N-乙酰半胱氨酸对AGEs诱导的微血管内皮细胞VCAM-1表达的抑制作用

用流式细胞仪测定晚期糖基化终末产物(advanced glycation end products，AGEs)刺激及N—乙酰半胱氨酸(NAC)干预前后小鼠心脏微血管内皮细胞血管细胞黏附分子1(VCAM—1)的表达，同时用放免法测定培养上清中TNF—α水平。结果发现AGEs刺激后微血管内皮细胞VCAM—1表达增加，TNF—α水平升高；NAC干预组VCAM—1表达降低，TNF—α水平下降并具有剂量依赖性。提示NAC能抑制AGEs诱导的微血管内皮细胞VCAM—1的表达，TNF—α的介导是可能的机制之一。     

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。     

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-acetylcysteine and neurodegenerative diseases: Basic and clinical pharmacology

Increasing lines of evidence suggest a key role of oxidative stress in neurodegenerative diseases. Alzheimer’s disease, Parkinson’s disease, myoclonus epilepsy of the Unverricht-Lundborg type, spinocerebellar degeneration, tardive dyskinesia and Down’s syndrome have been associated with several mitochondrial alterations Oxidative stress can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in cellular damage and programmed cell death. First, this review examines the mechanisms of action of N-acetylcysteine (NAC), an antioxidant and a free radical-scavenging agent that increases intracellular GSH, at the cellular level. NAC can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. The chemical properties of NAC include redox interactions particularly with other members of the group XIV elements (selenium, etc.) and ebselen, a lipid-soluble seleno-organic compound. Second, NAC has been shown to protect against oxidative stress-induced neuronal death in cultured granule neurons. Recent findings on the protective effect of NAC against 4-hydroxynonenal (HNE)-induced toxicity in cerebellar granule neurons are summarized. Finally, the protective pharmacokinetics of NAC in humans and the possible usefulness of NAC for the treatment of neurodegenerative diseases are discussed with reference to basic and clinical studies.     

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury.

Mitochondrial dysfunction and internucleosomal DNA fragmentation are well-recognized features of acetaminophen (AAP)-induced hepatocyte cell death. However, the endonucleases responsible for this effect have not been identified. Apoptosis-inducing factor (AIF) and endonuclease G are nucleases located in the intermembrane space of mitochondria. AIF is thought to trigger chromatin condensation and induce cleavage of DNA into high molecular weight fragments (50-300 kb), and endonuclease G can produce oligonucleosomal DNA fragments. Therefore, the objective of this investigation was to test the hypothesis that endonuclease G and AIF could be involved in AAP-induced nuclear DNA fragmentation. Using immunofluorescence microscopy, it was shown that in primary cultured mouse hepatocytes, endonuclease G and AIF translocated to the nucleus between 3 and 6 h after exposure to 5 mM AAP. In contrast, other mitochondrial intermembrane proteins such as cytochrome c or the second mitochondria-derived activator of caspases (Smac) did not accumulate in the nucleus. The translocation of AIF and endonuclease G correlated with mitochondrial dysfunction as indicated by the progressive loss of the mitochondrial membrane potential (measured with the JC-1 assay) and the appearance of nuclear DNA fragments in the cytosol (determined by an anti-histone ELISA). Pretreatment with 20mM N-acetylcysteine prevented mitochondrial dysfunction, the nuclear translocation of endonuclease G and AIF, and the nuclear DNA fragmentation. The data support the conclusion that endonuclease G and AIF translocate to the nucleus in response to AAP-induced mitochondrial dysfunction and may be responsible, at least in part, for the initial DNA fragmentation during AAP hepatotoxicity.     

Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man

The pharmacokinetics after oral administration of 200, 600 or 1200 mg of N-acetylcysteine (NAC) were studied in 10 healthy subjects. Normalized maximal plasma concentration was significantly higher after a 600 mg dose than after a 200 mg dose. Bioavailability of NAC significantly increased with increasing dose. Time for maximal plasma concentration also increased with increasing dose. The observations can be explained by a capacity-limited presystemic elimination of NAC. In an extension of the study, 600 mg of NAC was given twice a day for 5 days and the plasma concentrations were followed after the morning dose on day 6. No differences in the pharmacokinetic parameters were observed in comparison with the single 600 mg dose. This indicates that the beneficial clinical effects observed after repeated dosing can not be ascribed to an accumulation of NAC in plasma.     

Antioxidant effects of N-acetylcysteine on the male reproductive system: A systematic review

This study aimed to evaluate the effect of N-acetyl cysteine on the male reproductive system and consensus and classification of data found from previous studies. It is undeniable that N-acetyl cysteine as a powerful antioxidant compound can medicate many diseases such as cardiovascular, kidney, liver and reproductive system disorders. With the increasing environmental pollution that has a direct adverse effect on male fertility, the use of this compound is able to positively function on human fertility health. In this study, we have been collected the main data of scientific articles (1994–2020) about N-acetyl cysteine effects. By searching in the scientific databases of PubMed, Google Scholar, Science Direct, Wiley and Web of Science, related articles were extracted. As a result, all observations have confirmed that N-acetyl cysteine can improve and normalise the spermatogenesis in the male reproduction system.     

N-乙酰半胱氨酸对肠系膜上动脉夹闭后肠和肺损伤的防治效应

Ｎ－乙酰半胱氨酸（ＮＡＣ）是体内游离巯基的组成部分,既可补充体内谷胱甘肽,又具有清除自由基,保护细胞的作用。本实验观察了ＮＡＣ在大鼠肠系膜上动脉夹闭（ＳＭＡＯ）造成的肠缺血再灌损伤的继发性的操作时对肠、肺的保护效应,ＳＭＡＯ４５ｍｉｎ松夹闭于松夹前、后５分钟尾静脉注射ＮＡＣ,测定松夹后２、４、６ｈ肠、肺组织总巯基（ＴＳＨ）和游离巯基（ＮＰＳＨ）以及丙二醛（ＭＤＡ）和髓过氧化物酶（ＭＰＯ）的改变。结     

Evaluation of the metabolism,bioactivation and pharmacokinetics of triaminopyrimidine analogs toward selection of a potential candidate for antimalarial therapy

1.?During the course of metabolic profiling of lead Compound 1, glutathione (GSH) conjugates were detected in rat bile, suggesting the formation of reactive intermediate precursor(s). This was confirmed by the identification of GSH and N-acetylcysteine (NAC) conjugates in microsomal incubations.

2.?It was proposed that bioactivation of Compound 1 occurs via the formation of a di-iminoquinone reactive intermediate through the involvement of the C-2 and C-5 nitrogens of the pyrimidine core.

3.?To further investigate this hypothesis, structural analogs with modifications at the C-5 nitrogen were studied for metabolic activation in human liver microsomes supplemented with GSH/NAC.

4.?Compounds 1 and 2, which bear secondary nitrogens at the C-5 of the pyrimidine core, were observed to form significant amounts of GSH/NAC-conjugates in vitro, whereas compounds with tertiary nitrogens at C-5 (Compound 3 and 4) formed no such conjugates.

5.?These observations provide evidence that electron/hydrogen abstraction is required for the bioactivation of the triaminopyrimidines, potentially via a di-iminoquinone intermediate. The lack of a hydrogen and/or steric hindrance rendered Compound 3 and 4 incapable of forming thiol conjugates.

6.?This finding enabled advancement of compound 4, with a desirable potency, safety and PK profile, as a lead candidate for further development in the treatment of malaria.