Screening and analysis of ferroptosis related genes in peripheral blood mononuclear cells of patients with systemic lupus erythematosus / 中华风湿病学杂志

Objective:To analyze the differentially expressed genes in PBMCs of patients with systemic lupus erythematosus (SLE) by bioinformatics methods screening and analyzing the key genes related to ferroptosis, and explore the possible mechanism of ferroptosis involved in the pathogenesis of SLE at the transcription level.Methods:The data sets and samples of healthy people (HC) and SLE patients who met the screening criteria were retrieved from the Gene Expression Omnibus (GEO), a sub-database of the National Center for Biotechnology Information (NCBI). The differentially expressed genes, GO enrichment analysis and KEGG pathway enrichment analysis were analyzed by GEO2R, R language and related software packages. The protein interaction network (PPI) of differential genes was analyzed by STRING, Cytoscape and other tools to explore the key genes and pathways. In addition, real-time quantitative reverse transcription PCR (RT-qPCR) was used to verify the expression of key genes. Mann-Whitney U test was used to compare the expression of key genes in PBMCs between the two groups. Spearman rank correlation analysis was used to explore the relationship between SLE disease activity and the level of key genes. Results:Six data sets were included in this study. A total of 166 genes related to ferroptosis were differentially expressed between SLE and HC groups. The differential genes were specifically expressed in alveolar macrophages, neutrophils, CD49 + cells and CD31 + cells. GO enrichment analysis and KEGG pathway enrichment analysis showed that the differentially expressed genes were mainly involved in multiple signaling pathways closely related to SLE, such as oxidative stress response, infection and TNF signaling pathway. Hub genes screened by different algorithms all suggested RELA as a key gene, and RT-qPCR confirmed that compared with the RELA gene expression level in the HC group [0.75(0.37,1.13)], the expression level in SLE group [2.02 (1.19,4.06)] was increased, the difference was statistically significant ( Z=-3.08, P=0.002), and was positively correlated with the corresponding SLEDAI score of SLE samples ( r=0.52, P=0.019). Conclusion:The ferroptosis of many immune cells, including alveolar macrophages and CD49 + NK cells, is involved in the pathogenesis of SLE. RELA may be involved in the ferroptosis of PBMCs in SLE through the NF-κB pathway.

Inhibitory Effects of Simvastatin on Oxidized Low-Density Lipoprotein-Induced Endoplasmic Reticulum Stress and Apoptosis in Vascular Endothelial Cells / 中华医学杂志(英文版)

<p><b>Background</b>Oxidized low-density lipoprotein (ox-LDL)-induced oxidative stress and endothelial apoptosis are essential for atherosclerosis. Our previous study has shown that ox-LDL-induced apoptosis is mediated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2α-subunit (eIF2α)/CCAAT/enhancer-binding protein homologous protein (CHOP) endoplasmic reticulum (ER) stress pathway in endothelial cells. Statins are cholesterol-lowering drugs that exert pleiotropic effects including suppression of oxidative stress. This study aimed to explore the roles of simvastatin on ox-LDL-induced ER stress and apoptosis in endothelial cells.</p><p><b>Methods</b>Human umbilical vein endothelial cells (HUVECs) were treated with simvastatin (0.1, 0.5, or 2.5 μmol/L) or DEVD-CHO (selective inhibitor of caspase-3, 100 μmol/L) for 1 h before the addition of ox-LDL (100 μg/ml) and then incubated for 24 h, and untreated cells were used as a control group. Apoptosis, expression of PERK, phosphorylation of eIF2α, CHOP mRNA level, and caspase-3 activity were measured. Comparisons among multiple groups were performed with one-way analysis of variance (ANOVA) followed by post hoc pairwise comparisons using Tukey's tests. A value of P < 0.05 was considered statistically significant.</p><p><b>Results</b>Exposure of HUVECs to ox-LDL resulted in a significant increase in apoptosis (31.9% vs. 4.9%, P < 0.05). Simvastatin (0.1, 0.5, and 2.5 μmol/L) led to a suppression of ox-LDL-induced apoptosis (28.0%, 24.7%, and 13.8%, F = 15.039, all P < 0.05, compared with control group). Ox-LDL significantly increased the expression of PERK (499.5%, P < 0.05) and phosphorylation of eIF2α (451.6%, P < 0.05), if both of which in the control groups were considered as 100%. Simvastatin treatment (0.1, 0.5, and 2.5 μmol/L) blunted ox-LDL-induced expression of PERK (407.8%, 339.1%, and 187.5%, F = 10.121, all P < 0.05, compared with control group) and phosphorylation of eIF2α (407.8%, 339.1%, 187.5%, F = 11.430, all P < 0.05, compared with control group). In contrast, DEVD-CHO treatment had no significant effect on ox-LDL-induced expression of PERK (486.4%) and phosphorylation of eIF2α (418.8%). Exposure of HUVECs to ox-LDL also markedly induced caspase-3 activity together with increased CHOP mRNA level; these effects were inhibited by simvastatin treatment.</p><p><b>Conclusions</b>This study suggested that simvastatin could inhibit ox-LDL-induced ER stress and apoptosis in vascular endothelial cells.</p>

Role of PERK/eIF2α/CHOP Endoplasmic Reticulum Stress Pathway in Oxidized Low-density Lipoprotein Mediated Induction of Endothelial Apoptosis / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>PERK/eIF2α/CHOP is a major signaling pathway mediating endoplasmic reticulum (ER) stress related with atherosclerosis. Oxidized LDL (ox-LDL) also induces endothelial apoptosis and plays a vital role in the initiation and progression of atherosclerosis. The present study was conducted to explore the regulatory effect of ox-LDL on PERK/eIF2α/CHOP signaling pathway in vascular endothelial cells.</p><p><b>METHODS</b>The effects of ox-LDL on PERK and p-eIF2α protein expression of primary human umbilical vein endothelial cells (HUVECs) were investigated by Western blot analysis. PERK gene silencing and selective eIF2α phosphatase inhibitor, salubrinal were used to inhibit the process of ox-LDL induced endothelial cell apoptosis, caspase-3 activity, and CHOP mRNA level.</p><p><b>RESULTS</b>Ox-LDL treatment significantly increased the expression of PERK, PERK-mediated inactivation of eIF2α phosphorylation, and the expression of CHOP, as well as the caspase-3 activity and apoptosis. The effects of ox-LDL were markedly decreased by knocking down PERK with stable transduction of lentiviral shRNA or by selective eIF2α phosphatase inhibitor, salubrinal.</p><p><b>CONCLUSION</b>This study provides the first evidence that ox-LDL induces apoptosis in vascular endothelial cells mediated largely via the PERK/eIF2α/CHOP ER-stress pathway. It adds new insights into the molecular mechanisms underlying the pathogenesis and progression of atherosclerosis.</p>

Incidence and associated factors for single and recurrent falls among the elderly in an urban community of Beijing / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To investigate the incidence of falls and recurrent falls, and explore associated factors for single and recurrent falls among urban community-dwelling elderly in Beijing.</p><p><b>METHODS</b>A cross-sectional study was conducted in 472 elderly in the Longtan community of Dongcheng district, Beijing in 2009. Data regarding the incidence of fall and recurrent falls in the previous year, as well as associated factors were collected from the elderly through face-to-face interviews.</p><p><b>RESULTS</b>The incidence of falls and recurrent falls was 17.8% and 6.1%, respectively, and it increased with age (χ2for trend=21.06, 19.20, P=0.001, 0.002). Binary logistic stepwise regression analysis showed that age (OR=2.20), living alone (OR=4.67) and gait disturbance (OR=1.27) were risk factors, while housing with elevators (OR=0.35), appropriate width/height of stair steps (OR=0.78), sufficient lighting for stairway (OR=0.45) and regular exercise (OR=0.12) could lower the risk for single fall; factors such as low monthly family income (OR=1.39), poor vision (OR=1.83), low physical ability (OR=4.47), abnormal static balance (OR=2.48), and fear of falls(OR=2.23) were risk factors, while appropriate width/height of stair steps (OR=0.49) and easiness of access to daily supplies (OR=0.41) were protective factors for recurrent falls.</p><p><b>CONCLUSION</b>The incidence of falls in community-dwelling elderly people in Beijing is common, and falls and their related injuries have been associated with both intrinsic and extrinsic factors.</p>

Impact of dopamine receptor modulation on reduced anxiety-like behavior in neonatal rats after hypoxic-ischemic brain damage / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To observe the long-term changes in anxiety-like behavior and tyrosine hydroxylase (TH) expression in the substantia nigra (SN) after hypoxic-ischemic brain damage (HIBD) in a neonatal rat model and to further explore the relationship between dopamine (DA) level and long-term anxiety-like behavior using the DA receptor (DAR) antagonist.</p><p><b>METHODS</b>Seven-day-old (P7) neonatal Sprague-Dawley (SD) rats were randomized into normal control, sham-operated, HIBD and HIBD+DAR antagonist groups. HIBD model was prepared by ligating the right common carotid artery and 8% hypoxia exposure. The rats in the sham-operated group were sham-operated and were not subjected to right common carotid artery ligation and hypoxia exposure. The DAR antagonist was injected intraperitoneally before and after inducing HIBD. The same amount of normal saline was given to the other three groups as a control. Anxiety-like behavior was evaluated by elevated plus maze test, and TH expression in the SN was measured by immunohistochemistry on P14, P21, and P28.</p><p><b>RESULTS</b>On P21 and P28, the time spent in the open arms and the percentage of open arms entries in the HIBD group were significantly increased compared with those in the normal control, sham-operated and HIBD+DAR antagonist groups (P<0.05); in addition, the HIBD+DAR antagonist group showed a significantly longer time spent in the open arms than the normal control group (P<0.05). On P14, P21, and P28, TH expression in the HIBD and HIBD+DAR antagonist groups was significantly lower than that in the normal control and sham-operated groups, and TH level in the HIBD group was significantly lower than that in the HIBD+DAR antagonist group (P<0.05).</p><p><b>CONCLUSIONS</b>DAR antagonist allows the restoration of anxiety-like behavior and alleviates the damage to dopaminergic neurons in SD rats after HIBD.</p>

Meta-analysis of post-transfusion necrotizing enterocolitis in neonates / 中华儿科杂志

<p><b>OBJECTIVE</b>To quantitatively assess the association between transfusions and the risk of necrotizing enterocolitis (NEC) in neonates.</p><p><b>METHOD</b>Both Chinese and English literature published from Jan. 1985 to Nov. 2011 about the case-control study of the association between transfusions and neonatal NEC were retrieved by searching the electronic resource databases. A meta-analysis was then performed on the comparison and synthesis of findings from included studies. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using RevMan 5.0 software. Sensitivity analysis was conducted and possible publication bias was tested as well.</p><p><b>RESULT</b>A total of 7 case-control studies (480 blood transfusion cases, 2845 control cases) were included. The meta-analysis with a random-effects model found a pooled OR of 3.35 (95% CI: 1.54-7.27). Sensitivity analysis showed that OR for post-transfusion NEC within 48 h was 4.21 (95% CI: 2.17-8.16). The OR was 4.29 (95% CI: 1.39-13.24) after factors such as gestational age and birth weight were de-confounded. The fail-safe number was 263.</p><p><b>CONCLUSION</b>Blood transfusion can increase the risk of NEC in neonates. The clinical application of this conclusion should be cautious due to limited reports. High-quality randomized control trials are still needed for the further proof of the association between blood transfusion and neonatal NEC.</p>

Elevated platelet activating factor level in ischemia-related arrhythmia and its electrophysiological effect on myocardium / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>The mechanism through which platelet activating factor (PAF) induces cardiac electrical activity and arrhythmia is not well understood and previous studies have suggested a potential involvement of ion channels in its action. The present study was aimed to clarify the role of PAF in fatal arrhythmias following acute myocardia infarction (AMI) and the underlying mechanism.</p><p><b>METHODS</b>(1) Blood PAF levels were measured among 72 AMI patients at the time of diagnosis with AMI and 48 h later, and their electrocardiogram (ECG) was recorded continuously. (2) Ischemia simulation and surface electrocardiogram were conducted in 20 pigs and their PAF levels were measured. (3) PAF perfusion and standard microelectrode recording were performed on guinea pig papillary muscles.</p><p><b>RESULTS</b>In both humans and pigs, elevated PAF levels were detected in AMI and simulated ischemia, respectively, and even higher PAF levels were found when fatal arrhythmias occurred. In guinea pig myocardium, PAF induced a shortening of action potential duration at 90% level of repolarization (APD90)under non-ischemic conditions and a more pronounced shortening under early simulated ischemic conditions.</p><p><b>CONCLUSION</b>AMI and ischemia are associated with increased PAF levels in humans and pigs, which are further raised when fatal arrhythmia follows. The effects of PAF on the myocardium may be mediated by multiple ion channels.</p>

A prospective study on recurrent falls and related factors in elderly from the urban communities in Beijing / 中华流行病学杂志

<p><b>OBJECTIVE</b>To investigate the incidence and risk factors for recurrent falls in community-dwelling elderly in Beijing.</p><p><b>METHODS</b>A cross-sectional study was conducted in 472 elderly in the Longtan community of Dongcheng district,Beijing in 2009. Data on recurrent falls within the past 12 months were collected through face-to-face interview, with both single factor analysis and logistic regression analysis used to explore the related factors on recurrent falls in the elderly.</p><p><b>RESULTS</b>The incidence of recurrent falls among 472 older adults was 6.1% (29) within the past 12 months. Results from logistic regression analysis showed that factors as higher family monthly income(OR = 1.39, 95% CI:0.67-2.16), afraid of being fallen(OR = 2.23, 95% CI:1.47-3.85)and abnormal static balance(OR = 2.48, 95% CI:1.84-4.05)were risk factors, while bench height in the surrounding environment(OR = 0.49, 95% CI:0.21-1.12)and easiness of access to daily supplies (OR = 0.41, 95%CI:0.14-1.16)were protective factors for recurrent falls.</p><p><b>CONCLUSION</b>The incidence of recurrent falls among the elderly from the communities in Beijing was high. Since falls could be caused by various factors, intervention should be targeting on risk factors in a multi-dimensional way.</p>

Clinical features and prognosis of 188 Chinese patients with apical hypertrophic cardiomyopathy / 中华心血管病杂志

<p><b>OBJECTIVE</b>To analyze the clinical characteristics and prognosis of Chinese patients with apical hypertrophic cardiomyopathy (AHCM).</p><p><b>METHODS</b>A total of 188 patients with AHCM diagnosed at Fuwai Hospital were included in this retrospective study. Clinical characteristics, mortality and cardiovascular morbidity were analyzed. A multiple logistic regression was performed to adjust for potential confounding factors.</p><p><b>RESULTS</b>Males predominated with a number of 139 (73.9%) in this cohort. Patient's age ranged from 15 to 81 (51.9 ± 12.6) years. There were 120 patients (63.8%) with "pure" type and 68 patients (36.2%) with "mixed" type of AHCM, 171 patients were followed up for (5.0 ± 3.0) years, cardiovascular mortality was 1.2%, 28 patients (16.4%) experienced one or more cardiovascular events.</p><p><b>CONCLUSION</b>The prevalence of AHCM is high in Chinese HCM patients, pure type AHCM is more common, and AHCM patients have a benign clinical course.</p>

Comparison of benazepril monotherapy to amlodipine plus benazepril in the treatment of patients with mild and moderate hypertension: a multicentre, randomized, double-blind, parallel-controlled study / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and tolerability of the fixed combination of amlodipine 5 mg/benazepril 10 mg once-daily therapy, compared with benazepril, 10 mg, monotherapy in patients with mild and moderate hypertension, and to evaluate the 24 h antihypertensive efficacy and the duration of action by ambulatory blood pressure monitoring.</p><p><b>METHODS</b>In a multicenter, randomized, double-blind, parallel controlled trial, 356 cases of hypertensive patients after 2 weeks wash-out, and then given 4 weeks of benazepril 10 mg monotherapy, 220 patients with mean seated diastolic blood pressure (SeDBP) remained ≥ 90 mm Hg (1 mm Hg = 0.133 kPa) were randomly divided into benazepril 10 mg/amlodipine 5 mg (BZ10/AML5) fixed-dose combination therapy group (once a day, n = 113), and benazepril monotherapy group (daily 20 mg, n = 107). In the two groups the patients with SeDBP ≥ 90 mm Hg were doubled the dosage of the initial regimen at the end of 4-week treatment for additional 4 weeks, and the patients with SeDBP < 90 mm Hg remained the initial regimen for additional 4 weeks. The primary endpoint was to evaluate the improvement of SeDBP at the end of 8-week treatment. There were 74 patients (the combination therapy group n = 38, monotherapy therapy group n = 36) completed the 24 h ambulatory blood pressure monitoring which was included in the final efficacy analysis.</p><p><b>RESULTS</b>The randomized, double-blind treatment for 8 weeks, the mean value of SeDBP reduction, the reaching target blood pressure rate and total successful response rate to the treatment (a SeDBP < 90 mm Hg or a decrease of 10 mm Hg or more from baseline) were (11.7 ± 6.8) mm Hg, 65.7% and 88.5% in the combination therapy group, respectively, and were (7.7 ± 6.9) mm Hg, 35.5% and 65.5% in the monotherapy group, respectively. There were statistically significant difference between the combination therapy and the monotherapy groups in all the 3 indexs (P < 0.001). The fixed combination significantly reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) values throughout the 24 h. The trough to peak ratios of DBP/SBP in the fixed compound of benazepril/amlodipine (10 mg/5 mg) and benazepril (20 mg) alone were 83.1%/76.0% and 85.8%/79.5%, respectively. Adverse events rates were 16.8% in the combination therapy group and 35.5% in the monotherapy group (P < 0.001).</p><p><b>CONCLUSIONS</b>The combination therapy with benazepril/amlodipine was superior to benazepril monotherapy and was well tolerated in patients with essential hypertension and allowing a satisfactory BP control for 24 hours.</p>

Bone marrow mesenchymal cell transplantation reduces left ventricular remodeling in heart failure following acute myocardial infarction / 中华心血管病杂志

<p><b>OBJECTIVE</b>Bone marrow mesenchymal cell (MSC) transplantation has been shown to improve heart failure but the mechanism and the subsequent effects are unclear. We tested the hypothesis that MSC transplantation reduces left ventricular remodeling through the MMP/TIMP system in heart failure following acute myocardial infarction.</p><p><b>METHODS</b>Female SD rats underwent coronary artery ligation to induce myocardial infarction. Four weeks later, the rats were divided into the test group (n = 7) and the control group (n = 7), respectively. The donor MSCs were harvested and expanded from male SD rats (5 x 10(6) in 50 microl PBS) and injected into the ischemic myocardium, while the control group received the same volume of PBS. Left ventricular morphology was then evaluated in both groups through staining with H&E and Masson's trichrome. Immunohistochemical staining was used to examine the expressions of MMP2 and TIMP1, as well as type I and type III collagens, in the scar zones. The protein levels of MMP2 and TIMP1 were determined by Western blotting.</p><p><b>RESULTS</b>MSC differentiated into fibroblast-like cells at 21 days after transplantation in the test group. In addition, many inflammatory cells infiltrated and aggregated in the scar area, but this effect was reduced at day 7 after transplantation. The following changes were noted in the test group compared to the control group: ejection fraction and shortening fraction were higher [(63.43 +/- 3.97)% vs. (36.20 +/- 3.99)%, (31.71 +/- 1.98)% vs. (18.00 +/- 2.07)%, P < 0.05]; dp/dt(min) was reduced [(-4756.24 +/- 270.00) mm Hg/s vs. -2789.53 +/- 624.13) mm Hg/s, P < 0.05]; the left ventricular thinning ratio was significantly higher [(76.34 +/- 2.66)% vs. (64.37 +/- 2.36)%, P < 0.05]; the infarct size was smaller [(36.19 +/- 0.83)% vs. (42.12 +/- 1.88)%, P < 0.05]; type I collagen expression in the scar area was much higher; type III collagen expression was much lower; MMP2 expression was reduced and TIMP1 expression was increased.</p><p><b>CONCLUSION</b>MSC transplantation led to dynamic changes in the collagen network through regulation of MMP2/TIMP1 system and consequently interrupted the progress of adverse LV remodeling in heart failure following acute myocardial infarction.</p>