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.     

应用N-乙酰半胱氨酸治疗慢性乙型肝炎重度患者临床疗效初步研究

目的 探讨应用注射用 N-乙酰半胱氨酸(NAC)治疗慢性乙型肝炎重度患者的临床疗效。方法 2015年1月～2018年12月我院诊治的慢性乙型肝炎重度患者62例,被分为观察组32例和对照组30例。在对照组,给予护肝、降黄、抗病毒等综合治疗,观察组在对照组治疗的基础上加用NAC静脉滴注,连续治疗6 w。采用放射免疫法检测血清Ⅲ型前胶原(PC-Ⅲ)、IV型胶原(IV-C)、血清透明质酸(HA)和层黏连蛋白(LN)]水平,采用ELISA法检测血清白介素-1β(IL-1β)、IL-6、IL-8和肿瘤坏死因子-α(TNF-α)水平。结果 在治疗6 w末,观察组血清ALT和AST水平分别为(45.4±2.9)U/L和(74.3±8.7)U/L,与对照组比较无显著性差异,观察组血清TBIL水平为(85.1±54.6)μmol/L,显著低于对照组;观察组血清PC-Ⅲ、IV-C、HA和LN水平分别为(87.1±15.8)μg/L、(74.5±15.2)μg/L 、(95.7±13.7)μg/L和(83.9±16.5)μg/L,显著低于对照组;观察组血清IL-6、IL-8和TNF-α水平分别为(15.1±2.8)μg/L、(5.2±2.9)μg/L和(13.7±0.9) μg/L,显著低于对照组;观察组病情控制率为87.1%,显著高于对照组。结论 应用NAC治疗慢性乙型肝炎重度患者临床疗效显著且无明显的不良反应,能降低血清胆红素和肝纤维化指标水平,减轻炎症相关的细胞因子水平。     

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.     

Targeting maladaptive glutathione responses in lung disease

The lung is unique being exposed directly to the atmospheric environment containing xenobiotics, pathogens, and other agents which are continuously inhaled on a daily basis. Additionally, the lung is exposed to higher ambient oxygen levels which can promote the formation of a complex number of reactive oxygen and nitrogen species. Due to this constant barrage of potential damaging agents, the lung has developed a high degree of plasticity in dealing with ever changing conditions. In the present commentary, we will focus on glutathione (GSH) as a key antioxidant in the lung airways and discuss mechanisms by which the lung uses GSH to adapt to its rapidly changing environment. We will then examine the evidence on how defective and inadequate adaptive responses can lead to lung injury, inflammation and disease. Lastly, we will examine some of the recent attempts to alter lung GSH levels with therapies in a number of human lung diseases and discuss some of the limitations of such approaches.     

7-b, a novel amonafide analogue, cause growth inhibition and apoptosis in Raji cells via a ROS-mediated mitochondrial pathway

Previous studies have shown that 7-b (6-(dodecylamino)-2-(3-(4-methylpiperazin-1-yl)propyl)-1H-benzo-[de]isoquinoline-1,3(2H)-dione), a novel amonafide-based DNA intercalator, was generated as a new anticancer candidate. However, the effects induced by 7-b and the molecular mechanisms involved remain poorly understood in Burkitt's lymphoma. To shed light on these issues, we have investigated the effects of 7-b on proliferation, cell cycle progression, apoptosis activity and oxidative stress levels of lymphoma Raji cells in vitro. Our results showed that 7-b inhibited the proliferation of Raji cells and induced G1 cell cycle arrest in a dose-dependent manner. Moreover, 7-b treatment triggered programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (Δψm). Altogether our results showed that 7-b mediated its growth inhibitory effects on Raji cells via the activation of a ROS-mediated mitochondrial pathway and cell cycle checkpoint signaling pathway which subsequently targeted p21.     

环磷酰胺、大剂量N-乙酰半胱氨酸治疗特发性肺间质纤维化疗效分析

目的探讨特发性肺间质纤维化的临床有效治疗方法。方法将65例特发性肺间质纤维化患者分为治疗组1、治疗组2和对照组三组。对照组给予常规强的松治疗;治疗组1给予强的松加环磷酰胺治疗;治疗组2给予强的松加大剂量N-乙酰半胱氨酸治疗。观察并比较患者治疗前后临床症状体征、胸部影像学及肺功能的变化。结果治疗前各组间具有可比性。治疗后,治疗组1与对照组的疗效无明显差异;而治疗组2的疗效则明显好于治疗组1及对照组。结论强的松联合大剂量N-乙酰半胱氨酸是临床治疗特发性肺间质纤维化的有效手段。     

N-乙酰半胱氨酸对活性氧诱导耳蜗毛细胞凋亡的抑制作用的观察

目的探讨N-乙酰半胱氨酸(N-acetylcysteine,NAC)对活性氧诱导耳蜗毛细胞凋亡的抑制作用。方法选用新生1～5天SD大鼠24只,随机分为4组,每组6只12耳:①无血清培养基组;②0.1mmol/L H2O2组(H2O2组);③10mmol/L N-乙酰半胱氨酸组(NAC组);④10mmol/L NAC+0.1mmol/L H2O2组(NAC+H2O2组)。分离各组动物Corti器,分别放入相应培养液中培养,培养结束后用丫啶橙(YO)/碘化丙啶(PI)双重染色技术检测并计数凋亡毛细胞。结果 NAC组耳蜗基底膜的形态结构与无血清培养基组无明显差异,未见凋亡细胞;H2O2组可见大量凋亡细胞,细胞形态发生改变,出现水肿及碎裂,还有部分细胞缺失;NAC+H2O2组细胞仍保持完好形态,只见少许凋亡细胞。结论抗氧化剂NAC对外源性H2O2诱导的耳蜗毛细胞凋亡有抑制作用。     

N-乙酰半胱氨酸对汞致大鼠肾皮质线粒体能量代谢损伤的影响

目的通过亚急性汞染毒实验研究N-乙酰半胱氨酸(NAC)对汞所致大鼠肾皮质线粒体能量代谢的影响。方法将24只清洁级Wistar大鼠按体重随机分为分别为对照组、汞染毒组和NAC+汞染毒组,每组8只。对照组、汞染毒组大鼠腹腔注射生理盐水,NAC+汞染毒组腹腔注射0.480mmol/L的NAC,注射剂量为5ml/kg;2h后,对照组皮下注射生理盐水,汞染毒组和NAC+汞染毒组大鼠皮下注射368μmol/L的HgCl2溶液,注射剂量为5ml/kg。每天注射1次,连续注射14天。最后一次注射24h后,处死大鼠,取肾皮质,梯度离心得线粒体,测定丙二醛(MDA)含量、磷脂酶A2(PLA2)和琥珀酸脱氢酶(SDH)的活力以及线粒体膜电位。结果与对照组相比,汞染毒组大鼠肾皮质线粒体中MDA含量和PLA2活力以及膜电位升高,SDH活力下降,差异均有统计学意义(P0.05,P0.01);NAC+汞染毒组大鼠肾皮质线粒体中PLA2活力升高,差异有统计学意义(P0.05)。与汞染毒组相比,NAC+汞染毒组大鼠肾皮质线粒体中MDA含量和PLA2活力以及膜电位降低,SDH活力升高,差异均有统计学意义(P0.05,P0.01)。结论汞可导致大鼠肾皮质线粒体能量代谢的障碍;NAC预处理能降低汞所致大鼠肾皮质线粒体能量代谢的障碍。     

T3-induced liver AMP-activated protein kinase signaling: Redox dependency and upregulation of downstream targets

AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T₃)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver. METHODS: Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T₃/kg or T₃ vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T₃. Measurements included plasma and liver 8-isoprostane and serum β-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA). RESULTS: T₃ upregulates AMPK signaling, including the upstream kinases Ca²⁺-calmodulin-dependent protein kinase kinase-β and transforming growth factor-β-activated kinase-1, with T₃-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1α (CPT-1α) activation and higher expression of peroxisome proliferator-activated receptor-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes CPT-1α, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T₃ induced a significant increase in the serum levels of β-hydroxybutyrate, a surrogate marker for hepatic FAO. CONCLUSION: T₃ administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T₃ preconditioning against ischemia-reperfusion injury.     

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。