Insights Into Long COVID Fatigue Biology: Potential Treatment Implications Using Multi-Targeted Action of AXA1125, a Novel Endogenous Metabolic Modulator Composition AXA1125, a Novel Endogenous Metabolic Modulator Composition for Long COVID Fatigue Treatment
Main Article Content
Abstract
With ongoing global research efforts to tackle coronavirus disease 2019 (COVID-19), increasing attention is directed toward the long-term sequelae of COVID, entitled “long COVID” or post-acute sequelae of COVID-19. These long-COVID symptoms persist beyond 12 weeks in over 10%–40% of patients, with exertional fatigue predominant in at least 50%. Scientific evidence has linked long COVID fatigue with mitochondrial dysfunction and energetic dysregulation in multiple biological pathways. Single target-directed treatments could be insufficient to treat these heterogeneous disorders. A novel multi-targeted therapeutic strategy could better address long COVID fatigue by restoring mitochondrial function. Our systems biology platform identified mechanisms implicated in long COVID and prioritized the composition of endogenous metabolic modulators focused on amino acid combinations, related precursors, and metabolites with the potential to address mitochondrial dysfunction. AXA1125 is a novel composition of five amino acids (Leucine, Isoleucine, Valine, Arginine, and Glutamine) and an amino acid derivative (N-acetylcysteine) that could safely target multifactorial disease pathophysiology of fatigue-dominant long COVID. Our phase IIa, double-blind, randomized trial (NCT05152849) in exertional fatigue patients associated with long COVID interrogated this proposition and showed promising results. We hypothesize that AXA1125 holds the potential for improving functional clinical outcomes by targeting multiple disease pathways and improving mitochondrial function and energetics.
Keywords:
amino acid, energetic dysregulation, exercise tolerance, fatigue, long COVID, mitochondrial dysfunction, systems biology
Article Details
How to Cite
RUSSELL, Matthew et al.
Insights Into Long COVID Fatigue Biology: Potential Treatment Implications Using Multi-Targeted Action of AXA1125, a Novel Endogenous Metabolic Modulator Composition.
Medical Research Archives, [S.l.], v. 12, n. 4, may 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5364>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i4.5364.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. World Health Organization. Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. [updated 2023; cited 2023 Mar 27] Available from: https://covid19.who.int/.
2. Office for National Statistics. Ayoubkhani, D, Pawelek, P, Gaughan, C. Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK: 26 April 2020 to 1 August 2021. [updated 2021; cited 2023 Mar 27). Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021.
3. Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of long COVID prevalence and its relationship to Epstein-Barr virus reactivation. Pathogens. 2021;10:763. doi: 10.3390/pathogens10060763
4. Groff D, Sun A, Ssentongo AE, et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review. JAMA Netw Open. 2021;4: e2128568. doi: 10.1001/jamanetworkopen.2021.28568.
5. Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022;43:1157–72. doi: 10.1093/eurheartj/ehac031.
6. Sivan M, Taylor S. NICE guideline on long COVID. BMJ. 2020;371:m4938. doi: 10.1136/bmj.m4938.
7. Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of COVID-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2022;372:n136. doi: 10.1136/bmj.n136.
8. National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. [updated 2021; cited 2023 Mar 27]. Available from: www.nice.org.uk/guidance/ng188.
9. National Institute for Health. NIH launches new initiative to study "Long COVID." [updated 2021; cited 2023 Mar 27]. Available from: https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid.
10. Rubin R. As their numbers grow, COVID-19 "long haulers" stump experts. JAMA. 2020;324:1381–83. doi: 10.1001/jama .2020.17709.
11. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136.
12. Office for National Statistics. Ayoubkhani, D, King, S. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the U.K. [updated 2022; cited 2023 Mar 27]. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/30march2023
13. Krishna B, Wills M, Sithole N. Long COVID: what is known and what gaps need to be addressed. Br Med Bull. 2023;147(1):6–19. doi: 10.1093/bmb/ldad016.
14. Malik P, Patel K, Pinto C, et al. Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)-A systematic review and meta-analysis. J Med Virol. 2022;94:253–62. doi: 10.1002/jmv.27309.
15. Righi E, Mirandola M, Mazzaferri F, et al. Determinants of persistence of symptoms and impact on physical and mental wellbeing in Long COVID: a prospective cohort study. J Infect. 2022;84:566–72. doi: 10.1016/j.jinf.20 22.02.003.
16. Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond). 2021;53:737–54. doi: 10.1080/23744235.202 1.1924397.
17. Castanares-Zapatero D, Chalon P, Kohn L, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022;54:1473–87. doi: 10.1080/078538 90.2022.2076901.
18. Crook H, Raza S, Nowell J, Young M, Edison P. Long COVID-mechanisms, risk factors, and management. BMJ. 2021;374:n1 648. doi: 10.1136/bmj.n1648.
19. Su Y, Yuan D, Chen DG, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022;185:881–95.e20. doi: 10.1016/j.cell.2022.01.014.
20. Klein J, Wood J, JaycoxJ, et al. Distinguishing features of long COVID identified through immune profiling. medRxiv [Preprint]. 2022;2022.08.09.22278592. doi: 10.1101/2022.08.09.22278592.
21. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(6):408. doi: 10.1038/s41579-023-00896-0.
22. Huang L, Yao Q, Gu X, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021;398:747–58. doi: 10.1016/S0140-6736(2 1)01755-4.
23. Aiyegbusi OL, Hughes SE, Turner G, et al. Symptoms, complications and management of long COVID: a review. J R Soc Med. 2021;114:428–42. doi: 10.1177/014107 68211032850.
24. Tirelli U, Franzini M, Valdenassi L, et al. Fatigue in post-acute sequelae of SARS-CoV2 (PASC) treated with oxygen-ozone autohemotherapy – preliminary results on 100 patients. Eur Rev Med Pharmacol Sci. 2021;25 :5871–75. doi: 10.26355/eurrev_202109_26809.
25. Buttery S, Philip KEJ, Williams P, et al. Patient symptoms and experience following COVID-19: results from a UK-wide survey. BMJ Open Respir Res. 2021;8:e001075. doi: 10.1136/bmjresp-2021-001075.
26. Carfì A, Bernabei R, Landi F. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020;324:603–05. doi: 10.1001/jama. 2020.12603.
27. Mandal S, Barnett J, Brill SE, et al. 'Long-COVID': a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax. 2021;76:396–98. doi: 10.1 136/thoraxjnl-2020-215818.
28. Ryan FJ, Hope CM, Masavuli MG, et al. Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection. BMC Med. 2022;20:26. doi: 10.118 6/s12916-021-02228-6.
29. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020;15 :e0240784. doi: 10.1371/journal.pone.0240784.
30. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;2:601–15. doi: 10.1038/s41591-021-01283-z.
31. Nasserie T, Hittle M, Goodman SN. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. JAMA Netw Open. 2021;4:e2111417. doi: 10.1001/jama networkopen.2021.11417.
32. Baig AM. Deleterious outcomes in long-hauler COVID-19: the effects of SARS-CoV-2 on the CNS in chronic COVID syndrome. ACS Chem Neurosci. 2020;11:4017–20. doi: 10.10 21/acschemneuro.0c00725.
33. Wijeratne T, Crewther S. Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community. J Neurol Sci. 2020;419 :117179. doi: 10.1016/j.jns.2020.117179.
34. Asadi-Pooya AA, Akbari A, Emami A, et al. Long COVID syndrome-associated brain fog. J Med Virol. 2022;94:979–84. doi: 10.100 2/jmv.27404.
35. Fair Health Report. A detailed study of patients with long-haul COVID. [updated 2021; cited 2023 Mar 27]. Available from: https://www.fairhealth.org/publications/whitepapers.
36. Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 'long-haulers'?. Chronic Dis Transl Med. 2021;7:14–26. doi: 10.1016/j.cdtm.2020.11.002.
37. de Boer E, Petrache I, Goldstein NM, et al. Decreased fatty acid oxidation and altered lactate production during exercise in patients with post-acute COVID-19 syndrome. Am J Respir Crit Care Med. 2022;205:126-129. doi: 10.1164/rccm.202108-1903LE.
38. Guarnieri JW, Dybas JM, Fazelinia H, et al. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Sci Transl Med. 2023;15:eabq1533. doi: 10.1126/scitranslme d.abq1533.
39. Yong SJ, Liu S. Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies. Rev Med Virol. 2021;9:e2315. doi: 10.1002/rmv.2315.
40. Jaiswal S, Kumar M, Mandeep, Sunita, Singh Y, Shukla P. Systems Biology Approaches for Therapeutics Development Against COVID-19. Front Cell Infect Microbiol. 2020;10:560240. doi: 10.3389/fcimb.2020.560240.
41. Food and Drug Administration. Strengthening coronavirus models with systems biology and machine learning. [updated 2023; cited 2023 Mar 27]. Available from: https://www.fda.gov/emergency-preparedness-and-response/mcm-regulatory-science/strengthening-coronavirus-models-systems-biology-and-machine-learning.
42. Djordjevic M, Rodic A, Salom I, et al. A systems biology approach to COVID-19 progression in population. Adv Protein Chem Struct Biol. 2021;127:291–14. doi: 10.1016/bs .apcsb.2021.03.003.
43. Azer K, Barrett J, Trame M, Musante C. Overcoming Obstacles in Drug Discovery and Development. Systems biology and data science in research and translational medicine. Elsevier Academic Press, 2023. doi: 10.1016/B978-0-12-817134-9.00001-5.
44. Hamill MJ, Afeyan R, Chakravarthy MV, Tramontin T. Endogenous metabolic modulators: emerging therapeutic potential of amino acids. iScience. 2020;23:101628. doi: 10.1016/j.isci.2020.101628.
45. Harrison SA, Baum SJ, Gunn NT, et al. Safety, tolerability, and biologic activity of AXA1125 and AXA1957 in subjects with nonalcoholic fatty liver disease. Am J Gastroenterol. 2021;116:2399–09. doi: 10.14 309/ajg.0000000000001375.
46. Daou N, Viader A, Cokol M, et al. A novel, multi-targeted endogenous metabolic modulator composition impacts metabolism, inflammation, and fibrosis in nonalcoholic steatohepatitis-relevant primary human cell models. Sci Rep. 2021;11:11861. doi: 10.1038 /s41598-021-88913-1.
47. Ganji R, Reddy PH. Impact of COVID-19 on mitochondrial-based immunity in aging and age-related diseases. Front Aging Neurosci. 2021;12:614650. doi: 10.3389/fnag i.2020.614650.
48. Aguirre JD, Culotta VC. Battles with iron: manganese in oxidative stress protection. J Biol Chem. 2012;287:13541–48. doi: 10.1074/jbc.R111.312181.
49. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844–47. doi: 10.1111/jth.14768.
50. Swank Z, Senussi Y, Manickas-Hill Z, et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin Infect Dis. 2023;7 6(3):e487–90. doi: 10.1093/cid/ciac722.
51. Bergamaschi L, Mescia F, Turner L, et al. Immunity. 2021;54(6):1257–75.e8. doi: 10.101 6/j.immuni.2021.05.010.
52. Costa TJ, Potje SR, Fraga-Silva TFC, et al. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage. Vascul Pharmaco. 2022;142:106 946. doi: 10.1016/j.vph.2021.106946.
53. Wong AC, Devason AS, Umana IC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186(22):4851–67.e2 0. doi: 10.1016/j.cell.2023.09.013.
54. Delgado-Roche L, Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res. 2020;51:384–387. doi: 10.101 6/j.arcmed.2020.04.019.
55. Tzameli I. The evolving role of mitochondria in metabolism. Trends Endocrinol Metab. 2012;23:417-9. doi: 10.10 16/j.tem.2012.07.008.
56. Voet D, Voet JG, Pratt CW. Fundamentals of Biochemistry. 4th ed. John Wiley & Sons (2003). 1208 p.
57. Schulz E, Wenzel P, Münzel T, Daiber A. Mitochondrial redox signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox Signal. 2014;20:308–24. doi: 10.1089/ ars.2012.4609.
58. Naviaux RK. Metabolic features and regulation of the healing cycle-A new model for chronic disease pathogenesis and treatment. Mitochondrion. 2019;46:278–97. doi: 10.1016/j.mito.2018.08.001.
59. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. 2016;113: E5472–80. doi: 10.1073/pnas.1607571113.
60. Tomas C, Brown A, Strassheim V, Elson JL, Newton J, Manning P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS One. 2017;12 :1–16. doi: 10.1371/journal.pone.0186802.
61. Missailidis D, Annesley SJ, Allan CY, et al. An isolated complex V inefficiency and dysregulated mitochondrial function in immortalized lymphocytes from ME/CFS patients. Int J Mol Sci. 2020;21:1074. doi: 10.3390/ijms21031074.
62. Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis / chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014;29:19–36. doi: 10.1007/s11011-013-9435-x.
63. Meidaninikjeh S, Sabouni N, Marzouni HZ, Bengar S, Khalili A, Jafari R. Monocytes and macrophages in COVID-19: Friends and foes. Life Sci. 2021;269:119010. doi: 10.1016/ j.lfs.2020.119010.
64. Codo AC, Davanzo GG, Monteiro LdB, et al. Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis. Cell Metab. 2020;32:437–446.e5. doi: 10.1016/j.cmet.202 0.07.007.
65. Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV. Mitochondrial aging and age-related dysfunction of mitochondria. Bio Med Res Int. 2014;2014:23 8463. doi: 10.1155/2014/238463.
66. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8:2003–14. doi: 10.3969/j.issn.167 3-5374.2013.21.009.
67. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;44 3:787–95. doi: 10.1038/nature05292.
68. Kemp GJ, Ahmad RE, Nicolay K, Prompers JJ. Quantification of skeletal muscle mitochondrial function by 31P magnetic resonance spectroscopy techniques: a quantitative review. Acta Physiol (Oxf). 2015;213:107-44. doi: 10.1111/apha.12307.
69. Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders - A step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol. Basis Dis. 2017;18 63:1066–77. doi: 10.1016/j.bbadis.2016.11.010.
70. El-Hattab AW, Zarante AM, Almannai M, Scaglia F. Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab. 2017;122:1–9. doi: 10.1016/j.ymgme. 2017.09.009.
71. Hirano M, Emmanuele V, Quinzii CM. Emerging therapies for mitochondrial diseases. Essays Biochem. 2018;62:467–81. doi: 10.1042/EBC20170114.
72. Garone C, Viscomi C. Towards a therapy for mitochondrial disease: an update. Biochem Soc Trans. 2018;46:1247–61. doi: 10.1042/BST20180134.
73. Castro-Marrero J, Cordero MD, Segundo MJ, et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal. 2015;22:679–85. doi: 10.1089/ars.2014.6181.
74. Castro-Marrero J, Cordero MD, Segundo MJ, et al. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clin Nutr. 2016;35:826-34. doi: 10.1089/ars.2 014.6181.
75. Myhill S, Booth NE, McLaren-Howard J. Targeting mitochondrial dysfunction in the treatment of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) - A clinical audit. Int J Clin Exp Med. 2013;6:1–15.
76. Montoya JG, Anderson JN, Adolphs DL, et al. KPAX002 as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med. 2018;11:2890–00.
77. Cortese-Krott MM, Koning A, Kuhnle GGC, et al. The reactive species interactome: evolutionary emergence, biological significance, and opportunities for redox metabolomics and personalized medicine. Antioxid Redox Signal. 2017;27:684–12. doi: 10.1089/ars.2017.7083.
78. Hubens WHG, Vallbona-Garcia A, de Coo IFM, et al. Blood biomarkers for assessment of mitochondrial dysfunction: An expert review. Mitochondrion. 2022;62:187–04. doi: 10.1016/j.mito.2021.10.008.
79. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nature Med. 2018;24:908–22. doi: 10.1038/s 41591-018-0104-9.
80. Oliveira CP, Cotrim HP, Stefano JT, Siqueira ACG, Salgado ALA, Parise ER. N-acetylcysteine and/or ursodeoxycholic acid associated with metformin in nonalcoholic steatohepatitis: an open-label multicenter randomized controlled trial. Arq Gastroenterol. 2019;56:184–90. doi: 10.1590/ S0004-2803.201900000-36.
81. Patel PJ, Hayward KL, Rudra R, et al. Multimorbidity and polypharmacy in diabetic patients with NAFLD: implications for disease severity and management. Medicine (Baltimore). 2017;96:e6761. doi: 10.1097/MD. 0000000000006761.
82. Endari (L-glutamine oral powder) prescribing information (2017). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208587s000lbl.pdf [Accessed 14 August 2023].
83. Riley TR, Boss A, McClain D, Riley TT. Review of medication therapy for the prevention of sickle cell crisis. P T. 2018;43:417-421, 437.
84. Alruwaili H, Dehestani B, le Roux CW. Clinical impact of Liraglutide as a treatment of obesity. Clin Pharmacol. 2021;13:53-60. doi: 10.2147/CPAA.S276085. eCollection 2021.
85. Butterworth RF, McPhail MJW. L-Ornithine L-Aspartate (LOLA) for hepatic encephalopathy in cirrhosis: Results of randomized controlled trials and meta-analyses. Drugs. 2019;79:31–37. doi: 10.1007 /s40265-018-1024-1
86. Da Poian AT, El-Bacha T, Luz MRMP. Nutrient utilization in humans: metabolism pathways. Nature Education. 2010;9:11.
87. Gaggini M, Carli F, Rosso C, et al. Altered amino acid concentrations in NAFLD: impact of obesity and insulin resistance. Hepatology. 2018;67:145–58. doi: 10.1002/h ep.29465.
88. Kinny-Koster B, Bartels M, Becker S, et al. Plasma amino acid concentrations predict mortality in patients with end-stage liver disease. PLoS One. 2016;11:e0159205. doi: 10.1371/journal.pone.0159205.
89. Tarlungeanu DC, Deliu E, Dotter CP, et al. Impaired amino acid transport at the blood-brain barrier is a cause of autism spectrum disorder. Cell. 2016;167:1481-1494 e18. doi: 10.1016/j.cell.2016.11.013.
90. Finnigan LEM, Cassar MP, Koziel MJ, et al. Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study eClinicalMedicine. 2023;59:101 946. doi: 10.1016/j.eclinm.2023.101946.
91. Marukian, S, Hamill M, Hamm L, et al. Unique composition of endogenous metabolic modulators reprograms metabolic state and impacts markers of inflammation and fibrosis in NAFLD/NASH cell model systems. Abstract #2015. Oral presentation presented at the Keystone Symposia (2019).
92. Krishnan, S, Nordqvist H, Ambikan AT, et al. Metabolic perturbation associated with COVID-19 disease severity and SARS-CoV-2 replication. Mol Cell Proteomics. 2021;20:100 159. doi: 10.1016/j.mcpro.2021.100159.
93. D'Antona G, Ragni M, Cardile A, et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. 2010;12:362–72. doi: 10.1016/j.cmet.2010.08.016.
94. Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol. 2018;20:745–54. doi: 10.1038/s41556-018-0124-1.
95. Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J Nutr. 2006;136:207S-11S. doi: 10.1093/jn/136.1.207S.
96. Morris Jr SM. Arginases and arginine deficiency syndromes. Curr Opin Clin Nutr Metab Care. 2012;15:64–70. doi: 10.1097/M CO.0b013e32834d1a08.
97. Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Gautier JBO. Acquired amino acid deficiencies: A focus on arginine and glutamine. Nutr Clin Pract. 2017; 32:30S-47S. doi: 10.1177/0884533617691250.
98. Morris Jr SM. Arginine metabolism in vascular biology and disease. Vasc Med. 2005;10:S83-S87. doi: 10.1177/1358836X050 1000112.
99. Moncada S, Higgs EA. The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol. 2006;147 Suppl 1:S193–S201. doi: 10.1038/sj.bjp.0706458.
100. Palacios-Callender M, Quintero M, Hollis VS, Springett RJ, Moncada S. Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc Natl Acad Sci USA. 2004;101:76 30-5. doi: 10.1073/pnas.0401723101.
101. Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. 2021;23:362–69. doi: 10.1016/j.semcdb. 2012.02.002.
102. Tong X, Zhao F, Thompson CB. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev. 2009;19:32–7. doi: 10.1016/j.gde.2009. 01.002.
103. Chen J, Reheman A, Gushiken FC, et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest. 2011;121:593-603. doi: 10.1172/JCI41062.
104. Prasannan N, Heightman M, Hillman T, et al. Impaired exercise capacity in post-COVID-19 syndrome: the role of VWF-ADAMTS13 axis. Blood Adv. 2022;6:4041-4048. doi: 10.1182/bloodadvances.2021006944.
105. Pedre B, Barayeu U, Ezeriņa D, Dick TP. The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species. Pharmacol Ther. 2021;228:107 916. doi: 10.1016/j.pharmthera.2021.107916.
106. Wright DJ, Renoir T, Smith ZM, et al. N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease. Transl Psychiatry. 2015;5:e492. doi: 10.1038/tp.2014.131.
107. Shi Z, Puyo CA. N-Acetylcysteine to combat COVID-19: An evidence review. Ther Clin Risk Manag. 2020;16:1047–55. doi: 10.2147/TCRM.S273700.
108. Poe FL, Corn J. N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Med Hypotheses. 2020;143:109862. doi: 10.1016/j.mehy.2020.109862.
109. Glancy B, Kane DA, Kavazis AN, Goodwin ML, Willis WT, Gladden LB. Mitochondrial lactate metabolism: history and implications for exercise and disease. J Physiol. 2021;599:863–88. doi: 10.1113/JP278930.
110. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the mitochondrial medicine society. Genet Med. 2015;17:689-01. doi: 10.1038/gim.2014.177.
111. Magner M, Szentiványi K, Svandová I, et al. Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures. Eur J Paediatr Neurol. 2011;15: 101–08. doi: 10.1016/j.ejpn.2010.10.001.
2. Office for National Statistics. Ayoubkhani, D, Pawelek, P, Gaughan, C. Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK: 26 April 2020 to 1 August 2021. [updated 2021; cited 2023 Mar 27). Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021.
3. Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of long COVID prevalence and its relationship to Epstein-Barr virus reactivation. Pathogens. 2021;10:763. doi: 10.3390/pathogens10060763
4. Groff D, Sun A, Ssentongo AE, et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review. JAMA Netw Open. 2021;4: e2128568. doi: 10.1001/jamanetworkopen.2021.28568.
5. Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022;43:1157–72. doi: 10.1093/eurheartj/ehac031.
6. Sivan M, Taylor S. NICE guideline on long COVID. BMJ. 2020;371:m4938. doi: 10.1136/bmj.m4938.
7. Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of COVID-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2022;372:n136. doi: 10.1136/bmj.n136.
8. National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. [updated 2021; cited 2023 Mar 27]. Available from: www.nice.org.uk/guidance/ng188.
9. National Institute for Health. NIH launches new initiative to study "Long COVID." [updated 2021; cited 2023 Mar 27]. Available from: https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid.
10. Rubin R. As their numbers grow, COVID-19 "long haulers" stump experts. JAMA. 2020;324:1381–83. doi: 10.1001/jama .2020.17709.
11. Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136.
12. Office for National Statistics. Ayoubkhani, D, King, S. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the U.K. [updated 2022; cited 2023 Mar 27]. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/30march2023
13. Krishna B, Wills M, Sithole N. Long COVID: what is known and what gaps need to be addressed. Br Med Bull. 2023;147(1):6–19. doi: 10.1093/bmb/ldad016.
14. Malik P, Patel K, Pinto C, et al. Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)-A systematic review and meta-analysis. J Med Virol. 2022;94:253–62. doi: 10.1002/jmv.27309.
15. Righi E, Mirandola M, Mazzaferri F, et al. Determinants of persistence of symptoms and impact on physical and mental wellbeing in Long COVID: a prospective cohort study. J Infect. 2022;84:566–72. doi: 10.1016/j.jinf.20 22.02.003.
16. Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond). 2021;53:737–54. doi: 10.1080/23744235.202 1.1924397.
17. Castanares-Zapatero D, Chalon P, Kohn L, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022;54:1473–87. doi: 10.1080/078538 90.2022.2076901.
18. Crook H, Raza S, Nowell J, Young M, Edison P. Long COVID-mechanisms, risk factors, and management. BMJ. 2021;374:n1 648. doi: 10.1136/bmj.n1648.
19. Su Y, Yuan D, Chen DG, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022;185:881–95.e20. doi: 10.1016/j.cell.2022.01.014.
20. Klein J, Wood J, JaycoxJ, et al. Distinguishing features of long COVID identified through immune profiling. medRxiv [Preprint]. 2022;2022.08.09.22278592. doi: 10.1101/2022.08.09.22278592.
21. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(6):408. doi: 10.1038/s41579-023-00896-0.
22. Huang L, Yao Q, Gu X, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021;398:747–58. doi: 10.1016/S0140-6736(2 1)01755-4.
23. Aiyegbusi OL, Hughes SE, Turner G, et al. Symptoms, complications and management of long COVID: a review. J R Soc Med. 2021;114:428–42. doi: 10.1177/014107 68211032850.
24. Tirelli U, Franzini M, Valdenassi L, et al. Fatigue in post-acute sequelae of SARS-CoV2 (PASC) treated with oxygen-ozone autohemotherapy – preliminary results on 100 patients. Eur Rev Med Pharmacol Sci. 2021;25 :5871–75. doi: 10.26355/eurrev_202109_26809.
25. Buttery S, Philip KEJ, Williams P, et al. Patient symptoms and experience following COVID-19: results from a UK-wide survey. BMJ Open Respir Res. 2021;8:e001075. doi: 10.1136/bmjresp-2021-001075.
26. Carfì A, Bernabei R, Landi F. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020;324:603–05. doi: 10.1001/jama. 2020.12603.
27. Mandal S, Barnett J, Brill SE, et al. 'Long-COVID': a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax. 2021;76:396–98. doi: 10.1 136/thoraxjnl-2020-215818.
28. Ryan FJ, Hope CM, Masavuli MG, et al. Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection. BMC Med. 2022;20:26. doi: 10.118 6/s12916-021-02228-6.
29. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020;15 :e0240784. doi: 10.1371/journal.pone.0240784.
30. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;2:601–15. doi: 10.1038/s41591-021-01283-z.
31. Nasserie T, Hittle M, Goodman SN. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. JAMA Netw Open. 2021;4:e2111417. doi: 10.1001/jama networkopen.2021.11417.
32. Baig AM. Deleterious outcomes in long-hauler COVID-19: the effects of SARS-CoV-2 on the CNS in chronic COVID syndrome. ACS Chem Neurosci. 2020;11:4017–20. doi: 10.10 21/acschemneuro.0c00725.
33. Wijeratne T, Crewther S. Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community. J Neurol Sci. 2020;419 :117179. doi: 10.1016/j.jns.2020.117179.
34. Asadi-Pooya AA, Akbari A, Emami A, et al. Long COVID syndrome-associated brain fog. J Med Virol. 2022;94:979–84. doi: 10.100 2/jmv.27404.
35. Fair Health Report. A detailed study of patients with long-haul COVID. [updated 2021; cited 2023 Mar 27]. Available from: https://www.fairhealth.org/publications/whitepapers.
36. Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 'long-haulers'?. Chronic Dis Transl Med. 2021;7:14–26. doi: 10.1016/j.cdtm.2020.11.002.
37. de Boer E, Petrache I, Goldstein NM, et al. Decreased fatty acid oxidation and altered lactate production during exercise in patients with post-acute COVID-19 syndrome. Am J Respir Crit Care Med. 2022;205:126-129. doi: 10.1164/rccm.202108-1903LE.
38. Guarnieri JW, Dybas JM, Fazelinia H, et al. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Sci Transl Med. 2023;15:eabq1533. doi: 10.1126/scitranslme d.abq1533.
39. Yong SJ, Liu S. Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies. Rev Med Virol. 2021;9:e2315. doi: 10.1002/rmv.2315.
40. Jaiswal S, Kumar M, Mandeep, Sunita, Singh Y, Shukla P. Systems Biology Approaches for Therapeutics Development Against COVID-19. Front Cell Infect Microbiol. 2020;10:560240. doi: 10.3389/fcimb.2020.560240.
41. Food and Drug Administration. Strengthening coronavirus models with systems biology and machine learning. [updated 2023; cited 2023 Mar 27]. Available from: https://www.fda.gov/emergency-preparedness-and-response/mcm-regulatory-science/strengthening-coronavirus-models-systems-biology-and-machine-learning.
42. Djordjevic M, Rodic A, Salom I, et al. A systems biology approach to COVID-19 progression in population. Adv Protein Chem Struct Biol. 2021;127:291–14. doi: 10.1016/bs .apcsb.2021.03.003.
43. Azer K, Barrett J, Trame M, Musante C. Overcoming Obstacles in Drug Discovery and Development. Systems biology and data science in research and translational medicine. Elsevier Academic Press, 2023. doi: 10.1016/B978-0-12-817134-9.00001-5.
44. Hamill MJ, Afeyan R, Chakravarthy MV, Tramontin T. Endogenous metabolic modulators: emerging therapeutic potential of amino acids. iScience. 2020;23:101628. doi: 10.1016/j.isci.2020.101628.
45. Harrison SA, Baum SJ, Gunn NT, et al. Safety, tolerability, and biologic activity of AXA1125 and AXA1957 in subjects with nonalcoholic fatty liver disease. Am J Gastroenterol. 2021;116:2399–09. doi: 10.14 309/ajg.0000000000001375.
46. Daou N, Viader A, Cokol M, et al. A novel, multi-targeted endogenous metabolic modulator composition impacts metabolism, inflammation, and fibrosis in nonalcoholic steatohepatitis-relevant primary human cell models. Sci Rep. 2021;11:11861. doi: 10.1038 /s41598-021-88913-1.
47. Ganji R, Reddy PH. Impact of COVID-19 on mitochondrial-based immunity in aging and age-related diseases. Front Aging Neurosci. 2021;12:614650. doi: 10.3389/fnag i.2020.614650.
48. Aguirre JD, Culotta VC. Battles with iron: manganese in oxidative stress protection. J Biol Chem. 2012;287:13541–48. doi: 10.1074/jbc.R111.312181.
49. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844–47. doi: 10.1111/jth.14768.
50. Swank Z, Senussi Y, Manickas-Hill Z, et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin Infect Dis. 2023;7 6(3):e487–90. doi: 10.1093/cid/ciac722.
51. Bergamaschi L, Mescia F, Turner L, et al. Immunity. 2021;54(6):1257–75.e8. doi: 10.101 6/j.immuni.2021.05.010.
52. Costa TJ, Potje SR, Fraga-Silva TFC, et al. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage. Vascul Pharmaco. 2022;142:106 946. doi: 10.1016/j.vph.2021.106946.
53. Wong AC, Devason AS, Umana IC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186(22):4851–67.e2 0. doi: 10.1016/j.cell.2023.09.013.
54. Delgado-Roche L, Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res. 2020;51:384–387. doi: 10.101 6/j.arcmed.2020.04.019.
55. Tzameli I. The evolving role of mitochondria in metabolism. Trends Endocrinol Metab. 2012;23:417-9. doi: 10.10 16/j.tem.2012.07.008.
56. Voet D, Voet JG, Pratt CW. Fundamentals of Biochemistry. 4th ed. John Wiley & Sons (2003). 1208 p.
57. Schulz E, Wenzel P, Münzel T, Daiber A. Mitochondrial redox signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox Signal. 2014;20:308–24. doi: 10.1089/ ars.2012.4609.
58. Naviaux RK. Metabolic features and regulation of the healing cycle-A new model for chronic disease pathogenesis and treatment. Mitochondrion. 2019;46:278–97. doi: 10.1016/j.mito.2018.08.001.
59. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. 2016;113: E5472–80. doi: 10.1073/pnas.1607571113.
60. Tomas C, Brown A, Strassheim V, Elson JL, Newton J, Manning P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS One. 2017;12 :1–16. doi: 10.1371/journal.pone.0186802.
61. Missailidis D, Annesley SJ, Allan CY, et al. An isolated complex V inefficiency and dysregulated mitochondrial function in immortalized lymphocytes from ME/CFS patients. Int J Mol Sci. 2020;21:1074. doi: 10.3390/ijms21031074.
62. Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis / chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014;29:19–36. doi: 10.1007/s11011-013-9435-x.
63. Meidaninikjeh S, Sabouni N, Marzouni HZ, Bengar S, Khalili A, Jafari R. Monocytes and macrophages in COVID-19: Friends and foes. Life Sci. 2021;269:119010. doi: 10.1016/ j.lfs.2020.119010.
64. Codo AC, Davanzo GG, Monteiro LdB, et al. Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis. Cell Metab. 2020;32:437–446.e5. doi: 10.1016/j.cmet.202 0.07.007.
65. Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV. Mitochondrial aging and age-related dysfunction of mitochondria. Bio Med Res Int. 2014;2014:23 8463. doi: 10.1155/2014/238463.
66. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8:2003–14. doi: 10.3969/j.issn.167 3-5374.2013.21.009.
67. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;44 3:787–95. doi: 10.1038/nature05292.
68. Kemp GJ, Ahmad RE, Nicolay K, Prompers JJ. Quantification of skeletal muscle mitochondrial function by 31P magnetic resonance spectroscopy techniques: a quantitative review. Acta Physiol (Oxf). 2015;213:107-44. doi: 10.1111/apha.12307.
69. Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders - A step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol. Basis Dis. 2017;18 63:1066–77. doi: 10.1016/j.bbadis.2016.11.010.
70. El-Hattab AW, Zarante AM, Almannai M, Scaglia F. Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab. 2017;122:1–9. doi: 10.1016/j.ymgme. 2017.09.009.
71. Hirano M, Emmanuele V, Quinzii CM. Emerging therapies for mitochondrial diseases. Essays Biochem. 2018;62:467–81. doi: 10.1042/EBC20170114.
72. Garone C, Viscomi C. Towards a therapy for mitochondrial disease: an update. Biochem Soc Trans. 2018;46:1247–61. doi: 10.1042/BST20180134.
73. Castro-Marrero J, Cordero MD, Segundo MJ, et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal. 2015;22:679–85. doi: 10.1089/ars.2014.6181.
74. Castro-Marrero J, Cordero MD, Segundo MJ, et al. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clin Nutr. 2016;35:826-34. doi: 10.1089/ars.2 014.6181.
75. Myhill S, Booth NE, McLaren-Howard J. Targeting mitochondrial dysfunction in the treatment of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) - A clinical audit. Int J Clin Exp Med. 2013;6:1–15.
76. Montoya JG, Anderson JN, Adolphs DL, et al. KPAX002 as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med. 2018;11:2890–00.
77. Cortese-Krott MM, Koning A, Kuhnle GGC, et al. The reactive species interactome: evolutionary emergence, biological significance, and opportunities for redox metabolomics and personalized medicine. Antioxid Redox Signal. 2017;27:684–12. doi: 10.1089/ars.2017.7083.
78. Hubens WHG, Vallbona-Garcia A, de Coo IFM, et al. Blood biomarkers for assessment of mitochondrial dysfunction: An expert review. Mitochondrion. 2022;62:187–04. doi: 10.1016/j.mito.2021.10.008.
79. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nature Med. 2018;24:908–22. doi: 10.1038/s 41591-018-0104-9.
80. Oliveira CP, Cotrim HP, Stefano JT, Siqueira ACG, Salgado ALA, Parise ER. N-acetylcysteine and/or ursodeoxycholic acid associated with metformin in nonalcoholic steatohepatitis: an open-label multicenter randomized controlled trial. Arq Gastroenterol. 2019;56:184–90. doi: 10.1590/ S0004-2803.201900000-36.
81. Patel PJ, Hayward KL, Rudra R, et al. Multimorbidity and polypharmacy in diabetic patients with NAFLD: implications for disease severity and management. Medicine (Baltimore). 2017;96:e6761. doi: 10.1097/MD. 0000000000006761.
82. Endari (L-glutamine oral powder) prescribing information (2017). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208587s000lbl.pdf [Accessed 14 August 2023].
83. Riley TR, Boss A, McClain D, Riley TT. Review of medication therapy for the prevention of sickle cell crisis. P T. 2018;43:417-421, 437.
84. Alruwaili H, Dehestani B, le Roux CW. Clinical impact of Liraglutide as a treatment of obesity. Clin Pharmacol. 2021;13:53-60. doi: 10.2147/CPAA.S276085. eCollection 2021.
85. Butterworth RF, McPhail MJW. L-Ornithine L-Aspartate (LOLA) for hepatic encephalopathy in cirrhosis: Results of randomized controlled trials and meta-analyses. Drugs. 2019;79:31–37. doi: 10.1007 /s40265-018-1024-1
86. Da Poian AT, El-Bacha T, Luz MRMP. Nutrient utilization in humans: metabolism pathways. Nature Education. 2010;9:11.
87. Gaggini M, Carli F, Rosso C, et al. Altered amino acid concentrations in NAFLD: impact of obesity and insulin resistance. Hepatology. 2018;67:145–58. doi: 10.1002/h ep.29465.
88. Kinny-Koster B, Bartels M, Becker S, et al. Plasma amino acid concentrations predict mortality in patients with end-stage liver disease. PLoS One. 2016;11:e0159205. doi: 10.1371/journal.pone.0159205.
89. Tarlungeanu DC, Deliu E, Dotter CP, et al. Impaired amino acid transport at the blood-brain barrier is a cause of autism spectrum disorder. Cell. 2016;167:1481-1494 e18. doi: 10.1016/j.cell.2016.11.013.
90. Finnigan LEM, Cassar MP, Koziel MJ, et al. Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study eClinicalMedicine. 2023;59:101 946. doi: 10.1016/j.eclinm.2023.101946.
91. Marukian, S, Hamill M, Hamm L, et al. Unique composition of endogenous metabolic modulators reprograms metabolic state and impacts markers of inflammation and fibrosis in NAFLD/NASH cell model systems. Abstract #2015. Oral presentation presented at the Keystone Symposia (2019).
92. Krishnan, S, Nordqvist H, Ambikan AT, et al. Metabolic perturbation associated with COVID-19 disease severity and SARS-CoV-2 replication. Mol Cell Proteomics. 2021;20:100 159. doi: 10.1016/j.mcpro.2021.100159.
93. D'Antona G, Ragni M, Cardile A, et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. 2010;12:362–72. doi: 10.1016/j.cmet.2010.08.016.
94. Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol. 2018;20:745–54. doi: 10.1038/s41556-018-0124-1.
95. Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J Nutr. 2006;136:207S-11S. doi: 10.1093/jn/136.1.207S.
96. Morris Jr SM. Arginases and arginine deficiency syndromes. Curr Opin Clin Nutr Metab Care. 2012;15:64–70. doi: 10.1097/M CO.0b013e32834d1a08.
97. Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Gautier JBO. Acquired amino acid deficiencies: A focus on arginine and glutamine. Nutr Clin Pract. 2017; 32:30S-47S. doi: 10.1177/0884533617691250.
98. Morris Jr SM. Arginine metabolism in vascular biology and disease. Vasc Med. 2005;10:S83-S87. doi: 10.1177/1358836X050 1000112.
99. Moncada S, Higgs EA. The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol. 2006;147 Suppl 1:S193–S201. doi: 10.1038/sj.bjp.0706458.
100. Palacios-Callender M, Quintero M, Hollis VS, Springett RJ, Moncada S. Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc Natl Acad Sci USA. 2004;101:76 30-5. doi: 10.1073/pnas.0401723101.
101. Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. 2021;23:362–69. doi: 10.1016/j.semcdb. 2012.02.002.
102. Tong X, Zhao F, Thompson CB. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev. 2009;19:32–7. doi: 10.1016/j.gde.2009. 01.002.
103. Chen J, Reheman A, Gushiken FC, et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest. 2011;121:593-603. doi: 10.1172/JCI41062.
104. Prasannan N, Heightman M, Hillman T, et al. Impaired exercise capacity in post-COVID-19 syndrome: the role of VWF-ADAMTS13 axis. Blood Adv. 2022;6:4041-4048. doi: 10.1182/bloodadvances.2021006944.
105. Pedre B, Barayeu U, Ezeriņa D, Dick TP. The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species. Pharmacol Ther. 2021;228:107 916. doi: 10.1016/j.pharmthera.2021.107916.
106. Wright DJ, Renoir T, Smith ZM, et al. N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease. Transl Psychiatry. 2015;5:e492. doi: 10.1038/tp.2014.131.
107. Shi Z, Puyo CA. N-Acetylcysteine to combat COVID-19: An evidence review. Ther Clin Risk Manag. 2020;16:1047–55. doi: 10.2147/TCRM.S273700.
108. Poe FL, Corn J. N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Med Hypotheses. 2020;143:109862. doi: 10.1016/j.mehy.2020.109862.
109. Glancy B, Kane DA, Kavazis AN, Goodwin ML, Willis WT, Gladden LB. Mitochondrial lactate metabolism: history and implications for exercise and disease. J Physiol. 2021;599:863–88. doi: 10.1113/JP278930.
110. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the mitochondrial medicine society. Genet Med. 2015;17:689-01. doi: 10.1038/gim.2014.177.
111. Magner M, Szentiványi K, Svandová I, et al. Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures. Eur J Paediatr Neurol. 2011;15: 101–08. doi: 10.1016/j.ejpn.2010.10.001.