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。     

N-乙酰半胱氨酸通过AMPK/SIRT1途径抑制缺氧诱导的大鼠脑血管内皮细胞损伤

目的研究N-乙酰半胱氨酸(NAC)对缺氧诱导脑血管内皮细胞损伤的调节作用及分子机制。方法选择SD大鼠分离培养脑血管内皮细胞,分为常氧组、缺氧组、0. 5 NAC组(缺氧+0. 5 mol/L NAC)、1. 0 NAC组(缺氧+1. 0 mol/L NAC)、NAC+8-bAMP组(缺氧+1. 0 mol/L NAC+1. 0 mol/L 8-bAMP)。采用MTS法检测细胞增殖活力,采用TUNEL染色检测凋亡率,采用试剂盒检测氧化应激指标,采用Western blot检测凋亡基因、AMPK/SIRT1通路分子的表达量。结果缺氧组细胞OD490值、T-AOC含量及B淋巴细胞瘤2(Bcl-2)、p-AMP活化蛋白激酶(pAMPK)、去乙酰化酶Sirtuin1(SIRT1)表达量均明显低于常氧组;缺氧组细胞凋亡率、细胞中活性氧(ROS)、丙二醛(MDA)、8-羟基脱氧鸟苷(8-OHDG)含量及bcl-2相关X蛋白(bax)、细胞色素C(Cyt-C)、含半胱氨酸的天冬氨酸蛋白水解酶3(Caspase-3)的表达量均明显高于常氧组。0. 5 NAC组、1. 0 NAC组细胞OD490值、T-AOC量及Bcl-2、pAMPK、SIRT1表达量均明显高于缺氧组; 0. 5 NAC组、1. 0 NAC组细胞凋亡率、ROS、MDA、8-OHDG含量及Caspase-3、Cyt-C、Bax的表达量均明显低于缺氧组。NAC+8-bAMP组细胞OD490值、T-AOC及Bcl-2、p-AMPK、SIRT1表达量均明显低于1. 0 NAC组; NAC+8-bAMP组凋亡率、ROS、MDA、8-OHDG含量及Caspase-3、Cyt-C、Bax的表达量均明显高于1. 0 NAC组。结论 NAC能够通过激活AMPK/SIRT1通路来减轻氧化应激及线粒体凋亡介导的脑血管内皮细胞损伤。     

N-乙酰半胱氨酸对脂多糖诱导的血管内皮细胞炎症损伤的影响

目的:探讨N-乙酰半胱氨酸(NAC)是否对脂多糖(LPS)刺激的血管内皮细胞具有保护作用,为NAC用于治疗种植体周围炎、牙周炎等提供理论基础。方法:通过细胞计数试剂盒(CCK-8)法检测不同浓度的LPS或NAC对人脐静脉血管内皮细胞(HUVECs)增殖的影响,以获得刺激HUVECs的最适药物浓度。添加最佳药物浓度的LPS和(或)NAC处理HUVECs 24 h,实时半定量聚合酶链反应(RT-qPCR)检测炎症因子白细胞介素-8(IL-8)、肿瘤坏死因子-α(TNF-α)和细胞粘附分子-1(ICAM-1)的mRNA表达;酶联免疫吸附试验(ELISA)检测TNF-α和IL-8的蛋白表达;Western blot法检测ICAM-1和NF-κB信号通路的表达情况。结果:LPS刺激HUVECs过量表达炎症因子TNF-α、IL-8和ICAM-1。此外,LPS增加NF-κB通路的磷酸化P65(pP65)表达。然而,NAC预处理HUVECs后,显著抑制了LPS引起的TNF-α、IL-8和ICAM-1表达的增加及降低了pP65的分泌水平。结论:本结果表明NAC保护血管内皮细胞免受LPS介导的炎症损伤,从而减轻炎症反应,其潜在的机制可能与NF-κB信号通路有关。     

Involvement of Nrf2, JAK and COX pathways in acetaminophen-induced nephropathy: Role of some antioxidants

ObjectivesAcetaminophen (APAP)-induced nephrotoxicity is detrimental consequence for which there has not been a standardized therapeutic regimen. Although, N-acetylcysteine (NAC) is a well-known antidote used in APAP-induced hepatotoxicity, its benefit in nephrotoxicity caused by APAP is almost lacking. This study aimed to compare the possible protective effect of thymoquinone (TQ), curcumin (CR), and α-lipoic acid (α-LA), either in solo or in combination regimens with that of NAC against APAP-induced renal injury.Design and methodRats were divided into nine groups; control group, APAP intoxicated group (1000 mg/kg; orally), and the remaining seven groups received, in addition to APAP, oral doses of NAC, TQ, CR, α-LA, CR plus TQ, TQ plus α-LA, or CR plus α-LA. The first dose of the aforementioned antioxidants was given 24 h before APAP, and then the second dose was given 2 h after APAP, whereas the last dose was given 10 h after administration of APAP.ResultsTreatment with APAP elevated kidney markers like serum uric acid, urea, and creatinine. In addition, it increased the serum level of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and thiobarbituric acid reactive species (TBARS). Also, the protein expression of renal janus kinase (JAK) and cyclooxygenase (COX)-2 were all upregulated by APAP. In contrast, the expression of Nrf2 and the renal levels of superoxide dismutase and glutathione were downregulated. Treatment with the indicated natural antioxidants resulted in amelioration of the aberrated parameters through exhibiting anti-inflammatory, antioxidant and free radical-scavenging effects with a variable degree.ConclusionThe combined administration of CR and TQ exerted the most potent protection against APAP-induced nephrotoxicity through its anti-inflammatory and free radical-scavenging effects (antioxidant) which were comparable to that of NAC-treatment.     

N-乙酰半胱氨酸对心肺转流下心脏直视手术患者肺功能的影响

目的观察N-乙酰半胱氨酸(N-acetylcysteine,NAC)对心肺转流(cardiopulmonary bypass,CPB)下心脏直视手术患者肺功能参数的影响。方法择期在CPB下行心脏瓣膜置换术的风湿性心脏病患者40例,性别不限,年龄40~65岁,体重45~80kg,ASAⅡ或Ⅲ级,心功能Ⅰ~Ⅲ级,随机均分为NAC组和对照组(C组)。NAC组:麻醉诱导后CPB前静脉输注NAC 100mg/kg,CPB开始后静脉持续输注NAC 40mg/kg至术毕。C组:等剂量用生理盐水作为安慰剂静脉输注。于麻醉诱导后(T0)、开胸后CPB前(T1)、术毕关胸后(T2)、术后5h(T3)、24h(T4)和48h(T5)检测呼吸指数(RI)、氧合指数(OI)、肺泡-动脉氧分压差(A-aDO2)和气道阻力(R)。结果与T0时比较,T2~T4时两组患者RI、A-aDO2明显升高(P0.05)、OI明显降低(P0.05)、T2和T3时两组患者气道阻力明显升高(P0.05)。与C组比较,T2~T4时NAC组RI和A-aDO2明显降低(P0.05)、OI明显升高(P0.05)、T2和T3时NAC组气道阻力明显降低(P0.05)。结论 N-乙酰半胱氨酸可以减轻CPB导致的肺功能损伤,对肺脏可能具有保护作用。     

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.     

No Net Splanchnic Release of Glutathione in Man during N-Acetylcysteine Infusion

Glutathione and amino acid concentrations were measured in arterial and hepatic vein plasma in four healthy volunteers and two patients with cirrhosis. There was no significant splanchnic efflux of glutathione (95% confidence limits,-0.501 to 0.405 μmol/min). After infusion of N-acetylcysteine (NAC) in a high dose (150 mg/kg body weight primer plus 15 mg/(h × kg BW), corresponding to treatment of acetaminophen overdose, there was no change in the splanchnic glutathione efflux (95% confidence limits,-0.531 to 0.375 μmol/min). NAC increased hepatic plasma flow rate from 0.90 ± 0.531 min^-1 to 0.97 ± 0.11 (mean ± SEM; p < 0.05). The effects of NAC treatment on plasma amino acids corresponded to an increased load on hepatic metabolic N conversion and transamination among non-essential amino acids. Splanchnic uptake of serine, alanine, cystine, isoleucine, and phenylalanine increased after NAC compatible with stimulated hepatic glutathione synthesis. In contrast to the rat, plasma glutathione in man probably originates mainly from extrahepatic tissues.     

Lipopolysaccharide treatment reduces rat platelet aggregation independent of intracellular reactive-oxygen species generation

High production of reactive-oxygen species (ROS) by blood cells is involved in damage of the vascular endothelium and multiple organ dysfunction in sepsis. However, little is known about the intraplatelet ROS production in sepsis and its consequences on platelet reactivity. In this study, we evaluated whether the treatment of rats with lipopolysaccharide (LPS) affects platelet aggregation through intraplatelet ROS generation. Rats were injected with LPS (1?mg/kg, i.p.), and at 2 to 72?h thereafter, adenosine diphosphate (ADP) (3–10?µM) induced platelet aggregation was evaluated. Production of ROS in platelets was measured by flow cytometry using 2′,7′-dichlorofluorescein diacetate (DCFH-DA). Treatment of rats with LPS time-dependently inhibited ADP-induced platelet aggregation within 72?h. The inhibitory effect of LPS on platelet aggregation was further increased when the platelets were incubated with polyethylene glycol-superoxide dismutase (PEG-SOD; 30?U/mL), polyethylene glycol-catalase (PEG-CAT; 1000?U/mL) or the NADPH oxidase inhibitor diphenyleneiodonium (DPI; 10?µM). The ROS production in non-stimulated platelets did not differ between control and LPS-treated rats. However, in ADP-activated platelets, generation of ROS was increased by 3.0- and 7.0-fold, as evaluated at 8 and 48?h after LPS injection, respectively. This increased ROS production was significantly reduced when platelets were incubated in vitro with DPI, PEG-SOD or PEG-CAT. In contrast, treatment of rats with N-acetylcysteine (150?mg/kg, i.p.) significantly reduced the inhibitory effect of LPS on platelet aggregation, and prevented the increased ROS production by in vivo LPS. Our results indicate that the increased intraplatelet ROS production does not contribute to the inhibitory effect of LPS on platelet aggregation; however, the maintenance of redox balance in LPS-treated rats is fundamental to restore the normal platelet response in these animals.     

N-acetylcysteine for the prevention of contrast-induced nephropathy in patients with pre-existing renal insufficiency or diabetes: a systematic review and meta-analysis

Abstract

Purpose: To identify benefit of N-acetylcysteine (NAC) on patients with pre-existing renal insufficiency or diabetes. Background: NAC administration is a common method for prevention of contrast-induced nephropathy (CIN). Nevertheless, its benefit on patients with pre-existing renal insufficiency or diabetes remains uncertain and controversial. Methods: Randomized controlled trials (RCTs) to evaluate the efficacy of NAC for the prevention of CIN in patients with pre-existing renal insufficiency or diabetes were searched from the databases of MEDLINE, EMBASE, and Cochrane library. Pooled odds ratio (OR) with 95% confidence interval (95% CI) were calculated using fixed-effects model by the Mantel–Haenszel test. Results: Twenty RCTs involving 3466 subjects (1756 assigned to NAC and 1710 assigned to the control) were included in the pre-existing renal dysfunction group. Pooled analysis suggested a significant reduction in CIN among this group (OR, 0.76; 95% CI, 0.61–0.93; p?=?0.008). However, the nine trials comparing NAC versus control among patients with diabetes (NAC, 367 subjects; control, 358 subjects) showed no benefit of NAC for prevention of CIN (OR?=?0.87; 95% CI, 0.58–1.30; p?=?0.50). No significant heterogeneity was detected (p?=?0.07; I²?=?34% for the group of pre-existing renal dysfunction; p?=?0.40; I²?=?5% for the group of diabetes). Conclusion: Our results suggest that NAC decreases the incidence of contrast-induced nephropathy among patients with pre-existing renal insufficiency. The benefit was not existed in patients with diabetes.     

N-acetylcysteine attenuates renal alterations induced by senescence in the rat

The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) on renal function, as well as on sodium and water transporters, in the kidneys of aged rats. Normal, 8-month-old male Wistar rats were treated (n = 6) or not (n = 6) with NAC (600 mg/L in drinking water) and followed for 16 months. At the end of the follow-up period, we determined inulin clearance, serum thiobarbituric acid reactive substances (TBARS), serum cholesterol, and urinary phosphate excretion. In addition, we performed immunohistochemical staining for p53 and for ED-1-positive cells (macrophages/monocytes), together with Western blotting of kidney tissue for NKCC2, aquaporin 2 (AQP2), urea transporter A1 (UT-A1) and Klotho protein. At baseline, the two groups were similar in terms of creatinine clearance, proteinuria, cholesterol, and TBARS. At the end of the follow-up period, NAC-treated rats presented greater inulin clearance and reduced proteinuria, as well as lower serum cholesterol, serum TBARS, and urinary phosphate excretion, in comparison with untreated rats. In addition, NAC-treated rats showed upregulated expression of NKCC2, AQP2, and UT-A1; elevated Klotho protein expression, low p53 expression, and few ED-1 positive cells. In conclusion, we attribute these beneficial effects of NAC (the significant improvements in inulin clearance and in the expression of NKCC2, AQP2, and UT-A1) to its ability to decrease oxidative stress, inhibit p53 expression, minimize kidney inflammation, and stimulate Klotho expression.