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51.
Pavani Pingali Y. Jeffrey Wu Rio Boothello Chetna Sharon Howard Li Srinivas Sistla Nehru Viji Sankaranarayanan Umesh R. Desai Anh T. Le Robert C. Doebele Leslie L. Muldoon Bhaumik B. Patel Alexander Neuwelt 《Neoplasia (New York, N.Y.)》2021,23(3):348
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. 相似文献
52.
N-乙酰半胱氨酸对急性肺损伤的防治作用研究进展 总被引:3,自引:0,他引:3
N-乙酰半胱氨酸是L-半胱氨酸的乙酰化物,作为巯基的供体,不仅具有强大的抗氧化作用,还能有效补充机体内降低的还原型谷胱苷肽,保护细胞免受损伤,其对急性肺损伤的防治作用已获得动物实验和临床研究结果的支持。 相似文献
53.
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. 相似文献
54.
Dillioglugil MO Ilgazli A Maral H Sengul C Ozdemir G Ercin C 《Respirology (Carlton, Vic.)》2005,10(5):615-619
OBJECTIVE: Long-term inhalation of thinners may cause damage, both to the lungs and to other organ systems. It causes cellular damage via formation of reactive oxygen species. The lung is protected from oxidative stress by the glutathione (GSH) antioxidant system which can be augmented by the thiol drug, N-acetylcysteine (NAC). This study investigated the protective effect of NAC on peroxidative changes in rat lungs exposed to inhalation of thinners for 8 weeks. METHODOLOGY: Seventy-two male Wistar albino rats were used and divided into two groups: one group inhaled only thinners (TI), while the other inhaled TI plus NAC. Rats in the TI and TI + NAC groups were divided into four subgroups (each consisting of eight rats) according to the duration of exposure to TI: 2, 4, 6 and 8 weeks. A control group (n = 7) of rats inhaled neither TI nor NAC. Malondialdehyde (MDA) and GSH levels, and superoxide dismutase (SOD) activities were determined in the lung tissues. Histopathological findings were evaluated as acute and chronic changes in the alveoli and interstitium in the TI and TI + NAC groups and compared with those in the control group. RESULTS: While tissue MDA levels in the groups inhaling TI for 4, 6 and 8 weeks were significantly higher than those in the control groups (P < 0.01, P < 0.01, P < 0.0001, respectively), GSH levels were significantly lower (P < 0.05, P < 0.01, P < 0.01, respectively). Tissue SOD activities in the groups inhaling TI for 6 and 8 weeks were significantly lower than those in the control group (P < 0.05, P < 0.01, respectively). In the TI group, MDA levels were significantly increased (P < 0.01) with increasing duration of inhalation (from the second week through to the eighth week), while GSH levels and SOD activities were significantly decreased (P < 0.01, P < 0.01). Tissue MDA levels were significantly lower in the TI + NAC groups across all inhalation periods, when compared with the TI groups (P < 0.01, P < 0.0001, P < 0.0001, P < 0.0001, respectively). Tissue GSH levels in the TI + NAC groups were significantly higher than those of the TI groups (respective values: P < 0.05, P < 0.01, P < 0.01, P < 0.0001). Tissue SOD activities in the TI + NAC groups were significantly higher than those of the TI groups (respective values: P < 0.05, P < 0.0001, P < 0.05, P < 0.0001). Pathological examinations with light microscopy did not show any beneficial effect of NAC application in terms of deferring or alleviating the negative effects of TI. CONCLUSIONS: Thinners are agents that cause imbalance between oxidants and antioxidants produced by aerobic cellular systems. This imbalance between oxidant and antioxidant systems is decreased by the effect of NAC. However, ultrastructural studies may be needed to substantiate this evidence morphologically, as light microscopy was inconclusive. 相似文献
55.
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 总被引:1,自引:0,他引:1
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。 相似文献
56.
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。 相似文献
57.
Mitochondria play a central role in the production of reactive oxygen species as byproducts of metabolism and energy production. In order to protect cellular structures from oxidative stress-induced damage, cells have evolved elegant mechanisms for mitochondrial ROS detoxification. The mitochondrial sirtuin, SIRT3, is emerging as a pivotal regulator of oxidative stress by deacetylation of substrates involved in both ROS production and detoxification. This review will summarize recent findings on the regulation of mitochondrial ROS homeostasis by SIRT3. 相似文献
58.
Elliott L. Brandwene MD Saralyn R. Williams MD Cynthia Tunget-Johnson PHARMD Steve G. Turchen RN Anthony S. Manoguerra PHARMD Richard F. Clark MD 《The Journal of emergency medicine》1996,14(6):393-695
Treatment of an acetaminophen overdose with N-acetyl cysteine usually is based on the position of the 4-h acetaminophen (APAP) level on the Rumack-Matthew nomogram; however, there is disagreement on the level at which clinically relevant hepatotoxicity occurs. A retrospective review of all acute adult formulation APAP exposures reported to our poison center between 1986 and 1993 was performed and cases corresponding to the “possible risk or toxicity” range on the nomogram were identified. Our current poison center protocol for APAP poisoning does not recommend treatment with N-acetylcysteine (NAC) in low-risk patients if the 4-h serum APAP level or the extrapolated equivalent falls within the possible toxicity range on the nomogram. Seventeen cases met the inclusion criteria for the study and received no NAC; six additional patients met inclusion criteria but received one or two doses of NAC before therapy was discontinued. No patients in either group demonstrated clinical evidence of hepatotoxicity. This pilot study suggests that patients with no risk factors and APAP levels in the “possible risk” range may not require NAC therapy. 相似文献
59.
谷胱甘肽与N-乙酰半胱氨酸对谷氨酸诱导海马神经元损伤的影响 总被引:2,自引:0,他引:2
目的观察还原型谷胱甘肽(reducedglutathione,GSH)与N-乙酰半胱氨酸(N-Acetylcysteine,N-NAC)对不同浓度谷氨酸(glutamate,Glu)诱导的海马神经元损害的影响。方法选用新生Wistar大鼠原代培养海马神经元谷氨酸细胞毒性模型,采用台盼蓝活细胞拒染及TUNEL细胞凋亡原位检测等方法比较GSH与NAC对100μmol/L及500μmol/LGlu细胞毒性损伤的影响,并与MK-801比较。结果GSH与NAC能够降低100μmol/LGlu作用下神经元死亡率与凋亡率,NAC组细胞存活率高于同条件下GSH组,其中1mmol/LNAC组神经元存活率达到90.4%±5.2%,与10μmol/LMK-801组相比,差异无统计学意义;在500μmol/LGlu作用下,GSH与NAC则不能增加神经元的存活率,但1mmol/LNAC抗500μmol/LGlu诱导调亡的作用与MK-801相比无明显差异。结论GSH及NAC对轻度Glu细胞毒性神经损伤有保护作用。 相似文献
60.
A high plasma concentration of lipoprotein(a) [Lp(a)], a complex of low-density lipoprotein linked by disulphide bridges to apoprotein(a), is correlated with premature atherosclerosis. We determined whether the serum Lp(a) concentration could be decreased in vitro and in vivo by the reducing agent N-acetylcysteine (NAC), a drug used as a mucolytic agent, which acts by cleaving disulphide bonds. High concentrations of NAC (greater than or equal to 8 mg ml-1) resulted in dissociation of the Lp(a) antigen in vitro. However, the plasma level of Lp(a) was not changed by administration of NAC 1.2 g d-1 for 4 weeks in 7 subjects with a median Lp(a) concentration of 14.3 mg dl-1 (range 2.1-21.0 mg dl-1) or by doubling the dose to 2.4 g d-1 for a further 2 weeks. In 12 subjects with a high plasma level of Lp(a), median 87.0 mg dl-1 (range 42.0-201.6 mg dl-1), a small but significant decrease in Lp(a) concentration of 7% (P = 0.02) was observed after administration of NAC in a dose of 1.2 g d-1 for 6 weeks. These results indicate that NAC has only a limited capacity to reduce the concentration of Lp(a), which is not clinically significant. 相似文献