Aim To investigate the effect of ellagic acid (EA) on cognitive function in APP/PS 1 double- transgenic mice, and to explore the regulatory mechanism of ellagic acid on the level of oxidative stress in the hippocampus of double-transgenic mice based on the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3 (PI3K/AKT/GSK-3 β) signaling pathway. Methods Thirty-two SPF-grade 6-month-old APP/PS 1 double transgenic mice were randomly divided into four groups, namely, APP/PS 1 group, APP/PS1 + EA group, APP/PS1 + LY294002 group, APP/PS 1 + EA + LY294002 group, with eight mice in each group, and eight SPF-grade C57BL/6J wild type mice ( Wild type) were selected as the blank control group. The APP/PS 1 + EA group was given 50 mg · kg

Objective To assess the viability and efficacy of employing automated segmentation for whole breast radiotherapy with simultaneous integrated boost to the medial tumor beds,a comparative analysis was conducted on the disparities in geometry,dosimetry,and working time between the auto-segmentation(AS)and manual segmentation(MS)groups.Methods A total of 30 patients with early breast cancer,who had undergone conserving surgery and received hypofractionated radiotherapy with a boost to the medial tumor bed,were enrolled from the First People's Hospital of Zunyi.AccuContour software was used in the AS group to obtain the whole breast planning target volume and cardiopulmonary structure.Geometric differences between AS and MS groups were assessed using Dice similarity coefficient(DSC)and 95%Hausdorff distance(95HD).Subsequently,a comparison was made between the two groups regarding target and cardiopulmonary dosimetry for PlanA and PlanM.Additionally,the time spent by each group was also compared.Results The DSC of PGTV,PTV,lung,and heart were 0.94(0.91,0.96),0.88(0.86,0.91),0.98(0.97,0.98)and 0.94(0.93,0.95),respectively.And the 95 HD(cm)were 0.25(0.20,0.33),0.99(0.56,1.20),0.29(0.25,0.35)and 0.50(0.50,0.59)respectively.The dosimetric results showed that the V95,D95,and Dmean of PGTV and PTV in the AS group were significantly lower than those in the MS group(P<0.05);while the V20 and MLD of the left lung were significantly higher(P<0.05).No significant difference was observed in cardiac dose between the two groups.The mean absolute differences of PGTV and cardiopulmonary dose parameters between the two groups were less than 1 Gy/1%,respec-tively.In terms of work efficiency,the AS approach substantially reduced contouring and planning time with over 70%of cases approved within two days.Conclusions The differences in geometric and dosimetric parameters between the auto-segmentation and manual segmentation groups were found to be negligible for whole breast radiotherapy with medial tumor bed boost patients.It is recommended that the PTV be manually modified prior to plan optimiza-tion,leading to a significant improvement in work efficiency.

Ecto-nucleotide pyrophosphatases/phosphodiesterases(ENPPs)are involved in the hydrolysis of different purine nu-cleotides in a range of physiological processes.In recent years,it has also been found to be involved in tumor progression,with ENPP1 often overexpressed in local recurrence and tumor metas-tasis,which is associated with poor prognosis and survival in a range of solid tumors.The role of ENPP1 in tumors is mainly fo-cused on tumor proliferation,metastasis,immunity,recurrence,etc.,and it is speculated that ENPP1 can be used as a prognos-tic indicator for a variety of tumors.ENPP1 promotes the immu-nosuppressive tumor microenvironment by being obliquely in-volved in the regulation of ATP/adenosine homeostasis by com-bining with other components,which crosses with interferon gene stimulators to impair its potent immune response through the hy-drolysis of the effector 2',3'-cyclic GMP-AMP.Therefore,EN-PP1 blockade has become an effective means to induce immune remodeling and inhibit tumorigenesis and development.The ex-isting ENPP1 inhibitors mainly include natural small molecule compounds,nucleotide ENPP1 inhibitors,non-nucleotide EN-PP1 inhibitors,and novel small molecule ENPP1 inhibitors.So far,a small number of ENPP1 inhibitors have been developed and are rarely suitable for in vivo experiments,and they are still in the stage of developing effective compounds or lead com-pounds,and the research on ENPP1 inhibitors needs to be fur-ther studied.This review summarizes and discusses the role of ENPP1 in tumors,and summarizes the current research progress of various ENPP1 agents and their current research progress,in order to provide a reference for further research on the prepara-tion of drug candidates.

Tumor metastasis is the main cause of death in clinical patients. The proposal of the pre-metastatic microenvironment hypothesis offers a new research direction for tumor metastasis. Targeting and inhibiting the activation of the stimulator of interferon genes(STING) signals by tumor cell-derived microparticles may help reduce tumor metastasis. This study constructed a pre-metastatic microenvironment and pulmonary metastasis model using recombinant adeno-associated virus vector-mediated short hairpin RNA interference of STING(rAAV STING shRNA) to investigate the effects of STING interference on the pre-metastatic microenvironment and the impact of total Epimedium flavonoids(EFs) as an intervention. Drug-containing microparticles were prepared by incubating mouse Lewis lung cancer(LLC) cells with the total EFs(EFs-LLC-MPs), and EFs-LLC-MPs were characterized by measuring the average particle size, polydispersity index, zeta potential, and release profile. Western blot was used to examine changes in pre-metastatic microenvironment markers in mouse alveolar epithelial cells(MLE-12) after treatment with microparticles or total EFs. Drug loading capacity and the uptake of microparticles by MLE-12 and mouse alveolar macrophages(MH-S) cells were determined using HPLC and flow cytometry. The uptake experiments showed that after nasal administration of rAAV STING shRNA, STING expression was significantly inhibited, and the markers of the pre-metastatic microenvironment were markedly reduced. Micro-CT results indicated a reduction in lung metastases and nodules, and the anti-metastatic effect of total EFs was affected. The results showed that the microparticles were membrane vesicles with a particle size of(373.17±3.18)nm, a Zeta potential of(-35.40±1.08)mV, a protein concentration of 562.62 μg·mL~(-1), and a drug loading of 0.060 9 μg per microgram of protein. These microparticles were effectively taken up by MLE-12 and MH-S cells. Treatment of MLE-12 and MH-S cells with EFs-LLC-MPs reduced the expression of pre-metastatic microenvironment markers such as fibronectin and lysyl oxidase(LOX). Based on these findings, it was confirmed that STING was involved in the regulation of the formation of the pre-metastatic microenvironment in the lungs. Furthermore, total EFs microparticles were successfully prepared, showing potential to intervene in the inflammatory pre-metastatic microenvironment, which could be promising for controlling tumor metastasis.
Animals ; Flavonoids/chemistry* ; Mice ; Tumor Microenvironment/drug effects* ; Epimedium/chemistry* ; Lung Neoplasms/metabolism* ; Humans ; Mice, Inbred C57BL ; Neoplasm Metastasis ; Cell Line, Tumor ; Particle Size ; Drugs, Chinese Herbal/pharmacology* ; Membrane Proteins/metabolism*

Objective To investigate the factors affecting the efficacy of leflunomide combined with medium/low dose corticosteroids in the treatment of progressive IgA nephropathy (IgAN).Methods Clinical and pathological parameters were collected retrospectively in patients of primary IgAN with proteinuria＞ 1.0 g/24 h and chronic kidney disease (CKD) stage 1-3 treated with leflunomide combined with medium/low dose corticosteroids in Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University from Jan 2005 to Dec 2010.According to the treatment effects,patients were divided into complete remission group and non-complete remission group.The biochemical and pathological indexes of the two groups were compared.Results A total of 42 patients were included.The remission rates at 3,6,9 and 12 months were 62％,64％,67％ and 74％,respectively.Seventeen (40.5％) and fourteen (33.3％) patients achieved complete and partial remission after one-year treatment,and the remission rate remained stable within one year after withdrawal of drugs.The 24hour proteinuria was 1.50 (0.67,2.66) g,which was significantly reduced compared with the baseline 2.44 (1.36,3.74) g (P ＜ 0.01).The decrease rate was 31.3％.There was a slight decrease in proteinuriawithin one year after withdrawal of drugs.Estimated glomerular filtration rate (eGFR) remained stable during the treatment and a year of follow-up.No serious adverse event was observed during the followup period.Among 31 responder patients,6(19.4％) patients relapsed.Logistic multivariate regression analysis suggested that the degree of renal interstitial inflammatory infiltration was an independent predictor of complete remission with one-year treatment of leflunomide combined with medium / low dose corticosteroids (HR=0.067,95％ CI 0.008-0.535,P=0.011).Conclusions IgAN treated with leflunomide and medium/low dose corticosteroids can achieve remission in early stage,and the remission rate remains stable after withdrawal of drugs.It is a safe option for the treatment of IgAN.Renal interstitial inflammatory infiltration is an independent predictor of complete remission.

Objective To compare the efficacy and safety of leflunomide (LEF) combined with medium/low dose corticosteroids and full dose of corticosteroids in the treatment of IgA nephropathy. Method Primary IgAN patients diagnosed by renal biopsy with 18?65 years old and eGFR≥30 ml·min?1·(1.73 m2)?1 and proteinuria>0.5 g/24 h were enrolled in a prospective controlled clinical study. They were randomly divided into leflunomide combined with medium/low dose corticosteroids (LEF group) and corticosteroids alone (steroid group). The primary outcomes were (1) end stage renal disease or dialysis (2) 50% increase in serum creatinine above the baseline. Secondary outcome was the remission of proteinuria. Results Ninety patients completed the follow?up. The 24?hour proteinuria at baseline were 2.00(1.10, 2.88) g and 1.87(1.13 ,3.08) g in LEF group and steroid group respectively. Compared with baseline, it was significantly decreased in both groups at 6 months [0.30(0.11, 0.93) g, 0.30(0.14, 1.33) g] and 12 months [0.30(0.09, 0.82) g, 0.32(0.14, 0.66) g], (P<0.05). Estimated glomerular filtration rate (eGFR) at baseline, 6 months and 12 months were (80.39 ± 28.56), (87.12±28.70) and (88.20±30.26) ml·min-1·(1.73 m2)-1. It was decreased in steroid group (P<0.05), while no significant difference was detected in LEF group[baseline (87.63 ± 27.35), 6 months (86.91 ± 32.45), 12 months (90.06 ± 30.00) ml·min-1·(1.73 m2)-1, P>0.05]. At 6 and 12 months, there was no significant difference in terms of 24?hour proteinuria, serum creatinine and eGFR (CKD?EPI) between groups (P>0.05). There was no statistically significant difference in adverse events between groups during the treatment (9/40 cases in LEF group and 11/50 cases in steroid group, P>0.05). The average follow?up was 79 months, and there was no difference in the renal prognosis between the two groups. Multivariate Cox regression analysis revealed that serum creatinine at baseline and renal interstitial inflammatory cell infiltration predicted the risk of the progress of IgA nephropathy. Conclusion Leflunomide plus medium/low dose corticosteroids has a similar effect as full dose of corticosteroids in IgA nephropathy and does not increase the risk for adverse events during the treatment.

Objective To compare the complications and outcomes of urgent?start peritoneal dialysis (PD) and hemodialysis (HD) in end?stage renal disease (ESRD) patients, and explore the safety and effectiveness of PD which was as an urgent?start dialysis modality in ESRD patients. Methods All patients for urgent?start dialysis, who initiated dialysis without a long?term dialysis access or had the long?term dialysis access under 30 days in Renji Hospital from January 1st 2013 to December 31st 2014, were enrolled. According to the dialysis modalities, patients were divided into PD group and HD group. Participants were followed up until death, transferred to other centers, lost of follow up or January 1st 2016. Dialysis?related complications within 30 days of implantation, complications of reimplantation and the occurrence of bacteremia between two groups were compared, and their survival rates were tested by Kaplan?Meier curves. Results Among 178 patients in this study, there were 96 (53.9%) patients in PD group and 82 (46.1%) patients in HD group. Compared with those of HD group, patients of PD group presented more cardiovascular disease [21(21.9%) vs 8(9.8%), P=0.029], higher serum potassium [(4.5±0.8) mmol/L vs (4.3±0.8) mmol/L, P=0.038], but less heart failure (NYHA Ⅲ?Ⅳ) [26(30.2%) vs 40 (48.8%), P=0.014], lower brain natriuretic peptide (BNP) [328.5 (129.5, 776.8) ng/L vs 503.5(206.0, 1430.0) ng/L, P=0.008], higher hemoglobin [(81.5 ± 17.7) g/L vs (75.3 ± 22.5) g/L, P=0.039], higher serum albumin (33.5±5.7) g/L vs (31.3±6.7) g/L, P=0.022] and higher serum pre?albumin (304.5±78.0) mg/L vs (257.0 ± 86.1) mg/L, P<0.001]. PD group presented less dialysis?related complications [5 (5.2%) vs 20(24.4%), P<0.001], less dialysis?related complications requiring reimplantation [1(1.0%) vs 20(24.4%), P<0.001] and less bacteraemia [3(3.1%) vs 11(13.4%), P=0.011]. The 3?, 6?and 12?month patient survival rates of PD and HD group were 97.9% vs 98.4%, 97.9% vs 98.4%, and 92.1%vs 93.0% respectively, and no significant difference was found (Log ? rank=0.004, P=0.947). Conclusions Patients with urgent?start PD have less complications within 30 days of implantation and occurrence of bacteremia than patients with urgent?start HD, and the same survival rates. PD may be a feasible and safe urgent?start dialysis modality for ESRD patients.

OBJECTIVETo record the electrical activities of Antirior cingulate cortex (ACC) neurons by in vivo multi-channel recording methods using the model of complete freund's adjuvant (CFA) induced conditioned place avoidance (C-CPA), which has been set up in our previous studies.

METHODSThe electrode was self-made and the CPA responses were recorded by in vivo multi-channel recording method.

RESULTS(1) The electrical activities of ACC neurons could be successfully recorded by the self-made electrode. (2) Before or after the injection of CFA, rats were respectively conditioned to the different place. The firing rates of ACC neurons in the CFA-paired place vs that in the non-CFA-paired place was (0.853 ± 1.377) imp/s vs (0.221 ± 0.971) imp/s (P < 0.05, n = 26). (3) The CPA responses in the CFA-paired place vs that in the non-CFA-paired place were (303.55 ± 61.77)s vs (140.32 ± 33.52)s(P < 0.05, n = 6).

CONCLUSIONThe firing rates of rACC (rostral Anterior Cingulate Cortex) neurons were involved in the occurrence of the affective pain.

Animals ; Electrodes ; Freund's Adjuvant ; Gyrus Cinguli ; cytology ; Neurons ; cytology ; Pain ; diagnosis ; Pain Measurement ; methods ; Rats ; Rats, Sprague-Dawley

Objective To explore the effects of endoplasmic reticulum (ER) stress in the hyperoxia-induced lung injury in premature rats. Methods Forty-eight premature Wistar rats were randomized into two groups 12 hours after birth:hyperoxia group (n=24) inhaled 95%oxygen and control group (n=24) inhaled air. Eight rats were sacriifced in each group on day 1, 3, 7 after the treatment and the left lungs were embedded. The pathological changes in the HE stained sections of lung tissues were observed. The expressions of ER related protein ERp57 and c/EBP homologous protein CHOP were detected by immuno histo-chemistry and the apoptosis of lung cells was detected by TUNEL analysis. Results The typical pathological characteristics of acute lung injury were observed in hyperoxia group. The expressions of ERp57 and CHOP were increased with the exposure time in hyperoxia group, and were signiifcantly higher than in control group (P<0.05). The apoptosis rate of lung cells in hyperoxia group was signiifcantly higher than in control group (P<0.01). There was signiifcant positive correlation between cell apoptosis index and expressions of Erp57 and c/EBP homogeneous protein. Conclusions ER stress initiated apoptosis participates and plays an important role in the process of hyperoxia-induced lung injury in premature rats.

Objective To observe the effect ofmitochondrial division inhibitor (Mdivi-1) on the neuronal apoptosis via mitochondria signaling pathways in rats after cerebral ischemia/reperfusion (I/R) and its possible mechanism.Methods Sixty male adult healthy Wistar rats were chosen and randomly divided into sham-operated group,vehicle group and Mdivi-1 pre-conditioning group (n=20); animal models of middle cerebral artery occlusion/reperfusion in the later 2 groups were established by a filament method in the left extemal-internal carotid artery.Rats were injected with 1.2 mg/kg Mdivi-1 in the Mdivi-1 pre-conditioning group and dimethyl sulfoxide in the vehicle group 15 minutes before the cerebral ischemia.After 24 h of reperfusion,apoptotic cell death was assessed by TUNEL staining,the cytochrome C expression (Cyt C) was detected by SABC immunohistochemical staining,the protein level of Cyt C in the cerebral issues was detected by Western blotting and the mRNA expression was measured by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR).Results The apoptosis rate (45.49％±0.77％),Cyt C positive cell rate (55.12％±1.47％) and protein and mRNA expressions of Cyt C (0.932 ±0.001,0.789±0.009) in the vehicle group were significantly higher that in the sham-operated group (4.16％±0.25％,4.22％±0.20％,0.395±0.002,0.467±0.003,P＜0.05).The apoptosis rate (45.49％±0.77％),Cyt C positive cell rate (55.12％±1.47％) and protein and mRNA expressions of Cyt C (0.594±0.002,0.523±0.004) in the Mdivi-1 pre-conditioning group were significantly decreased as compared with those in the vehicle group (P＜0.05).Conclusion Mitochondrial division inhibitor Mdivi-1 might reduce neuronal apoptosis by inhibiting mitochondria cytochrome C apoptotic pathway to protect cerebral against ischemia/ reperfusion injury.