Abstract
Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system. Although remarkable progress has been made in treating MS, current therapies are less effective in protecting against the progression of the disease. Since cucurbitacins have shown an extreme range of pharmacological properties, in this study, we aimed to investigate the prophylactic effect of cucurbitacin B (CuB) in the experimental MS model. Experimental autoimmune encephalomyelitis (EAE) induced by subcutaneous immunization of MOG35-55 in C57BL/6 mice. CuB interventions (0.5 and 1 mg/kg, i.p.) were performed every other day from the first day of EAE induction. Assessment of clinical scores and motor function, inflammatory responses, and microglial activation were assessed by qRT-PCR, western blotting, and immunohistochemical (IHC) analyses. CuB (1 mg/kg) significantly decreased the population of CD45+ (P < 0.01), CD11b+ (P < 0.01) and CD45+/CD11b+ (P < 0.05) cells in cortical lesions of EAE mice. In addition, activation of STAT3 (P < 0.001), expression of IL-17 A and IL-23 A (both mRNA and protein), and transcription of Iba-1 significantly decreased. On the contrary, CuB (1 mg/kg) significantly increased the transcription of MBP and Olig-2. Furthermore, a significant decrease in the severity of EAE (P < 0.05), and an improvement in motor function (P < 0.05) and coordination (P < 0.05) were observed after treatment with a high dose of CuB. Our results suggest that CuB may have a wide-ranging effect on autoimmune responses in MS via a reduction in STAT3 activation, microgliosis, and adaptation of the IL-23/IL-17 axis. Further studies are needed to investigate the exact effect of CuB in glial cells and its efficiency and bioavailability in other neuroinflammatory diseases.
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The data that support the findings of this study are available from the corresponding author, upon reasonable request.
References
Abdo A, Tye GJ (2020) Interleukin 23 and autoimmune diseases: current and possible future therapies. Inflamm Res. https://doi.org/10.1007/s00011-020-01339-9
Aharoni R, Schottlender N, Bar-Lev DD, Eilam R, Sela M, Tsoory M, Arnon R (2019) Cognitive impairment in an animal model of multiple sclerosis and its amelioration by glatiramer acetate. Sci Rep. https://doi.org/10.1038/s41598-019-40713-4
Al-Ani MR, Raju TK, Hachim MY, Hachim IY, Elemam NM, Guimei M, Bendardaf R, Maghazachi AA (2020) Rituximab Prevents the Development of Experimental Autoimmune Encephalomyelitis (EAE): Comparison with Prophylactic, Therapeutic or Combinational Regimens. J Inflamm Res. https://doi.org/10.2147/JIR.S243514
Alghasham AA (2013) Cucurbitacins - a promising target for cancer therapy. Int J Health Sci. https://doi.org/10.12816/0006025
Bittner S, Afzali AM, Wiendl H, Meuth SG (2014) Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. https://doi.org/10.3791/51275. JoVE
Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM (2003) Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res 63(6):1270–1279
Bonfiglio T, Olivero G, Merega E, Di Prisco S, Padolecchia C, Grilli M, Milanese M, Di Cesare Mannelli L, Ghelardini C, Bonanno G, Marchi M, Pittaluga A (2017) Prophylactic versus therapeutic fingolimod: restoration of presynaptic defects in mice suffering from experimental autoimmune encephalomyelitis. PLoS One. https://doi.org/10.1371/journal.pone.0170825
Brandenburg S, Turkowski K, Mueller A, Radev YT, Seidlitz S, Vajkoczy P (2017) Myeloid cells expressing high level of CD45 are associated with a distinct activated phenotype in glioma. Immunol Res. https://doi.org/10.1007/s12026-017-8915-1
Burkett PR, Meyer zu Horste G, Kuchroo VK (2015) Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J Clin Invest. https://doi.org/10.1172/JCI78085
Chan KT, Li K, Liu SL, Chu KH, Toh M, Xie WD (2010) Cucurbitacin B inhibits STAT3 and the Raf/MEK/ERK pathway in leukemia cell line K562. Cancer Lett. https://doi.org/10.1016/j.canlet.2009.07.015
Chen C, Qiang S, Lou L, Zhao W (2009) Cucurbitane-type triterpenoids from the stems of Cucumis melo. J Nat Prod. https://doi.org/10.1021/np800692t
Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX (2005) Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep. https://doi.org/10.1039/b418841c
Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest. https://doi.org/10.1172/JCI25308
Clericuzio M, Tabasso S, Bianco MA, Pratesi G, Beretta G, Tinelli S, Zunino F, Vidari G (2006) Cucurbitane triterpenes from the fruiting bodies and cultivated mycelia of Leucopaxillus gentianeus. J Nat Prod. https://doi.org/10.1021/np060213n
Dandawate P, Subramaniam D, Panovich P, Standing D, Krishnamachary B, Kaushik G, Thomas SM, Dhar A, Weir SJ, Jensen RA, Anant S (2020) Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway. Sci Rep. https://doi.org/10.1038/s41598-020-57940-9
Dos Santos N, Novaes LS, Dragunas G, Rodrigues JR, Brandão W, Camarini R, Peron JPS, Munhoz CD (2019) High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice. Sci Rep. https://doi.org/10.1038/s41598-019-43217-3
Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, Takahashi H, Sun HW, Kanno Y, Powrie F, O’Shea JJ (2010) Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. https://doi.org/10.1016/j.immuni.2010.05.003. Immunity
Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, Ferrero B, Eid P, Novelli F (2009) T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol. https://doi.org/10.1002/ana.21652
Egwuagu CE, Larkin Iii J (2013) Therapeutic targeting of STAT pathways in CNS autoimmune diseases. https://doi.org/10.4161/jkst.24134. JAKSTAT
Filippi M, Rocca MA (2019) Cortical Lesions on 7-T MRI in Multiple Sclerosis: A Window into Pathogenetic Mechanisms? Radiology. https://doi.org/10.1148/radiol.2019190398
Garg S, Kaul SC, Wadhwa R (2018) Cucurbitacin B and cancer intervention: Chemistry, biology and mechanisms (Review). Int J Oncol. https://doi.org/10.3892/ijo.2017.4203
Goyal M, Khanna D, Rana PS, Khaibullin T, Martynova E, Rizvanov AA, Khaiboullina SF, Baranwal M (2019) Computational Intelligence Technique for Prediction of Multiple Sclerosis Based on Serum Cytokines. Front Neurol. https://doi.org/10.3389/fneur.2019.00781
Greenfield AL, Hauser SL (2018) B-cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol. https://doi.org/10.1002/ana.25119
Günaydın C, Önger ME, Avcı B, Bozkurt A, Terzi M, Bilge SS (2021) Tofacitinib enhances remyelination and improves myelin integrity in cuprizone-induced mice. Immunopharmacol Immunotoxicol Advance online publication. https://doi.org/10.1080/08923973.2021.1986063
Hamilton AM, Forkert ND, Yang R, Wu Y, Rogers JA, Yong VW, Dunn JF (2019) Central nervous system targeted autoimmunity causes regional atrophy: a 9.4T MRI study of the EAE mouse model of Multiple Sclerosis. Sci Rep. https://doi.org/10.1038/s41598-019-44682-6
Hauser SL, Cree BAC (2020) Treatment of Multiple Sclerosis: A Review. Am J Med. https://doi.org/10.1016/j.amjmed.2020.05.049
Houshmand F, Barati M, Golab F, Ramezani-Sefidar S, Tanbakooie S, Tabatabaei M, Amiri M, Sanadgol N (2019) Metformin-induced AMPK activation stimulates remyelination through induction of neurotrophic factors, downregulation of NogoA and recruitment of Olig2 + precursor cells in the cuprizone murine model of multiple sclerosis. https://doi.org/10.1007/s40199-019-00286-z. Daru
Huber AK, Wang L, Han P, Zhang X, Ekholm S, Srinivasan A, Irani DN, Segal BM, Neurology (2014) https://doi.org/10.1212/WNL.0000000000000908
Iwanski GB, Lee DH, En-Gal S, Doan NB, Castor B, Vogt M, Toh M, Bokemeyer C, Said JW, Thoennissen NH, Koeffler HP (2010) Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer. Br J Pharmacol. https://doi.org/10.1111/j.1476-5381.2010.00741.x
Jayaprakasam B, Seeram NP, Nair MG (2003) Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett. https://doi.org/10.1016/s0304-3835(02)00497-4
Karussis D (2014) The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review. J Autoimmun. https://doi.org/10.1016/j.jaut.2014.01.022
Kaushik U, Aeri V, Mir SR (2015) Cucurbitacins - An insight into medicinal leads from nature. Pharmacogn Rev. https://doi.org/10.4103/0973-7847.156314
Kim KH, Lee IS, Park JY, Kim Y, An EJ, Jang HJ (2018) Cucurbitacin B Induces Hypoglycemic Effect in Diabetic Mice by Regulation of AMP-Activated Protein Kinase Alpha and Glucagon-Like Peptide-1 via Bitter Taste Receptor Signaling. https://doi.org/10.3389/fphar.2018.01071. Front Pharmacol
Kim M, Park SY, Jin ML, Park G, Son HJ (2015) Cucurbitacin B inhibits immunomodulatory function and the inflammatory response in macrophages. Immunopharmacol Immunotoxicol. https://doi.org/10.3109/08923973.2015.1085065
Kirkham BW, Kavanaugh A, Reich K (2014) Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis. https://doi.org/10.1111/imm.12142. Immunology
Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. https://doi.org/10.1084/jem.20041257
Lassmann H, Bradl M (2017) Multiple sclerosis: experimental models and reality. Acta Neuropathol. https://doi.org/10.1007/s00401-016-1631-4
Lee DH, Thoennissen NH, Goff C, Iwanski GB, Forscher C, Doan NB, Said JW, Koeffler HP (2011) Synergistic effect of low-dose cucurbitacin B and low-dose methotrexate for treatment of human osteosarcoma. Cancer Lett. https://doi.org/10.1016/j.canlet.2011.03.001
Leray E, Moreau T, Fromont A, Edan G (2016) Epidemiology of multiple sclerosis. Rev Neurol (Paris). https://doi.org/10.1016/j.neurol.2015.10.006
Li H, Tsokos GC (2021) IL-23/IL-17 Axis in Inflammatory Rheumatic Diseases. Clin Rev Allergy Immunol. https://doi.org/10.1007/s12016-020-08823-4
Lin L, Deangelis S, Foust E, Fuchs J, Li C, Li PK, Schwartz EB, Lesinski GB, Benson D, Lü J, Hoyt D, Lin J (2010) A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells. Mol Cancer. https://doi.org/10.1186/1476-4598-9-217
Liu Y, Holdbrooks AT, De Sarno P, Rowse AL, Yanagisawa LL, McFarland BC, Harrington LE, Raman C, Sabbaj S, Benveniste EN, Qin H (2014) Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol. https://doi.org/10.4049/jimmunol.1301513
Lubberts E (2015) The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol. https://doi.org/10.1038/nrrheum.2015.53
McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O’Shea JJ, Cua DJ (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. https://doi.org/10.1038/ni.1698
Migliore S, Ghazaryan A, Simonelli I, Pasqualetti P, Squitieri F, Curcio G, Landi D, Palmieri MG, Moffa F, Filippi MM, Vernieri F (2017) Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis Patients with Very Mild Clinical Disability. https://doi.org/10.1155/2017/7404289. Behav Neurol
Monin L, Gaffen SL (2018) Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a028522
Murphy AC, Lalor SJ, Lynch MA, Mills KH (2010) Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. https://doi.org/10.1016/j.bbi.2010.01.014
Musza LL, Speight P, McElhiney S, Barrow CJ, Gillum AM, Cooper R, Killar LM (1994) Cucurbitacins, cell adhesion inhibitors from Conobea scoparioides. J Nat Prod. https://doi.org/10.1021/np50113a004
Omura S, Sato F, Martinez NE, Park AM, Fujita M, Kennett NJ, Cvek U, Minagar A, Alexander JS, Tsunoda I (2019) Bioinformatics Analyses Determined the Distinct CNS and Peripheral Surrogate Biomarker Candidates Between Two Mouse Models for Progressive Multiple Sclerosis. Front Immunol. https://doi.org/10.3389/fimmu.2019.00516
Park SY, Kim YH, Park G (2015) Cucurbitacins attenuate microglial activation and protect from neuroinflammatory injury through Nrf2/ARE activation and STAT/NF-κB inhibition. Neurosci Lett. https://doi.org/10.1016/j.neulet.2015.10.022
Patel DD, Lee DM, Kolbinger F, Antoni C (2013) Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2012-202371
Piras G, Rattazzi L, McDermott A, Deacon R, D’Acquisto F (2013) Emotional change-associated T cell mobilization at the early stage of a mouse model of multiple sclerosis. Front Immunol. https://doi.org/10.3389/fimmu.2013.00400
Poorebrahim M, Asghari M, Abazari MF, Askari H, Sadeghi S, Taheri-Kafrani A, Nasr-Esfahani MH, Ghoraeian P, Aleagha MN, Arab SS, Kennedy D, Montaseri A, Mehranfar M, Sanadgol N (2018) Immunomodulatory effects of a rationally designed peptide mimetic of human IFNβ in EAE model of multiple sclerosis. Prog Neuropsychopharmacol Biol Psychiatry. https://doi.org/10.1016/j.pnpbp.2017.11.028
Qin H, Yeh WI, De Sarno P, Holdbrooks AT, Liu Y, Muldowney MT, Reynolds SL, Yanagisawa LL, Fox TH 3rd, Park K, Harrington LE, Raman C, Benveniste EN (2012) Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.1117218109
Rasool R, Ullah I, Shahid S, Mubeen B, Imam SS, Alshehri S, Ghoneim MM, Alzarea SI, Murtaza BN, Nadeem MS, Kazmi I (2022) In Vivo Assessment of the Ameliorative Impact of Some Medicinal Plant Extracts on Lipopolysaccharide-Induced Multiple Sclerosis in Wistar Rats. https://doi.org/10.3390/molecules27051608. Molecules
Ramroodi N, Khani M, Ganjali Z, Javan MR, Sanadgol N, Khalseh R, Ravan H, Sanadgol E, Abdollahi M (2015) Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis. Immunol Invest. https://doi.org/10.3109/08820139.2015.1085391
Rangaraju S, Raza SA, Li NX, Betarbet R, Dammer EB, Duong D, Lah JJ, Seyfried NT, Levey AI (2018) Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects. Front Immunol. https://doi.org/10.3389/fimmu.2018.00405
Reich DS, Lucchinetti CF, Calabresi PA (2018) Multiple Sclerosis. N Engl J Med. https://doi.org/10.1056/NEJMra1401483
Reiszadeh-Jahromi S, Sepand MR, Ramezani-Sefidar S, Shahlaei M, Moradi S, Yazdankhah M, Sanadgol N (2019) Sepantronium Bromide (YM155), A Small Molecule Survivin Inhibitor, Promotes Apoptosis by Induction of Oxidative Stress, Worsens the Behavioral Deficits and Develops an Early Model of Toxic Demyelination: In Vivo and In-Silico Study. Neurochem Res. https://doi.org/10.1007/s11064-019-02865-7
Riccitelli G, Rocca MA, Pagani E, Rodegher ME, Rossi P, Falini A, Comi G, Filippi M (2011) Cognitive impairment in multiple sclerosis is associated to different patterns of gray matter atrophy according to clinical phenotype. Hum Brain Mapp. https://doi.org/10.1002/hbm.21125
Rotolo RA, Demuro J, Drummond G, Little C, Johns LD, Betz AJ (2021) Prophylactic exposure to oral riluzole reduces the clinical severity and immune-related biomarkers of experimental autoimmune encephalomyelitis. J Neuroimmunol. https://doi.org/10.1016/j.jneuroim.2021.577603
Sanadgol N, Barati M, Houshmand F, Hassani S, Clarner T, Shahlaei M, Golab F (2020) Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period. Pharmacol Rep. https://doi.org/10.1007/s43440-019-00019-8
Sanadgol N, Golab F, Askari H, Moradi F, Ajdary M, Mehdizadeh M (2018) Alpha-lipoic acid mitigates toxic-induced demyelination in the corpus callosum by lessening of oxidative stress and stimulation of polydendrocytes proliferation. Metab Brain Dis. https://doi.org/10.1007/s11011-017-0099-9
Sanadgol N, Golab F, Mostafaie A, Mehdizadeh M, Abdollahi M, Sharifzadeh M, Ravan H (2016b) Ellagic acid ameliorates cuprizone-induced acute CNS inflammation via restriction of microgliosis and down-regulation of CCL2 and CCL3 pro-inflammatory chemokines. Cell Mol Biol. https://doi.org/10.14715/cmb/2016.62.12.5
Sanadgol N, Golab F, Mostafaie A, Mehdizadeh M, Khalseh R, Mahmoudi M, Abdollahi M, Vakilzadeh G, Taghizadeh G, Sharifzadeh M (2016a) Low, but not high, dose triptolide controls neuroinflammation and improves behavioral deficits in toxic model of multiple sclerosis by dampening of NF-κB activation and acceleration of intrinsic myelin repair. Toxicol Appl Pharmacol. https://doi.org/10.1016/j.taap.2018.01.023
Sanadgol N, Zahedani SS, Sharifzadeh M, Khalseh R, Barbari GR, Abdollahi M (2017) Recent Updates in Imperative Natural Compounds for Healthy Brain and Nerve Function: A Systematic Review of Implications for Multiple Sclerosis. Curr Drug Targets. https://doi.org/10.2174/1389450118666161108124414
Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF (2013) How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat Med. https://doi.org/10.1038/nm.3260
Seo CR, Yang DK, Song NJ, Yun UJ, Gwon AR, Jo DG, Cho JY, Yoon K, Ahn JY, Nho CW, Park WJ, Yang SY, Park KW (2014) Cucurbitacin B and cucurbitacin I suppress adipocyte differentiation through inhibition of STAT3 signaling. Food Chem Toxicol. https://doi.org/10.1016/j.fct.2013.11.040
Shirazi MK, Azarnezhad A, Abazari MF, Poorebrahim M, Ghoraeian P, Sanadgol N, Bokharaie H, Heydari S, Abbasi A, Kabiri S, Aleagha MN, Enderami SE, Dashtaki AS, Askari H (2019) The role of nitric oxide signaling in renoprotective effects of hydrogen sulfide against chronic kidney disease in rats: Involvement of oxidative stress, autophagy and apoptosis. J Cell Physiol. https://doi.org/10.1002/jcp.27797
Shukla S, Sinha S, Khan S, Kumar S, Singh K, Mitra K, Maurya R, Meeran SM (2016) Cucurbitacin B inhibits the stemness and metastatic abilities of NSCLC via downregulation of canonical Wnt/β-catenin signaling axis. Sci Rep. https://doi.org/10.1038/srep21860
Sorensen PS, Sellebjerg F, Hartung HP, Montalban X, Comi G, Tintoré M (2020) The apparently milder course of multiple sclerosis: changes in the diagnostic criteria, therapy and natural history. https://doi.org/10.1093/brain/awaa145. Brain
Sumowski JF, Benedict R, Enzinger C, Filippi M, Geurts JJ, Hamalainen P, Hulst H, Inglese M, Leavitt VM, Rocca MA, Rosti-Otajarvi EM, Rao S (2018) Cognition in multiple sclerosis: State of the field and priorities for the future. Neurology. https://doi.org/10.1212/WNL.0000000000004977
Takemiya T, Takeuchi C (2013) Traveled distance is a sensitive and accurate marker of motor dysfunction in a mouse model of multiple sclerosis. ISRN Neurosci. https://doi.org/10.1155/2013/170316
Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O (2018) Multiple sclerosis. https://doi.org/10.1016/S0140-6736(18)30481-1. Lancet
Treaba CA, Granberg TE, Sormani MP, Herranz E, Ouellette RA, Louapre C, Sloane JA, Kinkel RP, Mainero C (2019) Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI. https://doi.org/10.1148/radiol.2019181719. Radiology
Tryfonos C, Mantzorou M, Fotiou D, Vrizas M, Vadikolias K, Pavlidou E, Giaginis C (2019) Dietary Supplements on Controlling Multiple Sclerosis Symptoms and Relapses: Current Clinical Evidence and Future Perspectives. Medicines (Basel). https://doi.org/10.3390/medicines6030095
van den Berg R, Laman JD, van Meurs M, Hintzen RQ, Hoogenraad CC (2016) Rotarod motor performance and advanced spinal cord lesion image analysis refine assessment of neurodegeneration in experimental autoimmune encephalomyelitis. J Neurosci Methods. https://doi.org/10.1016/j.jneumeth.2016.01.013
Wakimoto N, Yin D, O’Kelly J, Haritunians T, Karlan B, Said J, Xing H, Koeffler HP (2008) Cucurbitacin B has a potent antiproliferative effect on breast cancer cells in vitro and in vivo. Cancer Sci. https://doi.org/10.1111/j.1349-7006.2008.00899.x
Wallin MT, Culpepper WJ, Campbell JD, Nelson LM, Langer-Gould A, Marrie RA, Cutter GR, Kaye WE, Wagner L, Tremlett H, Buka SL, Dilokthornsakul P, Topol B, Chen LH, LaRocca NG, US (2019) Multiple Sclerosis Prevalence Workgroup. The prevalence of MS in the United States: A population-based estimate using health claims data. Neurology. https://doi.org/10.1212/WNL.0000000000007035
Wang Q, Ding SL, Li Y, Royall J, Feng D, Lesnar P, Graddis N, Naeemi M, Facer B, Ho A, Dolbeare T, Blanchard B, Dee N, Wakeman W, Hirokawa KE, Szafer A, Sunkin SM, Oh SW, Bernard A, Phillips JW, Hawrylycz M, Koch C, Zeng H, Harris JA, Ng L (2020) The Allen Mouse Brain Common Coordinate Framework: A 3D Reference Atlas. Cell. https://doi.org/10.1016/j.cell.2020.04.007
Wiart C (2012) The definition and significance of Cucurbitacin B a STAT3 inhibitors. Cancer Lett. https://doi.org/10.1016/j.canlet.2012.01.033
Xin P, Xu X, Deng C, Liu S, Wang Y, Zhou X, Ma H, Wei D, Sun S (2020) The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. https://doi.org/10.1016/j.intimp.2020.106210
Zhang M, Bian ZG, Zhang Y, Wang JH, Kan L, Wang X, Niu HY, He P (2014) Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells. Mol Med Rep. https://doi.org/10.3892/mmr.2014.2581
Zhang M, Sun C, Shan X, Yang X, Li-Ling J, Deng Y (2010) Inhibition of pancreatic cancer cell growth by cucurbitacin B through modulation of signal transducer and activator of transcription 3 signaling. https://doi.org/10.1097/MPA.0b013e3181ce719e. Pancreas
Zhang M, Zhang H, Sun C, Shan X, Yang X, Li-Ling J, Deng Y (2009) Targeted constitutive activation of signal transducer and activator of transcription 3 in human hepatocellular carcinoma cells by cucurbitacin B. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-008-0780-0
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SRJ, and MH: performed some experiments and formal analysis, interpreted results, and contribute to writing the manuscript. PM: provide the software, validate data, visualized results, and contribute to writing the manuscript. NS: performed the conceptualization, data curation, funding acquisition, methodology design, supervision, and was a major contributor to writing the manuscript. All authors read and approved the final manuscript.
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Reiszadeh-Jahromi, S., Haddadi, M., Mousavi, P. et al. Prophylactic effects of cucurbitacin B in the EAE Model of multiple sclerosis by adjustment of STAT3/IL-23/IL-17 axis and improvement of neuropsychological symptoms. Metab Brain Dis 37, 2937–2953 (2022). https://doi.org/10.1007/s11011-022-01083-5
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DOI: https://doi.org/10.1007/s11011-022-01083-5