药学学报, 2020, 55(12): 2785-2792
陈素娟, 庞晨晨, 刘彬, 皇甫超申. 活性氮对细胞保护和损伤作用研究进展[J]. 药学学报, 2020, 55(12): 2785-2792.
CHEN Su-juan, PANG Chen-chen, LIU Bin, HUANGFU Chao-shen. Research progress of reactive nitrogen species on cell protection and injury[J]. Acta Pharmaceutica Sinica, 2020, 55(12): 2785-2792.

陈素娟1, 庞晨晨1, 刘彬1, 皇甫超申2
1. 河南大学护理与健康学院, 河南 开封 475004;
2. 河南大学环境医学研究所, 河南 开封 475004
活性氮(reactive nitrogen species,RNS)影响细胞内氧化还原平衡,诱导蛋白质翻译后修饰(post-translational modification,PTM),在生理条件下作为信号分子参与细胞信号传导。但是过量的RNS会引起亚硝基化应激导致细胞的损伤,并与肿瘤的发生和发展以及治疗效果等密切相关。本文阐述RNS在生理条件下的作用及在肿瘤发生和发展中的研究进展,为新药的研发和疾病的治疗提供思路。
关键词:    活性氮      亚硝基化蛋白修饰      硝酸盐-亚硝酸盐-一氧化氮途径      肿瘤生长      肿瘤治疗     
Research progress of reactive nitrogen species on cell protection and injury
CHEN Su-juan1, PANG Chen-chen1, LIU Bin1, HUANGFU Chao-shen2
1. School of Nursing and Health, Henan University, Kaifeng 475004, China;
2. Institute of Environmental Medicine, Henan University, Kaifeng 475004, China
Reactive nitrogen species (RNS) affects intracellular redox balance and induces post-translational modification of proteins. Moreover, RNS, as the signal molecule, participates in the transduction of cellular signals under physiological conditions. However, excessive RNS can induce nitrosative stress and then damage cells, and thereby may play a role in the tumor initiation and progression. Thus, we discussed the role of RNS under physiological conditions and the tumor microenvironment, which may provide some novel ideas for the development of new drugs and the treatment of diseases.
Key words:    reactive nitrogen species    nitrosative protein modification    NO3--NO2--NO pathway    tumor growth    tumor treatment   
收稿日期: 2020-03-30
DOI: 10.16438/j.0513-4870.2020-0431
基金项目: 国家环保公益项目专项资助项目(200809115);省部共建河南大学科研项目(SBGJ090702).
通讯作者: 刘彬,Tel:86-378-3880585,E-mail:aozdlx1024@163.com;皇甫超申,E-mail:emdx1629@163.com
Email: aozdlx1024@163.com;emdx1629@163.com
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[1] Adams L, Franco MC, Estevez AG. Reactive nitrogen species in cellular signaling[J]. Exp Biol Med, 2015, 240:711-717.
[2] Ghimire K, Altmann HM, Straub AC, et al. Nitric oxide:what's new to NO?[J]. Am J Physiol Cell Physiol, 2017, 312:C254-C262.
[3] Hunyadi A. The mechanism(s) of action of antioxidants:From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites[J]. Med Res Rev, 2019, 39:2505-2533.
[4] Ramalingam M, Kim SJ. Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases[J]. J Neural Transm, 2012, 119:891-910.
[5] Kamm A, Przychodzen P, Kuban-Jankowska A, et al. Nitric oxide and its derivatives in the cancer battlefield[J]. Nitric Oxide, 2019, 93:102-114.
[6] Forstermann U, Sessa WC. Nitric oxide synthases:regulation and function[J]. Eur Heart J, 2012, 33:829-837.
[7] Thomas DD, Corey C, Hickok J, et al. Differential mitochondrial dinitrosyliron complex formation by nitrite and nitric oxide[J]. Redox Biol, 2018, 15:277-283.
[8] Speckmann B, Steinbrenner H, Grune T, et al. Peroxynitrite:from interception to signaling[J]. Arch Biochem Biophys, 2016, 595:153-160.
[9] Basu S, Grubina R, Huang J, et al. Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin[J]. Nat Chem Biol, 2007, 3:785-794.
[10] Um HC, Jang JH, Kim DH, et al. Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells[J]. Nitric Oxide, 2011, 25:161-168.
[11] Moldogazieva NT, Mokhosoev IM, Feldman NB, et al. ROS and RNS signaling:adaptive redox switches through oxidative/nitrosative protein modifications[J]. Free Radic Res, 2018, 52:507-543.
[12] Paulech J, Liddy KA, Engholm-Keller K, et al. Global analysis of myocardial peptides containing cysteines with irreversible sulfinic and sulfonic acid post-translational modifications[J]. Mol Cell Proteomics, 2015, 14:609-620.
[13] Xiong Y, Uys JD, Tew KD, et al. S-glutathionylation:from molecular mechanisms to health outcomes[J]. Antioxid Redox Signal, 2011, 15:233-270.
[14] Seth D, Hess DT, Hausladen A, et al. A multiplex enzymatic machinery for cellular protein S-nitrosylation[J]. Mol Cell, 2018, 69:451-464.e6.
[15] Stomberski CT, Hess DT, Stamler J. Protein S-nitrosylation:determinants of specificity and enzymatic regulation of S-nitrosothiol-based signaling[J]. Antioxid Redox Signal, 2019, 30:1331-1351.
[16] Kovacs I, Lindermayr C. Nitric oxide-based protein modification:formation and site-specificity of protein S-nitrosylation[J]. Front Plant Sci, 2013, 4:137.
[17] Zhang R, Hess DT, Reynolds JD, et al. Hemoglobin S-nitrosylation plays an essential role in cardioprotection[J]. J Clin Invest, 2016, 126:4654-4658.
[18] Faienza F, Lambrughi M, Rizza S, et al. S-nitrosylation affects TRAP1 structure and ATPase activity and modulates cell response to apoptotic stimuli[J]. Biochem Pharmacol, 2020, 176:113869.
[19] Wu W, Perrin-Sarrado C, Ming H, et al. Polymer nanocomposites enhance S-nitrosoglutathione intestinal absorption and promote the formation of releasable nitric oxide stores in rat aorta[J]. Nanomedicine, 2016, 12:1795-1803.
[20] Bartesaghi S, Radi R. Fundamentals on the biochemistry of peroxynitrite and protein tyrosine nitration[J]. Redox Biol, 2018, 14:618-625.
[21] Li H, Yang Z, Gao Z. Protein tyrosine nitration:chemistry and role in diseases[J]. Adv Mol Toxicol, 2020, 13:109-128.
[22] Hopper RA, Garthwaite J. Tonic and phasic nitric oxide signals in hippocampal long-term potentiation[J]. J Neurosci, 2006, 26:11513-11521.
[23] Costa ED, Rezende BA, Cortes SF, et al. Neuronal nitric oxide synthase in vascular physiology and diseases[J]. Front Physiol, 2016, 7:206.
[24] Dashwood MR, Crump A, Shi-Wen X, et al. Identification of neuronal nitric oxide synthase (nNOS) in human penis:a potential role of reduced neuronally-derived nitric oxide in erectile dysfunction[J]. Curr Pharm Biotechnol, 2011, 12:1316-1321.
[25] Lind M, Hayes A, Caprnda M, et al. Inducible nitric oxide synthase:good or bad?[J]. Biomed Pharmacother, 2017, 93:370-375.
[26] Qian Q, Zhang Z, Li M, et al. Hepatic lysosomal iNOS activity impairs autophagy in obesity[J]. Cell Mol Gastroenterol Hepatol, 2019, 8:95-110.
[27] Zhao Y, Vanhoutte PM, Leung SWS. Vascular nitric oxide:beyond eNOS[J]. J Pharmacol Sci, 2015, 129:83-94.
[28] Kuchan MJ, Frangos JA. Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells[J]. Am J Physiol, 1994, 266:C628-C636.
[29] Sessa WC. eNOS at a glance[J]. J Cell Sci, 2004, 117:2427-2429.
[30] Boo YC, Hwang J, Sykes M, et al. Shear stress stimulates phosphorylation of eNOS at Ser635 by a protein kinase A-dependent mechanism[J]. Am J Physiol Heart Circ Physiol, 2002, 283:H1819-H1828.
[31] Li S, Li Q, Lv X, et al. Aurantio-obtusin relaxes systemic arteries through endothelial PI3K/AKT/eNOS-dependent signaling pathway in rats[J]. J Pharmacol Sci, 2015, 128:108-115.
[32] Musicki B, Burnett AL. eNOS S-nitrosylation in erectile function[J]. Int J Impot Res, 2019, 31:52-53.
[33] Münzel T, Daiber A, Ullrich V, et al. Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase[J]. Arterioscler Thromb Vasc Biol, 2005, 25:1551-1557.
[34] Mahneva O, Caplan SL, Ivko P, et al. NO/cGMP/PKG activation protects Drosophila cells subjected to hypoxic stress[J]. Comp Biochem Physiol C Toxicol Pharmacol, 2019, 223:106-114.
[35] Rocha BS, Laranjinha J. Nitrate from diet might fuel gut microbiota metabolism:minding the gap between redox signaling and inter-kingdom communication[J]. Free Radic Biol Med, 2020, 149:37-43.
[36] Bahadoran Z, Mirmiran P, Jeddi S, et al. The nitrate-nitrite-nitric oxide pathway:findings from 20 years of the tehran lipid and glucose study[J]. Int J Endocrinol Metab, 2018, 16:e84775.
[37] Petit PC, Fine DH, Gregory B, et al. The pathophysiology of nitrogen dioxide during inhaled nitric oxide therapy[J]. ASAIO J, 2017, 63:7-13.
[38] Gube M, Brand J,ChakerA, et al. Biological effects of inhaled nitrogen dioxide in healthy human subjects[J]. Int Arch Occup Environ Health, 2016, 89:1017-1024.
[39] Yu B, Ichinose F, Bloch DB, et al. Inhaled nitric oxide[J]. Br J Pharmacol, 2019, 176:246-255.
[40] Janina F, Adrian A, Markus H, et al. STIM-orai channels and reactive oxygen species in the tumor microenvironment[J]. Cancers, 2019, 11:457.
[41] Cheng G, Pan J, Podsiadly R, et al. Increased formation of reactive oxygen species during tumor growth:ex vivo low-temperature EPR and in vivo bioluminescence analyses[J]. Free Radic Biol Med, 2020, 147:167-174.
[42] Scott DJ, Hull MA, Cartwright EJ, et al. Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc (Min/+) mouse[J]. Gastroenterology, 2001, 121:889-899.
[43] Kruk J, Aboul-Enein HY. Reactive oxygen and nitrogen species in carcinogenesis:implications of oxidative stress on the progression and development of several cancer types[J]. Mini Rev Med Chem, 2017, 17:904-919.
[44] De Sanctis F, Sandri S, Ferrarini G, et al. The emerging immunological role of post-translational modifications by reactive nitrogen species in cancer microenvironment[J]. Front Immunol, 2014, 5:69.
[45] Servato JPS, Vieira CU, Faria PR, et al. The importance of inducible nitric oxide synthase and nitrotyrosine as prognostic markers for oral squamous cell carcinoma[J]. J Oral Pathol Med, 2019, 48:967-975.
[46] Fujita M, Somasundaram V, Basudhar D, et al. Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype[J]. Redox Biol, 2019, 22:101158.
[47] Voss N, Kold-Petersen H, Bo edtkjer E. Enhanced nitric oxide signaling amplifies vasorelaxation of human colon cancer feed arteries[J]. Am J Physiol Heart Circ Physiol, 2019, 316:H245-H254.
[48] Li Z, Hao H, Tian W, et al. Nitric oxide, a communicator between tumor cells and endothelial cells, mediates the anti-tumor effects of Marsdenia Tenacissima extract (MTE)[J]. J Ethnopharmacol, 2020, 250:112524.
[49] Bogen B, Fauskanger M, Haabeth OA, et al. CD4+ T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models[J]. Cancer Immunol Immunother, 2019, 68:1865-1873.
[50] Granados-Principal S, Liu Y, Guevara ML, et al. Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer[J]. Breast Cancer Res, 2015, 17:25.
[51] Wang L, Chang Y, Feng Y, et al. Nitric oxide stimulated programmable drug release of nanosystem for multidrug resistance cancer therapy[J]. Nano Lett, 2019, 19:6800-6811.
[52] Teng L, Song G, Liu Y, et al. Nitric oxide-activated "dual-key-one-lock" nanoprobe for in vivo molecular imaging and high-specificity cancer therapy[J]. J Am Chem Soc, 2019, 141:13572-13581.
[53] Özenver N, Efferth T. Small molecule inhibitors and stimulators of inducible nitric oxide synthase in cancer cells from natural origin (phytochemicals, marine compounds, antibiotics)[J]. Biochem Pharmacol, 2020, 176:113792.
[54] Reinhardt C J, Xu R, Chan J. Nitric oxide imaging in cancer enabled by steric relaxation of a photoacoustic probe platform[J]. Chemical Sci, 2020, 11:1587-1592.
[55] Bonavida B. Sensitizing activities of nitric oxide donors for cancer resistance to anticancer therapeutic drugs[J]. Biochem Pharmacol, 2020, 176:113913.
[56] Oláh G, Módis K, Törö G, et al. Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation[J]. Biochem Pharmacol, 2018, 149:186-204.
[57] Scicinski JJ, Oronsky B, Ning S, et al. NO to cancer:the complex and multifaceted role of nitric oxide and the epigenetic nitric oxide donor, RRx-001[J]. Redox Biol, 2015, 6:1-8.
[58] Liu B, Huang X, Li Y, et al. JS-K, a nitric oxide donor, induces autophagy as a complementary mechanism inhibiting ovarian cancer[J]. BMC Cancer, 2019, 19:645.
[59] Dejam A, Hunter CJ, Tremonti C, et al. Nitrite infusion in humans and nonhuman primates:endocrine effects, pharmacokinetics, and tolerance formation[J]. Circulation, 2007, 116:1821-1831.
[60] Siddiqi N, Bruce M, Neil CJ, et al. Protocol:does sodium nitrite administration reduce ischaemia-reperfusion injury in patients presenting with acute ST segment elevation myocardial infarction? Nitrites in acute myocardial infarction (NIAMI)[J]. J Transl Med, 2013, 11:116.