Objective:To investigate protective mechanism of resveratrol(RES)on brain injury after ischemic stroke(IS)and its regulatory mechanism on nico-tinamide adenine dinucleotide phosphate oxidase 2(NOX2)mediated polarization of microglia.Methods:Low and high doses of RES were used for intervention.Tetrabromocinnamic acid(TBCA),a specific agonist of NOX2,was used to save function.PC12 and LMAI Bio cell models with oxygen-glucose deprivation/reoxygenation(OGD/R)were constructed.TUNEL was used to detect apoptosis of PC12 cells.Immunofluorescence was used to detect polarization of LMAI Bio cells.Western blot was used to detect expressions of NOX2,NF-κB,TNF-α,IL-1β,IL-10 and TGF-β in PC12 and LMAI Bio cells.Results:RES could significantly inhibit apoptosis of PC12 cells induced by OGD/R,and regulate LMAI Bio cells polarization to M2 type.Western blot showed that RES could significantly down-regulate NOX2,NF-κB,TNF-α and IL-1β expressions in OGD/R cells,up-regulate IL-10 and TGF-β expressions,while TBCA could partially reverse protective effect of RES on neurons.Conclusion:RES can inhibit neuronal apoptosis after IS,which may be related to its regulation of NOX2-mediated polarization of microglia.

Objective·To investigate the association of insulin resistance with left ventricular(LV)remodeling after ST-segment elevation myocardial infarction(STEMI)in patients without a history of diabetes mellitus.Methods·This study consecutively enrolled STEMI patients without a history of diabetes mellitus who underwent percutaneous coronary intervention in the Department of Cardiology of Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,from January 2014 to December 2022.The patients were followed up for 6 months.Age,gender,smoking status,blood pressure,body mass index,biochemical indexes(liver function,kidney function,lipid profiles,glycemic levels and peak troponin levels,etc.)and pharmacological treatment were recorded.Homeostasis model assessment of insulin resistance(HOMA-IR)was used to evaluate insulin resistance and mean values of visit-to-visit HOMA-IR were calculated.Patients were divided into 4 groups(low-level group,low-to-medium-level group,medium-to-high-level group,and high-level group)according to the quartiles of mean HOMA-IR levels.Echocardiography was performed at baseline and during follow-up.Then the association between mean values of insulin resistance and post-infarction LV remodeling was analyzed.Results·A total of 219 patients were finally included,with an average age of(62.7±11.9)years,and male patients accounted for 85.4％(187 cases).The average follow-up time was(6.4±1.8)months.During follow-up,the average number of HOMA-IR measurements was(4.32±2.18),and the mean value of visit-to-visit HOMA-IR was 2.41(1.58,3.98),which was higher than normal range.The results showed that post-infarction LV end-diastolic diameter(P=0.027)and LV end-diastolic volume index(P=0.013)generally showed a trend for dilation with increasing mean HOMA-IR levels.Pearson correlation analysis revealed the mean values of visit-to-visit HOMA-IR were positively correlated to changes in LV dimensions(△ LV end-diastolic volume index:r=0.20,P=0.003;△ LV end-diastolic diameter:r=0.21,P=0.002).Multivariate regression analysis demonstrated that higher HOMA-IR was independently associated with greater LV dilation after STEMI,even after adjusting for age,gender,traditional risk factors(history of hypertension,body mass index,smoking status,renal function and lipid profiles),pharmacological treatment,baseline LV ejection fraction and peak troponin levels.Compared with patients with the lowest quartile of HOMA-IR,those with the highest HOMA-IR quartile exhibited a 7.727 mL/m2 increase in LV end-diastolic volume index(P＜0.001).Conclusion·This study reveals that insulin resistance is prevalent in STEMI patients without a history of diabetes mellitus.Insulin resistance is an independent predictor of adverse LV remodeling in this population.

Objective:To investigate protective mechanism of resveratrol(RES)on brain injury after ischemic stroke(IS)and its regulatory mechanism on nico-tinamide adenine dinucleotide phosphate oxidase 2(NOX2)mediated polarization of microglia.Methods:Low and high doses of RES were used for intervention.Tetrabromocinnamic acid(TBCA),a specific agonist of NOX2,was used to save function.PC12 and LMAI Bio cell models with oxygen-glucose deprivation/reoxygenation(OGD/R)were constructed.TUNEL was used to detect apoptosis of PC12 cells.Immunofluorescence was used to detect polarization of LMAI Bio cells.Western blot was used to detect expressions of NOX2,NF-κB,TNF-α,IL-1β,IL-10 and TGF-β in PC12 and LMAI Bio cells.Results:RES could significantly inhibit apoptosis of PC12 cells induced by OGD/R,and regulate LMAI Bio cells polarization to M2 type.Western blot showed that RES could significantly down-regulate NOX2,NF-κB,TNF-α and IL-1β expressions in OGD/R cells,up-regulate IL-10 and TGF-β expressions,while TBCA could partially reverse protective effect of RES on neurons.Conclusion:RES can inhibit neuronal apoptosis after IS,which may be related to its regulation of NOX2-mediated polarization of microglia.

Objective·To investigate the association of insulin resistance with left ventricular(LV)remodeling after ST-segment elevation myocardial infarction(STEMI)in patients without a history of diabetes mellitus.Methods·This study consecutively enrolled STEMI patients without a history of diabetes mellitus who underwent percutaneous coronary intervention in the Department of Cardiology of Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,from January 2014 to December 2022.The patients were followed up for 6 months.Age,gender,smoking status,blood pressure,body mass index,biochemical indexes(liver function,kidney function,lipid profiles,glycemic levels and peak troponin levels,etc.)and pharmacological treatment were recorded.Homeostasis model assessment of insulin resistance(HOMA-IR)was used to evaluate insulin resistance and mean values of visit-to-visit HOMA-IR were calculated.Patients were divided into 4 groups(low-level group,low-to-medium-level group,medium-to-high-level group,and high-level group)according to the quartiles of mean HOMA-IR levels.Echocardiography was performed at baseline and during follow-up.Then the association between mean values of insulin resistance and post-infarction LV remodeling was analyzed.Results·A total of 219 patients were finally included,with an average age of(62.7±11.9)years,and male patients accounted for 85.4％(187 cases).The average follow-up time was(6.4±1.8)months.During follow-up,the average number of HOMA-IR measurements was(4.32±2.18),and the mean value of visit-to-visit HOMA-IR was 2.41(1.58,3.98),which was higher than normal range.The results showed that post-infarction LV end-diastolic diameter(P=0.027)and LV end-diastolic volume index(P=0.013)generally showed a trend for dilation with increasing mean HOMA-IR levels.Pearson correlation analysis revealed the mean values of visit-to-visit HOMA-IR were positively correlated to changes in LV dimensions(△ LV end-diastolic volume index:r=0.20,P=0.003;△ LV end-diastolic diameter:r=0.21,P=0.002).Multivariate regression analysis demonstrated that higher HOMA-IR was independently associated with greater LV dilation after STEMI,even after adjusting for age,gender,traditional risk factors(history of hypertension,body mass index,smoking status,renal function and lipid profiles),pharmacological treatment,baseline LV ejection fraction and peak troponin levels.Compared with patients with the lowest quartile of HOMA-IR,those with the highest HOMA-IR quartile exhibited a 7.727 mL/m2 increase in LV end-diastolic volume index(P＜0.001).Conclusion·This study reveals that insulin resistance is prevalent in STEMI patients without a history of diabetes mellitus.Insulin resistance is an independent predictor of adverse LV remodeling in this population.

Objective Network pharmacology,Molecular docking and Label-free DIA quantitative phosphoproteomics were used to reveal the potential mechanism of Peiminine against colon cancer.Methods 1The target of peiminine was obtained by SwissTargetPrediction,TargetNet and pharmmapper,and the target of colon cancer was obtained by DisGeNET,GeneCards and OMIM.Then the intersection target of Peiminine and Colon cancer was obtained by Venny2.1.0 online platform.Then,String database and Cytoscape3.8.2 software were used to map the PPI network of intersection targets,and the main targets of Peiminine against Colon cancer were obtained.GO analysis and KEGG pathway analysis were carried out through David database and Weisenxin visual cloud platform.② MOE(molecular operating environment)software was used to perform molecular docking of peiminine and the main target.③ Label-free DIA quantitative phosphoproteomics was used to detect and analyze the biological function of DT group(DT1-DT3)treated with Peiminine and control group(NC1-NC3).Results ① There were 275 intersection targets between peiminine and colon cancer.Molecular docking showed that peiminine could stably dock and interact with the protein structures of AKT1,EGFR,HSP90AA1 and SRC:Peiminine interacted with the amino acid residues of AKT1 mainly through hydrogen bonding.Peiminine interacted with amino acid residues of EGFR,HSP90AA1 and SRC mainly through ionic bond and hydrogen bonding.② Phosphoproteomics analysis showed that:Compared with the NC group,880 phosphorylated modification sites were significantly up-regulated in the DT group(including S124 and S126 sites of AKT1 and T648 and S643 sites of EGFR),and 425 phosphorylated modification sites were significantly down-regulated in the DT group(including T317 sites of HSP90AA1).③ Comparing the results of network pharmacology and phosphoproteomics analysis,it was found that:The main targets of Peiminine against Colon cancer are AKT1,EGFR and HSP90AA1.It promotes apoptosis of colon cancer cells by regulating 17 pathways including AMPK signaling pathway,mTOR signaling pathway and Choline metabolism in cancer.Conclusion This study revealed the potential mechanism of peiminine in the treatment of colon cancer with multiple targets and multiple pathways,and provided a certain direction and reference for subsequent research.

Objective:To provide evidence-based recommendations for the prevention and management of lower limb ischemia in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) patients during treatment according to search, evaluate, and summarize the best evidence on the prevention and management of lower limb ischemia in patients with VA-ECMO.Methods:Based on the PIPOST framework (population, intervention, professional, outcome, setting, and type of evidence), an evidence-based question was formulated. A systematic search was conducted according to the "6S" evidence pyramid model in both domestic and international databases, as well as professional association websites, for all evidence related to the prevention and management of lower limb ischemia in VA-ECMO patients (aged ≥18 years). The types of evidence included clinical decisions, guidelines, expert consensus, systematic reviews, evidence summaries, and original studies. The search was conducted from the construction of the databases to February 2024. Two researchers independently conducted a literature quality evaluation, extracted and summarized evidence from the studies that met the quality criteria.Results:A total of 13 articles were included, consisting of 3 clinical decisions, 3 guidelines, 3 expert consensus, 3 systematic reviews, and 1 randomized controlled trial. A total of 18 pieces of evidence in 7 dimensions were summarized, including risk factors of VA-ECMO lower limb ischemia, evaluation before catheterization, evaluation and monitoring during treatment, prevention of lower limb ischemia, treatment of lower limb ischemia, management of distal perfusion catheter (DPC), and monitoring after VA-ECMO weaning.Conclusion:This evidence summary provides evidence-based recommendations for the prevention and management of lower limb ischemia in VA-ECMO patients, aiming to assist clinical healthcare professionals in developing tailored strategies for the prevention and management of lower limb ischemia based on during VA-ECMO support.

Objective:To investigate the clinical features and therapeutic efficacy of patients with hereditary leiomyomatosis and renal cell carcinoma(RCC) syndrome-associated RCC (HLRCC-RCC) in China.Methods:The clinical data of 119 HLRCC-RCC patients with fumarate hydratase (FH) germline mutation confirmed by genetic diagnosis from 15 medical centers nationwide from January 2008 to December 2021 were retrospectively analyzed. Among them, 73 were male and 46 were female. The median age was 38(13, 74) years. The median tumor diameter was 6.5 (1.0, 20.5) cm. There were 38 cases (31.9%) in stage Ⅰ-Ⅱand 81 cases (68.1%) in stage Ⅲ-Ⅳ. In this group, only 11 of 119 HLRCC-RCC patients presented with skin smooth muscle tumors, and 44 of 46 female HLRCC-RCC patients had a history of uterine fibroids. The pathological characteristics, treatment methods, prognosis and survival of the patients were summarized.Results:A total of 86 patients underwent surgical treatment, including 70 cases of radical nephrectomy, 5 cases of partial nephrectomy, and 11 cases of reductive nephrectomy. The other 33 patients with newly diagnosed metastasis underwent renal puncture biopsy. The results of genetic testing showed that 94 patients had FH gene point mutation, 18 had FH gene insertion/deletion mutation, 4 had FH gene splicing mutation, 2 had FH gene large fragment deletion and 1 had FH gene copy number mutation. Immunohistochemical staining showed strong 2-succinocysteine (2-SC) positive and FH negative in 113 patients. A total of 102 patients received systematic treatment, including 44 newly diagnosed patients with metastasis and 58 patients with postoperative metastasis. Among them, 33 patients were treated with tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI), 8 patients were treated with bevacizumab combined with erlotinib, and 61 patients were treated with TKI monotherapy. Survival analysis showed that the median progression-free survival (PFS) of TKI combined with ICI was 18 (5, 38) months, and the median overall survival (OS) was not reached. The median PFS and OS were 12 (5, 14) months and 30 (10, 32) months in the bevacizumab combined with erlotinib treatment group, respectively. The median PFS and OS were 10 (3, 64) months and 44 (10, 74) months in the TKI monotherapy group, respectively. PFS ( P=0.009) and OS ( P=0.006) in TKI combined with ICI group were better than those in bevacizumab combined with erlotinib group. The median PFS ( P=0.003) and median OS ( P=0.028) in TKI combined with ICI group were better than those in TKI monotherapy group. Conclusions:HLRCC-RCC is rare but has a high degree of malignancy, poor prognosis and familial genetic characteristics. Immunohistochemical staining with strong positive 2-SC and negative FH can provide an important basis for clinical diagnosis. Genetic detection of FH gene germ line mutation can confirm the diagnosis. The preliminary study results confirmed that TKI combined with ICI had a good clinical effect, but it needs to be confirmed by the results of a large sample multi-center randomized controlled clinical study.

Objective Network pharmacology,Molecular docking and Label-free DIA quantitative phosphoproteomics were used to reveal the potential mechanism of Peiminine against colon cancer.Methods 1The target of peiminine was obtained by SwissTargetPrediction,TargetNet and pharmmapper,and the target of colon cancer was obtained by DisGeNET,GeneCards and OMIM.Then the intersection target of Peiminine and Colon cancer was obtained by Venny2.1.0 online platform.Then,String database and Cytoscape3.8.2 software were used to map the PPI network of intersection targets,and the main targets of Peiminine against Colon cancer were obtained.GO analysis and KEGG pathway analysis were carried out through David database and Weisenxin visual cloud platform.② MOE(molecular operating environment)software was used to perform molecular docking of peiminine and the main target.③ Label-free DIA quantitative phosphoproteomics was used to detect and analyze the biological function of DT group(DT1-DT3)treated with Peiminine and control group(NC1-NC3).Results ① There were 275 intersection targets between peiminine and colon cancer.Molecular docking showed that peiminine could stably dock and interact with the protein structures of AKT1,EGFR,HSP90AA1 and SRC:Peiminine interacted with the amino acid residues of AKT1 mainly through hydrogen bonding.Peiminine interacted with amino acid residues of EGFR,HSP90AA1 and SRC mainly through ionic bond and hydrogen bonding.② Phosphoproteomics analysis showed that:Compared with the NC group,880 phosphorylated modification sites were significantly up-regulated in the DT group(including S124 and S126 sites of AKT1 and T648 and S643 sites of EGFR),and 425 phosphorylated modification sites were significantly down-regulated in the DT group(including T317 sites of HSP90AA1).③ Comparing the results of network pharmacology and phosphoproteomics analysis,it was found that:The main targets of Peiminine against Colon cancer are AKT1,EGFR and HSP90AA1.It promotes apoptosis of colon cancer cells by regulating 17 pathways including AMPK signaling pathway,mTOR signaling pathway and Choline metabolism in cancer.Conclusion This study revealed the potential mechanism of peiminine in the treatment of colon cancer with multiple targets and multiple pathways,and provided a certain direction and reference for subsequent research.

【Objective】 To investigate the risk factors and predictive effectiveness of prostate imaging reporting and data system (PI-RADS) score for patients with clinically significant prostate cancer (CsPCa) whose PI-RADS score was 3, so as to provide evidence for the diagnosis and treatment. 【Methods】 The clinical and multi-parameter magnetic resonance imaging (mpMRI) data of 153 CsPCa patients treated during Jan.2017 and Dec.2021 whose PI-RADS score was 3 were retrospectively analyzed. With PI-RADS score of 3 as the independent risk factor for CsPCa, the other relevant independent risk factors in predicting CsPCa were evaluated. 【Results】 Univariate and multivariate analyses showed that prostate-specific antigen (PSA) density and apparent dispersion coefficient (ADC) were independent risk factors for the diagnosis of CsPCa (P<0.05). Analysis of receiver operating characteristic (ROC) curve showed that combined PSA density and ADC were more effective than PSA density and ADC alone (P<0.05). 【Conclusion】 The combination of PSA density and ADC can guide clinicians to identify high-risk CsPCa patients from patients with PI-RADS score of 3 points.

Cell Cycle Proteins ; Microtubule-Associated Proteins