 5 cycles after ICI administration,with non-specific clinical manifestations,which lead to a diagnosis of exclusion.Despite a generally favorable prognosis,severe ICIH can be fatal,particularly in patients with primary liver cancer.Prompt discontinuation of ICIs and initiation of Corticosteroid therapy can lead to timely improvement of patient's condition.

AIM:To explore the mechanism of Salvia miltiorrhiza(Danshen)-derived exosome-like nanoparti-cles(DDN)in attenuating oxidative damage in endothelial cells through the activation of the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB/Akt)/endothelial nitric oxide synthase(eNOS)signaling pathway.METHODS:The DDN were characterized by transmission electron microscopy and dynamic light scattering.Fluorescence microscopy and flow cytometry were used to evaluate the uptake of DDN by human umbilical vein endothelial cells(HUVECs).The viability,migration and invasion of HUVECs were assessed using CCK8 assay,wound-healing assay and Transwell assay,respec-tively.The HUVECs were induced by angiotensin II(Ang II)for oxidative stress and intervened with DDN or LY294002(a PI3K inhibitor).The levels of reactive oxygen species were determined by flow cytometry,and intracellular nitric oxide(NO)content was measured using a biochemical assay kit.Additionally,the protein levels of NADPH oxidase 4(NOX4),NOX2,endothelial nitric oxide syntnase(eNOS),p-eNOS,Akt and p-Akt were examined by Western blot.RESULTS:(1)Transmission electron microscopy and dynamic light scattering analysis revealed that DDN had good bio-compatibility and stability.(2)According to fluorescence images and flow cytometry results,DDN were strongly taken up by HUVECs.(3)Compared with control group,DDN significantly promoted the viability,migration and invasion of HUVECs,showing a dose-dependent effect.(4)Compared with control group,DDN remarkably increased intracellular NO levels,thereby enhancing endothelial cell vasodilation via activating the PI3K/Akt/eNOS signaling pathway.(5)The PI3K/Akt/eNOS pathway played a critical role in mitigating oxidative stress and improving cellular function in response to DDN treat-ment.CONCLUSION:The DDN mediate PI3K/Akt/eNOS signaling pathway activation to significantly alleviate Ang II-induced oxidative damage in endothelial cells,suggesting a potential vascular protective effect of DDN.

OBJECTIVE To systematically evaluate risk prediction models for chemotherapy-induced myelosuppression in breast cancer， and provide a scientific reference for clinical healthcare workers in selecting or developing effective predictive models. METHODS A systematic search was conducted for studies on predictive models of the risk of chemotherapy-induced myelosuppression in breast cancer across the CNKI， VIP， Wanfang， PubMed， Web of Science， Cochrane Library， Embase， and Scopus databases， with a time frame of the establishment of the database to May 7， 2024. Literature was independently screened by 2 investigators， data were extracted according to critical appraisal and data extraction for systematic reviews of predictive model studies， and the risk of bias evaluation tool for predictive model studies was used to analyze the risk of bias and applicability of the included studies. RESULTS There were totally 7 studies， comprising 12 models. Among them， 11 models indicated an area under the subject operating characteristic curve of 0.600-0.908； 2 models indicated calibration. The common predictor variables of the included models were age， pre-chemotherapy neutrophil count， pre-chemotherapy lymphocyte count， and pre-chemotherapy albumin. The overall risk of bias of the 7 studies was high， which was mainly attributed to the flaws in the study design， insufficient sample sizes， inappropriate treatment of variables， non-reporting of missing data， and the lack of indicators for the assessment of the models， but the applicability was good. CONCLUSIONS The predictive performance of risk predictive models for chemotherapy-induced myelosuppression in breast cancer remains to be further enhanced， and the overall risk of model bias is high. Future studies should follow the specifications of model development and reporting， then combine machine learning algorithms to develop risk predictive models with good predictive performance， high stability， and low risk of bias， so as to provide a decision-making basis for the clinic.

Objective To explore the relationship between triglyceride-glucose index(TyG)and acute ischemic stroke with large vessel occlusion(AIS-LVO)of anterior circulation.Methods A retrospective study was conducted on patients with anterior circulation AIS-LVO who underwent emergency endovascular thrombectomy at Neurovascular Center of The First Affiliated Hospital of Naval Medical University from Jan.2018 to Dec.2019.According to modified Rankin scale(mRS)score 90 d after operation,the patients were assigned to favorable outcome group(mRS score 0-2)or unfavorable outcome group(mRS score 3-6),and the TyG was compared.According to the median of TyG,the patients were assigned to low-TyG group(TyG＜8.57)or high-TyG group(TyG ≥8.57),and the clinical data,laboratory indexes,and imaging characteristics were compared.Receiver operating characteristic curve was used to evaluate the predictive value of TyG for poor prognosis.Results A total of 135 patients were enrolled,with 72 in the favorable outcome group and 63 in the unfavorable outcome group.The TyG of the unfavorable outcome group was significantly higher than that of the favorable outcome group(8.82+0.63 vs 8.43+0.60,P＜0.001).There were 67 patients in the low-TyG group and 68 in the high-TyG group.Compared with the low-TyG group,the proportion of patients with hyperlipidemia history(P=0.003),systolic blood pressure at admission(P=0.018),fasting blood glucose level(P＜0.001),and triglyceride level(P＜0.001)were significantly higher in the high-TyG group,the infarct core volume was significantly larger(P=0.025),the high density lipoprotein-cholesterol level was significantly lower(P=0.013),and the mRS score 90 d after operation was significantly higher(3[1,5]vs 1[0,5],P=0.049).The TyG had certain predictive value for poor prognosis in anterior circulation AIS-LVO patients(area under curve value=0.662,95％confidence interval 0.571-0.753).Conclusion TyG is elevated in anterior circulation AIS-LVO patients with poor prognosis,and may be a potential prognostic indicator for anterior circulation AIS-LVO patients.

Objective To investigate the safety and effectiveness of endovascular treatment in patients with acute ischemic stroke due to large vessel occlusion(AIS-LVO)over 24 h after onset.Methods The clinical data of AIS-LVO patients who received endovascular treatment in Neurovascular Center of The First Affiliated Hospital of Naval Medical University from Jan.2018 to Dec.2022 were retrospectively analyzed,including baseline characteristics,imaging findings,treatment,degree of vascular recanalization(modified thrombolysis in cerebral infarction grade 2b and 3 for successful recanalization)and prognosis.Results A total of 57 patients were included,including 42 males and 15 females,aged from 30 to 84 years old.The most common risk factors were hypertension(39 cases,68.4%),followed by smoking history(24 cases,42.1%),diabetes mellitus(17 cases,29.8%),previous stroke history(16 cases,28.1%),and atrial fibrillation(9 cases,15.8%).Before treatment,the National Institutes of Health stroke scale score was 12.84±7.04,and the Alberta Stroke Program early computed tomography score was 9.00(7.00,10.00).Vascular occlusion sites included middle cerebral artery occlusion in 27(47.4%)cases,internal carotid artery occlusion in 24(42.1%)cases,and tandem lesions in 6(10.5%)cases.The time from onset to femoral artery puncture was 38.30(28.17,53.71)h,and the time from femoral artery puncture to vascular recanalization was 52.00(38.50,92.50)min.General anesthesia was the main anesthesia method,accounting for 64.9%(37/57).The etiological types of stroke were mainly large artery atherosclerosis(38 cases,66.7%),cardiogenic embolism(9 cases,15.8%),unknown causes(6 cases,10.5%),and other clear causes(4 cases,7.0%).Mechanical thrombectomy was the first choice in 41(71.9%)cases,balloon dilatation/stenting was used in 35(61.4%)cases,of which 15(26.3%)cases were the first choice.Finally,53(93.0%)cases were recanalized successfully.In terms of complications,1(1.8%)case had symptomatic intracranial hemorrhage.The 90-d prognosis rate was 59.6%(34/57),and 3(5.3%)cases died.Conclusion Endovascular treatment for AIS-LVO patients over 24 h after onset has high recanalization rate and good safety,but it still needs to be further verified by randomized controlled trials.