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The synthesis and activity in vitro of a series of 8-difluoromethoxy quinolones: Analogues of gemifloxacin

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Chinese Chemical Letters 2007年第10期18卷 1169-1172页

作者： Jin Jiang Jiu Yu liu hui Yuan guo Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China

7-[4-（Aminomethyl）-3-（methoxyimino）pyrrolidin- 1-yl]- 1-cyclopropyl-6-fluoro-8-difluoromethoxy- 1,4-dihydro-4-oxoquino- line-3-carboxylic acid and its analogues have been prepared and evaluated for antibacterial a... 详细信息

关键词： Quinolone Synthesis Antibacterial activity

Synthesis of Quinolone Analogues: 7-[2-Aminomethylaziridin-l-yl]-quinolones

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Chinese Chemical Letters 2006年第11期17卷 1431-1434页

作者： Jin JIANG Jiu Yu liu hui Yuan guo Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050

New quinolone derivatives of 7-[2-aminomethylaziridin-l-yl]quinolone-3-carboxylic acids were synthesized. The structures of these compounds were characterized by IH NMR and HRESI-MS.

关键词： Aziridine quinolone synthesis.

Role of endoplasmic reticular stress in aortic endothelial apoptosis induced by intermittent/persistent hypoxia

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Chinese Medical Journal 2013年第23期126卷 4517-4523页

作者： YANG Yuan-yuan SHANG Jin liu hui-guo Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China

Background Accumulated evidence shows that hypoxia can induce endothelial apoptosis,however the mechanism is still *** hypothesized whether intermittent or persistent hypoxia could induce endoplasmic reticular stress,leading to endothelial *** Twenty-four 8-week male Sprague Dawley （SD） rats were divided into three groups：normoxia （NC） group,intermittent hypoxia （IH） group and persistent hypoxia （PH） *** staining was performed to detect aortic arch endotheliar apoptosis,and immunohistochemistry for BIP,CHOP and caspase12 to test protein expression;human umbilical vein endothelial cells （HUVECs） of the line ECV304 were cultured （with or without taurodeoxycholic acid （TUDCA） 10 mmol/L,100 mmol/L） and divided into four groups：NC group （20.8％ O2 for 4 hours）,PH1 group （5％ O2 for 4 hours）,PH2 group （5％ O2 for 12 hours） and IH group （20.8％ O2 and 5％ O2 alternatively for 8 hours）.Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis in each *** expressions of GRP78,CHOP and caspase12 were detected by real-time quantitative reverse-transcription *** Intermittent and persistent hypoxia could increase the rate of endothelium apoptosis and the expressions of GRP78,CHOP and caspase12 compared with the control,induction by intermittent hypoxia was slightly higher than persistent *** the HUVEC experiment,TUDCA significantly reduced apoptosis and the expressions of GRP78,CHOP and *** Hypoxia,especially intermittent,can induce endothelial cell apoptosis possibly through endoplasmic reticulum stress pathway,which can be attenuated by taurodeoxycholic acid.

关键词： intermittent/persistent hypoxia endoplasmic reticulum stress apoptosis CHOP/caspase12

Ang II type 1 receptor expression in rat aorta exposed to chronic intermittent hypoxia： effects of p38MAPK and ERK1/2 signaling

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Chinese Medical Journal 2013年第17期126卷 3264-3269页

作者： SHANG Jin YANG Yuan-yuan guo Xue-ling liu hui-guo Department of Respiratory and Critical Care Medicine Tongji Hospital Huazhong University of Science and Technology Wuhan Hubei 430030 China

Background Obstructive sleep apnea is a frequent medical condition consisting of repetitive sleep-related episodes of upper air ways obstruction and can lead to hypertension. Ang II type 1 receptor （AT1R） played important roles in hypertension since it binds with Ang II, controlling salt-water and blood pressure homeostasis. This study explores rat aorta AT1R expression during intermittent hypoxia （IH） and the signaling pathways involved. Methods A rat model and a cell model used a BioSpherix-OxyCycler A84 system and a ProOx C21 system respectively. The arterial blood pressure was recorded by a Nihon Kohden Polygraph System. Immunohistochemic was used to focus and analyze the expression of AT1R in rat aorta. Real-time PCR and Western blotting were used to explore the signaling pathways that participated in AT1R expression. Results In this study, we found that chronic intermittent hypoxia （CIH） induced AT1R transcription which increased the blood pressure in rat aorta compared to normoxia and to sustained hypoxia. The AT1R protein expression in the aorta was similar to the real-time PCR results. We explored the signaling mechanisms involved in the AT1R induction in both rat aorta and the aortic endothelial cells by real-time PCR and Western blotting. Compared to normoxia, CIH increased ERK1 mRNA transcription but not ERK2 or p38MAPK in the aorta; whereas sustained hypoxia （SH） upregulated ERK2 but not ERK1 or p38MAPK mRNA. In cells, IH induced AT1R expression with ERK1/2 phosphorylation but reduced p38MAPKs phosphorylation, whereas SH induced only ERK1/2 phosphorylation. The ERK1/2 inhibitor PD98059 attenuated the IH- induced AT1R increase but the p38MAPK inhibitor SB203580 did not. Conclusions Our results indicate that CIH induced the elevation of rat blood pressure and aorta AT1R expression. Moreover, ATIR expression in IH and sustained hypoxia might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 sign

关键词： intermittent hypoxia hypertension Ang II type 1 receptor ERK1/2 p38MAPK

ERK signaling mediates enhanced angiotensin II-induced rat aortic constriction following chronic intermittent hypoxia

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Chinese Medical Journal 2013年第17期126卷 3251-3258页

作者： guo Xue-ling DENG Yan SHANG Jin liu Kui XUYong-jian liu hui-guo Department of Respiratory and Critical Care Medicine Tongji Hospital Huazhong University of Science and Technology Key Laboratory of Respiratory Disease of the Ministry of Health Wuhan Hubei 430030 China

Background Obstructive sleep apnea （OSA） has been recognized as an independent risk factor for systemic hypertension. The study investigated the functional consequences of chronic intermittent hypoxia （CIH） on aortic constriction induced by angiotensin II （Ang II） and the possible signaling involving ERK1/2 and contractile proteins such as myosin light chain kinase （MLCK）, myosin phosphatase targeting subunit （MYPT1） and myosin light chain （MLC）. Methods Male Wistar rats were randomly divided into CIH group and normoxia group and exposed to either CIH procedure or air-air cycles. Phosphorylation of ERK1/2, MYPT1 and MLC was assessed by Western blotting following constrictor studies in the presence or absence of PD98059 （10 μmol/L）. Results CIH-exposure resulted in more body weight gain and elevated blood pressure, which could be attenuated by pretreatment with PD98059. Endothelium-removed aortic rings from CIH rats exhibited higher constrictor sensitivity to Ang II （Emax：（138.56±5.78）% versus （98.45±5.31）% of KCI; pD2：7.98±0.14 versus 8.14±0.05, respectively）. CIH procedure exerted complex effects on ERK expressions （total ERK1/2 decreased whereas the ratio of phosphorylated to total ERK1/2 increased）. CIH aortas had higher MLCK mRNA and basal phosphorylation of MYPT1 and MLC. In parallel to greater increases in phosphorylation of ERK1/2, MYPT1 and MLC, Ang II-induced aortic constriction was significantly enhanced in CIH rats, which was largely reversed by PD98059. However vascular constriction of normoxia rats remained unchanged despite similar but smaller changing tendency of proteins phosphorylation. Conclusion These data suggest that CIH exposure results in aortic hyperresponsiveness to Ang II, presumably owing to more activated ERK1/2 signaling pathway.

关键词： chronic intermittent hypoxia ERK1/2 myosin phosphatase targeting subunit myosin light chain vasoconstriction

Thioredoxin and impaired spatial learning and memory in the rats exposed to intermittent hypoxia

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Chinese Medical Journal 2012年第17期125卷 3074-3080页

作者： YANG Xiu-hong liu hui-guo liu Xue CHEN Jun-nan Department of Respiratory and Critical Care Medicine Tongji HospitalTong3i Medical CollegeHuazhong University of Science and Technology Key Laboratory of Respiratory Disease of the Ministry of Health WuhanHubei 430030China

Background Obstructive sleep apnea （OSA） can cause cognitive dysfunction and may be a reversible cause of cognitive loss in patients with Alzheimer＇s disease （AD）. Chronic exposure to intermittent hypoxia （IH）, such as encountered in OSA, is marked by neurodegenerative changes in rat brain. We investigated the change of thioredoxin （Trx）, spatial learning and memory in rats exposed to chronic intermittent hypoxia （CIH）. Methods Forty healthy male Sprague-Dawley （SD） rats were randomly divided into four groups of ten each： a CIH＋normal saline （CIH＋NS group）, a N-acetylcystein-treated CIH （CIH＋NAC） group, a sham CIH group （sham CIH＋NS）, and a sham NAC-treated sham CIH （CIH＋NAC） group. Spatial learning and memory in each group was assessed with the Morris water maze. Real-time PCR and Western blotting were used to examine mRNA and protein expression of Trx in the hippocampus tissue. The terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling （TUNEL） method was used to detect the apoptotic cells of the hippocampus CA1 region. Results CIH-rats showed impaired spatial learning and memory in the Morris water maze, including longer mean latencies for the target platform, reduced numbers of passes over the previous target platform and a smaller percentage of time spent in the target quadrant. Trx mRNA and protein levels were significantly decreased in the CIH-hippocampus, meanwhile, an elevated apoptotic index revealed apoptosis of hippocampal neurons of rats exposed to CIH. The rats, which acted better in the Morris water maze, showed higher levels of the Trx mRNA and protein in the hippocampus; apoptotic index of the neurons in the hippocampus of each group was negatively correlated with the Trx mRNA and protein levels. Conclusion The Trx deficit likely plays an important role in the impaired spatial learning and memory in the rats exposed to CIH and may work through the apoptosis of neurons in the hippocampus.

关键词： intermittent hypoxia thioredoxin spatial learning oxidative stress sleep apnea

Relationship between reduced nicotinamide adenine dinucleotide phosphate oxidase subunit p22phox gene polymorphism and obstructive sleep apnea-hypopnea syndrome in the Chinese Han population

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Chinese Medical Journal 2009年第12期122卷 1369-1374页

作者： liu hui-guo liu Kui ZHOU Yan-ning XU Yong-jian Department of Respiratory Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Respiratory Disease Ministry of Health Wuhan Hubei 430030 China

Background Increased production of reactive oxygen species （ROS） is thought to play a major role in the pathogenesis of obstructive sleep apnea-hypopnea syndrome （OSAHS）. The reduced nicotinamide adenine dinucleotide phosphate （NADPH） oxidase complex is an important source of ROS. The p22phox subunit is polymorphic with a C242T variant that changes histidine-72 for a tyrosine in the potential heme binding site. This study aimed to investigate the relationship between NADPH oxidase subunit p22phox gene polymorphism and OSAHS. Methods The genotypes of p22phox polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphisms （PCR-RFLP） assay in 176 unrelated subjects of the Han population in southern region of China （including 107 OSAHS subjects and 69 non-OSAHS subjects）, while the plasma concentration of superoxide dismutase （SOD） was detected in the two groups, and p22phox mRNA expression in peripheral blood mononuclear cell （PBMC） was determined with reverse transcription polymerase chain reaction （RT-PCR）. Results The phagocyte NADPH oxidase subunit p22phox mRNA expression was significantly increased in the OSAHS group than that in the non-OSAHS group （P 〈0.01）. Compared with the non-OSAHS control group （（85.31±9.23） U/ml）, the levels of SOD were lower in patients with OSAHS （（59.65±11.61） U/ml （P 〈0.01）. There were significant differences in genotypes distribution in p22phox polymorphism between the two groups （P=0.02）. Compared with the non-OSAHS control group, the OSAHS group had a significantly higher T allele frequency in p22phox polymorphism （P=0.03）. There were independent effects of p22phox polymorphism on body mass index （BMI）, neck circumference （NC）, waist-to-hip ratio （WHR） in the OSAHS group, and the carriers of the T allele of p22phox polymorphism had greater NC, WHR, systolic blood pressure （SBP）, diastolic blood pressure （DBP） and apnea-hypopnea index （AHI）（P 〈0.05）, but the carriers of the T allele had lower SOD

关键词： obstructive sleep apnea syndrome reduced nicotinamide adenine dinucleotide phosphate oxidase p22phox gene polymorphism

Effects of Continuous Positive Airway Pressure on Cognitive Deficits in Middle-aged Patients with Obstructive Sleep Apnea Syndrome： A Meta-analysis of Randomized Controlled Trials

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Chinese Medical Journal 2015年第17期128卷 2365-2373页

作者： Yue-Ying Pan Yan Deng Xiu Xu Ya-Ping liu hui-guo liu Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Respiratory Disease of the Ministry of Health Wuhan Hubei 430030 China

Background： Current views on continuous positive airway pressure （CPAP） treatment to improve the cognitive deficits of patients with obstructive sleep apnea syndrome （OSAS） are controversial, so we performed a meta-analysis. Methods： A comprehensive literature search was undertaken in PubMed, CINAHL, Medline, Psyclnfo, EMBASE, Cochrane Library, CNKI, WanFang, VIP, and CBMdisc for studies published from June 1971 to July 2014. The outcome measures included neuropsychological tests of the 7 cognitive domains detailed below. Results： After screening the titles and abstracts and thoroughly reading the fuU text, we obtained 13 studies with little risk of bias that incorporated 1744 middle-aged obese participants with mild to severe OSAS. The studies were published from 1994 to 2012. Treatment durations varied from 1 to 24 weeks. The effect sizes of attention, vigilance, processing speed, working memory, memory, verbal fluency, and visuoconstructive skills domains were -0.10 （P = 0.24）, -0.12 （P = 0.04）, -0.08 （P = 0.16）, 0.00 （P = 0.95）, -0.04 （P = 0.30）, -0.06 （P = 0.34）, and -0.01 （P = 0.92）, respectively. Conclusions： Cognition partially improved in patients with OSAS after CPAP treatment. The only domain with significant improvement was vigilance. Rigorous randomized controlled trials need to be performed to obtain clear results.

关键词： Cognition Continuous Positive Airway Pressure Meta-analysis Obstructive Sleep Apnea Syndrome

P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress

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Chinese Medical Journal 2015年第16期128卷 2168-2175页

作者： Yan Deng Xue-Ling guo Xiao Yuan Jin Shang Die Zhu hui-guo liu Department of Respiratory and Critical Care Medicine Tongji HospitalHuazhong University of Science and TechnologyWuhanHubei 430030China

Background：The mechanism of the neural injury caused by chronic intermittent hypoxia （CIH） that characterizes obstructive sleep apnea syndrome （OSAS） is not clearly *** purpose of this study was to investigate whether P2X7 receptor （P2X7R） is responsible for the CIH-induced neural injury and the possible pathway it ***：Eight-week-old male C57BL/6 mice were *** each exposure time point,eight mice divided in room air （RA） and IH group were assigned to the study of P2X7R *** in the 21 days-Brilliant Blue G （BBG,a selective P2X7R antagonist） study,48 mice were randomly divided into CIH group,BBG-treated CIH group,RA group and BBG-treated RA *** hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction （PCR）.The spatial learning was analyzed by Morris water *** nuclear factor kappa B （NFκB） and NADPH oxidase 2 （NOX2） expressions were analyzed by Westem *** expressions of tumor necrosis factor α,interleukin 1 β （IL-β）,IL-18,and IL-6 were measured by real-time *** malondialdehyde and superoxide dismutase levels were detected by colorimetric *** damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling ***：The P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH *** the BBG study,the CIH mice showed severer neuronal cell damage and poorer performance in the behavior *** increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH *** alleviated CIH-induced neural injury and consequent functional ***：The P2X7R antagonism attenuates the CIH-induced neuroinflammation,oxidative stress,and spatial deficits,demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

关键词： Inflammation Intermittent Hypoxia Oxidative Stress P2X7 Receptor Sleep Apnea