A Comprehensive Review on the Significance of Cysteine in Various
Metabolic Disorders; Particularly CVD, Diabetes, Renal Dysfunction, and
Ischemic Stroke

Namra      Aziz; Pranay      Wal; Rishika      Sinha; Prashant   Ramesh   Shirode; GunoSindhu      Chakraborthy; Mukesh   Chandra   Sharma; Pankaj      Kumar
Abstract

Metabolic disorders have long been a challenge for medical professionals and are a leading cause of mortality in adults. Diabetes, cardiovascular disorders (CVD), renal dysfunction, and ischemic stroke are the most prevalent ailments contributing to a high mortality rate worldwide. Reactive oxygen species are one of the leading factors that act as a fundamental root cause of metabolic syndrome. All of these disorders have their respective treatments, which, to some degree, sabotage the pathological worsening of the disease and an inevitable death. However, they pose a perilous health hazard to humankind. Cysteine, a functional amino acid shows promise for the prevention and treatment of metabolic disorders, such as CVD, Diabetes mellitus, renal dysfunction, and ischemic stroke. In this review, we explored whether cysteine can eradicate reactive oxygen species and subsequently prevent and treat these diseases.
Graphical Abstract

[1]
Acharyya, A.; Shahjahan, M.D.; Mesbah, F.; Dey, S.; Ali, L. Association of metabolic syndrome with chronic obstructive pulmonary disease in an Indian population. Lung,  2016, 33(4), 385-390.
 [http://dx.doi.org/10.4103/0970-2113.184871] [PMID: 27578930]

[2]
Meher, T.; Sahoo, H. The epidemiological profile of metabolic syndrome in Indian population: A comparative study between men and women. Clin. Epidemiol. Glob. Health,  2020, 8(4), 1047-1052.
 [http://dx.doi.org/10.1016/j.cegh.2020.03.018]

[3]
Huang, F.; Han, X.; Xiao, X.; Zhou, J. Covalent warheads targeting cysteine residue: The promising approach in drug development. Molecules,  2022, 27(22), 7728.
 [http://dx.doi.org/10.3390/molecules27227728] [PMID: 36431829]

[4]
Wu, G. Functional amino acids in nutrition and health. Amino Acids,  2013, 45(3), 407-11.
 [http://dx.doi.org/10.1007/s00726-013-1500-6]

[5]
Okekunle, A.P.; Li, Y.; Liu, L.; Du, S.; Wu, X.; Chen, Y.; Li, Y.; Qi, J.; Sun, C.; Feng, R. Abnormal circulating amino acid profiles in multiple metabolic disorders. Diabetes Res. Clin. Pract.,  2017, 132, 45-58.
 [http://dx.doi.org/10.1016/j.diabres.2017.07.023] [PMID: 28783532]

[6]
Muthuraman, A.; Ramesh, M.; Shaikh, S.A.; Aswinprakash, S.; Jagadeesh, D. Physiological and pathophysiological role of cysteine metabolism in human metabolic syndrome. Drug Metab. Lett.,  2021, 14(3), 177-192.
 [http://dx.doi.org/10.2174/1872312814666211210111820] [PMID: 34895129]

[7]
Aliu, E.; Kanungo, S.; Arnold, G.L. Amino acid disorders. Ann. Transl. Med.,  2018, 6(24), 471.
 [http://dx.doi.org/10.21037/atm.2018.12.12] [PMID: 30740402]

[8]
Dumas, M.E.; Kinross, J.; Nicholson, J.K. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology,  2014, 146(1), 46-62.
 [http://dx.doi.org/10.1053/j.gastro.2013.11.001] [PMID: 24211299]

[9]
Vona, R.; Gambardella, L.; Cittadini, C.; Straface, E.; Pietraforte, D. Biomarkers of oxidative stress in metabolic syndrome and associated diseases. Oxid. Med. Cell. Longev.,  2019, 2019, 1-19.
 [http://dx.doi.org/10.1155/2019/8267234] [PMID: 31191805]

[10]
Paul, B.D.; Sbodio, J.I.; Snyder, S.H. Cysteine metabolism in neuronal redox homeostasis. Trends Pharmacol. Sci.,  2018, 39(5), 513-524.
 [http://dx.doi.org/10.1016/j.tips.2018.02.007] [PMID: 29530337]

[11]
Song, T.; Qin, W.; Lai, Z.; Li, H.; Li, D.; Wang, B.; Deng, W.; Wang, T.; Wang, L.; Huang, R. Dietary cysteine drives body fat loss via FMRFamide signaling in Drosophila and mouse. Cell Res.,  2023, 33(6), 434-447.
 [http://dx.doi.org/10.1038/s41422-023-00800-8] [PMID: 37055592]

[12]
Pastore, A.; Alisi, A.; di Giovamberardino, G.; Crudele, A.; Ceccarelli, S.; Panera, N.; Dionisi-Vici, C.; Nobili, V. Plasma levels of homocysteine and cysteine increased in pediatric NAFLD and strongly correlated with severity of liver damage. Int. J. Mol. Sci.,  2014, 15(11), 21202-21214.
 [http://dx.doi.org/10.3390/ijms151121202] [PMID: 25407526]

[13]
Sameem, B.; Khan, F.; Niaz, K. Nonvitamin and Nonmineral Nutritional Supplements; Elsevier: Amsterdam, 2019, pp. 53-58.

[14]
Atkuri, K.R.; Mantovani, J.J.; Herzenberg, L.A.; Herzenberg, L.A. N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Curr. Opin. Pharmacol.,  2007, 7(4), 355-359.
 [http://dx.doi.org/10.1016/j.coph.2007.04.005] [PMID: 17602868]

[15]
Bhatti, J.S.; Bhatti, G.K.; Reddy, P.H. Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies. Biochim. Biophys. Acta Mol. Basis Dis.,  2017, 1863(5), 1066-1077.
 [http://dx.doi.org/10.1016/j.bbadis.2016.11.010] [PMID: 27836629]

[16]
Rehman, T.; Shabbir, M.A.; Inam-Ur-Raheem, M.; Manzoor, M.F.; Ahmad, N.; Liu, Z.W.; Ahmad, M.H.; Siddeeg, A.; Abid, M.; Aadil, R.M. Cysteine and homocysteine as biomarker of various diseases. Food Sci. Nutr.,  2020, 8(9), 4696-4707.
 [http://dx.doi.org/10.1002/fsn3.1818] [PMID: 32994931]

[17]
Pace, N.J.; Weerapana, E. Diverse functional roles of reactive cysteines. ACS Chem. Biol.,  2013, 8(2), 283-296.
 [http://dx.doi.org/10.1021/cb3005269] [PMID: 23163700]

[18]
Carballal, S.; Banerjee, R. Overview of cysteine metabolism.Redox Chemistry and Biology of Thiols; Academic Press: Cambridge, Massachusetts, 2022, pp. 423-450.

[19]
Swetha, P.; Kumar, A.S. Phosphomolybdic acid nano-aggregates immobilized nafion membrane modified electrode for selective cysteine electrocatalytic oxidation and anti-dermatophytic activity. Electrochim. Acta,  2013, 98, 54-65.
 [http://dx.doi.org/10.1016/j.electacta.2013.03.023]

[20]
Kwon, Y. Possible beneficial effects of N-Acetylcysteine for treatment of triple-negative breast cancer. Antioxidants (Basel),  2021, 10(2), 169.
 [http://dx.doi.org/10.3390/antiox10020169]

[21]
(a) Ezeriņa, D.; Takano, Y.; Hanaoka, K.; Urano, Y.; Dick, T.P. N-acetyl cysteine functions as a fast-acting antioxidant by triggering intracellular H2S and sulfane sulphur production.  Cell Chem. Bio.,  2018, 25(4), 447-59.; 
(b) Kader, T; Porteous, C Ribose-cysteine increases glutathione-based antioxidant status and reduces LDL in human lipoprotein (a) mice. Atherosclerosis,  2014, 237(2), 725-733.
 [PMID: 25463112]

[22]
Tenório, M.C.S.; Graciliano, N.G.; Moura, F.A.; Oliveira, A.C.M.; Goulart, M.O.F. N-Acetylcysteine (NAC): Impacts on human health. Antioxidants,  2021, 10(6), 967.
 [http://dx.doi.org/10.3390/antiox10060967] [PMID: 34208683]

[23]
Safari, M.R.; Noroozi, R.; Omrani, M.D.; Taheri, M.; Ghafouri-Fard, S. Analysis of association between RAGE polymorphisms and stroke risk. Meta Gene,  2019, 22, 100612.
 [http://dx.doi.org/10.1016/j.mgene.2019.100612]

[24]
Ferla, M. P.; Patrick, W. M. Bacterial methionine biosynthesis. Microbiology (Reading),  2014, 160(Pt 8), 11571-1584.
 [http://dx.doi.org/10.1099/mic.0.077826-0]

[25]
Sbodio, J.I.; Snyder, S.H.; Paul, B.D. Regulators of the transsulphuration pathway. Br. J. Pharmacol., 2018.
 [PMID: 30007014]

[26]
Xiao, Y.; Zhang, Y.; Wang, M.; Li, X.; Xia, M.; Ling, W. Dietary protein and plasma total homocysteine, cysteine concentrations in coronary angiographic subjects. Nutr. J.,  2013, 12(1), 144.
 [http://dx.doi.org/10.1186/1475-2891-12-144] [PMID: 24195518]

[27]
Rao, N.L.; Kotian, G.B.; Shetty, J.K.; Shelley, B.P.; Dmello, M.K.; Lobo, E.C.; Shankar, S.P.; Almeida, S.D.; Shah, S.R. Receptor for advanced glycation end product, organ crosstalk, and pathomechanism targets for comprehensive molecular therapeutics in diabetic ischemic stroke. Biomolecules,  2022, 12(11), 1712.
 [http://dx.doi.org/10.3390/biom12111712] [PMID: 36421725]

[28]
Jurcau, A.; Ardelean, A.I. Oxidative stress in ischemia/reperfusion injuries following acute ischemic stroke. Biomedicines,  2022, 10(3), 574.
 [http://dx.doi.org/10.3390/biomedicines10030574] [PMID: 35327376]

[29]
Parkhitko, A.A.; Jouandin, P.; Mohr, S.E.; Perrimon, N. Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species. Aging Cell,  2019, 18(6), e13034.
 [http://dx.doi.org/10.1111/acel.13034] [PMID: 31460700]

[30]
Khalid, M.; Petroianu, G.; Adem, A. Advanced glycation end products and diabetes mellitus: Mechanisms and perspectives. Biomolecules,  2022, 12(4), 542.
 [http://dx.doi.org/10.3390/biom12040542] [PMID: 35454131]

[31]
Mohorko, N.; Petelin, A.; Jurdana, M.; Biolo, G.; Jenko-P., Z. Elevated serum levels of cysteine and tyrosine: Early biomarkers in asymptomatic adults at increased risk of developing metabolic syndrome. Biomed. Res. Int.,  2015, 2015, 418681.
 [http://dx.doi.org/10.1155/2015/418681]

[32]
Ezeriņa, D.; Takano, Y.; Hanaoka, K.; Urano, Y.; Dick, T.P. N-acetyl cysteine functions as a fast-acting antioxidant by triggering intracellular H2S and sulfane sulphur production. Cell Chem. Biol.,  2018, 25(4), 447-459.e4.
 [http://dx.doi.org/10.1016/j.chembiol.2018.01.011] [PMID: 29429900]

[33]
Dominique, D. Importance du métabolisme des protéines et des acides aminés dans la prévention et la prise en charge du syndrome métabolique. Modulation par les acides gras n -3. Cahiers de Nutr. et de Diététique,  2018, 53(5), 002.
 [http://dx.doi.org/10.1016/j.cnd.2018.06.002]

[34]
Baez-Duarte, B.G.; Zamora-Ginez, I.; De Jésus, K.L.; Torres-Rasgado, E.; González-Mejía, M.E.; Porchia, L.; Ruiz-Vivanco, G.; Pérez-Fuentes, R. Association of the metabolic syndrome with antioxidant defense and outstanding superoxide dismutase activity in Mexican subjects. Metab. Syndr. Relat. Disord.,  2016, 14(3), 154-160.
 [http://dx.doi.org/10.1089/met.2015.0088] [PMID: 26859464]

[35]
Rendra, E.; Riabov, V.; Mossel, D.M.; Sevastyanova, T.; Harmsen, M.C.; Kzhyshkowska, J. Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology, 2018.
 [PMID: 30739804]

[36]
Thieme, K.; Da Silva, K.S.; Fabre, N.T.; Catanozi, S.; Monteiro, M.B.; Santos-Bezerra, D.P.; Costa-Pessoa, J.M.; Oliveira-Souza, M.; Machado, U.F.; Passarelli, M.; Correa-Giannella, M.L. N-acetyl cysteine attenuated the deleterious effects of advanced glycation end-products on the kidney of non-diabetic rats. Cell. Physiol. Biochem.,  2016, 40(3-4), 608-620.
 [http://dx.doi.org/10.1159/000452574] [PMID: 27898405]

[37]
Abete, I.; Goyenechea, E.; Zulet, M.A.; Martínez, J.A. Obesity and metabolic syndrome: Potential benefit from specific nutritional components. Nutr. Metab. Cardiovasc. Dis.,  2011, 21(Suppl. 2), B1-B15.
 [http://dx.doi.org/10.1016/j.numecd.2011.05.001] [PMID: 21764273]

[38]
Tobon-Velasco, C.; Cuevas, J. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol. Disord. Drug Targets,  2014, 13(9), 1615-26.

[39]
Mokhtari, V.; Afsharian, P.; Shahhoseini, M.; Kalantar, S.M.; Moini, A. A review on various uses of N-acetyl cysteine. Cell J.,  2017, 19(1), 11-17.
 [PMID: 28367412]

[40]
Krata, N.; Zagożdżon, R.; Foroncewicz, B.; Mucha, K. Oxidative stress in kidney diseases: The cause on the consequence? Exp.,  2018, 66, 211-220.

[41]
Hutcheson, R.; Rocic, P. The metabolic syndrome, oxidative stress, environment, and cardiovascular disease: The great exploration. J. Diab. Res.,  2012, 13, 1-13.
 [http://dx.doi.org/10.1155/2012/271028]

[42]
Wu, X.Q.; Zhang, D.D.; Wang, Y.N.; Tan, Y.Q.; Yu, X.Y.; Zhao, Y.Y. AGE/RAGE in diabetic kidney disease and ageing kidney. Free Radic. Biol. Med.,  2021, 171, 260-271.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.025] [PMID: 34019934]

[43]
Francisqueti, F.V.; Chiaverini, L.C.T.; Santos, K.C.; Minatel, I.O.; Ronchi, C.B.; Ferron, A.J.T.; Ferreira, A.L.A.; Corrêa, C.R. The role of oxidative stress on the pathophysiology of metabolic syndrome. Rev. Assoc. Med. Bras.,  2017, 63(1), 85-91.
 [http://dx.doi.org/10.1590/1806-9282.63.01.85] [PMID: 28225880]

[44]
Zatalia, S.R.; Sanusi, H. The role of antioxidants in the pathophysiology, complications, and management of diabetes mellitus. Acta Med. Indones.,  2013, 45(2), 141-147.
 [PMID: 23770795]

[45]
Piste, P. Cysteine–master antioxidant. Int. J. Pharm. Chem. Biol. Sci.,  2013, 3(1), 143-149.

[46]
Go, Y.M.; Jones, D.P. Cysteine/cystine redox signaling in cardiovascular disease. Free Radic. Biol. Med.,  2011, 50(4), 495-509.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2010.11.029] [PMID: 21130865]

[47]
Yubero-Serrano, E.M.; Pérez-Martínez, P. Advanced glycation end products and their involvement in cardiovascular disease. Angiology,  2020, 71(8), 698-700.
 [http://dx.doi.org/10.1177/0003319720916301] [PMID: 32242451]

[48]
Senoner, T.; Dichtl, W. Oxidative stress in cardiovascular diseases: Still a therapeutic target? Nutrients,  2019, 11(9), 2090.
 [http://dx.doi.org/10.3390/nu11092090] [PMID: 31487802]

[49]
Lee, H.W.; Gu, M.J.; Kim, Y.; Lee, J.Y.; Lee, S.; Choi, I.W.; Ha, S.K. Glyoxal-lysine dimer, an advanced glycation end product, induces oxidative damage and inflammatory response by interacting with RAGE. Antioxidants,  2021, 10(9), 1486.
 [http://dx.doi.org/10.3390/antiox10091486] [PMID: 34573117]

[50]
Mangge, H.; Becker, K.; Fuchs, D.; Gostner, J.M. Antioxidants, inflammation and cardiovascular disease. World J. Cardiol.,  2014, 6(6), 462-477.
 [http://dx.doi.org/10.4330/wjc.v6.i6.462] [PMID: 24976919]

[51]
Sarangarajan, R.; Meera, S.; Rukkumani, R.; Sankar, P.; Anuradha, G. Antioxidants: Friend or foe? Asian Pac. J. Trop. Med.,  2017, 10(12), 1111-1116.
 [http://dx.doi.org/10.1016/j.apjtm.2017.10.017] [PMID: 29268965]

[52]
Combs, Joseph The non-essential amino acid cysteine becomes essential for tumor proliferation and survival. Cancers,  2019, 11(5), 678.

[53]
Tappia, P.S.; Xu, Y-J.; Rodriguez-Leyva, D.; Aroutiounova, N.; Dhalla, N.S. Cardioprotective effects of cysteine alone or in combination with taurine in diabetes. Physiol. Res.,  2013, 62(2), 171-178.
 [http://dx.doi.org/10.33549/physiolres.932388] [PMID: 23234413]

[54]
Dludla, P.V.; Nkambule, B.B.; Dias, S.C.; Johnson, R. Cardioprotective potential of N-acetyl cysteine against hyperglycaemia-induced oxidative damage: A protocol for a systematic review. Syst. Rev.,  2017, 6(1), 96.
 [http://dx.doi.org/10.1186/s13643-017-0493-8] [PMID: 28499416]

[55]
Masella, R.; Di Benedetto, R.; Varì, R.; Filesi, C.; Giovannini, C. Novel mechanisms of natural antioxidant compounds in biological systems: Involvement of glutathione and glutathione-related enzymes. J. Nutr. Biochem.,  2005, 16(10), 577-586.
 [http://dx.doi.org/10.1016/j.jnutbio.2005.05.013] [PMID: 16111877]

[56]
Konukoglu, D; Uzun, H Endothelial dysfunction and hypertension. Adv Exp Med Biol,  2017, 956, 511-540.

[57]
Rodrigo, R.; Fernandez-Gajardo, R.; Gutierrez, R. Oxidative stress and pathophysiology of ischemic stroke: Novel therapeutic opportunities. CNS Neurol Disord Drug Targets,  2013, 12(5), 689-714.

[58]
Kasperczyk, S.; Dobrakowski, M.; Kasperczyk, A.; Romuk, E.; Rykaczewska-Czerwińska, M.; Pawlas, N.; Birkner, E. Effect of N -acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers. Toxicol. Ind. Health,  2016, 32(9), 1607-1618.
 [http://dx.doi.org/10.1177/0748233715571152] [PMID: 25731901]

[59]
Nakamura, M.; Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol.,  2018, 15(7), 387-407.
 [http://dx.doi.org/10.1038/s41569-018-0007-y] [PMID: 29674714]

[60]
Higashi, Y.; Maruhashi, T.; Noma, K.; Kihara, Y. Oxidative stress and endothelial dysfunction: Clinical evidence and therapeutic implications. Trends Cardiovasc. Med.,  2014, 24(4), 165-169.
 [http://dx.doi.org/10.1016/j.tcm.2013.12.001] [PMID: 24373981]

[61]
Öztürk, Z. Diabetes, oxidative stress and endothelial dysfunction. Bezmialem Sci.,  2019, 7(1), 52-57.
 [http://dx.doi.org/10.14235/bas.galenos.2017.2145]

[62]
Mahmoudinezhad, M; Ghavami, Z; Jamilian, P; Zarezadeh, M; Ostadrahimi, A. The effect of N-acetylcysteine supplementation on endothelial function: A systematic review Clin. Nutr. Open Sci.,  2023, 52, 136-150.

[63]
Su, J.B. Vascular endothelial dysfunction and pharmacological treatment. World J. Cardiol.,  2015, 7(11), 719-741.
 [http://dx.doi.org/10.4330/wjc.v7.i11.719] [PMID: 26635921]

[64]
Kattoor, A.J.; Pothineni, N.V.K.; Palagiri, D.; Mehta, J.L. Oxidative stress in atherosclerosis. Curr. Atheroscler. Rep.,  2017, 19(11), 42.
 [http://dx.doi.org/10.1007/s11883-017-0678-6] [PMID: 28921056]

[65]
Zhang, S; Hong, F; Ma, C; Yang, S Hepatic lipid metabolism disorder and atherosclerosis. Endocr. Metab. Immune Disord. Drug Targets,  2022, 22(6), 590-600.
 [http://dx.doi.org/10.2174/1871530322666211220110810]

[66]
Khosravi, M.; Poursaleh, A.; Ghasempour, G.; Farhad, S.; Najafi, M. The effects of oxidative stress on the development of atherosclerosis. Biol. Chem.,  2019, 400(6), 711-732.
 [http://dx.doi.org/10.1515/hsz-2018-0397] [PMID: 30864421]

[67]
Cui, Y.; Zhu, Q.; Hao, H.; Flaker, G.C.; Liu, Z. N-acetylcysteine and atherosclerosis: Promises and challenges. Antioxidants,  2023, 12(12), 2073.
 [http://dx.doi.org/10.3390/antiox12122073] [PMID: 38136193]

[68]
Ganguly, P.; Alam, S.F. Role of homocysteine in the development of cardiovascular disease. Nutr. J.,  2015, 14(1), 6.
 [http://dx.doi.org/10.1186/1475-2891-14-6] [PMID: 25577237]

[69]
Shah, A.K.; Bhullar, S.K.; Elimban, V.; Dhalla, N.S. Oxidative stress as a mechanism for functional alterations in cardiac hypertrophy and heart failure. Antioxidants,  2021, 10(6), 931.
 [http://dx.doi.org/10.3390/antiox10060931] [PMID: 34201261]

[70]
Mushtaq, S.; Ali, T.; Javed, Q.; Tabassum, S.; Murtaza, I. N-acetyl cysteine inhibits endothelin-1-induced ROS dependent cardiac hypertrophy through superoxide dismutase regulation. Cell J.,  2015, 17(2), 355-360.
 [PMID: 26199914]

[71]
Al Hariri, M.; Zibara, K.; Farhat, W.; Hashem, Y.; Soudani, N.; Al Ibrahim, F.; Hamade, E.; Zeidan, A.; Husari, A.; Kobeissy, F. Cigarette smoking-induced cardiac hypertrophy, vascular inflammation and injury are attenuated by antioxidant supplementation in an animal model. Front. Pharmacol.,  2016, 7, 397.
 [http://dx.doi.org/10.3389/fphar.2016.00397] [PMID: 27881962]

[72]
Kemp, C.D.; Conte, J.V. The pathophysiology of heart failure. Cardiovasc. Pathol.,  2012, 21(5), 365-371.
 [http://dx.doi.org/10.1016/j.carpath.2011.11.007] [PMID: 22227365]

[73]
Van der Pol, A.; Van Gilst, W.H.; Voors, A.A.; Van der Meer, P. Treating oxidative stress in heart failure: Past, present and future. Eur. J. Heart Fail.,  2019, 21(4), 425-435.
 [http://dx.doi.org/10.1002/ejhf.1320] [PMID: 30338885]

[74]
Costa, C.R.M.; Seara, F.A.C.; Peixoto, M.S.; Ramos, I.P.; Barbosa, R.A.Q.; Carvalho, A.B.; Fortunato, R.S.; Silveira, A.L.B.; Olivares, E.L. Progression of heart failure is attenuated by antioxidant therapy with N-acetylcysteine in myocardial infarcted female rats. Mol. Biol. Rep.,  2020, 47(11), 8645-8656.
 [http://dx.doi.org/10.1007/s11033-020-05907-4] [PMID: 33048324]

[75]
Phipps, M.S.; Cronin, C.A. Management of acute ischemic stroke. BMJ,  2020, 368, l6983.
 [http://dx.doi.org/10.1136/bmj.l6983] [PMID: 32054610]

[76]
Jadavji, N.M.; Mosnier, H.; Kelly, E.; Lawrence, K.; Cruickshank, S.; Stacey, S.; McCall, A.; Dhatt, S.; Arning, E.; Bottiglieri, T.; Smith, P.D. One-carbon metabolism supplementation improves outcome after stroke in aged male MTHFR-deficient mice. Neurobiol. Dis.,  2019, 132, 104613.
 [http://dx.doi.org/10.1016/j.nbd.2019.104613] [PMID: 31525435]

[77]
Shahripour, B.R.; Harrigan, M.R.; Alexandrov, A.V. Nacetylcysteine (NAC) in neurological disorders: Mechanisms of action and therapeutic opportunities. Brain Behav.,  2014, 4(2), 108-122.
 [http://dx.doi.org/10.1002/brb3.208] [PMID: 24683506]

[78]
Stanzione, R.; Cotugno, M.; Bianchi, F.; Marchitti, S.; Forte, M.; Volpe, M.; Rubattu, S. Pathogenesis of ischemic stroke: Role of epigenetic mechanisms. Genes (Basel),  2020, 11(1), 89.
 [http://dx.doi.org/10.3390/genes11010089] [PMID: 31941075]

[79]
Olmez, I.; Ozyurt, H. Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int.,  2012, 60(2), 208-12.
 [http://dx.doi.org/10.1016/j.neuint.2011.11.009]

[80]
Chen, H.; He, Y.; Chen, S.; Qi, S.; Shen, J. Therapeutic targets of oxidative/nitrosative stress and neuroinflammation in ischemic stroke: Applications for natural product efficacy with omics and systemic biology. Pharmacol. Res.,  2020, 158, 104877.
 [http://dx.doi.org/10.1016/j.phrs.2020.104877] [PMID: 32407958]

[81]
Ma, W.Q.; Qu, Q.R.; Zhao, Y.; Liu, N.F. Association of RAGE gene Gly82Ser polymorphism with coronary artery disease and ischemic stroke. Medicine (Baltimore),  2016, 95(49), e5593.
 [http://dx.doi.org/10.1097/MD.0000000000005593] [PMID: 27930580]

[82]
Sapkota, A.; Park, S.J.; Choi, J.W. Receptor for advanced glycation end products is involved in LPA5-mediated brain damage after a transient ischemic stroke. Life (Basel),  2021, 11(2), 80.
 [http://dx.doi.org/10.3390/life11020080] [PMID: 33499230]

[83]
Cojocaru, I.M.; Cojocaru, M.; Sapira, V.; Ionescu, A. Evaluation of oxidative stress in patients with acute ischemic stroke. Rom. J. Intern. Med.,  2013, 51(2), 97-106.
 [PMID: 24294813]

[84]
Liu, Y.; Min, J.W.; Feng, S.; Subedi, K.; Qiao, F.; Mammenga, E.; Callegari, E.; Wang, H. Therapeutic role of a cysteine precursor, OTC, in ischemic stroke is mediated by improved proteostasis in mice. Transl. Stroke Res.,  2020, 11(1), 147-160.
 [http://dx.doi.org/10.1007/s12975-019-00707-w] [PMID: 31049841]

[85]
Hankey, G.J. Potential new risk factors for ischemic stroke: What is their potential? Stroke,  2006, 37(8), 2181-2188.
 [http://dx.doi.org/10.1161/01.STR.0000229883.72010.e4] [PMID: 16809576]

[86]
Tuo, Q.; Zhang, S.; Lei, P. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications. Med. Res. Rev.,  2022, 42(1), 259-305.
 [PMID: 33957000]

[87]
Davis, S.M.; Pennypacker, K.R. Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke. Neurochem. Int.,  2017, 107, 23-32.
 [http://dx.doi.org/10.1016/j.neuint.2016.12.007] [PMID: 28043837]

[88]
Üstün, Y.; Engin-Üstün, Y.; Öztürk, Ö.; Alanbay, I.; Yaman, H. Ischemia-modified albumin as an oxidative stress marker in preeclampsia. J. Matern. Fetal Neonatal Med.,  2011, 24(3), 418-421.
 [http://dx.doi.org/10.3109/14767058.2010.497879] [PMID: 20617896]

[89]
Hong, D.K.; Kho, A.R.; Lee, S.H.; Jeong, J.H.; Kang, B.S.; Kang, D.H.; Park, M.K.; Park, K.H.; Lim, M.S.; Choi, B.Y.; Suh, S.W. Transient Receptor Potential Melastatin 2 (TRPM2) inhibition by antioxidant, N-Acetyl-l-Cysteine, reduces global cerebral ischemia-induced neuronal death. Int. J. Mol. Sci.,  2020, 21(17), 6026.
 [http://dx.doi.org/10.3390/ijms21176026] [PMID: 32825703]

[90]
Deepthi, B.; Sowjanya, K.; Lidiya, B.; Bhargavi, R.S.; Babu, P.S. A modern review of diabetes mellitus: An annihilatory metabolic disorder. J. In Silico In Vitro Pharmacol,  2017, 3(1)

[91]
Skapek, S.X.; Ferrari, A.; Gupta, A.A.; Lupo, P.J.; Butler, E.; Shipley, J.; Barr, F.G.; Hawkins, D.S.; Viswanathan, V. Rhabdomyosarcoma. Nat. Rev. Dis. Primers,  2019, 5(1), 1-8.
 [http://dx.doi.org/10.1038/s41572-018-0051-2] [PMID: 30617281]

[92]
Baluchnejadmojarad, T.; Kiasalari, Z.; Afshin-Majd, S.; Ghasemi, Z.; Roghani, M. S-allyl cysteine ameliorates cognitive deficits in streptozotocin-diabetic rats via suppression of oxidative stress, inflammation, and acetylcholinesterase. Eur. J. Pharmacol.,  2017, 794, 69-76.
 [http://dx.doi.org/10.1016/j.ejphar.2016.11.033] [PMID: 27887948]

[93]
Hameed, I.; Masoodi, S.R.; Mir, S.A.; Nabi, M.; Ghazanfar, K.; Ganai, B.A. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J. Diabetes,  2015, 6(4), 598-612.
 [http://dx.doi.org/10.4239/wjd.v6.i4.598] [PMID: 25987957]

[94]
Rani, V.; Deep, G. Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies. Life Sci.,  2016, 2016, S0024320516300522.

[95]
Singh, R.; Devi, S.; Gollen, R. Role of free radical in atherosclerosis, diabetes and dyslipidaemia: Larger-than-life. Diabetes Metab. Res. Rev.,  2015, 31(2), 113-126.
 [http://dx.doi.org/10.1002/dmrr.2558] [PMID: 24845883]

[96]
Karunakaran, U.; Park, K.G. A systematic review of oxidative stress and safety of antioxidants in diabetes: Focus on islets and their defense. Diabetes Metab. J.,  2013, 37(2), 106-112.
 [http://dx.doi.org/10.4093/dmj.2013.37.2.106] [PMID: 23641350]

[97]
Manna, P.; Das, J.; Sil, P.C. Role of sulfur containing amino acids as an adjuvant therapy in the prevention of diabetes and its associated complications. Curr. Diabetes Rev.,  2013, 9(3), 237-248.
 [http://dx.doi.org/10.2174/1573399811309030005] [PMID: 23547683]

[98]
Markova, I. The effect of lipotoxicity on renal dysfunction in a nonobese rat model of metabolic syndrome: A urinary proteomic approach J. Diabetes Res.,  2019, 2019, 8712979.

[99]
Kondakçı, G.; Aydın, A.F.; Doğru-Abbasoğlu, S.; Uysal, M. The effect of N-acetylcysteine supplementation on serum homocysteine levels and hepatic and renal oxidative stress in homocysteine thiolactone-treated rats. Arch. Physiol. Biochem.,  2017, 123(2), 128-133.
 [http://dx.doi.org/10.1080/13813455.2016.1273365] [PMID: 28100069]

[100]
Kalantar-Zadeh, K.; Jafar, T.H.; Nitsch, D.; Neuen, B.L.; Perkovic, V. Chronic kidney disease. Lancet,  2021, 398(10302), 786-802.
 [http://dx.doi.org/10.1016/S0140-6736(21)00519-5] [PMID: 34175022]

[101]
Sandireddy, R.; Yerra, V.G.; Areti, A.; Komirishetty, P.; Kumar, A. Neuroinflammation and oxidative stress in diabetic neuropathy: Futuristic strategies based on these targets. Int. J. Endocrinol.,  2014, 2014, 1-10.
 [http://dx.doi.org/10.1155/2014/674987] [PMID: 24883061]

[102]
Schwalfenberg, G.K. N-acetylcysteine: A review of clinical usefulness (an old drug with new tricks). J. Nutr. Metab.,  2021, 2021, 1-13.
 [http://dx.doi.org/10.1155/2021/9949453] [PMID: 34221501]

[103]
Oyenihi, AB; Ayeleso, AO; Mukwevho, E; Masola, B Antioxidant strategies in the management of diabetic neuropathy. Biomed. Res. Int.,  2015, 2015, 515042.
 [http://dx.doi.org/10.1155/2015/515042]

[104]
Stitt, A.W.; Curtis, T.M.; Chen, M.; Medina, R.J.; McKay, G.J.; Jenkins, A.; Gardiner, T.A.; Lyons, T.J.; Hammes, H.P.; Simó, R.; Lois, N. The progress in understanding and treatment of diabetic retinopathy. Prog. Retin. Eye Res.,  2016, 51, 156-186.
 [http://dx.doi.org/10.1016/j.preteyeres.2015.08.001] [PMID: 26297071]

[105]
Calderon, G.D.; Juarez, O.H.; Hernandez, G.E.; Punzo, S.M.; De la Cruz, Z.D. Oxidative stress and diabetic retinopathy: Development and treatment. Eye (Lond.),  2017, 31(8), 1122-1130.
 [http://dx.doi.org/10.1038/eye.2017.64] [PMID: 28452994]

[106]
Kowluru, R.A.; Mishra, M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim. Biophys. Acta Mol. Basis Dis.,  2015, 1852(11), 2474-2483.
 [http://dx.doi.org/10.1016/j.bbadis.2015.08.001]

[107]
Zhu, Y.; Zhang, X.L.; Zhu, B.F.; Ding, Y.N. Effect of antioxidant N-acetylcysteine on diabetic retinopathy and expression of VEGF and ICAM-1 from retinal blood vessels of diabetic rats. Mol. Biol. Rep.,  2012, 39(4), 3727-3735.
 [http://dx.doi.org/10.1007/s11033-011-1148-9] [PMID: 21952821]

[108]
Sagoo, MK; Gnudi, L Diabetic nephropathy: An overview. Methods Mol. Biol.,  2020, 2067(4), 3-7.
 [http://dx.doi.org/10.1007/978-1-4939-9841-8_1]

[109]
Sagoo, M.K.; Gnudi, L. Diabetic nephropathy: Is there a role for oxidative stress? Free Radic. Biol. Med.,  2018, 116, 50-63.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2017.12.040] [PMID: 29305106]

[110]
Nogueira, G.B.; Punaro, G.R.; Oliveira, C.S.; Maciel, F.R.; Fernandes, T.O.; Lima, D.Y.; Rodrigues, A.M.; Mouro, M.G.; Araujo, S.R.R.; Higa, E.M.S. N-acetylcysteine protects against diabetic nephropathy through control of oxidative and nitrosative stress by recovery of nitric oxide in rats. Nitric Oxide,  2018, 78, 22-31.
 [http://dx.doi.org/10.1016/j.niox.2018.05.003] [PMID: 29778909]

[111]
Muzurović, E; Kraljević, I; Solak, M; Dragnić, S; Mikhailidis, DP Homocysteine and diabetes: Role in macrovascular and microvascular complications. J. Diabetes Complications,  2021, 35(3), 107834.
 [http://dx.doi.org/10.1016/j.jdiacomp.2020.107834]

[112]
Small, D.M.; Coombes, J.S.; Bennett, N.; Johnson, D.W.; Gobe, G.C. Oxidative stress, anti-oxidant therapies and chronic kidney disease. Nephrology (Carlton),  2012, 17(4), 311-321.
 [http://dx.doi.org/10.1111/j.1440-1797.2012.01572.x] [PMID: 22288610]

[113]
Elbini Dhouib, I.; Jallouli, M.; Annabi, A.; Gharbi, N.; Elfazaa, S.; Lasram, M.M. A minireview on N -acetylcysteine: An old drug with new approaches. Life Sci.,  2016, 151, 359-363.
 [http://dx.doi.org/10.1016/j.lfs.2016.03.003] [PMID: 26946308]

[114]
Micucci, C.; Valli, D.; Matacchione, G.; Catalano, A. Current perspectives between metabolic syndrome and cancer. Oncotarget,  2016, 7(25), 38959-38972.
 [http://dx.doi.org/10.18632/oncotarget.8341] [PMID: 27029038]

[115]
Zhitkovich, A. N -Acetylcysteine: Antioxidant, aldehyde scavenger, and more. Chem. Res. Toxicol.,  2019, 32(7), 1318-1319.
 [http://dx.doi.org/10.1021/acs.chemrestox.9b00152] [PMID: 31046246]

[116]
Esposito, K.; Capuano, A.; Giugliano, D. Metabolic syndrome and cancer: Holistic or reductionist? Endocrine,  2014, 45(3), 362-364.
 [http://dx.doi.org/10.1007/s12020-013-0056-2] [PMID: 24065310]

[117]
Ammirati, A.L. Chronic kidney disease. Rev. Assoc. Med. Bras.,  2020, 66(66)(Suppl. 1), s03-s09.
 [http://dx.doi.org/10.1590/1806-9282.66.s1.3] [PMID: 31939529]

[118]
Daenen, K.; Andries, A.; Mekahli, D.; Van Schepdael, A.; Jouret, F.; Bammens, B. Oxidative stress in chronic kidney disease. Pediatr. Nephrol.,  2019, 34(6), 975-991.
 [http://dx.doi.org/10.1007/s00467-018-4005-4] [PMID: 30105414]

[119]
Ling, X.C.; Kuo, K.L. Oxidative stress in chronic kidney disease. Renal Replacement Ther.,  2018, 4(1), 53.
 [http://dx.doi.org/10.1186/s41100-018-0195-2]

[120]
Ghorbani, A.; Shahbazian, H.; Shayanpour, S. Evaluation of administration of oral N-acetylcysteine to reduce oxidative stress in chronic hemodialysis patients: A double-blind, randomized, controlled clinical trial. Saudi J. Kidney Dis. Transpl.,  2016, 27(1), 88-93.
 [http://dx.doi.org/10.4103/1319-2442.174084] [PMID: 26787572]

[121]
Gerogianni, SK; Babatsikou, FP Psychological aspects in chronic renal failure. Health Sci. J.,  2014, 8(2), 205-214.

[122]
Jakovljevic, B.; Gasic, B.; Kovacevic, P.; Rajkovaca, Z.; Kovacevic, T. Homocystein as a risk factor for developing complications in chronic renal failure. Mater. Sociomed.,  2015, 27(2), 95-98.
 [http://dx.doi.org/10.5455/msm.2015.27.95-98] [PMID: 26005384]

[123]
Ostrakhovitch, E.A.; Tabibzadeh, S. Homocysteine in chronic kidney disease. Adv. Clin. Chem.,  2015, 72, 77-106.
 [http://dx.doi.org/10.1016/bs.acc.2015.07.002] [PMID: 26471081]

[124]
Wang, Q.; Mazur, A.; Guerrero, F.; Lambrechts, K.; Buzzacott, P.; Belhomme, M.; Theron, M. Antioxidants, endothelial dysfunction, and DCS: In vitro and in vivo study. J. Appl. Physiol.,  2015, 119(12), 1355-1362.
 [http://dx.doi.org/10.1152/japplphysiol.00167.2015] [PMID: 26472863]

[125]
Fang, X; Liu, L; Zhou, S; Zhu, M; Wang, B N-acetylcysteine inhibits atherosclerosis by correcting glutathione-dependent methylglyoxal elimination and dicarbonyl/oxidative stress in the aorta of diabetic mice. Mol. Med. Rep.,  2021, 23(3), 201.

[126]
Tossios, P.; Bloch, W.; Huebner, A.; Raji, M.R.; Dodos, F.; Klass, O.; Suedkamp, M.; Kasper, S.M.; Hellmich, M.; Mehlhorn, U. N-acetylcysteine prevents reactive oxygen species–mediated myocardial stress in patients undergoing cardiac surgery: Results of a randomized, double-blind, placebo-controlled clinical trial. J. Thorac. Cardiovasc. Surg.,  2003, 126(5), 1513-1520.
 [http://dx.doi.org/10.1016/S0022-5223(03)00968-1] [PMID: 14666027]

[127]
Khanna, A.K.; Xu, J.; Mehra, M.R. Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model. Lab. Invest.,  2012, 92(2), 224-235.
 [http://dx.doi.org/10.1038/labinvest.2011.146] [PMID: 21968809]

[128]
Sekhon, B.; Sekhon, C.; Khan, M.; Patel, S.J.; Singh, I.; Singh, A.K. N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res.,  2003, 971(1), 1-8.
 [http://dx.doi.org/10.1016/S0006-8993(03)02244-3] [PMID: 12691831]

[129]
Turkmen, S.; Cekic Gonenc, O.; Karaca, Y.; Mentese, A.; Demir, S.; Beyhun, E.; Sahin, A.; Gunduz, A.; Yulug, E.; Turedi, S. The effect of ethyl pyruvate and N-acetylcysteine on ischemia-reperfusion injury in an experimental model of ischemic stroke. Am. J. Emerg. Med.,  2016, 34(9), 1804-1807.
 [http://dx.doi.org/10.1016/j.ajem.2016.06.003] [PMID: 27324856]

[130]
Ribeiro, G.; Roehrs, M.; Bairros, A.; Moro, A.; Charão, M.; Araújo, F.; Valentini, J.; Arbo, M.; Brucker, N.; Moresco, R.; Leal, M.; Morsch, V.; Garcia, S.C. N -acetylcysteine on oxidative damage in diabetic rats. Drug Chem. Toxicol.,  2011, 34(4), 467-474.
 [http://dx.doi.org/10.3109/01480545.2011.564179] [PMID: 21770721]

[131]
Kamboj, S.S.; Vasishta, R.K.; Sandhir, R. N -acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy. J. Neurochem.,  2010, 112(1), 77-91.
 [http://dx.doi.org/10.1111/j.1471-4159.2009.06435.x] [PMID: 19840221]

[132]
Heloisa, M.; Shimizu, M.; Coimbra, T.M.; De Araujo, M.; Menezes, L.F.; Seguro, A.C. N-acetylcysteine attenuates the progression of chronic renal failure. Kidney Int.,  2005, 68(5), 2208-2217.
 [http://dx.doi.org/10.1111/j.1523-1755.2005.00677.x] [PMID: 16221220]

[133]
Luo, J.; Tsuji, T.; Yasuda, H.; Sun, Y.; Fujigaki, Y.; Hishida, A. The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats. Nephrol. Dial. Transplant.,  2008, 23(7), 2198-2205.
 [http://dx.doi.org/10.1093/ndt/gfn090] [PMID: 18385389]

[134]
Sabetghadam, M.; Mazdeh, M.; Abolfathi, P.; Mohammadi, Y.; Mehrpooya, M. Evidence for a beneficial effect of oral N-acetylcysteine on functional outcomes and inflammatory biomarkers in patients with acute ischemic stroke. Neuropsychiatr. Dis. Treat.,  2020, 16, 1265-1278.
 [http://dx.doi.org/10.2147/NDT.S241497] [PMID: 32547030]

[135]
Coyle, L.C.; Rodriguez, A.; Jeschke, R.E.; Simon-Lee, A.; Abbott, K.C.; Taylor, A.J. Acetylcysteine In Diabetes (AID): A randomized study of acetylcysteine for the prevention of contrast nephropathy in diabetics. Am. Heart J.,  2006, 151(5), 1032.e9-1032.e12.
 [http://dx.doi.org/10.1016/j.ahj.2006.02.002] [PMID: 16644332]

[136]
Sisillo, E.; Ceriani, R.; Bortone, F.; Juliano, G.; Salvi, L.; Veglia, F.; Fiorentini, C.; Marenzi, G. N-acetylcysteine for prevention of acute renal failure in patients with chronic renal insufficiency undergoing cardiac surgery: A prospective, randomized, clinical trial. Crit. Care Med.,  2008, 36(1), 81-86.
 [http://dx.doi.org/10.1097/01.CCM.0000295305.22281.1D] [PMID: 18090169]

[137]
Liao, C.Y.; Chung, C.H.; Wu, C.C.; Lin, F.H.; Tsao, C.H.; Wang, C.C.; Chien, W.C. Protective effect of N -acetylcysteine on progression to end-stage renal disease: Necessity for prospective clinical trial. Eur. J. Intern. Med.,  2017, 44, 67-73.
 [http://dx.doi.org/10.1016/j.ejim.2017.06.011] [PMID: 28633804]

[138]
Talasaz, A.H.; Khalili, H.; Fahimi, F.; Jenab, Y.; Broumand, M.A.; Salarifar, M.; Darabi, F. Effects of N-acetylcysteine on the cardiac remodeling biomarkers and major adverse events following acute myocardial infarction: A randomized clinical trial. Am. J. Cardiovasc. Drugs,  2014, 14(1), 51-61.
 [http://dx.doi.org/10.1007/s40256-013-0048-x] [PMID: 24105017]

[139]
Pereira, J.E.G.; El Dib, R.; Braz, L.G.; Escudero, J.; Hayes, J.; Johnston, B.C. N-acetylcysteine use among patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized trials. PLoS One,  2019, 14(5), e0213862.
 [http://dx.doi.org/10.1371/journal.pone.0213862] [PMID: 31071081]

[140]
Hamed, T.; Ibrahim, M.; Salem, H. Possible ameliorating effect of N-acetyl Cysteine on Type II Diabetic Nephropathy: Clinical trial. AIJPMS,  2023, 3(2), 61-69.
 [http://dx.doi.org/10.21608/aijpms.2023.155638.1159]
Cite As
Current Protein & Peptide Science

A Comprehensive Review on the Significance of Cysteine in Various Metabolic Disorders; Particularly CVD, Diabetes, Renal Dysfunction, and Ischemic Stroke

Abstract

Graphical Abstract
