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Current Pharmaceutical Design

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ISSN (Online): 1873-4286

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Research Article

Huangqi Guizhi Wuwu Decoction Improves Inflammatory Factor Levels in Chemotherapy-induced Peripheral Neuropathy by Regulating the Arachidonic Acid Metabolic Pathway

Author(s): Shanshan Wang, Xiaohui Du, Guangli Yan, Le Yang, Hui Sun, Xiwu Zhang, Ling Kong, Ying Han, Di Han, Songyuan Tang and Xijun Wang*
(E-pub Abstract Ahead of Print)

DOI: 10.2174/0113816128308622240709102830

Price: $95

Abstract

Background: Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common complication that arises from the use of anticancer drugs. Huangqi Guizhi Wuwu Decoction (HGWWD) is an effective classic prescription for treating CIPN however, the mechanism of the activity is not entirely understood.

Objective: This study aimed to investigate the remedial effects and mechanisms of HGWWD on CIPN.

Methods: Changes in behavioral biochemical histopathological and biomarker indices were used to evaluate the efficacy of HGWWD treatment. Ultra-high-performance liquid chromatography/mass spectrometry combined with the pattern recognition method was used to screen biomarkers and metabolic pathways related to CIPN. The results of pathway analyses were verified by protein blotting experiments.

Results: A total of 29 potential biomarkers were identified and 13 metabolic pathways were found to be involved in CIPN. In addition HGWWD reversed the levels of 19 biomarkers. Prostaglandin H2 and 17α 21-dihydroxypregnenolone were targeted as core biomarkers.

Conclusion: This study provides scientific evidence to support the finding that HGWWD mainly inhibits the inflammatory response during CIPN by regulating arachidonic acid metabolism.

[1]
Grisold W, Cavaletti G, Windebank AJ. Peripheral neuropathies from chemotherapeutics and targeted agents: Diagnosis, treatment, and prevention. Neuro-oncol 2012; 14(Suppl 4) (Suppl. 4): iv45-54.
[http://dx.doi.org/10.1093/neuonc/nos203] [PMID: 23095830]
[2]
Cavaletti G, Pizzamiglio C, Man A, Engber TM, Comi C, Wilbraham D. Studies to assess the utility of serum neurofilament light chain as a biomarker in chemotherapy-induced peripheral neuropathy. Cancers (Basel) 2023; 15(17): 4216.
[http://dx.doi.org/10.3390/cancers15174216] [PMID: 37686492]
[3]
Molassiotis A, Cheng HL, Lopez V, et al. Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy. BMC Cancer 2019; 19(1): 132.
[http://dx.doi.org/10.1186/s12885-019-5302-4] [PMID: 30736741]
[4]
Wang CY, Lin TT, Hu L, et al. Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathy. EBioMedicine 2023; 90: 104499.
[http://dx.doi.org/10.1016/j.ebiom.2023.104499] [PMID: 36870200]
[5]
Postma TJ, Vermorken JB, Liefting AJM, Pinedo HM, Heimans JJ. Paclitaxel-induced neuropathy. Ann Oncol 1995; 6(5): 489-94.
[http://dx.doi.org/10.1093/oxfordjournals.annonc.a059220] [PMID: 7669713]
[6]
Yang CC, Wang MH, Soung HS, et al. Through its powerful antioxidative properties, L-theanine ameliorates vincristine-induced neuropathy in rats. Antioxidants 2023; 12(4): 803.
[http://dx.doi.org/10.3390/antiox12040803] [PMID: 37107178]
[7]
Ma J, Kavelaars A, Dougherty PM, Heijnen CJ. Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer 2018; 124(11): 2289-98.
[http://dx.doi.org/10.1002/cncr.31248] [PMID: 29461625]
[8]
Desforges AD, Hebert CM, Spence AL, et al. Treatment and diagnosis of chemotherapy-induced peripheral neuropathy: An update. Biomed Pharmacother 2022; 147: 112671.
[http://dx.doi.org/10.1016/j.biopha.2022.112671] [PMID: 35104697]
[9]
Staff NP, Grisold A, Grisold W, Windebank AJ. Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol 2017; 81(6): 772-81.
[http://dx.doi.org/10.1002/ana.24951] [PMID: 28486769]
[10]
Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002; 249(1): 9-17.
[http://dx.doi.org/10.1007/PL00007853] [PMID: 11954874]
[11]
Zhang S. Chemotherapy-induced peripheral neuropathy and rehabilitation: A review. Semin Oncol 2021; 48(3): 193-207.
[http://dx.doi.org/10.1053/j.seminoncol.2021.09.004] [PMID: 34607709]
[12]
Malacrida A, Meregalli C, Rodriguez-Menendez V, Nicolini G. Chemotherapy-induced peripheral neuropathy and changes in cytoskeleton. Int J Mol Sci 2019; 20(9): 2287.
[http://dx.doi.org/10.3390/ijms20092287] [PMID: 31075828]
[13]
Boukelmoune N, Laumet G, Tang Y, et al. Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice. Brain Behav Immun 2021; 93: 43-54.
[http://dx.doi.org/10.1016/j.bbi.2020.12.011] [PMID: 33316379]
[14]
Xu N, Han X, Zhang X, et al. Huangqi-Guizhi-Wuwu decoction regulates differentiation of CD4+ T cell and prevents against experimental autoimmune encephalomyelitis progression in mice. Phytomedicine 2023; 125: 155239.
[http://dx.doi.org/10.1016/j.phymed.2023.155239] [PMID: 38308917]
[15]
Cheng X, Huo J, Wang D, et al. Herbal medicine AC591 prevents oxaliplatin-induced peripheral neuropathy in animal model and cancer patients. Front Pharmacol 2017; 8: 344.
[http://dx.doi.org/10.3389/fphar.2017.00344] [PMID: 28638341]
[16]
Chai Y, Zhao F, Ye P, et al. A prospective, randomized, placebo- controlled study assessing the efficacy of Chinese herbal medicine (Huangqi Guizhi Wuwu decoction) in the treatment of albumin-bound paclitaxel-induced peripheral neuropathy. J Clin Med 2023; 12(2): 505.
[http://dx.doi.org/10.3390/jcm12020505] [PMID: 36675434]
[17]
Lv Z, Shen J, Gao X, et al. Herbal formula Huangqi Guizhi Wuwu decoction attenuates paclitaxel-related neurotoxicity via inhibition of inflammation and oxidative stress. Chin Med 2021; 16(1): 76.
[http://dx.doi.org/10.1186/s13020-021-00488-1] [PMID: 34376246]
[18]
Zhang Z, Ye J, Liu X, et al. Huangqi Guizhi Wuwu decoction alleviates oxaliplatin-induced peripheral neuropathy via the gut-peripheral nerve axis. Chin Med 2023; 18(1): 114.
[http://dx.doi.org/10.1186/s13020-023-00826-5] [PMID: 37679804]
[19]
Li M, Li Z, Ma X, et al. Huangqi Guizhi Wuwu decoction can prevent and treat oxaliplatin-induced neuropathic pain by TNFα/IL-1β/IL-6/MAPK/NF-kB pathway. Aging (Albany NY) 2022; 14(12): 5013-22.
[http://dx.doi.org/10.18632/aging.203794] [PMID: 35759577]
[20]
Ren J, Yang L, Qiu S, Zhang AH, Wang XJ. Efficacy evaluation, active ingredients, and multitarget exploration of herbal medicine. Trends Endocrinol Metab 2023; 34(3): 146-57.
[http://dx.doi.org/10.1016/j.tem.2023.01.005] [PMID: 36710216]
[21]
Schrimpe-Rutledge AC, Codreanu SG, Sherrod SD, McLean JA. Untargeted metabolomics strategies-challenges and emerging directions. J Am Soc Mass Spectrom 2016; 27(12): 1897-905.
[http://dx.doi.org/10.1007/s13361-016-1469-y] [PMID: 27624161]
[22]
Zhao X, Modur V, Carayannopoulos LN, Laterza OF. Biomarkers in pharmaceutical research. Clin Chem 2015; 61(11): 1343-53.
[http://dx.doi.org/10.1373/clinchem.2014.231712] [PMID: 26408531]
[23]
Marchev AS, Vasileva LV, Amirova KM, Savova MS, Balcheva-Sivenova ZP, Georgiev MI. Metabolomics and health: From nutritional crops and plant-based pharmaceuticals to profiling of human biofluids. Cell Mol Life Sci 2021; 78(19-20): 6487-503.
[http://dx.doi.org/10.1007/s00018-021-03918-3] [PMID: 34410445]
[24]
Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: Beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol 2016; 17(7): 451-9.
[http://dx.doi.org/10.1038/nrm.2016.25] [PMID: 26979502]
[25]
Zhang A, Fang H, Wang Y, et al. Discovery and verification of the potential targets from bioactive molecules by network pharmacology-based target prediction combined with high-throughput metabolomics. RSC Advances 2017; 7(81): 51069-78.
[http://dx.doi.org/10.1039/C7RA09522H]
[26]
Xie J, Zhang A, Wang X. Metabolomic applications in hepatocellular carcinoma: toward the exploration of therapeutics and diagnosis through small molecules. RSC Advances 2017; 7(28): 17217-26.
[http://dx.doi.org/10.1039/C7RA00698E]
[27]
Li X, Zhang A, Sun H, et al. Metabolic characterization and pathway analysis of berberine protects against prostate cancer. Oncotarget 2017; 8(39): 65022-41.
[http://dx.doi.org/10.18632/oncotarget.17531] [PMID: 29029409]
[28]
Khamis MM, Adamko DJ, El-Aneed A. Mass spectrometric based approaches in urine metabolomics and biomarker discovery. Mass Spectrom Rev 2017; 36(2): 115-34.
[http://dx.doi.org/10.1002/mas.21455] [PMID: 25881008]
[29]
Li HY, Sun H, Zhang AH, et al. Therapeutic effect and mechanism of Si-Miao-Yong-An-Tang on thromboangiitis obliterans based on the urine metabolomics approach. Front Pharmacol 2022; 13: 827733.
[http://dx.doi.org/10.3389/fphar.2022.827733] [PMID: 35273504]
[30]
He Y, Zhang M, Li T, et al. Metabolomics analysis coupled with UPLC/MS on therapeutic effect of jigucao capsule against dampness-heat jaundice syndrome. Front Pharmacol 2022; 13: 822193.
[http://dx.doi.org/10.3389/fphar.2022.822193] [PMID: 35153793]
[31]
Han D, Wang SS, Tang SY, et al. Chemical composition analysis and characterization of reference sample of Huangqi Guizhi Wuwutang based on UPLC-Q-TOF-MS. Zhongguo Shiyan Fangjixue Zazhi 2021; 28: 141-9.
[32]
Mihara Y, Egashira N, Sada H, et al. Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats. Mol Pain 2011; 7: 1744-8069-7-8.
[http://dx.doi.org/10.1186/1744-8069-7-8] [PMID: 21247499]
[33]
Li Q, Ren J, Yang L, et al. Parsing the Q-markers of Baoyin Jian to treat abnormal uterine bleeding by high-throughput chinmedomics strategy. Pharmaceuticals (Basel) 2023; 16(5): 719.
[http://dx.doi.org/10.3390/ph16050719] [PMID: 37242503]
[34]
Zhang Z, Yi P, Yang J, et al. Integrated network pharmacology analysis and serum metabolomics to reveal the cognitive improvement effect of Bushen Tiansui formula on Alzheimer’s disease. J Ethnopharmacol 2020; 249: 112371.
[http://dx.doi.org/10.1016/j.jep.2019.112371] [PMID: 31683034]
[35]
Yamamoto S, Ono H, Kume K, Ohsawa M. Oxaliplatin treatment changes the function of sensory nerves in rats. J Pharmacol Sci 2016; 130(4): 189-93.
[http://dx.doi.org/10.1016/j.jphs.2015.12.004] [PMID: 26790975]
[36]
Friesland A, Weng Z, Duenas M, Massa SM, Longo FM, Lu Q. Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75NTR. Neurotoxicology 2014; 45: 81-90.
[http://dx.doi.org/10.1016/j.neuro.2014.09.005] [PMID: 25277379]
[37]
Araldi D, Khomula EV, Bonet IJM, Bogen O, Green PG, Levine JD. Role of pattern recognition receptors in chemotherapy-induced neuropathic pain. Brain 2024; 147(3): 1025-42.
[http://dx.doi.org/10.1093/brain/awad339] [PMID: 37787114]
[38]
Li Y, North RY, Rhines LD, et al. DRG voltage-gated sodium channel 1.7 is upregulated in paclitaxel-induced neuropathy in rats and in humans with neuropathic pain. J Neurosci 2018; 38(5): 1124-36.
[http://dx.doi.org/10.1523/JNEUROSCI.0899-17.2017] [PMID: 29255002]
[39]
Cavaletti G, Tredici G, Petruccioli MG, et al. Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer 2001; 37(18): 2457-63.
[http://dx.doi.org/10.1016/S0959-8049(01)00300-8] [PMID: 11720843]
[40]
Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: Peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004; 361(1-3): 184-7.
[http://dx.doi.org/10.1016/j.neulet.2003.12.007] [PMID: 15135924]
[41]
Wang XM, Lehky TJ, Brell JM, Dorsey SG. Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. Cytokine 2012; 59(1): 3-9.
[http://dx.doi.org/10.1016/j.cyto.2012.03.027] [PMID: 22537849]
[42]
Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989; 63(2): 139-46.
[http://dx.doi.org/10.1093/bja/63.2.139] [PMID: 2669905]
[43]
Kwon J, Choi YI, Jo HJ, et al. The role of prostaglandin E1 as a pain mediator through facilitation of hyperpolarization-activated cyclic nucleotide-gated channel 2 via the EP2 receptor in trigeminal ganglion neurons of mice. Int J Mol Sci 2021; 22(24): 13534.
[http://dx.doi.org/10.3390/ijms222413534] [PMID: 34948328]
[44]
Zhi-hong L, Qi-bing M. Research progress on the role of cyclooxygenase in neuropathic pain. Foreign Med Sci Sect Pharm 2004; 31: 274.
[45]
Wang B, Wu L, Chen J, et al. Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets. Signal Transduct Target Ther 2021; 6(1): 94.
[http://dx.doi.org/10.1038/s41392-020-00443-w] [PMID: 33637672]
[46]
Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Curr Opin Neurol 2015; 28(5): 500-7.
[http://dx.doi.org/10.1097/WCO.0000000000000234] [PMID: 26197027]
[47]
Tofthagen CS, Cheville AL, Loprinzi CL. The physical consequences of chemotherapy-induced peripheral neuropathy. Curr Oncol Rep 2020; 22(5): 50.
[http://dx.doi.org/10.1007/s11912-020-00903-0] [PMID: 32323068]
[48]
Balayssac D, Ferrier J, Descoeur J, et al. Chemotherapy-induced peripheral neuropathies: From clinical relevance to preclinical evidence. Expert Opin Drug Saf 2011; 10(3): 407-17.
[http://dx.doi.org/10.1517/14740338.2011.543417] [PMID: 21210753]
[49]
Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Nat Rev Neurol 2010; 6(12): 657-66.
[http://dx.doi.org/10.1038/nrneurol.2010.160] [PMID: 21060341]
[50]
Maihöfner C, Diel I, Tesch H, Quandel T, Baron R. Chemotherapy-induced peripheral neuropathy (CIPN): Current therapies and topical treatment option with high-concentration capsaicin. Support Care Cancer 2021; 29(8): 4223-38.
[http://dx.doi.org/10.1007/s00520-021-06042-x] [PMID: 33624117]
[51]
Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413(6852): 203-10.
[http://dx.doi.org/10.1038/35093019] [PMID: 11557989]
[52]
Branca JJV, Maresca M, Morucci G, et al. Oxaliplatin-induced blood brain barrier loosening: A new point of view on chemotherapy-induced neurotoxicity. Oncotarget 2018; 9(34): 23426-38.
[http://dx.doi.org/10.18632/oncotarget.25193] [PMID: 29805744]
[53]
Carozzi VA, Canta A, Chiorazzi A. Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci Lett 2015; 596: 90-107.
[http://dx.doi.org/10.1016/j.neulet.2014.10.014] [PMID: 25459280]
[54]
Abd-Elmawla MA, Abdelalim E, Ahmed KA, Rizk SM. The neuroprotective effect of pterostilbene on oxaliplatin-induced peripheral neuropathy via its anti-inflammatory, anti-oxidative and anti-apoptotic effects: Comparative study with celecoxib. Life Sci 2023; 315: 121364.
[http://dx.doi.org/10.1016/j.lfs.2022.121364] [PMID: 36610639]
[55]
Meyer-ter-Vehn T, Gebhardt S, Sebald W, et al. p38 inhibitors prevent TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. Invest Ophthalmol Vis Sci 2006; 47(4): 1500-9.
[http://dx.doi.org/10.1167/iovs.05-0361] [PMID: 16565385]
[56]
Pierre S, Zhang DD, Suo J, Kern K, Tarighi N, Scholich K. Myc binding protein 2 suppresses M2-like phenotypes in macrophages during zymosan-induced inflammation in mice. Eur J Immunol 2018; 48(2): 239-49.
[http://dx.doi.org/10.1002/eji.201747129] [PMID: 29067676]
[57]
Ma P, Cui X, Wang S, et al. Nitric oxide post-transcriptionally up- regulates LPS-induced IL-8 expression through p38 MAPK activation. J Leukoc Biol 2004; 76(1): 278-87.
[http://dx.doi.org/10.1189/jlb.1203653] [PMID: 15178710]
[58]
Baulieu EE. Neurosteroids: A novel function of the brain. Psychoneuroendocrinology 1998; 23(8): 963-87.
[http://dx.doi.org/10.1016/S0306-4530(98)00071-7] [PMID: 9924747]
[59]
Benarroch EE. Neurosteroids. Neurology 2007; 68(12): 945-7.
[http://dx.doi.org/10.1212/01.wnl.0000257836.09570.e1] [PMID: 17372131]
[60]
Krisanova N, Sivko R, Kasatkina L, Borisova T. Neuroprotection by lowering cholesterol: A decrease in membrane cholesterol content reduces transporter-mediated glutamate release from brain nerve terminals. Biochim Biophys Acta Mol Basis Dis 2012; 1822(10): 1553-61.
[http://dx.doi.org/10.1016/j.bbadis.2012.06.005] [PMID: 22713486]
[61]
Ning Y, Chen S, Li X, Ma Y, Zhao F, Yin L. Cholesterol, LDL, and 25-hydroxycholesterol regulate expression of the steroidogenic acute regulatory protein in microvascular endothelial cell line (bEnd.3). Biochem Biophys Res Commun 2006; 342(4): 1249-56.
[http://dx.doi.org/10.1016/j.bbrc.2006.02.093] [PMID: 16516145]
[62]
Peri A. Neuroprotective effects of estrogens: The role of cholesterol. J Endocrinol Invest 2016; 39(1): 11-8.
[http://dx.doi.org/10.1007/s40618-015-0332-5] [PMID: 26084445]
[63]
Reyland ME, Evans RM, White EK. Lipoproteins regulate expression of the steroidogenic acute regulatory protein (StAR) in mouse adrenocortical cells. J Biol Chem 2000; 275(47): 36637-44.
[http://dx.doi.org/10.1074/jbc.M006456200] [PMID: 10960482]
[64]
Chen JH, Sun Y, Ju PJ, Wei JB, Li QJ, Winston JH. Estrogen augmented visceral pain and colonic neuron modulation in a double-hit model of prenatal and adult stress. World J Gastroenterol 2021; 27(30): 5060-75.
[http://dx.doi.org/10.3748/wjg.v27.i30.5060] [PMID: 34497435]
[65]
Mechanism of estrogen and estrogen receptors in pathologic pain. Chinese General Pract 2023; 1.6.
[66]
Dong F, Xie W, Strong JA, Zhang JM. Mineralocorticoid receptor blocker eplerenone reduces pain behaviors in vivo and decreases excitability in small-diameter sensory neurons from local inflamed dorsal root ganglia in vitro. Anesthesiology 2012; 117(5): 1102-12.
[http://dx.doi.org/10.1097/ALN.0b013e3182700383] [PMID: 23023156]
[67]
Rickard AJ, Young MJ. Corticosteroid receptors, macrophages and cardiovascular disease. J Mol Endocrinol 2009; 42(6): 449-59.
[http://dx.doi.org/10.1677/JME-08-0144] [PMID: 19158233]
[68]
Li X, Meng Y, Wu P, Zhang Z, Yang X. Angiotensin II and Aldosterone stimulating NF-κB and AP-1 activation in hepatic fibrosis of rat. Regul Pept 2007; 138(1): 15-25.
[http://dx.doi.org/10.1016/j.regpep.2006.07.011] [PMID: 16971004]
[69]
Neves MF, Amiri F, Virdis A, Diep QN, Schiffrin EL. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol 2005; 83(11): 999-1006.
[http://dx.doi.org/10.1139/y05-068] [PMID: 16391708]
[70]
Zang Y, He XH, Xin WJ, et al. Inhibition of NF-kappaB prevents mechanical allodynia induced by spinal ventral root transection and suppresses the re-expression of Nav1.3 in DRG neurons in vivo and in vitro. Brain Res 2010; 1363: 151-8.
[http://dx.doi.org/10.1016/j.brainres.2010.09.048] [PMID: 20858468]
[71]
Li WX, Li MM, Niu L, et al. Study on the mechanism of activating blood and removing stasis of naoxintong capsule based on plasma metabolomics and network pharmacology. Chinese J Integ Trad Western Med 2023; 43: 441-8.
[72]
Nicholson JK, Wilson ID. Opinion: Understanding ‘global’ systems biology: Metabonomics and the continuum of metabolism. Nat Rev Drug Discov 2003; 2(8): 668-76.
[http://dx.doi.org/10.1038/nrd1157] [PMID: 12904817]
[73]
Bujak R, Struck-Lewicka W, Markuszewski MJ, Kaliszan R. Metabolomics for laboratory diagnostics. J Pharm Biomed Anal 2015; 113: 108-20.
[http://dx.doi.org/10.1016/j.jpba.2014.12.017] [PMID: 25577715]
[74]
Pang H, Jia W, Hu Z. Emerging applications of metabolomics in clinical pharmacology. Clin Pharmacol Ther 2019; 106(3): 544-56.
[http://dx.doi.org/10.1002/cpt.1538] [PMID: 31173340]
[75]
Cao D, Yang L, Gao X, et al. A non-targeted metabolomics reveals therapeutical effect and mechanism of sanmiao pill on adjuvant-induced arthritis rats. Curr Pharm Des 2023; 29(17): 1379-89.
[http://dx.doi.org/10.2174/1381612829666230511161308] [PMID: 37171005]

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