Inhibition of the CEBPß-NFκB interaction by nanocarrier-packaged Carnosic acid ameliorates glia-mediated neuroinflammation and improves cognitive function in an Alzheimer's disease model.

Neuroinflammation occurs early in Alzheimer's disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of Aß clearance and disruption of synaptic connection. CEBPß, a member of the CCAAT-enhancer-binding protein (CEBP) family, modulates the expression of inflammation-associated genes, and its expression is elevated in brains undergoing degeneration and injured brains. However, the mechanism underlying CEBPß-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBPß facilitated the interaction of CEBPß with the NFκB p65 subunit, increasing the transcription of proinflammatory cytokines in the APP/PS1 mouse brain. Oral administration of nanocarrier-packaged carnosic acid (CA) reduced the aberrant activation of microglia and astrocytes and diminished mature IL-1ß, TNFα and IL-6 production in the APP/PS1 mouse brain. CA administration reduced ß-amyloid (Aß) deposition and ameliorated cognitive impairment in APP/PS1 mice. We observed that CA blocked the interaction of CEBPß with NFκB p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NFκB target genes TNFα and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced Aß secretion by inhibiting the CEBPß-NFκB signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBEßCD) was used as the encapsulation agent for the CA-loaded nanocarrier to overcome the poor water solubility and enhance the brain bioavailability of CA. The CA nanoparticles (NPs) had no obvious toxicity. We demonstrated a feasible SBEßCD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment.

Establishment and validation of predictive model for histologic chorioamnionitis during expected treatment of preterm premature rupture of membrane before 34 weeks of gestation / 中华围产医学杂志

Objective:To establish and verify a model to predict histologic chorioamnionitis (HCA) for women during expected management of preterm premature rupture of membranes (PPROM) at 24-34 weeks of gestation.Methods:This retrospective study enrolled 493 pregnant women who were diagnosed with PPROM at 24-33 +6 weeks of gestation and delivered in Peking University Third Hospital from January 1, 2012, to December 31, 2020. They were randomly divided into the modeling set ( n=345) and validation set ( n=148) at a ratio of 7∶3. Basic information, risk factors, clinical treatment, and maternal and infant outcomes were compared between participants with and without HCA using Chi-square test, t test, or Mann-Whitney U test. Multivariate logistic regression analysis was performed to analyze the independent risk factors for HCA. The predictive values of different indexes for HCA were compared and the predictive model was then established and verified using the receiver operating characteristic (ROC) curve and area under curve (AUC). Results:There were no significant differences in the basic information, common risk factors for premature rupture of membranes (PROM), or the use of tocolytics, antibiotics or dexamethasone between women in the HCA and non-HCA groups (all P>0.05). Compared with the non-HCA group, the HCA group showed an earlier onset of PROM [31.3 (24.0-33.9) vs 32.3 (27.0-33.9) gestational weeks, U=4 103.00, P=0.017], longer expected treatment [66.5 (0.7-895.3) vs 18.0 (0.3-1 123.0) h, U=1 791.00, P<0.001] and higher incidence of neonatal asphyxia, sepsis, and intracranial hemorrhage [24.3% (58/239) vs 13.2% (14/106), χ 2=5.44; 9.6% (23/239) vs 2.8% (3/106), χ 2=4.86; 41.0% (98/239) vs 17.9% (19/106), χ 2=17.45; all P<0.05]. Moreover, the positive rate of bacterial culture, C-reactive protein (CRP) level, neutrophil/lymphocyte ratio (NLR), white blood cell (WBC) and neutrophil counts were significantly increased in the HCA group [37.2% (89/239) vs 22.6% (24/106), χ 2=7.10; 8.2 (0.0-273.0) vs 5.0 (0.0-218.9) ng/ml, U=2 419.00; 5.6 (1.2-58.6) vs 4.6 (1.7-18.7), U=2 357.50; 11.9 (4.5-30.0)×10 9/L vs 10.1 (5.8-21.8)×10 9/L, U=4 074.50; 9.5 (2.5-28.1)×10 9/L vs 7.6 (3.5-18.5)×10 9/L, U=4 021.50; all P<0.05], while the lymphocyte count was decreased [1.5 (0.5-3.7)×10 9/L vs 1.6 (0.7-3.9)×10 9/L, U=4 237.00, P=0.017]. CRP level, NLR, the gestational week at the onset of PROM and the duration of expected treatment were independent risk factors for HCA ( OR=1.069, 95% CI: 1.024-1.117; OR=1.192, 95% CI: 1.048-1.356; OR=0.906, 95% CI: 0.867-0.947; OR=1.017, 95% CI: 1.007-1.026). Based on the four risk factors, the predictive model was established and ROC curve was drawn. AUC for evaluating the performance of the predictive model was 0.880, which indicated a clinical significance. Conclusion:The model established based on the four risk factors, which were CRP level, NLR, the gestational week at onset of PROM and the duration of expected treatment, performs well in the prediction of HCA in women with PPROM during expected treatment and has good clinical practical value.

Objective analysis of corneal subbasal nerve tortuosity and its changes in patients with dry eye and diabetes / 中华实验眼科杂志

Objective To construct an objective analysis system of corneal nerve tortuosity and detect the changes of corneal subbasal nerve tortuosity in patients with dry eye and diabetes. Methods GradeⅠtoⅣnerve tortuosity were evaluated and 80 photos of each grade were randomly chosen from the in vivo confocal microscopy library. Nerve fibers were extracted,segmented and then analyzed by 6 tortuosity related parameters including L C, Seg L C mean,Cur mean,Specific p,ICM and SCC mean. After verifying the validaty of parameters above,a cross-sectional study was conducted. Subjects were collected from June,2018 to February,2019 in Peking University Third Hospital,and were divided into healthy control group (28 persons 56 eyes),dry eye without diabetes group (28 patients 56 eyes),diabetes without dry eye group(24 patients 48 eyes),diabetes with dry eye group (23 patients 46 eyes) . Basic and dry eye information includes sex,age,ocular surface disease index ( OSDI) ,tear film break-up time (TBUT),Schirmer Ⅰ test (SⅠt) and corneal fluorescence staining (CFS) score. Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were detected in diabetic patients. Cochet-Bonnet examination (C-BE) was detected to evaluate corneal sensation and 2 corneal subbasal nerve photos of each eye were selected for effective tortuosity and density related parameters analysis. Data was analyzed by SPSS and diagnostic test were perfomed by MedCalc. This study followed the Declaration of Helsinki. This study protocol was approved by Ethic Committee of Peking University Third Hospital ( No. IRB00006761-M2017354 ) . Written informed consent was obtained from each subject prior to entering study cohort. Results L C,Seg L C mean,Cur mean,Specific p,ICM and SCC mean increased as the nerve tortuosity increased from Grade Ⅰ to Grade Ⅳ,with an overall significance among 4 groups (F=39. 100, 36. 367,57. 743,4. 043,6. 818,33. 493;all at P<0. 01). Among the above 6 parameters,Cur mean and L C of any two groups were of significant difference (all at P<0. 01). Twenty three to twenty eight persons were enrolled in each group of the cross-sectional study. Sex and age were comparable among 4 groups. Diagnostic criteria were met in dry eye and diabetes. Corneal sensation parameter C-BE decreased in diabetes without dry eye group and diabetes with dry eye group compared with healthy control group ( all at Adj P<0. 05 ) , other than in dry eye without diabetes group (AdjP≥0. 05). Nerve density of diabetes without dry eye group and diabetes with dry eye group was lower compared with healthy control group(all at P<0. 001),while no significant difference between dry eye without diabetes group and healthy control group(P≥0. 05). Among the effective parameters of tortuosity,L C,Cur mean,Seg L C mean and SCC mean of dry eye without diabetes group,diabetes without dry eye group,diabetes with dry eye group were higher compared with healthy control group ( all at P<0. 05 ) . Diagnostic tests of tortuosity related parameters all showed an area under curve (AUC) from 0. 5 to 0. 7. Conclusions L C and Cur mean can be used to analyze corneal nerve curvature more reliably. Compared with normal volunteers,patients of dry eye or diabetes show higher corneal subbasal nerve tortuosity.

Effect of IL-8 on mitochondrial fusion and fission gene expression in hu-man lung adenocarcinoma cell line A549 during cell migration / 中国病理生理杂志

[ ABSTRACT] AIM:To investigate the changes of migration of lung adenocarcinoma cells promoted by IL-8 and the inner and outer mitochondrial membrane dynamic changes during this process.METHODS:Human lung adenocarci-noma cell line A549 was divided into control group and IL-8 group.Cell migration was analyzed by scratch detection and Transwell assay.The secretion of endogenous IL-8 was detected by ELISA.The protein levels of mitochondrial cytochrome C ( Cyt C) and mitochondrial outer membrane protein Tom20 was detected by Western blot.The mRNA expression of mito-chondrial fusion genes Mfn1, Mfn2 and OPA1 and fission genes Fis1, Drp1 and MTP18 was detected by RT-PCR.The morphological changes of mitochondria were observed by MitoTracker Red CMXRos dye staining and confocal microscopy. RESULTS:The migratory rate of A549 cells and endogenous secretion of IL-8 in A549 cells were higher than those in SPC-A-1 cells.The migratory rate of A549 cells was improved by IL-8 in a time-dependent manner.Compared with control group, the Tom20 protein expression was increased ( P0.05).Under confocal microscope, the punctate aggregates in the mitochondria of the A549 cells treated with IL-8 were observed.CONCLU-SION:The migratory rate of A549 cells is increased by IL-8, which is related to the changes of mitochondrial fusion genes and the fission genes.

Clinical significance and change curve of ADH in central diabetes insipidus after neurosurgical operation / 吉林大学学报(医学版)

Objective To study the change curve of ADH in central diabetes insipidus after neurosurgical operation,and analyse the clinical significance of differentiating the types of central diabetes insipidus through the change curve.Methods The serum level of ADH was observed in 158 central diabetes insipidus patients undergone neurosurgical operation.The change curve of ADH in different types of central diabetes insipidus were painted,including transient,continuous and triphasic diabetes insipidus.Results The serum concentrations of ADH in transient and triphasic diabetes insipidus decreased after operation,and arrived the low point(41.7% and 63.6% of the preoperative serum concentration of ADH) after 2 d. The serum concentration of ADH in transient diabetes insipidus recovered to the preoperative level after 10 d.The serum concentration of ADH in triphasic diabetes insipidus arrived the peak after 7 d,then descended.The serum concentration of ADH in continuous diabetes insipidus fell in postoperative 1 d,and arrived the low point(33.3% of the preoperative serum level of ADH) after 7 d.The serum concentration of ADH in continuous diabetes insipidus postoperative 2 weeks was lower than preoperation.Conclusion Though the concentration change curve of ADH,the transient diabetes insipidus can be distinguished from continuous and triphasic diabetes insipidus.The correct differential diagnosis and seemly treatment are beneficial for patients' prognosis.

Expression of ROCK Ⅰ and TGF-?_1 in pulmonary arterioles of rat with chronic thromboembolism pulmonary hypertension / 中国病理生理杂志

AIM: To investigate the dynamic expression of Rho kinase(ROCK I) and transforming growth factor ?1(TGF-?1) in pulmonary arterioles of rat with chronic thromboembolic pulmonary hypertension.METHODS: Sixty-four male Wister rats were randomly divided into eight groups: beginning control group,embolism for 3 d,1 week,2 weeks,4 weeks,8 weeks,12 weeks groups and end control group.The pulmonary thromboembolism(PTE) model was established by injecting thrombin into jugular vein two times in two weeks and each rat underwent peritoneal injection with tranexamic acid one time a day during experiment to prevent thrombolysis.The mean pulmonary artery pressure(mPAP),right ventricular hypertrophy index(RVHI),relative medial thickness of small pulmonary arteries(PAMT) and vessel wall area/total area(WA/TA) were measured.The levels of ROCK I mRNA and TGF-?1 protein in rat pulmonary artery were determined by in situ hybridization,immunohistochemistry and image analysis,respectively.RESULTS: mPAP,PAMT and WA/TA were higher respectively in embolism from 4 weeks group to 12 weeks group than those in beginning control group(mPAP: all P