甲基苯丙胺与HIV-Tat蛋白协同改变大鼠血脑屏障通透性的氧化应激作用机制

目的 观察甲基苯丙胺与HIV-Tat蛋白协同对大鼠血脑屏障的作用机制.方法 雄性SD大鼠每天2次腹腔注射给予MA10 mg/kg的同时尾静脉注射给予HIV-Tat 400 ng/kg,连续7d,给药结束24 h后随机取10只大鼠尾静脉注射伊文思蓝检测脑组织EB含量,随机取5只大鼠断颈取脑,用于SOD活力、GSH和MDA含量的测定.余下2只大鼠快速断颈取脑,戊二醛-锇酸溶液固定前额叶皮质部分,透射电镜观察结构变化.结果 与正常对照组相比,实验组脑组织中EB含量不同程度增加,提示实验组血脑屏障通透性增加(P＜0.05);MDA含量升高、SOD活力和GSH含量不同程度降低,提示实验组氧化应激反应增强(P＜0.05).MA+Tat组与MA组、Tat组相比,EB含量升高明显,提示MA与HIV-Tat蛋白联用能协同增加血脑屏障通透性;MDA含量显著升高,SOD活力、GSH含量明显下降,提示MA与HIV-Tat蛋白联用能协同增强大鼠脑组织氧化应激反应(P＜0.01);NAC+MA+Tat组与MA+Tat组相比,EB含量降低,提示NAC能一定程度拮抗MA与HIV-Tat蛋白对血脑屏障通透性的影响(P＜0.01);MDA含量下降,SOD活力、GSH含量明显升高,反映NAC能在一定程度拮抗MA与HIV-Tat蛋白对大鼠脑内氧化应激反应增强作用(P＜0.01).各实验组在电镜下观察到血脑屏障一系列超微结构改变,如脑微血管内皮细胞肿胀变薄,血管周围胶质细胞和星形胶质细胞肿胀,胞饮小泡增加等,这些改变以MA+Tat组最为显著.结论 MA和HIV-Tat蛋白能改变血脑屏障通透性,两者具有协同作用,协同作用机制可能与氧化应激有关.     

N-乙酰半胱氨酸对葡聚糖硫酸钠诱导的小鼠溃疡性结肠炎的保护作用

目的观察N-乙酰半胱氨酸(NAC)灌肠对小鼠急性溃疡性结肠炎的作用。方法5%葡聚糖硫酸钠(DSS)自由饮用7 d诱导小鼠急性溃疡性结肠炎,同时予以生理盐水(NS)、5-氨基水杨酸(5-ASA)、NAC保留灌肠,观察小鼠体重、粪便性状、隐血便血,计算疾病活动度(DAI)积分,检测结肠长度、结肠过氧化物酶(MPO)活性、血清过氧化物歧化酶(SOD)活力和丙二醛(MDA)含量及肠黏膜病理改变。结果NAC组小鼠隐血、便血、体重下降、DAI积分、病理改变等均好于模型组、NS组(P<0.05),与5-ASA组疗效相似。NAC组SOD活力高于模型组,MPO活性、MDA含量则低于模型组(P<0.05)。结论NAC对DSS诱导的小鼠急性溃疡性结肠炎黏膜损伤有保护作用,其机制可能与抗氧化应激有关。     

N-乙酰半胱氨酸对肝损伤大鼠体内NO水平及NOS活性的影响

目的:探讨N-乙酰半胱氨酸(N-Acetylcysteine,NAC)对肝损伤大鼠肝脏病理的影响及对肝脏损伤保护的作用机制.方法:选用36只SD大鼠随机分为3组,正常对照组:腹腔注射生理盐水10ml/kg 1次;肝损伤模型组:给予D-gal 1g/kg腹腔注射1次;NAC实验组:于腹腔注射D-gal 1g/kg后6、12、18 h分别腹腔注射NAC 0.1mmol/kg 1次.急性肝损伤模型建立后24h取血及肝组织标本,观察比较各组大鼠肝组织病理改变,测定其血清、肝组织NO水平及肝组织NOS活性.结果:NAC实验组大鼠的肝脏病理形态较肝损伤模型组有所改善,其血清NO水平较肝损伤模型组增高,而肝组织中NO水平较模型组降低,均具有统计学差异.NAC组大鼠肝组织中cNOS活性较模型组有明显提高,而iNOS活性较模型组明显降低(P均＜0 05).结论:NAC可以改善急性肝损伤大鼠的肝脏病理改变,该保护作用可能通过影响不同型别的NOS活性而改变体内不同部位的NO水平有关.     

N-乙酰半胱氨酸对呼吸道病毒辅助治疗的研究进展和药学监护

目的:采用文献检索的方法对N-乙酰半胱氨酸辅助治疗呼吸道病毒的研究进行汇总分析,评价其有效性与安全性,对现阶段临床辅助治疗新型冠状病毒肺炎提供理论依据和临床证据。方法:以"乙酰半胱氨酸""N-acetylcysteine""流感病毒"为关键词,系统检索CNKI、万方、维普、SinoMed、Pubmed数据库,筛选文章,提取数据,进行分析。结果:共纳入16篇研究论文,包括动物试验、细胞试验以及案例报道,病毒涉及流感病毒、呼吸道合胞病毒以及腺病毒。N-乙酰半胱氨酸主要通过抑制NF-κB向细胞核的移位和MAPK p38的磷酸化两条途径发挥其抗氧化作用,进而抑制减轻肺组织炎症、肺水肿。结论:相关的细胞研究与动物研究证明N-乙酰半胱氨酸对呼吸道病毒有一定的抑制作用,能够减轻流感和流感样发作。并且由于其良好的祛痰作用,对于新冠肺炎患者症状可能有较好的改善作用。     

Protective effect of N-acetylcysteine against BDE-209-induced neurotoxicity in primary cultured neonatal rat hippocampal neurons in vitro

Globally, brominated diphenyl ether-209 (BDE-209) is the most widely used polybrominated diphenyl ether (PBDEs). It has been reported that BDE-209 induces developmental neurotoxicity in vivo. The purpose of this study was to use an antioxidant, N-acetylcysteine (NAC), as an antidote for the neurotoxic effect of BDE-209. We used primary hippocampal neurons from rats for the in vitro cultures. BDE-209 was added to the cultures in increasing concentrations and co-cultured with NAC in order to assess the effect of NAC on BDE-209-induced neurotoxicity. We measured cell viability, apoptosis, expression of phosphorylated p38 mitogen-activated protein kinases (MAPK), intracellular calcium content, and intracellular reactive oxygen species (ROS) levels. The difference between the BDE-209 groups without NAC and the blank control groups was significant (P < 0.05). The difference between the NAC treatment groups and the BDE-209 groups without NAC was also significant (P < 0.05), showing that BDE-209 increased apoptosis, the expression of p38 MAPK, the calcium ion concentration, and the ROS level and decreased cell viability. In contrast, NAC reduced the degree of cellular cytotoxicity induced by BDE-209. The results suggested that NAC may be able to attenuate BDE-209-induced neurotoxicity.     

Effects of phenylethyl isothiocyanate and its metabolite on cell-cycle arrest and apoptosis in LNCaP human prostate cancer cells

Abstract

Cruciferous vegetable consumption is associated with decreased risk of several cancers, including prostate cancer. Gluconasturtiin, one of the predominant glucosinolates in cruciferous vegetables, is hydrolyzed to yield phenylethyl isothiocyanate (PEITC). PEITC absorption and metabolism in humans involves glutathione conjugation followed by conversion via the mercapturic acid pathway to an N-acetylcysteine (NAC) conjugate that is excreted in the urine. We observed an inhibitory effect of PEITC and its metabolite, NAC-PEITC, on cancer cell proliferation, cell-cycle progression, and apoptosis in LNCaP human prostate cancer cells. PEITC and NAC?PEITC suppressed LNCaP cell proliferation in a dose-dependent manner, and exposure to 5 μM PEITC or NAC-PEITC reduced cell proliferation by 25% and 30%, respectively. Cell-cycle analysis revealed that cells treated with 5 μM PEITC or NAC-PEITC arrested at the G₂/M phase. In addition, the percentage of cells in the S phase decreased from 46% to 25% following 48 h of incubation with PEITC or NAC-PEITC. The G₂/M-phase cell-cycle arrest of LNCaP cells grown in the presence of PEITC or NAC-PEITC is correlated with the downregulation of Cdk1 and cyclin B₁ protein expression. Apoptosis was observed at the later stages of 24-h and 48-h treatments with 5 μM PEITC and NAC-PEITC. In conclusion, PEITC and NAC-PEITC are potential chemopreventive/chemotherapeutic agents against LNCaP human prostate cancer cells.     

High dose acetaminophen inhibits STAT3 and has free radical independent anti-cancer stem cell activity

High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor efficacy in early phase clinical trials. However, the mechanism of action (MOA) of AAP''s anticancer effects remains elusive. Using clinically relevant AAP concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in vivo in lung cancer and melanoma cells with diverse driver mutations. Associated mechanisms were also studied. Our results demonstrated that AAP inhibited 3D spheroid formation, self-renewal, and expression of CSC markers when human cancer cells were grown in serum-free CSC media. Similarly, anti-CSC activity was demonstrated in vivo in xenograft models - tumor formation following in vitro treatment and ex-vivo spheroid formation following in vivo treatment. Intriguingly, NAC, used to mitigate AAP''s liver toxicity, did not rescue cells from AAP''s anti-CSC effects, and AAP failed to reduce glutathione levels in tumor xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly binds to STAT3 with an affinity in the low micromolar range and a high degree of specificity for STAT3 relative to STAT1. These findings have high immediate translational significance concerning advancing AAP with NAC rescue to selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of selective STAT3 inhibition has implications for developing rational anticancer combinations and better patient selection (predictive biomarkers) for clinical studies and developing novel selective STAT3 inhibitors using AAP''s molecular scaffold.     

Preventing radiocontrast-induced nephropathy in chronic kidney disease patients undergoing coronary angiography

Radiocontrast-induced nephropathy(RCIN) is an acute and severe complication after coronary angiography,particularly for patients with pre-existing chronic kidney disease(CKD).It has been associated with both short-and long-term adverse outcomes,including the need for renal replacement therapy,increased length of hospital stay,major cardiac adverse events,and mortality.RCIN is generally defined as an increase in serum creatinine concentration of 0.5 mg/dL or 25%above baseline within 48 h after contrast administration.There is no effective therapy once injury has occurred,therefore,prevention is the cornerstone for all patients at risk for acute kidney injury(AKI).There is a small but growing body of evidence that prevention of AKI is associated with a reduction in later adverse outcomes.The optimal strategy for preventing RCIN has not yet been established.This review discusses the principal risk factors for RCIN,evaluates and summarizes the evidence for RCIN prophylaxis,and proposes recommendations for preventing RCIN in CKD patients undergoing coronary angiography.     

N-乙酰半胱氨酸对苯再生障碍性贫血小鼠氧化指标的影响观察

目的:初步探讨苯在小鼠体内引起损伤的可能机制以及N-乙酰半胱氨酸(NAC)的保护作用。方法:CD1小鼠50只,随机分成3组,A组10只,为玉米油对照组,单纯皮下注射玉米油4ml/kg,每周3次,共25次;B组20只,每周3次于小鼠背侧皮下注射苯2ml/kg(苯用等量玉米油稀释,均匀混合);C组20只,在皮下注射苯的基础上同时口服NAC,按400mg·kg-1·d-1给予。分别处理各组小鼠并检测相关指标。结果:①B、C组与A组比较外周血WBC、Hb、Ret等指标显著降低;②C组与B组比较,除PLT无显著性差异外,WBC、Hb、Ret均有明显改善,均P<0.05,提示NAC对苯的血液学毒性有一定的预防作用;③与A组比较,B、C组各氧化指标均显著增高,其中B组与A组比较活性氧、丙二醛(MDA)、超氧化物岐化酶(SOD)、过氧化氢酶(CAT)均P<0.01,总抗氧化物(T-AOC)P<0.05,GSH含量无明显变化,巯基(-SH)下降P<0.01;C组与A组相比活性氧P<0.05、MDA、SOD、CAT均P<0.01,T-AOCP<0.05,还原型谷胱甘肽(GSH)含量升高,P<0.01,-SH含量无显著变化;④C组与B组相比各氧化指标均显著降低,活性氧、MDA、SOD、CAT均P<0.01、T-AOCP<0.05。结论:①苯诱发小鼠造血损伤的机制中有氧化损伤作用的参与;②NAC在小鼠体内一定程度上减轻了苯的血液学毒性,其中NAC的抗氧化作用是一个重要因素。     

阿托伐他汀与N-乙酰半胱氨酸预防PCI术后造影剂肾病的效果比较

目的:比较阿托伐他汀与N-乙酰半胱氨酸对冠心病患者经皮冠状动脉介入治疗(PCI)后造影剂肾病的预防效果。方法:将150例冠心病患者随机分为阿托伐他汀治疗组(50例),N-乙酰半胱氨酸治疗组(50例)和对照组(50例)。在充分水化治疗的基础上,阿托伐他汀组在PCI术前1 d口服阿托伐他汀80 mg,PCI术后每天口服阿托伐他汀40 mg,持续3 d;N-乙酰半胱氨酸组在PCI术前1 d分两次服用N-乙酰半胱氨酸泡腾片1 200 mg,术后连续服用3 d;对照组不做进一步处理。然后分别测定并比较3组患者造影前及造影后24 h、48 h、72 h的血肌酐(Scr)和造影剂肾病(CIN)的发生率。结果:术后72 h两治疗组Scr增加值及CIN的发生率均明显低于对照组(P<0.05),其中阿托伐他汀治疗组Scr增加值及CIN的发生率明显低于N-乙酰半胱氨酸治疗组(P<0.05)。结论:阿托伐他汀及N-乙酰半胱氨酸对冠心病患者PCI术后造影剂肾病的发生都有一定的预防保护作用,阿托伐他汀的预防保护作用更明显。