Investigating the basis for the antidepressant effects of Gleditsiae spina using an integrated metabolomic strategy

Document Type : Original Article

Authors

1 School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China

2 The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, RP China

Abstract

Objective(s): Gleditsiae spina (GS) is a natural antidepressant but its mechanisms of action remain unclear. In the present study, taxifolin (Tax) was selected to determine the role of flavonoids in the antidepressant effects of GS.
Materials and Methods: Urine samples from C57BL/6 mice were analyzed based on  ultra performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q/TOF-MS). Then, we investigated the therapeutic effects of GS and Tax in depression models in vivo. An integrated metabolomic approach was used to examine the metabolic profiles of GS/Tax groups and corticosterone model groups (Cor). Metabolic networks in response to GS/Tax treatment were established for the comparison of antidepressant activities.
Results: Corticosterone exposure significantly increased serum levels of corticosterone but decreased serum levels of 5-hydroxytryptamine and sucrose consumption (p <0.01). Treatment with GS and Tax improved all measured variables compared to those of the corticosterone-exposed group (p < 0.01). The antidepressant effects of GS and Tax involved the regulation of pentose and glucuronate interconversions, arginine and proline metabolism, phenylalanine metabolism, taurine and hypotaurine metabolism, and the citrate cycle.
Conclusion: These findings indicate that flavonoids form the pharmacodynamic basis of the antidepressant effects of GS. Moreover, our findings highlight that integrated metabolomics provides a powerful tool to study the mechanisms and material basis of Chinese herbs.

Keywords

References

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2. Kurhe Y, Mahesh R, Gupta D, Devadoss T. QCM-4, a serotonergic type 3 receptor modulator attenuates depression co-morbid with obesity in mice: An approach based on behavioral and biochemical investigations. Eur J Pharmacol 2014;5:611-618.
3. Clarke TK, Obsteter J, Hall LS, Hayward C, Thomson PA, Smith BH, et al. Investigating shared aetiology between type 2 diabetes and major depressive disorder in a population based cohort. Am J Med Genet B Neuropsychiatr Genet 2017;174: 227-234.   
4. Schüle C. Neuroendocrinological mechanisms of actions of antidepressant drugs. J Neuroendocrinol 2007;19:213-226.
5. Nabavi SM, Daglia M, Braidy N, Nabavi SF. Natural products, micronutrients, and nutraceuticals for the treatment of depression: A short review. Nutr Neurosci 2017; 20:180-194.
6. Huang KL, Lu WC, Wang YY, Hu GC, Lu CH, Lee WY, et al. Comparison of agomelatine and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors in major depressive disorder: A meta-analysis of head-to-head randomized clinical trials. Aust N Z J Psychiatry 2014;48:663-671.
7. Lee G, Bae H. Therapeutic effects of phytochemicals and medicinal herbs on depression. Biomed Res Int 2017;2017:1-11.
8. Wang D, Wang H, Gu L. The antidepressant and cognitive improvement activities of the traditional chinese herb cistanche. Evid Based Complement Alternat Med 2017;2017:3925903.
9. Yi JM, Kim J, Park JS, Lee J, Lee YJ, Hong JT, et al. In vivo anti-tumor effects of the ethanol extract of Gleditsia sinensis thorns and its active constituent. Cytochalasin H Biol Pharm Bull 2015;38:909-912.
10. Fang LH, Wang RP, Hu SY, Teng YH, Xie WB. The effect of tou nong san on transplanted tumor growth in nude mice. Evid Based Complement Alternat Med 2015;2015:518454.
11. Shin TY. The extract of Gleditsiae spina inhibits mast cell-mediated allergic reactions through the inhibition of histamine release and inflammatory cytokine production. Nat Prod Res 2010;16:185-191.
12. Lee SJ, Park SS, Kim WJ, Moon S. Gleditsia sinensis thorn extract inhibits proliferation and TNF-ɑ-induced MMP-9 expression in vascular smooth muscle cells. Am J Chin Med 2012;40:373-386.
13. Li J, Jiang K, Wang LJ, Yin G, Wang J, Wang Y. HPLC-MS/MS determination of flavonoids in Gleditsiae spina for its quality assessment. Sep Sci 2018;41:1752-1763.
14. Yu J, Zhao L, Sun X, Sun C, Wang X. Application of choline chloride deep eutectic solvents and high-speed counter-current chromatography to the extraction and purification of flavonoids from the thorns of Gleditsia sinensis Lam. Phytochem Anal 2020.
15. Saito S, Yamamoto Y, Maki T, Hattori Y, Ito H, Mizuno K, et al. Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy. Acta Neuropathol Commun 2017;5:26-41.
16. Kuang H, Tang Z, Zhang C, Wang Z, Li W, Yang C, et al. Taxifolin activates the Nrf2 anti-oxidative stress pathway in mouse skin epidermal JB6 P+ cells through epigenetic modifications. Int J Mol Sci 2017;18:1546-1559.
17. Park SY, Kim HY, Park HJ, Shin HK, Hong KW, Kim CD. Concurrent treatment with taxifolin and cilostazol on the lowering of β-amyloid accumulation and neurotoxicity via the suppression of P-JAK2/P-STAT3/NF-κB/BACE1 signaling pathways. PLoS One 2016;11:e0168286.
18. Inoue T, Saito S, Tanaka M, Yamakage H, Kusakabe T, Shimatsu A, et al. Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy. Proc Natl Acad Sci USA 2019;116:10031-10038.
19. Gunesch S, Soriano-Castell D, Lamer S, Schlosser A, Maher P, Decker M. Development and application of a chemical probe based on a neuroprotective flavonoid hybrid for target identification using activity-based protein profiling. ACS Chem Neurosci 2020;11:3823-3837.
20. Liu CC, Wu YF, Feng GM, Gao XX, Zhou YZ, Hou WJ, et al. Plasma-metabolite-biomarkers for the therapeutic response in depressed patients by the traditional Chinese medicine formula Xiaoyaosan: A (1)H NMR-based metabolomics approach. Affect Disord 2015;185:156-163.
21. Nyer M, Mischoulon D, Alpert JE, Holt DJ, Brill CD, Yeung A, et al. College students with depressive symptoms with and without fatigue: Differences in functioning, suicidality, anxiety, and depressive severity. Ann Clin Psychiatry 2015; 27:100-108.
22. Enko D, Wagner H, Kriegshäuser G, Brandmayr W, Halwachs-Baumann G, Schnedl WJ, et al. Assessment of tryptophan metabolism and signs of depression in individuals with carbohydrate malabsorption. Psychiatry Res 2018;262:595-599.
23. Wurtman RJ, Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity and depression. Obes Res 1995;Suppl 4:477-480.
24. Umar S, van der Laarse A. Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem 2010;333:191-201.
25. Böger RH. The pharmacodynamics of L-arginine. Altern Ther Health Med 2014;20:48-54.
26. He HY, Henderson AC, Du YL, Ryan KS. Two-enzyme pathway links l-arginine to nitric oxide in N-nitroso biosynthesis. J Am Chem Soc 2019;141:4026-4033.
27. Chong CM, Ai N, Ke M, Tan Y, Huang Z, Li Y, et al. Roles of nitric oxide synthase isoforms in neurogenesis. Mol Neurobiol 2018;55:2645-2652.
28. Joca SRL, Sartim AG, Roncalho AL, Diniz CFA, Wegener G. Nitric oxide signalling and antidepressant action revisited. Cell Tissue Res 2019;377:45-58.
29. Sanders KM, Ward SM. Nitric oxide and its role as a non-adrenergic, non-cholinergic inhibitory neurotransmitter in the gastrointestinal tract. Br J Pharmacol 2019;176:212-227.
30. Zhang Q, Deng Y, Zhang W, Liu Y, Zha D. Drag-reducing polymers increase exercise tolerance in an ischemic hind-limb rat model. Vascular 2016;24:241-245.
31. Hess S, Baker G, Gyenes G, Tsuyuki R, Newman S, Melledo LJM. Decreased serum L-arginine and L-citrulline levels in major depression. Psychopharmacology 2017;234:3241-3247.
32. Ali-Sisto T, Tolmunen T, Viinamäki H, Mäntyselkä P, Valkonen-Korhonen M, Koivumaa-Honkanen H, et al. Global arginine bioavailability ratio is decreased in patients with major depressive disorder. J Affect Disord 2018;229:145-151.
33. Markus W, Rima KD. Creatine and creatinine metabolism. Physiol Rev 2000; 80:1107-1213.
34. Ji L, Zhao X, Zhang B, Kang L, Song W, Zhao B, et al. Slc6a8-mediated creatine uptake and accumulation reprogram macrophage polarization via regulating cytokine responses. Immunity 2019;51:272-284.
35. Tarnopolsky MA. Caffeine and creatine use in sport. Ann Nutr Metab 2010;57 Suppl 2:1-8.
36. Cappelletti P, Tallarita E, Rabattoni V, Campomenosi P, Sacchi S, Pollegioni L. Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line. PLoS One 2018;13:e0196283.
37. Hull J, Usmari Moraes M, Brookes E, Love S, Conway ME. Distribution of the branched-chain ɑ-ketoacid dehydrogenase complex E1ɑ subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism. Neurochem Int 2018;112:49-58.
38. Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna) 2014;121:799-817.
39. Fouad IA, Sharaf NM, Abdelghany RM, Dine ESNSE. Neuromodulatory effect of thymoquinone in attenuating glutamate-mediated neurotoxicity targeting the amyloidogenic and apoptotic pathways. Front Neurol 2018;9:236.
40. Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 2010;460:525-542.
41. Ge Y, Borne E, Stewart S, Hansen MR, Arturo EC, Jaffe EK, et al. Simulations of the regulatory ACT domain of human phenylalanine hydroxylase (PAH) unveil its mechanism of phenylalanine binding. Biol Chem 2018;293:19532-19543.
42. Mitchell JJ, Trakadis YJ, Scriver CR. Phenylalanine hydroxylase deficiency. Genet Med 2011;13:697-707.
43. Cieńska M, Labus K, Lewańczuk M, Koźlecki T, Liesiene J, Bryjak J. Effective L-tyrosine hydroxylation by native and immobilized tyrosinase. PLoS One 2016; 11:e0164213.
44. Paulucio D, Terra A, Santos CG, Cagy M, Velasques B, Ribeiro P, et al. Acute effect of Ethanol and Taurine on frontal cortex absolute beta power before and after exercise. PLoS One 2018;13:e0194264.
45. Hansen AW, Almeida FB, Bandiera S, Pulcinelli RR, Caletti G, Agnes G, et al. Correlations between subunits of GABAA and NMDA receptors after chronic alcohol treatment or withdrawal, and the effect of taurine in the hippocampus of rats. Alcohol 2020;82:63-70.
46. Wei L, Xue R, Zhang P, Wu Y, Li X, Pei F. 1H NMR-Based metabolomics and neurotoxicity study of cerebrum and cerebellum in rats treated with cinnabar, a traditional chinese medicine. OMICS 2015;19:490-498.
47. Belluzzi O, Puopolo M, Benedusi M, Kratskin I. Selective neuroinhibitory effects of taurine in slices of rat main olfactory bulb. Neuroscience 2004;124:929-944.
48. Wu GF, Ren S, Tang RY, Xu C, Zhou JQ, Lin SM, et al. Antidepressant effect of taurine in chronic unpredictable mild stress-induced depressive rats. Sci Rep 2017; 7:4989-5002.
49. Kori Y, Sidoli S, Yuan ZF, Lund PJ, Zhao X, Garcia BA. Proteome-wide acetylation dynamics in human cells. Sci Rep 2017;7:10296-10309.
50. Lauterbach MA, Hanke JE, Serefidou M, Mangan MSJ, Kolbe CC, Hess T, et al. Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via atp-citrate lyase. Immunity 2019;51:997-1011.
51. Suh SW, Hamby AM, Gum ET, Shin BS, Won SJ, Sheline CT. Sequential release of nitric oxide, zinc, and superoxide in hypoglycemic neuronal death. J Cereb Blood Flow Metab 2018;28:1697-1706.



The results described in this paper were part of student thesis.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the Central Leading Local Science and Technology Development Special Foundation ((2016)149). Henan Province High-level Personnel Special Support (ZYQR201810080). Chinese National Natural Science Foundation (81903805).
Reference
1. Ahern E, Kinsella S, Semkovska M. Clinical efficacy and economic evaluation of online cognitive behavioral therapy for major depressive disorder: a systematic review and meta-analysis. Expert Rev Pharmacoecon Outcomes Res 2018;18:25-41.
2. Kurhe Y, Mahesh R, Gupta D, Devadoss T. QCM-4, a serotonergic type 3 receptor modulator attenuates depression co-morbid with obesity in mice: an approach based on behavioral and biochemical investigations. Eur J Pharmacol 2014;5:611-618.
3. Clarke TK, Obsteter J, Hall LS, Hayward C, Thomson PA, Smith BH, et al. Investigating shared aetiology between type 2 diabetes and major depressive disorder in a population based cohort. Am J Med Genet B Neuropsychiatr Genet 2017;174: 227-234.   
4. Schüle C. Neuroendocrinological mechanisms of actions of antidepressant drugs. J Neuroendocrinol 2007;19:213-226.
5. Nabavi SM, Daglia M, Braidy N, Nabavi SF. Natural products, micronutrients, and nutraceuticals for the treatment of depression: A short review. Nutr Neurosci 2017; 20:180-194.
6. Huang KL, Lu WC, Wang YY, Hu GC, Lu CH, Lee WY, et al. Comparison of agomelatine and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors in major depressive disorder: A meta-analysis of head-to-head randomized clinical trials. Aust N Z J Psychiatry 2014;48:663-671.
7. Lee G, Bae H. Therapeutic Effects of Phytochemicals and Medicinal Herbs on Depression. Biomed Res Int 2017;2017:1-11.
8. Wang D, Wang H, Gu L. The Antidepressant and Cognitive Improvement Activities of the Traditional Chinese Herb Cistanche. Evid Based Complement Alternat Med 2017;2017:3925903.
9. Yi JM, Kim J, Park JS, Lee J, Lee YJ, Hong JT, et al. In Vivo Anti-tumor Effects of the Ethanol Extract of Gleditsia sinensis Thorns and Its Active Constituent. Cytochalasin H Biol Pharm Bull 2015;38:909-912.
10. Fang LH, Wang RP, Hu SY, Teng YH, Xie WB. The effect of tou nong san on transplanted tumor growth in nude mice. Evid Based Complement Alternat Med 2015;2015:518454.
11. Shin TY. The extract of Gleditsiae Spina inhibits mast cell-mediated allergic reactions through the inhibition of histamine release and inflammatory cytokine production. Nat Prod Res 2010;16:185-191.
12. Lee SJ, Park SS, Kim WJ, Moon S. Gleditsia sinensis thorn extract inhibits proliferation and TNF-ɑ-induced MMP-9 expression in vascular smooth muscle cells. Am J Chin Med 2012;40:373-386.
13. Li J, Jiang K, Wang LJ, Yin G, Wang J, Wang Y. HPLC-MS/MS determination of flavonoids in Gleditsiae Spina for its quality assessment. Sep Sci 2018;41:1752-1763.
14. Yu J, Zhao L, Sun X, Sun C, Wang X. Application of choline chloride deep eutectic solvents and high-speed counter-current chromatography to the extraction and purification of flavonoids from the thorns of Gleditsia sinensis Lam. Phytochem Anal 2020;17.
15. Saito S, Yamamoto Y, Maki T, Hattori Y, Ito H, Mizuno K, et al. Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy. Acta Neuropathol Commun 2017;5:26.
16. Kuang H, Tang Z, Zhang C, Wang Z, Li W, Yang C, et al. Taxifolin Activates the Nrf2 Anti-Oxidative Stress Pathway in Mouse Skin Epidermal JB6 P+ Cells through Epigenetic Modifications. Int J Mol Sci 2017;18:1546.
17. Park SY, Kim HY, Park HJ, Shin HK, Hong KW, Kim CD. Concurrent Treatment with Taxifolin and Cilostazol on the Lowering of β-Amyloid Accumulation and Neurotoxicity via the Suppression of P-JAK2/P-STAT3/NF-κB/BACE1 Signaling Pathways. PLoS One 2016;11:e0168286.
18. Inoue T, Saito S, Tanaka M, Yamakage H, Kusakabe T, Shimatsu A, et al. Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy. Proc Natl Acad Sci USA 2019;116:10031-10038.
19. Gunesch S, Soriano-Castell D, Lamer S, Schlosser A, Maher P, Decker M. Development and Application of a Chemical Probe Based on a Neuroprotective Flavonoid Hybrid for Target Identification Using Activity-Based Protein Profiling. ACS Chem Neurosci 2020;11:3823-3837.
Liu CC, Wu YF, Feng GM, Gao XX, Zhou YZ, Hou WJ, et al. Plasma-metabolite-biomarkers for the therapeutic response in depressed patients by the traditional Chinese medicine formula Xiaoyaosan: A (1)H NMR-based metabolomics approach. Affect Disord 2015;185:156-163.
Nyer M, Mischoulon D, Alpert JE, Holt DJ, Brill CD, Yeung A, et al. College students with depressive symptoms with and without fatigue: Differences in functioning, suicidality, anxiety, and depressive severity. Ann Clin Psychiatry 2015; 27:100-108.
Enko D, Wagner H, Kriegshäuser G, Brandmayr W, Halwachs-Baumann G, Schnedl WJ, et al. Assessment of tryptophan metabolism and signs of depression in individuals with carbohydrate malabsorption. Psychiatry Res 2018;262:595-599.
Wurtman RJ, Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity and depression. Obes Res 1995;Suppl 4:477-480.
Umar S, van der Laarse A. Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem 2010;333:191-201.
Böger RH. The pharmacodynamics of L-arginine. Altern Ther Health Med 2014;20:48-54.
He HY, Henderson AC, Du YL, Ryan KS. Two-Enzyme Pathway Links l-Arginine to Nitric Oxide in N-Nitroso Biosynthesis. J Am Chem Soc 2019;141:4026-4033.
Chong CM, Ai N, Ke M, Tan Y, Huang Z, Li Y, et al. Roles of Nitric Oxide Synthase Isoforms in Neurogenesis. Mol Neurobiol 2018;55:2645-2652.
Joca SRL, Sartim AG, Roncalho AL, Diniz CFA, Wegener G. Nitric oxide signalling and antidepressant action revisited. Cell Tissue Res 2019;377:45-58.
Sanders KM, Ward SM. Nitric oxide and its role as a non-adrenergic, non-cholinergic inhibitory neurotransmitter in the gastrointestinal tract. Br J Pharmacol 2019;176:212-227.
Zhang Q, Deng Y, Zhang W, Liu Y, Zha D. Drag-reducing polymers increase exercise tolerance in an ischemic hind-limb rat model. Vascular 2016;24:241-245.
Hess S, Baker G, Gyenes G, Tsuyuki R, Newman S, Melledo LJM. Decreased serum L-arginine and L-citrulline levels in major depression. Psychopharmacology 2017;234:3241-3247.
Ali-Sisto T, Tolmunen T, Viinamäki H, Mäntyselkä P, Valkonen-Korhonen M, Koivumaa-Honkanen H, et al. Global arginine bioavailability ratio is decreased in patients with major depressive disorder. J Affect Disord 2018;229:145-151.
Markus W, Rima KD. Creatine and Creatinine Metabolism. Physiol Rev 2000; 80:1107-1213.
Ji L, Zhao X, Zhang B, Kang L, Song W, Zhao B, et al. Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses. Immunity 2019;51:272-284.
Tarnopolsky MA. Caffeine and creatine use in sport. Ann Nutr Metab 2010;57 Suppl 2:1-8.
Cappelletti P, Tallarita E, Rabattoni V, Campomenosi P, Sacchi S, Pollegioni L. Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line. PLoS One 2018;13:e0196283.
Hull J, Usmari Moraes M, Brookes E, Love S, Conway ME. Distribution of the branched-chain ɑ-ketoacid dehydrogenase complex E1ɑ subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism. Neurochem Int 2018;112:49-58.
Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna) 2014;121:799-817.
Fouad IA, Sharaf NM, Abdelghany RM, Dine ESNSE. Neuromodulatory Effect of Thymoquinone in Attenuating Glutamate-Mediated Neurotoxicity Targeting the Amyloidogenic and Apoptotic Pathways. Front Neurol 2018;9:236.
Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 2010;460:525-542.
Ge Y, Borne E, Stewart S, Hansen MR, Arturo EC, Jaffe EK, et al. Simulations of the regulatory ACT domain of human phenylalanine hydroxylase (PAH) unveil its mechanism of phenylalanine binding. Biol Chem 2018;293:19532-19543.
Mitchell JJ, Trakadis YJ, Scriver CR. Phenylalanine hydroxylase deficiency. Genet Med 2011;13:697-707.
Cieńska M, Labus K, Lewańczuk M, Koźlecki T, Liesiene J, Bryjak J. Effective L-Tyrosine Hydroxylation by Native and Immobilized Tyrosinase. PLoS One 2016; 11:e0164213.
Paulucio D, Terra A, Santos CG, Cagy M, Velasques B, Ribeiro P, et al. Acute effect of Ethanol and Taurine on frontal cortex absolute beta power before and after exercise. PLoS One 2018;13:e0194264.
Hansen AW, Almeida FB, Bandiera S, Pulcinelli RR, Caletti G, Agnes G, et al. Correlations between subunits of GABAA and NMDA receptors after chronic alcohol treatment or withdrawal, and the effect of taurine in the hippocampus of rats. Alcohol 2020;82:63-70.
Wei L, Xue R, Zhang P, Wu Y, Li X, Pei F. 1H NMR-Based Metabolomics and Neurotoxicity Study of Cerebrum and Cerebellum in Rats Treated with Cinnabar, a Traditional Chinese Medicine. OMICS 2015;19:490-498.
Belluzzi O, Puopolo M, Benedusi M, Kratskin I. Selective neuroinhibitory effects of taurine in slices of rat main olfactory bulb. Neuroscience 2004;124:929-944.
Wu GF, Ren S, Tang RY, Xu C, Zhou JQ, Lin SM, et al. Antidepressant effect of taurine in chronic unpredictable mild stress-induced depressive rats. Sci Rep 2017;  7:4989.
Kori Y, Sidoli S, Yuan ZF, Lund PJ, Zhao X, Garcia BA. Proteome-wide acetylation dynamics in human cells. Sci Rep 2017;7:10296.
Lauterbach MA, Hanke JE, Serefidou M, Mangan MSJ, Kolbe CC, Hess T, et al. Toll-like Receptor Signaling Rewires Macrophage Metabolism and Promotes Histone Acetylation via ATP-Citrate Lyase. Immunity 2019;51:997-1011.
Suh SW, Hamby AM, Gum ET, Shin BS, Won SJ, Sheline CT. Sequential release of nitric oxide, zinc, and superoxide in hypoglycemic neuronal death. J Cereb Blood Flow Metab 2018;28:1697-1706.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 4
April 2021
Pages 524-530

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