Withania somnifera and Its Withanolides Attenuate Oxidative and Inflammatory Responses and Up-Regulate Antioxidant Responses in BV-2 Microglial Cells
Abstract
Withania somnifera (L.) Dunal, commonly known as Ashwagandha, has been used in Ayurvedic medicine for promoting health and quality of life. Recent clinical trials together with experimental studies indicated significant neuroprotective effects of Ashwagandha and its constituents. This study is aimed to investigate anti-inflammatory and anti-oxidative properties of this botanical and its two withanolide constituents, namely, Withaferin A and Withanolide A, using the murine immortalized BV-2 microglial cells. Ashwagandha extracts not only effectively inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) and reactive oxygen species (ROS) production in BV-2 cells, but also stimulates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, leading to induction of heme oxygenase-1 (HO-1), both in the presence and absence of LPS. Although the withanolides were also capable of inhibiting LPS-induced NO production and stimulating Nrf2/HO-1 pathway, Withaferin A was tenfold more effective than Withanolide A. In serum-free culture, LPS can also induce production of long thin processes (filopodia) between 4 and 8 h in BV-2 cells. This morphological change was significantly suppressed by Ashwagandha and both withanolides at concentrations for suppressing LPS-induced NO production. Taken together, these results suggest an immunomodulatory role for Ashwagandha and its withanolides, and their ability to suppress oxidative and inflammatory responses in microglial cells by simultaneously down-regulating the NF-kB and upregulating the Nrf2 pathways.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Withaferin A and Withanolide A have a potent immunomodulatory effect in BV-2 microglial cells by triggering the Nrf2 pathway, leading to production of heme oxygenase-1.
“Withaferin A and Withanolide A suggested to have a potent immunomodulatory effect in BV-2 microglial cells by triggering the Nrf2 pathway, leading to production of the neuroprotective protein, such as heme oxygenase-1 [158].”
From Indian Medicinal Herbs and Formulations for Alzheimer’s Disease, from Traditional Knowledge to Scientific Assessment (2020) · cites this paper as [158]
Cites
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224 · see citing works
Nevalainen, H. K. M., & Peterson, R. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2014.00075 · Cited by 1,615 · see citing works
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,262 · see citing works
Self-citationDissecting molecular cross-talk between Nrf2 and NF-κB response pathways
Wardyn, J. D., Ponsford, A. H., & Sanderson, C. M. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150014 · Cited by 1,200 · cited 2× · see citing works
“Therefore, there are substantial interest to further research to understand possible cross talk mechanism(s) underlying regulation of NF-jB and the Nrf2 pathways (Wardyn et al. 2015).”
BackgroundCalabrese, V., Cornelius, C., Dinkova‐Kostova, A. T., Calabrese, E. J., & Mattson, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.3074 · Cited by 803 · see citing works
Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential
Paine, A., Eiz‐Vesper, B., Blasczyk, R., & Immenschuh, S. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.07.014 · Cited by 698 · see citing works
Steroidal Lactones from Withania somnifera, an Ancient Plant for Novel Medicine
Mirjalili, M. H., Moyano, E., Bonfill, M., Cusido, R. M., & Palazón, J. (2009) · Molecules · doi:10.3390/molecules14072373 · Cited by 657 · see citing works
African Journal of Traditional, Complementary and Alternative Medicines
Sa-Caputo, D. C., Dionello, C. D. F., Frederico, E. H. F. F., Paineiras- Domingos, L. L., Sousa-Gonçalves, C. R., Morel, D. S., Moreira-Marconi, E., Unger, M., & Bernardo-Filho, M. (2016) · African Journal of Traditional Complementary and Alternative Medicines · doi:10.21010/ajtcam · Cited by 605 · see citing works
An Overview on Ashwagandha: A Rasayana (Rejuvenator) of Ayurveda
Singh, N., Bhalla, M., De Jager, P., & Gilca, M. (2011) · African Journal of Traditional, Complementary and Alternative Medicines · doi:10.4314/ajtcam.v8i5s.9 · Cited by 544 · see citing works
Sublime Microglia: Expanding Roles for the Guardians of the CNS
Salter, M. W., & Beggs, S. (2014) · Cell · doi:10.1016/j.cell.2014.06.008 · Cited by 531 · see citing works
The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation
Innamorato, N. G., Rojo, A. I., García‐Yagüe, Á. J., Yamamoto, M. P., CEBALLOS, M. L. D., & Cuadrado, A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.1.680 · Cited by 479 · see citing works
Withania somnifera: an Indian ginseng
Kulkarni, S. K., & Dhir, A. (2008) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2007.09.011 · Cited by 416 · see citing works
Chen, Z., & Trapp, B. D. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13062 · Cited by 413 · see citing works
Scapagnini, G., Vasto, S., Nader, A. G., Caruso, C., Zella, D., & Galvano, F. (2011) · Molecular Neurobiology · doi:10.1007/s12035-011-8181-5 · Cited by 403 · see citing works
Pharmacologic overview of Withania somnifera, the Indian Ginseng
Dar, N. J., Hamid, A., & Ahmad, M. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2012-1 · Cited by 391 · see citing works
NRF2-regulation in brain health and disease: Implication of cerebral inflammation
Sandberg, M., Patil, J., D’Angelo, B., Weber, S. G., & Mallard, C. E. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.11.004 · Cited by 389 · see citing works
Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases
Gan, L., & Johnson, J. A. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.12.011 · Cited by 288 · see citing works
Chen, J.-C., Ho, F., Chao, P.-D. L., Chen, C., Jeng, K.-C. G., Hsu, H.-B., Lee, S. T., Wu, W. T., & Lin, W. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.08.005 · Cited by 266 · see citing works
The Nrf2-ARE Pathway: A Valuable Therapeutic Target for the Treatment of Neurodegenerative Diseases
Gururaj Joshi, A., & Johnson, J. A. (2012) · Recent Patents on CNS Drug Discovery · doi:10.2174/157488912803252023 · Cited by 246 · see citing works
Molecular insight in the multifunctional activities of Withaferin A
Berghe, W. V., Sabbe, L., Kaileh, M., Haegeman, G., & Heyninck, K. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.08.027 · Cited by 242 · see citing works
Botanical Phenolics and Brain Health
Sun, A. Y., Wang, Q., Simonyi, Á., & Sun, G. Y. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8052-z · Cited by 225 · see citing works
Self-citationTargeting Heme Oxygenase-1 for Neuroprotection and Neuroinflammation in Neurodegenerative Diseases
Jaźwa, A., & Cuadrado, A. (2010) · Current Drug Targets · doi:10.2174/1389450111009011517 · Cited by 209 · see citing works
Ven Murthy, M. R., K. Ranjekar, P., Ramassamy, C., & Deshpande, M. (2010) · Central Nervous System Agents in Medicinal Chemistry · doi:10.2174/1871524911006030238 · Cited by 178 · see citing works
Sun, G. Y., Chen, Z., Jasmer, K. J., Chuang, D. Y., Gu, Z., Hannink, M., & Simonyi, Á. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141509 · Cited by 177 · see citing works
Self-citationForesti, R., Bains, S. K., Pitchumony, T. S., Brás, L. E. D. C., Drago, F., Dubois‐Randé, J., Bucolo, C., & Motterlini, R. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.07.010 · Cited by 176 · see citing works
Nair, S., Doh, S. T., Chan, J. Y., Kong, A.-N., & Cai, L. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604703 · Cited by 167 · see citing works
Regulation of haeme oxygenase‐1 for treatment of neuroinflammation and brain disorders
Syapin, P. J. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.342 · Cited by 161 · see citing works
Sheng, W., Zong, Y., Mohammad, A., Ajit, D., Cui, J., Han, D., Hamilton, J. L., Simonyi, Á., Sun, A. Y., Gu, Z., et al. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-121 · Cited by 161 · see citing works
Self-citationLee, J., Jo, D., Park, D., Chung, H. Y., & Mattson, M. P. (2014) · Pharmacological Reviews · doi:10.1124/pr.113.007757 · Cited by 154 · see citing works
Kang, C.-H., Choi, Y. H., Moon, S.-K., Kim, W.-J., & Kim, G.-Y. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.09.009 · Cited by 138 · see citing works
Kim, H., Kang, C., Jayasooriya, R. G. P. T., Dilshara, M. G., Lee, S., Choi, Y. H., Seo, Y. T., & Kim, G. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.03.022 · Cited by 136 · see citing works
Vyas, A. R., & Singh, S. V. (2013) · The AAPS Journal · doi:10.1208/s12248-013-9531-1 · Cited by 132 · see citing works
Kuboyama, T., Tohda, C., & Komatsu, K. (2014) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b14-00022 · Cited by 127 · see citing works
Sulforaphane suppresses LPS-induced inflammation in primary rat microglia
Brandenburg, L., Kipp, M., Lucius, R., Pufe, T., & Wruck, C. J. (2009) · Inflammation Research · doi:10.1007/s00011-009-0116-5 · Cited by 126 · see citing works
Kurapati, K. R. V., Atluri, V., Samikkannu, T., & Nair, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077624 · Cited by 117 · see citing works
Durg, S., Dhadde, S. B., Vandal, R., Shivakumar, B. S., & Charan, C. S. (2015) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.12398 · Cited by 110 · see citing works
Chuang, D. Y., Simonyi, Á., Kotzbauer, P. T., Gu, Z., & Sun, G. Y. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0419-0 · Cited by 110 · see citing works
Self-citationThe clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders
Hybertson, B. M., Gao, B., & Doan, A. (2014) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s35078 · Cited by 110 · see citing works
Patil, D., Gautam, M., Mishra, S. K., Suresh, K., Gairola, S., Jadhav, S. S., Pawar, S., & Patwardhan, B. (2013) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2013.03.001 · Cited by 108 · see citing works
Withaferin A Alters Intermediate Filament Organization, Cell Shape and Behavior
Grin, B., Mahammad, S., Wedig, T., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039065 · Cited by 108 · see citing works
Kurapati, K. R. V., Atluri, V. S. R., Samikkannu, T., Garcia, G., & Nair, M. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01444 · Cited by 108 · see citing works
Oh, J. H., Lee, T.-J., Park, J., & Kwon, T. K. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.09.017 · Cited by 104 · see citing works
Carbon monoxide and the CNS : challenges and achievements
Queiroga, C. S. F., Vercelli, A., & Vieira, H. L. A. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12729 · Cited by 102 · see citing works
Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells
Chuang, D. Y., Chan, M., Zong, Y., et al. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-15 · Cited by 99 · see citing works
Immunoregulatory effects of HO-1: how does it work?
Soares, M. P., Marguti, I., Cunha, A., & Larsen, R. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.05.008 · Cited by 97 · see citing works
Parada, E., Buendía, I., Navarro, E., Avendaño, C., Egea, J., & López, M. G. (2015) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201500279 · Cited by 86 · see citing works
Shah, N., Singh, R., Sarangi, U., Saxena, N., Chaudhary, A., Kaur, G., Kaul, S. C., & Wadhwa, R. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120554 · Cited by 73 · see citing works
Min, K., Choi, K.-H., & Kwon, T. K. (2011) · International Immunopharmacology · doi:10.1016/j.intimp.2011.02.029 · Cited by 62 · see citing works
Inhibition of microglial activation by elderberry extracts and its phenolic components
Simonyi, Á., Chen, Z., Jiang, J., Zong, Y., Chuang, D. Y., Gu, Z., Lu, C., Fritsche, K. L., Greenlief, C. M., Rottinghaus, G. E., et al. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.01.037 · Cited by 53 · see citing works
Self-citationNootropic potential of Ashwagandha leaves: Beyond traditional root extracts
Wadhwa, R., Konar, A., & Kaul, S. C. (2015) · Neurochemistry International · doi:10.1016/j.neuint.2015.09.001 · Cited by 43 · see citing works
Terazawa, R., Akimoto, N., Kato, T., Itoh, T., Fujita, Y., Hamada, N., Deguchi, T., Iinuma, M., Noda, M., Nozawa, Y., et al. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.02.002 · Cited by 40 · see citing works
Jiang, J., Chuang, D. Y., Zong, Y., Patel, J., Brownstein, K. J., Lei, W., Lu, C., Simonyi, Á., Gu, Z., Cui, J., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089748 · Cited by 34 · see citing works
Self-citationGrunz‐Borgmann, E. A., Mossine, V. V., Fritsche, K. L., & Parrish, A. R. (2015) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-015-0958-z · Cited by 29 · see citing works
Self-citationNarayan, M., Seeley, K. W., & Jinwal, U. K. (2015) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2015.09.024 · Cited by 22 · see citing works
Ashkenazi, S., Plotnikov, A. N., Bahat, A., et al. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00895-15 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Natural Products as a Potential Modulator of Microglial Polarization in Neurodegenerative Diseases
Jin, X., Liu, M.-Y., Zhang, D.-F., Zhong, X., Du, K., Qian, P., Gao, H., & Wei, M.-J. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104253 · Cited by 109 · see citing works
Mehla, J., Gupta, P., Pahuja, M., Diwan, D., & Diksha, D. (2020) · Brain Sciences · doi:10.3390/brainsci10120964 · Cited by 108 · see citing works
- Authors
- Sun, G. Y., Li, R., Cui, J., Hannink, M., Gu, Z., Fritsche, K. L., Lubahn, D. B., & Simonyi, A.
- Affiliations
- University of Missouri (US)
- Corresponding author
- Sun, Grace Y.
- Venue
- NeuroMolecular Medicine
- Published
- 2016-05-21
- Volume
- 18
- Issue
- 3
- Pages
- 241-252
- ISSN
- 1535-1084 (ISSN-L)
- 1559-1174
- OpenAlex
- W2399040283
- Cited by
- 95
- References
- 55
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 11 · 2023: 11 · 2022: 10 · 2021: 11 · 2020: 16 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 1
- FWCI
- 12.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NeuroMolecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Complementary and Alternative Medicine (P50AT006273)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
- Health Sciences › Medicine › Pharmacology › Pharmacological Effects of Medicinal Plants
- Health Sciences › Medicine › Physiology › Biofield Effects and Biophysics
- Keywords
- Withania somnifera, withanolides, withaferin A, withanolide A, BV-2 cells, neuroinflammation, oxidative stress, Nrf2/HO-1 pathway, NF-κB signaling, nitric oxide, reactive oxygen species, lipopolysaccharide, filopodia, immunomodulation, neuroprotection, Ayurveda
- MeSH terms
- Animals, Cell Line, Gene Expression Regulation, Immunologic Factors, Plant Extracts, NF-kappa B, Microglia, Oxidative Stress, Neuroprotective Agents, Withania, NF-E2-Related Factor 2, Mice, Withanolides
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review