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Home / Equine Research Bank / Front Vet Sci / Withaferin A Inhibits Neutrophil Adhesion, Migration, and Re...
Frontiers in veterinary science2022; 9; 900453; doi: 10.3389/fvets.2022.900453

Withaferin A Inhibits Neutrophil Adhesion, Migration, and Respiratory Burst and Promotes Timely Neutrophil Apoptosis.

Abstract: Neutrophils play a major role in many equine conditions, including equine asthma, laminitis, and intestinal ischemia and reperfusion injury, and therefore represent an attractive target for innovative therapeutic approaches. Novel strategies for reducing neutrophilic inflammation include modulation of neutrophil functions and lifespan. Withaferin A (WFA) is a phytochemical with well-established and anti-inflammatory properties, but its direct effects on neutrophils are largely unknown. We hypothesized that WFA would inhibit adhesion, migration, and respiratory burst by equine neutrophils and promote timely apoptosis of primed equine neutrophils. Consistent with this hypothesis, our data show that WFA causes a significant, concentration-dependent inhibition of equine neutrophil adhesion, migration, and respiratory burst in response to diverse stimuli. Further, WFA treatment increased apoptosis of equine neutrophils exposed to GM-CSF for 24 h. This pro-apoptotic effect of WFA was not observed in unprimed neutrophils, nor at the 2-h time point relevant to our functional neutrophil experiments. Our data demonstrate that WFA may reduce neutrophil-mediated inflammation through multiple mechanisms, including suppression of inflammatory responses and promotion of apoptosis. Additional research is needed to elucidate the molecular mechanisms for these effects and evaluate the potential clinical use of WFA in veterinary and human patients.
Copyright © 2022 Bayless, Sheats and Jones.
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Publication Date: 2022-06-17 PubMed ID: 35782542PubMed Central: PMC9247543DOI: 10.3389/fvets.2022.900453Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article discusses how Withaferin A (WFA), a plant-based chemical, can obstruct certain functions of neutrophils, a type of white blood cell, in horses and encourage their timely death, consequently reducing inflammation. The study shows the potential for using WFA in treating conditions in horses like asthma and laminitis, that involve dysfunction of neutrophils.

Introduction: Neutrophils and their Role

  • Neutrophils, a type of white blood cell, play a crucial role in numerous health issues in horses, including asthma, laminitis, and intestinal ischemia and reperfusion injury.
  • The paper presents the argument that neutrophils are potentially significant targets for developing new methods for therapeutic intervention.

Objective of the Research

  • The objective of the study was to explore the effects of Withaferin A (WFA), a naturally occurring chemical, on horse neutrophils.
  • The researchers hypothesized that WFA would hinder several neutrophil activities such as adhesion, migration, and respiratory burst – all of these contribute to inflammation in the body.
  • Another presumed effect of WFA was to promote the timely death – also known as apoptosis – of activated neutrophils, thereby controlling the inflammation process.

Results of the Experiment

  • The outcomes of the study were in line with the initial hypothesis.
  • WFA demonstrated a significant and concentration-dependent inhibition of various functions of horse neutrophils – adhesion, migration, and respiratory burst.
  • Further, when neutrophils were exposed to Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) for 24 hours, WFA treatment resulted in an increase in apoptosis. So, WFA could accelerate the death of activated neutrophils, thus bringing the inflammation process under control.

Limitations and Scope of the Study

  • However, WFA didn’t induce apoptosis in neutrophils that were not activated and this pro-apoptotic effect was not observed at the 2-hour time point, which was relevant to this study.
  • The results suggest that WFA could potentially help reduce inflammation caused by neutrophils by both suppressing inflammatory responses and promoting controlled, timely apoptosis.
  • These findings open up avenues for further research to fully understand the molecular mechanisms involved and to evaluate the potential clinical use of WFA in veterinary and medical practice.

Cite This Article

APA
Bayless RL, Sheats MK, Jones SL. (2022). Withaferin A Inhibits Neutrophil Adhesion, Migration, and Respiratory Burst and Promotes Timely Neutrophil Apoptosis. Front Vet Sci, 9, 900453. https://doi.org/10.3389/fvets.2022.900453

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 9
Pages: 900453
PII: 900453

Researcher Affiliations

Bayless, Rosemary L
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Sheats, M Katie
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Jones, Samuel L
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.

Grant Funding

  • T32 OD011130 / NIH HHS

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

This article includes 114 references
  1. Uberti B, Morán G. Role of neutrophils in equine asthma.. Anim Health Res Rev 2018 Jun;19(1):65-73.
    doi: 10.1017/S146625231800004Xpubmed: 29792391google scholar: lookup
  2. Davis KU, Sheats MK. The Role of Neutrophils in the Pathophysiology of Asthma in Humans and Horses.. Inflammation 2021 Apr;44(2):450-465.
    doi: 10.1007/s10753-020-01362-2pubmed: 33150539google scholar: lookup
  3. de la Rebière de Pouyade G, Serteyn D. The role of activated neutrophils in the early stage of equine laminitis.. Vet J 2011 Jul;189(1):27-33.
    doi: 10.1016/j.tvjl.2010.06.008pubmed: 20655252google scholar: lookup
  4. Leise B. The role of neutrophils in equine laminitis.. Cell Tissue Res 2018 Mar;371(3):541-550.
    doi: 10.1007/s00441-018-2788-zpubmed: 29397426google scholar: lookup
  5. Gayle JM, Blikslager AT, Jones SL. Role of neutrophils in intestinal mucosal injury.. J Am Vet Med Assoc 2000 Aug 15;217(4):498-500.
    doi: 10.2460/javma.2000.217.498pubmed: 10953711google scholar: lookup
  6. Moore RM, Bertone AL, Bailey MQ, Muir WW, Beard WL. Neutrophil accumulation in the large colon of horses during low-flow ischemia and reperfusion.. Am J Vet Res 1994 Oct;55(10):1454-63.
    pubmed: 7998704
  7. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis.. Lancet 2006 Jul 8;368(9530):157-69.
    doi: 10.1016/S0140-6736(06)69005-3pubmed: 16829300google scholar: lookup
  8. Gifford AM, Chalmers JD. The role of neutrophils in cystic fibrosis.. Curr Opin Hematol 2014 Jan;21(1):16-22.
    doi: 10.1097/MOH.0000000000000009pubmed: 24253427google scholar: lookup
  9. Bhatia M, Saluja AK, Hofbauer B, Lee HS, Frossard JL, Steer ML. The effects of neutrophil depletion on a completely noninvasive model of acute pancreatitis-associated lung injury.. Int J Pancreatol 1998 Oct;24(2):77-83.
    doi: 10.1007/BF02788564pubmed: 9816540google scholar: lookup
  10. Johnson KC, Mackin A. Canine immune-mediated polyarthritis: part 1: pathophysiology.. J Am Anim Hosp Assoc 2012 Jan-Feb;48(1):12-7.
    doi: 10.5326/JAAHA-MS-5756pubmed: 22190602google scholar: lookup
  11. Slocombe RF, Malark J, Ingersoll R, Derksen FJ, Robinson NE. Importance of neutrophils in the pathogenesis of acute pneumonic pasteurellosis in calves.. Am J Vet Res 1985 Nov;46(11):2253-8.
    pubmed: 4073635
  12. Bouti P, Webbers SDS, Fagerholm SC, Alon R, Moser M, Matlung HL, Kuijpers TW. β2 Integrin Signaling Cascade in Neutrophils: More Than a Single Function.. Front Immunol 2020;11:619925.
    doi: 10.3389/fimmu.2020.619925pmc: PMC7930317pubmed: 33679708google scholar: lookup
  13. Berton G, Yan SR, Fumagalli L, Lowell CA. Neutrophil activation by adhesion: mechanisms and pathophysiological implications.. Int J Clin Lab Res 1996;26(3):160-77.
    doi: 10.1007/BF02592978pubmed: 8905448google scholar: lookup
  14. Brazil JC, Parkos CA. Pathobiology of neutrophil-epithelial interactions.. Immunol Rev 2016 Sep;273(1):94-111.
    doi: 10.1111/imr.12446pmc: PMC5000857pubmed: 27558330google scholar: lookup
  15. Gayle J, Jones SL, Argenzio RA, Blikslager AT. Neutrophils increase paracellular permeability of restituted ischemic-injured porcine ileum.. Surgery 2002 Sep;132(3):461-70.
    doi: 10.1067/msy.2002.125320pubmed: 12324760google scholar: lookup
  16. Nash S, Stafford J, Madara JL. Effects of polymorphonuclear leukocyte transmigration on the barrier function of cultured intestinal epithelial monolayers.. J Clin Invest 1987 Oct;80(4):1104-13.
    doi: 10.1172/JCI113167pmc: PMC442353pubmed: 3116044google scholar: lookup
  17. Nusrat A, Parkos CA, Liang TW, Carnes DK, Madara JL. Neutrophil migration across model intestinal epithelia: monolayer disruption and subsequent events in epithelial repair.. Gastroenterology 1997 Nov;113(5):1489-500.
    doi: 10.1053/gast.1997.v113.pm9352851pubmed: 9352851google scholar: lookup
  18. Kantrow SP, Shen Z, Jagneaux T, Zhang P, Nelson S. Neutrophil-mediated lung permeability and host defense proteins.. Am J Physiol Lung Cell Mol Physiol 2009 Oct;297(4):L738-45.
    doi: 10.1152/ajplung.00045.2009pmc: PMC2770784pubmed: 19648288google scholar: lookup
  19. van der Linden M, Meyaard L. Fine-tuning neutrophil activation: Strategies and consequences.. Immunol Lett 2016 Oct;178:3-9.
    doi: 10.1016/j.imlet.2016.05.015pubmed: 27262927google scholar: lookup
  20. McCracken JM, Allen LA. Regulation of human neutrophil apoptosis and lifespan in health and disease.. J Cell Death 2014;7:15-23.
    doi: 10.4137/JCD.S11038pmc: PMC4167320pubmed: 25278783google scholar: lookup
  21. Lahoz-Beneytez J, Elemans M, Zhang Y, Ahmed R, Salam A, Block M, Niederalt C, Asquith B, Macallan D. Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives.. Blood 2016 Jun 30;127(26):3431-8.
    doi: 10.1182/blood-2016-03-700336pmc: PMC4929930pubmed: 27136946google scholar: lookup
  22. Lee A, Whyte MK, Haslett C. Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators.. J Leukoc Biol 1993 Oct;54(4):283-8.
    doi: 10.1002/jlb.54.4.283pubmed: 8409750google scholar: lookup
  23. Kobayashi SD, Voyich JM, Whitney AR, DeLeo FR. Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor.. J Leukoc Biol 2005 Dec;78(6):1408-18.
    doi: 10.1189/jlb.0605289pubmed: 16204629google scholar: lookup
  24. Kobayashi SD, Voyich JM, Braughton KR, DeLeo FR. Down-regulation of proinflammatory capacity during apoptosis in human polymorphonuclear leukocytes.. J Immunol 2003 Mar 15;170(6):3357-68.
    doi: 10.4049/jimmunol.170.6.3357pubmed: 12626596google scholar: lookup
  25. Whyte MK, Meagher LC, MacDermot J, Haslett C. Impairment of function in aging neutrophils is associated with apoptosis.. J Immunol 1993 Jun 1;150(11):5124-34.
    pubmed: 8388425
  26. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.. J Clin Invest 1998 Feb 15;101(4):890-8.
    doi: 10.1172/JCI1112pmc: PMC508637pubmed: 9466984google scholar: lookup
  27. Krista KM, White NA, Barrett JG, Furr MO, Buechner-Maxwell VA. Evaluation of neutrophil apoptosis in horses with acute abdominal disease.. Am J Vet Res 2013 Jul;74(7):999-1004.
    doi: 10.2460/ajvr.74.7.999pubmed: 23802671google scholar: lookup
  28. Niedzwiedz A, Jaworski Z, Tykalowski B, Smialek M. Neutrophil and macrophage apoptosis in bronchoalveolar lavage fluid from healthy horses and horses with recurrent airway obstruction (RAO).. BMC Vet Res 2014 Jan 24;10:29.
    doi: 10.1186/1746-6148-10-29pmc: PMC3903020pubmed: 24460911google scholar: lookup
  29. Anderson SL, Singh B. Neutrophil apoptosis is delayed in an equine model of colitis: Implications for the development of systemic inflammatory response syndrome.. Equine Vet J 2017 May;49(3):383-388.
    doi: 10.1111/evj.12576pubmed: 27037704google scholar: lookup
  30. Taneja R, Parodo J, Jia SH, Kapus A, Rotstein OD, Marshall JC. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity.. Crit Care Med 2004 Jul;32(7):1460-9.
    doi: 10.1097/01.CCM.0000129975.26905.77pubmed: 15241089google scholar: lookup
  31. Jimenez MF, Watson RW, Parodo J, Evans D, Foster D, Steinberg M, Rotstein OD, Marshall JC. Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome.. Arch Surg 1997 Dec;132(12):1263-9; discussion 1269-70.
    doi: 10.1001/archsurg.1997.01430360009002pubmed: 9403528google scholar: lookup
  32. McKeon DJ, Condliffe AM, Cowburn AS, Cadwallader KC, Farahi N, Bilton D, Chilvers ER. Prolonged survival of neutrophils from patients with Delta F508 CFTR mutations.. Thorax 2008 Jul;63(7):660-1.
    doi: 10.1136/thx.2008.096834pubmed: 18587042google scholar: lookup
  33. Moriceau S, Lenoir G, Witko-Sarsat V. In cystic fibrosis homozygotes and heterozygotes, neutrophil apoptosis is delayed and modulated by diamide or roscovitine: evidence for an innate neutrophil disturbance.. J Innate Immun 2010;2(3):260-6.
    doi: 10.1159/000295791pubmed: 20375556google scholar: lookup
  34. Uddin M, Nong G, Ward J, Seumois G, Prince LR, Wilson SJ, Cornelius V, Dent G, Djukanovic R. Prosurvival activity for airway neutrophils in severe asthma.. Thorax 2010 Aug;65(8):684-9.
    doi: 10.1136/thx.2009.120741pubmed: 20685741google scholar: lookup
  35. Jie H, He Y, Huang X, Zhou Q, Han Y, Li X, Bai Y, Sun E. Necrostatin-1 enhances the resolution of inflammation by specifically inducing neutrophil apoptosis.. Oncotarget 2016 Apr 12;7(15):19367-81.
    doi: 10.18632/oncotarget.8346pmc: PMC4991389pubmed: 27027357google scholar: lookup
  36. Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis.. Nat Med 2006 Sep;12(9):1056-64.
    doi: 10.1038/nm1468pubmed: 16951685google scholar: lookup
  37. Tsai YF, Chu TC, Chang WY, Wu YC, Chang FR, Yang SC, Wu TY, Hsu YM, Chen CY, Chang SH, Hwang TL. 6-Hydroxy-5,7-dimethoxy-flavone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury.. Free Radic Biol Med 2017 May;106:379-392.
    doi: 10.1016/j.freeradbiomed.2017.03.002pubmed: 28263828google scholar: lookup
  38. Liou KT, Shen YC, Chen CF, Tsao CM, Tsai SK. The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production.. Eur J Pharmacol 2003 Aug 15;475(1-3):19-27.
    doi: 10.1016/S0014-2999(03)02121-6pubmed: 12954355google scholar: lookup
  39. Tsai YF, Chen CY, Lin IW, Leu YL, Yang SC, Syu YT, Chen PJ, Hwang TL. Imperatorin Alleviates Psoriasiform Dermatitis by Blocking Neutrophil Respiratory Burst, Adhesion, and Chemotaxis Through Selective Phosphodiesterase 4 Inhibition.. Antioxid Redox Signal 2021 Oct 10;35(11):885-903.
    doi: 10.1089/ars.2019.7835pubmed: 33107318google scholar: lookup
  40. Nosáí R, DráBiková K, Jančinová V, Mačičková T, Pečivová J, Perečko T, Harmatha J. Pharmacological intervention with oxidative burst in human neutrophils.. Interdiscip Toxicol 2017 Oct;10(2):56-60.
    doi: 10.1515/intox-2017-0009pmc: PMC6096857pubmed: 30123038google scholar: lookup
  41. Behl T, Sharma A, Sharma L, Sehgal A, Zengin G, Brata R, Fratila O, Bungau S. Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives.. Biomedicines 2020 Dec 6;8(12).
    doi: 10.3390/biomedicines8120571pmc: PMC7762146pubmed: 33291236google scholar: lookup
  42. Gao S, Li H, Zhou XQ, You JB, Tu DN, Xia G, Jiang JX, Xin C. Withaferin A attenuates lipopolysaccharide-induced acute lung injury in neonatal rats.. Cell Mol Biol (Noisy-le-grand) 2015 Jul 31;61(3):102-6.
    pubmed: 26255139
  43. Kanak MA, Shahbazov R, Yoshimatsu G, Levy MF, Lawrence MC, Naziruddin B. A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis.. J Gastroenterol 2017 Mar;52(3):352-365.
    doi: 10.1007/s00535-016-1238-5pubmed: 27418337google scholar: lookup
  44. Tiruveedi VL, Bale S, Khurana A, Godugu C. Withaferin A, a novel compound of Indian ginseng (Withania somnifera), ameliorates Cerulein-induced acute pancreatitis: Possible role of oxidative stress and inflammation.. Phytother Res 2018 Dec;32(12):2586-2596.
    doi: 10.1002/ptr.6200pubmed: 30307087google scholar: lookup
  45. Sabina EP, Chandal S, Rasool MK. Inhibition of monosodium urate crystal-induced inflammation by withaferin A.. J Pharm Pharm Sci 2008;11(4):46-55.
    doi: 10.18433/J35K58pubmed: 19183513google scholar: lookup
  46. Zhao HM, Gao ZW, Xie SX, Han X, Sun QS. Withaferin A attenuates ovalbumin induced airway inflammation.. Front Biosci (Landmark Ed) 2019 Jan 1;24(3):576-596.
    doi: 10.2741/4737pubmed: 30468675google scholar: lookup
  47. Szarc vel Szic K, Op de Beeck K, Ratman D, Wouters A, Beck IM, Declerck K, Heyninck K, Fransen E, Bracke M, De Bosscher K, Lardon F, Van Camp G, Vanden Berghe W. Pharmacological levels of Withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells.. PLoS One 2014;9(2):e87850.
    doi: 10.1371/journal.pone.0087850pmc: PMC3912072pubmed: 24498382google scholar: lookup
  48. Chung SS, Wu Y, Okobi Q, Adekoya D, Atefi M, Clarke O, Dutta P, Vadgama JV. Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells.. Mediators Inflamm 2017;2017:5958429.
    doi: 10.1155/2017/5958429pmc: PMC5476880pubmed: 28676732google scholar: lookup
  49. Kuppusamy P, Nagalingam A, Muniraj N, Saxena NK, Sharma D. Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice.. Sci Rep 2017 Dec 20;7(1):17943.
    doi: 10.1038/s41598-017-18190-4pmc: PMC5738353pubmed: 29263422google scholar: lookup
  50. Samadi AK, Mukerji R, Shah A, Timmermann BN, Cohen MS. A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo.. Surgery 2010 Dec;148(6):1228-36; discussion 1236.
    doi: 10.1016/j.surg.2010.09.026pmc: PMC3088305pubmed: 21134556google scholar: lookup
  51. Grommes J, Soehnlein O. Contribution of neutrophils to acute lung injury.. Mol Med 2011 Mar-Apr;17(3-4):293-307.
    doi: 10.2119/molmed.2010.00138pmc: PMC3060975pubmed: 21046059google scholar: lookup
  52. Abraham E, Carmody A, Shenkar R, Arcaroli J. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury.. Am J Physiol Lung Cell Mol Physiol 2000 Dec;279(6):L1137-45.
    doi: 10.1152/ajplung.2000.279.6.L1137pubmed: 11076804google scholar: lookup
  53. Fujimoto K, Hosotani R, Doi R, Wada M, Lee JU, Koshiba T, Miyamoto Y, Imamura M. Role of neutrophils in cerulein-induced pancreatitis in rats: possible involvement of apoptosis.. Digestion 1997;58(5):421-30.
    doi: 10.1159/000201478pubmed: 9383632google scholar: lookup
  54. Pastor CM, Vonlaufen A, Georgi F, Hadengue A, Morel P, Frossard JL. Neutrophil depletion--but not prevention of Kupffer cell activation--decreases the severity of cerulein-induced acute pancreatitis.. World J Gastroenterol 2006 Feb 28;12(8):1219-24.
    doi: 10.3748/wjg.v12.i8.1219pmc: PMC4124432pubmed: 16534874google scholar: lookup
  55. So AK, Martinon F. Inflammation in gout: mechanisms and therapeutic targets.. Nat Rev Rheumatol 2017 Nov;13(11):639-647.
    doi: 10.1038/nrrheum.2017.155pubmed: 28959043google scholar: lookup
  56. Reutershan J, Basit A, Galkina EV, Ley K. Sequential recruitment of neutrophils into lung and bronchoalveolar lavage fluid in LPS-induced acute lung injury.. Am J Physiol Lung Cell Mol Physiol 2005 Nov;289(5):L807-15.
    doi: 10.1152/ajplung.00477.2004pubmed: 15951336google scholar: lookup
  57. Chen CM, Chung YP, Liu CH, Huang KT, Guan SS, Chiang CK, Wu CT, Liu SH. Withaferin A protects against endoplasmic reticulum stress-associated apoptosis, inflammation, and fibrosis in the kidney of a mouse model of unilateral ureteral obstruction.. Phytomedicine 2020 Dec;79:153352.
    doi: 10.1016/j.phymed.2020.153352pubmed: 33007732google scholar: lookup
  58. Che X, Chi F, Wang L, Jong TD, Wu CH, Wang X, Huang SH. Involvement of IbeA in meningitic Escherichia coli K1-induced polymorphonuclear leukocyte transmigration across brain endothelial cells.. Brain Pathol 2011 Jul;21(4):389-404.
    doi: 10.1111/j.1750-3639.2010.00463.xpmc: PMC8094254pubmed: 21083634google scholar: lookup
  59. Chang HW, Li RN, Wang HR, Liu JR, Tang JY, Huang HW, Chan YH, Yen CY. Withaferin A Induces Oxidative Stress-Mediated Apoptosis and DNA Damage in Oral Cancer Cells.. Front Physiol 2017;8:634.
    doi: 10.3389/fphys.2017.00634pmc: PMC5594071pubmed: 28936177google scholar: lookup
  60. Hahm ER, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is associated with suppression of inhibitor of apoptosis family protein expression.. Cancer Lett 2013 Jun 28;334(1):101-8.
    doi: 10.1016/j.canlet.2012.08.026pmc: PMC3530008pubmed: 22935676google scholar: lookup
  61. Xia S, Miao Y, Liu S. Withaferin A induces apoptosis by ROS-dependent mitochondrial dysfunction in human colorectal cancer cells.. Biochem Biophys Res Commun 2018 Sep 18;503(4):2363-2369.
    doi: 10.1016/j.bbrc.2018.06.162pubmed: 29966656google scholar: lookup
  62. Aliebrahimi S, Kouhsari SM, Arab SS, Shadboorestan A, Ostad SN. Phytochemicals, withaferin A and carnosol, overcome pancreatic cancer stem cells as c-Met inhibitors.. Biomed Pharmacother 2018 Oct;106:1527-1536.
    doi: 10.1016/j.biopha.2018.07.055pubmed: 30119228google scholar: lookup
  63. Hahm ER, Moura MB, Kelley EE, Van Houten B, Shiva S, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species.. PLoS One 2011;6(8):e23354.
    doi: 10.1371/journal.pone.0023354pmc: PMC3154436pubmed: 21853114google scholar: lookup
  64. Malik F, Kumar A, Bhushan S, Khan S, Bhatia A, Suri KA, Qazi GN, Singh J. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine.. Apoptosis 2007 Nov;12(11):2115-33.
    doi: 10.1007/s10495-007-0129-xpubmed: 17874299google scholar: lookup
  65. Mayola E, Gallerne C, Esposti DD, Martel C, Pervaiz S, Larue L, Debuire B, Lemoine A, Brenner C, Lemaire C. Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2.. Apoptosis 2011 Oct;16(10):1014-27.
    doi: 10.1007/s10495-011-0625-xpubmed: 21710254google scholar: lookup
  66. Liu X, Chen L, Liang T, Tian XD, Liu Y, Zhang T. Withaferin A induces mitochondrial-dependent apoptosis in non-small cell lung cancer cells via generation of reactive oxygen species.. J BUON 2017 Jan-Feb;22(1):244-250.
    pubmed: 28365961
  67. Mandal C, Dutta A, Mallick A, Chandra S, Misra L, Sangwan RS, Mandal C. Withaferin A induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade.. Apoptosis 2008 Dec;13(12):1450-64.
    doi: 10.1007/s10495-008-0271-0pubmed: 18987975google scholar: lookup
  68. Mehrotra A, Kaul D, Joshi K. LXR-α selectively reprogrammes cancer cells to enter into apoptosis.. Mol Cell Biochem 2011 Mar;349(1-2):41-55.
    doi: 10.1007/s11010-010-0659-3pubmed: 21125317google scholar: lookup
  69. Guo R, Gan L, Lau WB, Yan Z, Xie D, Gao E, Christopher TA, Lopez BL, Ma X, Wang Y. Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling.. Circ J 2019 Jul 25;83(8):1726-1736.
    doi: 10.1253/circj.CJ-18-1391pubmed: 31217391google scholar: lookup
  70. Yan Z, Guo R, Gan L, Lau WB, Cao X, Zhao J, Ma X, Christopher TA, Lopez BL, Wang Y. Withaferin A inhibits apoptosis via activated Akt-mediated inhibition of oxidative stress.. Life Sci 2018 Oct 15;211:91-101.
    doi: 10.1016/j.lfs.2018.09.020pubmed: 30213729google scholar: lookup
  71. Tekula S, Khurana A, Anchi P, Godugu C. Withaferin-A attenuates multiple low doses of Streptozotocin (MLD-STZ) induced type 1 diabetes.. Biomed Pharmacother 2018 Oct;106:1428-1440.
    doi: 10.1016/j.biopha.2018.07.090pubmed: 30119216google scholar: lookup
  72. Zhao X, Wang J, Tang L, Li P, Ru J, Bai Y. Withaferin A protects against hyperuricemia induced kidney injury and its possible mechanisms.. Bioengineered 2021 Dec;12(1):589-600.
    doi: 10.1080/21655979.2021.1882761pmc: PMC8806220pubmed: 33517833google scholar: lookup
  73. Yan X, Huang G, Liu Q, Zheng J, Chen H, Huang Q, Chen J, Huang H. Withaferin A protects against spinal cord injury by inhibiting apoptosis and inflammation in mice.. Pharm Biol 2017 Dec;55(1):1171-1176.
    doi: 10.1080/13880209.2017.1288262pmc: PMC6130570pubmed: 28228044google scholar: lookup
  74. Martin EM, Till RL, Sheats MK, Jones SL. Misoprostol Inhibits Equine Neutrophil Adhesion, Migration, and Respiratory Burst in an In Vitro Model of Inflammation.. Front Vet Sci 2017;4:159.
    doi: 10.3389/fvets.2017.00159pmc: PMC5626936pubmed: 29034248google scholar: lookup
  75. Sheats MK, Pescosolido KC, Hefner EM, Sung EJ, Adler KB, Jones SL. Myristoylated Alanine Rich C Kinase Substrate (MARCKS) is essential to β2-integrin dependent responses of equine neutrophils.. Vet Immunol Immunopathol 2014 Aug 15;160(3-4):167-76.
    doi: 10.1016/j.vetimm.2014.04.009pmc: PMC4108539pubmed: 24857637google scholar: lookup
  76. Gupta S, Chan DW, Zaal KJ, Kaplan MJ. A High-Throughput Real-Time Imaging Technique To Quantify NETosis and Distinguish Mechanisms of Cell Death in Human Neutrophils.. J Immunol 2018 Jan 15;200(2):869-879.
    doi: 10.4049/jimmunol.1700905pmc: PMC5760330pubmed: 29196457google scholar: lookup
  77. Lee W, Kim TH, Ku SK, Min KJ, Lee HS, Kwon TK, Bae JS. Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models.. Toxicol Appl Pharmacol 2012 Jul 1;262(1):91-8.
    doi: 10.1016/j.taap.2012.04.025pubmed: 22561332google scholar: lookup
  78. Chen BW, Chen YY, Lin YC, Huang CY, Uvarani C, Hwang TL. Capsisteroids A-F, withanolides from the leaves of Solanum capsicoides. RSC Adv (2015) 5:88841–7.
    doi: 10.1039/C5RA12014Dgoogle scholar: lookup
  79. Anderson SL, Townsend HGG, Singh B. Role of toll-like receptor 4 and caspase-3, -8, and -9 in lipopolysaccharide-induced delay of apoptosis in equine neutrophils.. Am J Vet Res 2018 Apr;79(4):424-432.
    doi: 10.2460/ajvr.79.4.424pubmed: 29583049google scholar: lookup
  80. Savoie A, Lavastre V, Pelletier M, Hajto T, Hostanska K, Girard D. Activation of human neutrophils by the plant lectin Viscum album agglutinin-I: modulation of de novo protein synthesis and evidence that caspases are involved in induction of apoptosis.. J Leukoc Biol 2000 Dec;68(6):845-53.
    doi: 10.1189/jlb.68.6.845pubmed: 11129652google scholar: lookup
  81. Derouet M, Thomas L, Cross A, Moots RJ, Edwards SW. Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1.. J Biol Chem 2004 Jun 25;279(26):26915-21.
    doi: 10.1074/jbc.M313875200pubmed: 15078892google scholar: lookup
  82. Liles WC, Dale DC, Klebanoff SJ. Glucocorticoids inhibit apoptosis of human neutrophils.. Blood 1995 Oct 15;86(8):3181-8.
    doi: 10.1182/blood.V86.8.3181.3181pubmed: 7579413google scholar: lookup
  83. Saffar AS, Dragon S, Ezzati P, Shan L, Gounni AS. Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase regulate induction of Mcl-1 and survival in glucocorticoid-treated human neutrophils.. J Allergy Clin Immunol 2008 Feb;121(2):492-498.e10.
    doi: 10.1016/j.jaci.2007.10.003pubmed: 18036649google scholar: lookup
  84. Saffar AS, Ashdown H, Gounni AS. The molecular mechanisms of glucocorticoids-mediated neutrophil survival.. Curr Drug Targets 2011 Apr;12(4):556-62.
    doi: 10.2174/138945011794751555pmc: PMC3267167pubmed: 21504070google scholar: lookup
  85. Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes.. J Immunol 1995 May 1;154(9):4719-25.
    pubmed: 7722324
  86. Noh EJ, Kang MJ, Jeong YJ, Lee JY, Park JH, Choi HJ, Oh SM, Lee KB, Kim DJ, Shin JA, Cho SD, Park JH. Withaferin A inhibits inflammatory responses induced by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in macrophages.. Mol Med Rep 2016 Jul;14(1):983-8.
    doi: 10.3892/mmr.2016.5326pubmed: 27220676google scholar: lookup
  87. Kaileh M, Vanden Berghe W, Heyerick A, Horion J, Piette J, Libert C, De Keukeleire D, Essawi T, Haegeman G. Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity.. J Biol Chem 2007 Feb 16;282(7):4253-4264.
    doi: 10.1074/jbc.M606728200pubmed: 17150968google scholar: lookup
  88. Heyninck K, Lahtela-Kakkonen M, Van der Veken P, Haegeman G, Vanden Berghe W. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ.. Biochem Pharmacol 2014 Oct 15;91(4):501-9.
    doi: 10.1016/j.bcp.2014.08.004pubmed: 25159986google scholar: lookup
  89. Mohan R, Hammers HJ, Bargagna-Mohan P, Zhan XH, Herbstritt CJ, Ruiz A, Zhang L, Hanson AD, Conner BP, Rougas J, Pribluda VS. Withaferin A is a potent inhibitor of angiogenesis.. Angiogenesis 2004;7(2):115-22.
    doi: 10.1007/s10456-004-1026-3pubmed: 15516832google scholar: lookup
  90. Oh JH, Lee TJ, Park JW, Kwon TK. Withaferin A inhibits iNOS expression and nitric oxide production by Akt inactivation and down-regulating LPS-induced activity of NF-kappaB in RAW 264.7 cells.. Eur J Pharmacol 2008 Dec 3;599(1-3):11-7.
    doi: 10.1016/j.ejphar.2008.09.017pubmed: 18838070google scholar: lookup
  91. Oh JH, Kwon TK. Withaferin A inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules by inactivation of Akt and NF-kappaB in human pulmonary epithelial cells.. Int Immunopharmacol 2009 May;9(5):614-9.
    doi: 10.1016/j.intimp.2009.02.002pubmed: 19236958google scholar: lookup
  92. McLeish KR, Knall C, Ward RA, Gerwins P, Coxon PY, Klein JB, Johnson GL. Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-alpha and GM-CSF.. J Leukoc Biol 1998 Oct;64(4):537-45.
    doi: 10.1002/jlb.64.4.537pubmed: 9766635google scholar: lookup
  93. Takami M, Terry V, Petruzzelli L. Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1.. J Immunol 2002 May 1;168(9):4559-66.
    doi: 10.4049/jimmunol.168.9.4559pubmed: 11971003google scholar: lookup
  94. Eckert RE, Sharief Y, Jones SL. p38 mitogen-activated kinase (MAPK) is essential for equine neutrophil migration.. Vet Immunol Immunopathol 2009 Jun 15;129(3-4):181-91.
    doi: 10.1016/j.vetimm.2008.11.007pubmed: 19095309google scholar: lookup
  95. Nick JA, Avdi NJ, Young SK, Knall C, Gerwins P, Johnson GL, Worthen GS. Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.. J Clin Invest 1997 Mar 1;99(5):975-86.
    doi: 10.1172/JCI119263pmc: PMC507906pubmed: 9062356google scholar: lookup
  96. Zu YL, Qi J, Gilchrist A, Fernandez GA, Vazquez-Abad D, Kreutzer DL, Huang CK, Sha'afi RI. p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation.. J Immunol 1998 Feb 15;160(4):1982-9.
    pubmed: 9469462
  97. Nick JA, Avdi NJ, Gerwins P, Johnson GL, Worthen GS. Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide.. J Immunol 1996 Jun 15;156(12):4867-75.
    pubmed: 8648136
  98. Behnen M, Leschczyk C, Möller S, Batel T, Klinger M, Solbach W, Laskay T. Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcγRIIIB and Mac-1.. J Immunol 2014 Aug 15;193(4):1954-65.
    doi: 10.4049/jimmunol.1400478pubmed: 25024378google scholar: lookup
  99. Kamata N, Kutsuna H, Hato F, Kato T, Oshitani N, Arakawa T, Kitagawa S. Activation of human neutrophils by granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha: role of phosphatidylinositol 3-kinase.. Int J Hematol 2004 Dec;80(5):421-7.
    doi: 10.1532/IJH97.04122pubmed: 15646653google scholar: lookup
  100. Lane HC, Anand AR, Ganju RK. Cbl and Akt regulate CXCL8-induced and CXCR1- and CXCR2-mediated chemotaxis.. Int Immunol 2006 Aug;18(8):1315-25.
    doi: 10.1093/intimm/dxl064pubmed: 16798838google scholar: lookup
  101. Sandoval AJ, Riquelme JP, Carretta MD, Hancke JL, Hidalgo MA, Burgos RA. Store-operated calcium entry mediates intracellular alkalinization, ERK1/2, and Akt/PKB phosphorylation in bovine neutrophils.. J Leukoc Biol 2007 Nov;82(5):1266-77.
    doi: 10.1189/jlb.0307196pubmed: 17684040google scholar: lookup
  102. Gong J, Liu H, Wu J, Qi H, Wu ZY, Shu HQ, Li HB, Chen L, Wang YX, Li B, Tang M, Ji YD, Yuan SY, Yao SL, Shang Y. MARESIN 1 PREVENTS LIPOPOLYSACCHARIDE-INDUCED NEUTROPHIL SURVIVAL AND ACCELERATES RESOLUTION OF ACUTE LUNG INJURY.. Shock 2015 Oct;44(4):371-80.
    doi: 10.1097/SHK.0000000000000434pubmed: 26196844google scholar: lookup
  103. Chen Q, Powell DW, Rane MJ, Singh S, Butt W, Klein JB, McLeish KR. Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils.. J Immunol 2003 May 15;170(10):5302-8.
    doi: 10.4049/jimmunol.170.10.5302pubmed: 12734380google scholar: lookup
  104. Zhang P, Fu Y, Ju J, Wan D, Su H, Wang Z, Rui H, Jin Q, Le Y, Hou R. Estradiol inhibits fMLP-induced neutrophil migration and superoxide production by upregulating MKP-2 and dephosphorylating ERK.. Int Immunopharmacol 2019 Oct;75:105787.
    doi: 10.1016/j.intimp.2019.105787pubmed: 31401382google scholar: lookup
  105. Lai KH, Chen PJ, Chen CC, Yang SH, El-Shazly M, Chang YC, Wu YH, Wu YH, Wang YH, Hsieh HL, Hwang TL. Lophatherum gracile Brongn. attenuates neutrophilic inflammation through inhibition of JNK and calcium.. J Ethnopharmacol 2021 Jan 10;264:113224.
    doi: 10.1016/j.jep.2020.113224pubmed: 32800928google scholar: lookup
  106. Bullone M, Moran K, Lavoie-Lamoureux A, Lavoie JP. PI3K and MAPKs regulate neutrophil migration toward the airways in heaves.. J Vet Intern Med 2013 Jan-Feb;27(1):164-70.
    doi: 10.1111/jvim.12008pubmed: 23194017google scholar: lookup
  107. Pickles KJ, Brooks AC, Rickards KJ, Cunningham FM. Expression of annexin-1 in equine leucocytes and the effects of the N-terminal annexin-1 peptide, Ac2-26, on equine neutrophil superoxide production.. Vet Immunol Immunopathol 2010 Jun 15;135(3-4):226-33.
    doi: 10.1016/j.vetimm.2009.12.002pubmed: 20079938google scholar: lookup
  108. Klein JB, Rane MJ, Scherzer JA, Coxon PY, Kettritz R, Mathiesen JM, Buridi A, McLeish KR. Granulocyte-macrophage colony-stimulating factor delays neutrophil constitutive apoptosis through phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways.. J Immunol 2000 Apr 15;164(8):4286-91.
    doi: 10.4049/jimmunol.164.8.4286pubmed: 10754327google scholar: lookup
  109. Rane MJ, Klein JB. Regulation of neutrophil apoptosis by modulation of PKB/Akt activation.. Front Biosci (Landmark Ed) 2009 Jan 1;14(7):2400-12.
    doi: 10.2741/3386pubmed: 19273208google scholar: lookup
  110. François S, El Benna J, Dang PM, Pedruzzi E, Gougerot-Pocidalo MA, Elbim C. Inhibition of neutrophil apoptosis by TLR agonists in whole blood: involvement of the phosphoinositide 3-kinase/Akt and NF-kappaB signaling pathways, leading to increased levels of Mcl-1, A1, and phosphorylated Bad.. J Immunol 2005 Mar 15;174(6):3633-42.
    doi: 10.4049/jimmunol.174.6.3633pubmed: 15749901google scholar: lookup
  111. Hahm ER, Lee J, Singh SV. Role of mitogen-activated protein kinases and Mcl-1 in apoptosis induction by withaferin A in human breast cancer cells.. Mol Carcinog 2014 Nov;53(11):907-16.
    doi: 10.1002/mc.22050pmc: PMC3859703pubmed: 24019090google scholar: lookup
  112. Aoyama M, Kotani J, Usami M. Butyrate and propionate induced activated or non-activated neutrophil apoptosis via HDAC inhibitor activity but without activating GPR-41/GPR-43 pathways.. Nutrition 2010 Jun;26(6):653-61.
    doi: 10.1016/j.nut.2009.07.006pubmed: 20004081google scholar: lookup
  113. Patel SB, Rao NJ, Hingorani LL. Safety assessment of Withania somnifera extract standardized for Withaferin A: Acute and sub-acute toxicity study.. J Ayurveda Integr Med 2016 Mar;7(1):30-7.
    doi: 10.1016/j.jaim.2015.08.001pmc: PMC4910650pubmed: 27297507google scholar: lookup
  114. Pires N, Gota V, Gulia A, Hingorani L, Agarwal M, Puri A. Safety and pharmacokinetics of Withaferin-A in advanced stage high grade osteosarcoma: A phase I trial.. J Ayurveda Integr Med 2020 Jan-Mar;11(1):68-72.
    doi: 10.1016/j.jaim.2018.12.008pmc: PMC7125369pubmed: 30904387google scholar: lookup

Citations

This article has been cited 2 times.
  1. Atteeq M. Evaluating anticancer properties of Withaferin A-a potent phytochemical. Front Pharmacol 2022;13:975320.
    doi: 10.3389/fphar.2022.975320pubmed: 36339589google scholar: lookup
  2. Jiang J, Chen Y, Su Y, Zhang L, Qian H, Song X, Xu JF. Identification and experimental validation of diagnostic and prognostic genes CX3CR1, PID1 and PTGDS in sepsis and ARDS using bulk and single-cell transcriptomic analysis and machine learning. Front Immunol 2024;15:1480542.
    doi: 10.3389/fimmu.2024.1480542pubmed: 39763654google scholar: lookup
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