Skip to main content
SpringerLink
Log in

Withania somnifera Extract/Withaferin A as a Prospective Anti-pigmenting Agent

  • Chapter
  • First Online:
Science of Ashwagandha: Preventive and Therapeutic Potentials

  • 1201 Accesses

Abstract

A screening test was used to assess more than 400 kinds of herbal extracts and related chemicals for their ability to interrupt the endothelin (EDN)1- and/or stem cell factor (SCF)-activated interacellular signaling that leads to the increased activity of tyrosinase in normal human melanocytes (NHMs). A Withania somnifera extract (WSE) and one of its active compounds withaferin A (WFA) showed distinct abrogating effects on the EDN1- and SCF- stimulation of tyrosinase activity without any direct inhibitory effect on tyrosinase, which suggests that the WSE and WFA interrupt signaling pathways upstream of tyrosinase expression. In addition, in a co-culture system using UVB-exposed normal human keratinocytes (NHKs) and NHMs, WFA has a potent ability to abrogate the UVB-stimulated tyrosinase activity in NHMs by abolishing the increased secretion of the intrinsic melanogenic cytokine EDN1 in UVB-exposed NHKs as well as by interrupting signaling pathways upstream of tyrosinase expression in NHMs. Consistently, signaling analysis with immunoblots revealed that in WSE-treated human melanoma cells or NHMs in culture, there is a marked deficiency in the EDN1-stimulated phosphorylation of Raf-1, MEK, ERK, CREB and MITF at 15 min after EDN1 treatment. The absence of an inhibitory effect on EDN1-induced intracellular calcium mobilization in NHMs suggests that the WSE inhibits EDN1-triggered PKC activity and/or abolishes its activation. In NHMs treated with SCF, the WSE also has a distinct potential to abrogate the stimulated phosphorylation of ERK, MITF and CREB, but not of Raf-1 and MEK, which indicates that the WSE attenuates the SCF-triggered phosphorylation of ERK by inhibiting MEK kinase activity. In WFA-treated NHMs, there is a marked deficiency in the SCF-stimulated series of phosphorylations of c-KIT, Shc, Raf-1, MEK, ERK, CREB and MITF. Taken together, the analysis of SCF binding and the effect of dithiothreitol (DTT) revealed that WFA attenuates the SCF-induced activation of c-KIT in NHMs by interrupting the auto-phosphorylation of c-KIT through DTT-suppressible Michael addition thioalkylation reactions without interrupting the binding of SCF to the c-KIT receptor. In human epidermal equivalents consisting of multilayered NHKs and NHMs, addition of the WSE or WFA elicits a marked depigmenting effect on EDN1- or SCF-stimulated pigmentation accompanied by a significant decrease in eumelanin content. Real-time RT-PCR and Western blotting revealed that the stimulated expression of melanocyte-specific mRNAs and proteins, including tyrosinase and microphthalmia associated transcription factor (MITF), is significantly suppressed at days 7–10 of culture by the WSE and by WFA. The sum of these findings strongly suggests that the WSE and WFA can serve as potent melanogenic signaling-interruption type anti-pigmenting agents without any risk of hypopigmentation, thus they are prospective therapeutic candidates for treating hyperpigmentary disorders such as UVB-melanosis, solar lentigo and melasma where the over-expression of SCF and/or EDN1 is involved in the hyperpigmentation mechanism.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aalinkeel R, Hu Z, Nair BB, Sykes DE, Reynolds JL, Mahajan SD, Schwartz SA (2010) Genomic analysis highlights the role of the JAK-STAT signaling in the anti-proliferative effects of dietary flavonoid-‘Ashwagandha’ in prostate cancer cells. Evid Based Complement Alternat Med 7:177–187

    Article  PubMed  Google Scholar 

  • Abdel-Malek Z, Swope VB, Suzuki I, Akcali C, Harriger MD, Boyce ST, Urabe K, Hearing VJ (1995) Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci U S A 92:1789–1793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adams JD Jr, Yang J, Mishra LC, Singh BB (2002) Effects of Ashwagandha in a rat model of stroke. Altern Ther Health Med 8:18–19

    PubMed  Google Scholar 

  • Agarwal R, Diwanay S, Patki P, Patwardhan B (1999) Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extract in experimental immune inflammation. J Ethnopharmacol 67:27–35

    Article  CAS  PubMed  Google Scholar 

  • Ahmad M, Saleem S, Ahmad AS, Ansari MA, Yousuf S, Hoda MN, Islam F (2005) Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkisonism in rats. Hum Exp Toxicol 24:137–147

    Article  PubMed  Google Scholar 

  • Amae S, Fuse N, Yasumoto K, Sato S, Yajima I, Yamamoto H, Udono T, Durlu YK, Tamai M, Takahashi K, Shibahara S (1998) Identification of a novel isoform of microphthalmia-associated transcription factor that is enriched in retinal pigment epithelium. Biochem Biophys Res Commun 247:710–715

    Article  CAS  PubMed  Google Scholar 

  • An SM, Koh JS, Boo YC (2010) p-Coumaric acid not only inhibits human tyrosinase activity in vitro but also melanogenesis in cells exposed to UVB. Phytother Res 24:1175–1180

    CAS  PubMed  Google Scholar 

  • Ando H, Funasaka Y, Oka M, Ohashi A, Furumura M, Matsunaga J, Matsunaga N, Hearing VJ, Ichihashi M (1999) Possible involvement of proteolytic degradation of tyrosinase in the regulatory effect of fatty acids on melanogenesis. J Lipid Res 40:1312–1316

    CAS  PubMed  Google Scholar 

  • Bernier M, Kwon YK, Pandey SK, Zhu TN, Zhao RJ, Maciuk A, He HJ, Decabo R, Kole S (2006) Binding of manumycin A inhibits IkappaB kinase beta activity. J Biol Chem 281:2551–2561

    Article  CAS  PubMed  Google Scholar 

  • Blume-Jensen P, Claesson-Welsh L, Siegbahn A, Zsebo KM, Westermark B, Heldin CH (1991) Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J 10:4121–4128

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cha SH, Ko SC, Kim D, Jeon YJ (2011) Screening of marine algae for potential tyrosinase inhibitor: those inhibitors reduced tyrosinase activity and melanin synthesis in zebrafish. J Dermatol 38:354–363

    Article  CAS  PubMed  Google Scholar 

  • Chi H, Barry SP, Roth RJ, Wu JJ, Jones EA, Bennett AM, Flavell RA (2006) Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci U S A 103:2274–2279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung KW, Park YJ, Choi YJ, Park MH, Ha YM, Uehara Y, Yoon JH, Chun P, Moon HR, Chung HY (2012) Evaluation of in vitro and in vivo anti-melanogenic activity of a newly synthesized strong tyrosinase inhibitor (E)-3-(2,4 dihydroxybenzylidene)pyrrolidine- 2,5-dione (3-DBP). Biochim Biophys Acta 1820:962–969

    Article  CAS  PubMed  Google Scholar 

  • Codreanu SG, Adams DG, Dawson ES, Wadzinski BE, Liebler DC (2006) Inhibition of protein phosphatase 2A activity by selective electrophile alkylation damage. Biochemistry 45:10020–10029

    Article  CAS  PubMed  Google Scholar 

  • Cutler RL, Liu L, Damen JE, Krystal G (1993) Multiple cytokines induce the tyrosine phosphorylation of Shc and its association with Grb2 in hemopoietic cells. J Biol Chem 268:21463–21465

    CAS  PubMed  Google Scholar 

  • Devi PU, Sharada AC, Solomon FE, Kamath MS (1992) In vivo growth inhibitory effect of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, sarcoma 180. Indian J Exp Biol 30:169–172

    CAS  PubMed  Google Scholar 

  • Devi PU, Sharada AC, Solomon FE (1995) In vivo growth inhibitory and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma. Cancer Lett 95:189–193

    Article  CAS  PubMed  Google Scholar 

  • Devi PU, Akagi K, Ostapenko V, Tanaka Y, Sugahara T (1996) Withaferin A: a new radiosentizer form the Indian medicinal plant Withania somnifera. Int J Radiat Biol 69:193–197

    Article  CAS  PubMed  Google Scholar 

  • Devi PU, Kamath R, Rao BS (2000) Radiosensitization of a mouse melanoma by withaferin A: in vivo studies. Indian J Exp Biol 38:432–437

    CAS  PubMed  Google Scholar 

  • Emami S, Hosseinimehr SJ, Shahrbandi K, Enayati AA, Esmaeeli Z (2012) Synthesis and evaluation of 2(3H)-thiazole thiones as tyrosinase inhibitors. Arch Pharm 345:629–637

    Article  CAS  Google Scholar 

  • Foley TD, Armstrong JJ, Kupchak BR (2004) Identification and H2O2 sensitivity of the major constitutive MAPK phosphatase from rat brain. Biochem Biophys Res Commun 315:568–574

    Article  CAS  PubMed  Google Scholar 

  • Gupta SK, Mohanty I, Talwar KK, Dinda A, Joshi S, Bansal P, Saxena A, Arya DS (2004) Cardioprotection from ischemia and reperfusion injury by Withania somnifera: a hemodynamic, biochemical and histopathological assessment. Mol Cell Biochem 260:39–47

    Article  PubMed  Google Scholar 

  • Hachiya A, Kobayashi A, Ohuchi A, Takema Y, Imokawa G (2001) The paracrine role of stem cell factor/c-kit signaling in the activation of human melanocytes in ultraviolet-B-induced pigmentation. J Invest Dermatol 116:578–586

    Article  CAS  PubMed  Google Scholar 

  • Hachiya A, Kobayashi A, Yoshida Y, Kitahara T, Takema Y, Imokawa G (2004) Biphasic expression of two paracrine melanogenic cytokines, stem cell factor and endothelin-1, in ultraviolet B-induced human melanogenesis. Am J Pathol 165:2099–2109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hattori H, Kawashima M, Ichikawa Y, Imokawa G (2004) The epidermal stem cell factor is over-expressed in lentigo senilis: implication for the mechanism of hyperpigmentation. J Invest Dermatol 122:1256–1265

    Article  CAS  PubMed  Google Scholar 

  • Hehner SP, Hofmann TG, Dröge W, Schmitz ML (1999) The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. J Immunol 163:5617–5623

    CAS  PubMed  Google Scholar 

  • Humphries KM, Deal MS, Taylor SS (2005) Enhanced dephosphorylation of cAMP-dependent protein kinase by oxidation and thiol modification. J Biol Chem 280:2750–2758

    Article  CAS  PubMed  Google Scholar 

  • Ichikawa H, Takada Y, Shishodia S, Jayaprakasam B, Nair MG, Aggarwal BB (2006) Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-nB (NF-nB) activation and NF-nB-regulated gene expression. Mol Cancer Ther 5:1434–1445

    Article  CAS  PubMed  Google Scholar 

  • Imokawa G (2014) Mechanistic difference and similarity compared to occupational vitiligo and vitiligo vulgaris. Fragr J 9:41–54

    Google Scholar 

  • Imokawa G, Ishida K (2014) Inhibitors of intracellular signaling pathways that lead to stimulated epidermal pigmentation: perspective of anti-pigmenting agents. Int J Mol Sci 15:8293–8315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imokawa G, Yada Y, Miyagishi M (1992) Endothelins secreted from human keratinocytes are intrinsic mitogens for human melanocytes. J Biol Chem 267:24675–24680

    CAS  PubMed  Google Scholar 

  • Imokawa G, Miyagishi M, Yada Y (1995) Endothelin-1 as a new melanogen: coordinated expression of its gene and the tyrosinase gene in UVB-exposed human epidermis. J Invest Dermatol 105:32–37

    Article  CAS  PubMed  Google Scholar 

  • Imokawa G, Yada Y, Kimura M (1996) Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes. Biochem J 314:305–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imokawa G, Kobayashi T, Miyagishi M, Higashi K, Yada Y (1997) The role of endothelin-1 in epidermal hyperpigmentation and signaling mechanisms of mitogenesis and melanogenesis. Pigment Cell Res 10:218–228

    Article  CAS  PubMed  Google Scholar 

  • Imokawa G, Yada Y, Morisaki N, Kimura M (1998) Biological characterization of human fibroblast-derived mitogenic factors for human melanocytes. Biochem J 330:1235–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imokawa G, Kobayasi T, Miyagishi M (2000) Intracellular signaling mechanisms leading to synergistic effects of endothelin-1 and stem cell factor on proliferation of cultured human melanocytes cross-talk via trans-activation of the tyrosine kinase c-kit receptor. J Biol Chem 275:33321–33328

    Article  CAS  PubMed  Google Scholar 

  • Ito S, Fujita K (1985) Microanalysis of eumelanin and pheomelanin in hair and melanomas by chemical degradation and liquid chromatography. Anal Biochem 144:527–536

    Article  CAS  PubMed  Google Scholar 

  • Kadono S, Manak I, Kawashima M, Kobayashi T, Imokawa G (2001) The role of the epidermal endothelin cascade in the hyperpigmentation mechanism of lentigo senilis. J Invest Dermatol 116:571–577

    Article  CAS  PubMed  Google Scholar 

  • Kaileh M, Vanden Berghe W, Heyerick A, Horion J, Piette J, Libert C, De Keukeleire D, Malik F, Kumar A, Bhushan S, Khan S, Bhatia A, Suri KA, Qazi GN, Singh J (2007) Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity. J Biol Chem 82:4253–4264

    Article  Google Scholar 

  • Kang HY, Hwang JS, Lee JY, Ahn JH, Kim JY, Lee ES, Kang WH (2006) The dermal stem cell factor and c-kit are overexpressed in melasma. Br J Dermatol 154:1094–1099

    Article  CAS  PubMed  Google Scholar 

  • Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C (2010) Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther 9:202–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR (1993) Protein kinase Cα activates RAF-1 by direct phosphorylation. Nature 364:249–252

    Article  CAS  PubMed  Google Scholar 

  • Kray AE, Carter RS, Pennington KN, Gomez RJ, Sanders LE, Llanes JM, Llanes JM, Khan WN, Ballard DW, Wadzinski BE (2005) Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A. J Biol Chem 280:35974–35982

    Article  CAS  PubMed  Google Scholar 

  • Lennartsson J, Blume-Jensen P, Hermanson M, Pontén E, Carlberg M, Rönnstrand L (1999) Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction. Oncogene 18:5546–5553

    Article  CAS  PubMed  Google Scholar 

  • Liang MC, Bardhan S, Li C, Pace EA, Porco JA Jr, Gilmore TD (2003) Jesterone dimer, a synthetic derivative of the fungal metabolite jesterone, blocks activation of transcription factor nuclear factor kappaB by inhibiting the inhibitor of kappaB kinase. Mol Pharmacol 64:123–131

    Article  CAS  PubMed  Google Scholar 

  • Liang MC, Bardhan S, Pace EA, Rosman D, Beutler JA, Porco JA Jr, Gilmore TD (2006) Inhibition of transcription factor NF-kappaB signaling proteins IKKbeta and p65 through specific cysteine residues by epoxyquinone A monomer: correlation with its anti-cancer cell growth activity. Biochem Pharmacol 71:634–645

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Damen JE, Cutler RL, Krystal G (1994) Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc. Mol Cell Biol 14:6926–6935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malik F, Kumar A, Bhushan S, Khan S, Bhatia A, Suri KA, Qazi GN, Singh J (2007) 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 12:2115–2133

    Article  CAS  PubMed  Google Scholar 

  • Mandal C, Dutta A, Mallick A, Chandra S, Misra L, Sangwan RS, Mandal C (2008) 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 13:1450–1464

    Article  CAS  PubMed  Google Scholar 

  • Marais R, Light Y, Mason C, Paterson H, Olson MF, Marshall CJ (1998) Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C. Science 280:109–112

    Article  CAS  PubMed  Google Scholar 

  • Mason CS, Springer CJ, Cooper RG, Superti-Furga G, Marshall CJ, Marais R (1999) Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J 18:2137–2148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mulabagal V, Subbaraju GV, Rao CV, Sivaramakrishna C, Dewitt DL, Holmes D, Sung B, Aggarwal BB, Tsay HS, Nair MG (2009) Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferation. Phytother Res 23:987–992

    Article  CAS  PubMed  Google Scholar 

  • Na HK, Surh YJ (2006) Transcriptional regulation via cysteine thiol modification: a novel molecular strategy for chemoprevention and cytoprotection. Mol Carcinog 45:368–380

    Article  CAS  PubMed  Google Scholar 

  • Nakajima H, Wakabayashi Y, Wakamatsu K, Imokawa G (2011a) An extract of Melia toosendan attenuates endothelin-1-stimulated pigmentation in human epidermal equivalents through the interruption of PKC activity within melanocytes. Arch Dermatol Res 303:263–276

    Google Scholar 

  • Nakajima H, Wakabayashi Y, Wakamatsu K, Imokawa G (2011b) An extract of Withania somnifera attenuates endothelin-1-stimulated pigmentation in human epidermal equivalents through the interruption of PKC activity within melanocytes. Phytother Res 25:1398–1411

    Google Scholar 

  • Nakajima H, Ezaki Y, Nagai T, Yoshioka R, Imokawa G (2012a) Epithelial-mesenchymal interaction during UVB-induced up-regulation of neutral endopeptidase. Biochem J 443:297–305

    Article  CAS  PubMed  Google Scholar 

  • Nakajima H, Fukazawa K, Wakabayashi Y, Wakamatsu K, Imokawa G (2012b) Withania somnifera extract attenuates stem cell factor-stimulated pigmentation in human epidermal equivalents through interruption of ERK phosphorylation within melanocytes. J Nat Med 66:435–446

    Article  PubMed  Google Scholar 

  • Nakajima H, Fukazawa K, Wakabayashi Y, Wakamatsu K, Senda K, Imokawa G (2012c) Abrogating effect of a xanthophyll carotenoid astaxanthin on the stem cell factor-induced stimulation of human epidermal pigmentation. Arch Dermatol Res 304:803–816

    Article  CAS  PubMed  Google Scholar 

  • Niwano T, Terazawa S, Nakajima H, Wakabayashi Y, Imokawa G (2015) Astaxanthin and withaferin A block paracrine cytokine interactions between UVB-exposed human keratinocytes and human melanocytes via the attenuation of endothelin-1 secretion and its downstream intracellular signaling. Cytokine 73:184–197

    Article  CAS  PubMed  Google Scholar 

  • Noh JM, Kwak SY, Kim DH, Lee YS (2007) Kojic acid-tripeptide amide as a new tyrosinase inhibitor. Biopolymers 88:300–307

    Article  CAS  PubMed  Google Scholar 

  • Oh JH, Kwon TK (2009) 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 9:614–619

    Article  CAS  PubMed  Google Scholar 

  • Oh JH, Lee TJ, Park JW, Kwon TK (2008) 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 599:11–17

    Article  CAS  PubMed  Google Scholar 

  • Owais M, Sharad KS, Shehbaz A, Saleemuddin M (2005) Antibacterial efficacy of Withania somnifera (Ashwagandha) an indigenous medicinal plant against experimental murine salmonellosis. Phytomedicine 12:229–235

    Article  CAS  PubMed  Google Scholar 

  • Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M (2001) An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway. J Invest Dermatol 116:587–595

    Article  CAS  PubMed  Google Scholar 

  • Peyregne VP, Kar S, Ham SW, Wang M, Wang Z, Carr BI (2005) Novel hydroxyl naphthoquinones with potent Cdc25 antagonizing and growth inhibitory properties. Mol Cancer Ther 4:595–602

    Article  CAS  PubMed  Google Scholar 

  • Prajapati S, Verma U, Yamamoto Y, Kwak YT, Gaynor RB (2004) Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity. J Biol Chem 279:1739–1746

    Article  CAS  PubMed  Google Scholar 

  • Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens R, Zhu C, Louis-dit-Sully C, Moutschen M, Jiang W, Mustelin T (2006) Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat Cell Biol 8:524–531

    Article  CAS  PubMed  Google Scholar 

  • Rasool M, Varalakshmi P (2006) Immunomodulatory role of Withania somnifera root powder on experimental induced inflammation: an in vivo and in vitro study. Vasc Pharmacol 44:406–410

    Article  CAS  Google Scholar 

  • Reynaert NL, van der Vliet A, Guala AS, McGovern T, Hristova M, Pantano C, Heintz NH, Heim J, Ho YS, Matthews DE, Wouters EF, Janssen-Heininger YM (2006) Dynamic redox control of NF-kappaB through glutaredoxin-regulated S-glutathionylation of inhibitory kappaB kinase beta. Proc Natl Acad Sci U S A 103:13086–13091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosazza JP, Nicholas AW, Gustafson ME (1978) Microbial transformations of natural antitumor agents. 7. 14-alpha-hydroxylation of withaferin-A by Cunninghamella elegans (NRRL 1393). Steroids 31:671–679

    Article  CAS  PubMed  Google Scholar 

  • Salojin KV, Owusu IB, Millerchip KA, Potter M, Platt KA, Oravecz T (2006) Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol 176:1899–1907

    Article  CAS  PubMed  Google Scholar 

  • Sato-Jin K, Nishimura EK, Akasaka E, Huber W, Nakano H, Miller A, Du J, Wu M, Hanada K, Sawamura D, Fisher DE, Imokawa G (2008) Epistatic connections between MITF and endothelin signaling in Waardenburg syndrome and other pigmentary disorders. FASEB J 22:1155–1168

    Article  CAS  PubMed  Google Scholar 

  • Schonwasser DC, Marais RM, Marshall CJ, Parker PJ (1998) Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol 18:790–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sen N, Banerjee B, Das BB, Ganguly A, Sen T, Pramanik S, Mukhopadhyay S, Majumder HK (2007) Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex. Cell Death Differ 14:358–367

    Article  CAS  PubMed  Google Scholar 

  • Seth D, Rudolph J (2006) Redox regulation of MAP kinase phosphatase 3. Biochemistry 45:8476–8487

    Article  CAS  PubMed  Google Scholar 

  • Shin HM, Lee YR, Chang YS, Lee JY, Kim BH, Min KR, Kim Y (2006) Suppression of interleukin-6 production in macrophages by furonaphthoquinone NFD-37. Int Immunopharmacol 6:916–923

    Article  CAS  PubMed  Google Scholar 

  • Singh D, Aggarwal A, Maurya R, Naik S (2007) Withania somnifera inhibits NF-kB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells. Phytother Res 21:905–913

    Article  CAS  PubMed  Google Scholar 

  • Srinivasan S, Ranga RS, Burikhanov R, Han SS, Chendil D (2007) Par-4-dependent apoptosis by the dietary compound withaferin A in prostate cancer cells. Cancer Res 67:246–253

    Article  CAS  PubMed  Google Scholar 

  • Suzuki I, Cone RD, Im S, Nordlund J, Abdel-Malek ZA (1996) Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. Endocrinology 137:1627–1633

    Article  CAS  PubMed  Google Scholar 

  • Terazawa S, Nakajima H, Fukasawa K, Imokawa G (2015) Withaferin A abolishes the stem cell factor-stimulated pigmentation of human epidermal equivalents by interrupting the autophosphorylation of c-KIT in human melanocytes. Arch Dermatol Res 307:73–88

    Article  CAS  PubMed  Google Scholar 

  • Troppmair J, Bruder JT, App H, Cai H, Liptak L, Szeberényi J (1992) Ras controls coupling of growth factor receptors and protein kinase C in the membrane to Raf-1 and B-Raf protein serine kinases in the cytosol. Oncogene 7:1867–1873

    CAS  PubMed  Google Scholar 

  • Ueda K, Usui T, Nakayama H, Ueki M, Takio K, Ubukata M, Osada H (2002) 4-Isoavenaciolide covalently binds and inhibits VHR, a dual-specificity phosphatase. FEBS Lett 525:48–52

    Article  CAS  PubMed  Google Scholar 

  • Vasudevan SA, Skoko J, Wang K, Burlingame SM, Patel PN, Lazo JS, Nuchtern JG, Yang J (2005) MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. Biochem Biophys Res Commun 330:511–518

    Article  CAS  PubMed  Google Scholar 

  • Vontzalidou A, Zoidis G, Chaita E, Makropoulou M, Aligiannis N, Lambrinidis G, Mikros E, Skaltsounis AL (2012) Design, synthesis and molecular simulation studies of dihydrostilbene derivatives as potent tyrosinase inhibitors. Bioorg Med Chem Lett 22:5523–5526

    Article  CAS  PubMed  Google Scholar 

  • Wan P, Hu Y, He L (2011) Regulation of melanocyte pivotal transcription factor MITF by some other transcription factors. Mol Cell Biochem 354:241–246

    Article  CAS  PubMed  Google Scholar 

  • Winder AJ, Harris H (1991) New assays for the tyrosine hydroxylase and dopa oxidase activities of tyrosinase. Eur J Biochem 198:317–326

    Article  CAS  PubMed  Google Scholar 

  • Yada Y, Higuchi K, Imokawa G (1991) Effects of endothelins on signal transduction and proliferation in human melanocytes. J Biol Chem 266:18352–18357

    CAS  PubMed  Google Scholar 

  • Yang H, Shi G, Dou QP (2007) The tumor proteasome is a primary target for the natural anticancer compound Withaferin A isolated from Indian winter cherry. Mol Pharmacol 71:426–437

    Article  CAS  PubMed  Google Scholar 

  • Yokota Y, Bargagna-Mohan P, Ravindranath PP, Kim KB, Mohan R (2006) Development of withaferin A analogs as probes of angiogenesis. Bioorg Med Chem Lett 16:2603–2607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Institute for Biological Functions, Chubu University, 1200 Matsumoto, Kasugai, Aichi, 4878501, Japan

    Genji Imokawa

Authors
  1. Genji Imokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Genji Imokawa .

Editor information

Editors and Affiliations

  1. DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki, Japan

    Sunil C. Kaul

  2. DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki, Japan

    Renu Wadhwa

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Imokawa, G. (2017). Withania somnifera Extract/Withaferin A as a Prospective Anti-pigmenting Agent. In: Kaul, S., Wadhwa, R. (eds) Science of Ashwagandha: Preventive and Therapeutic Potentials. Springer, Cham. https://doi.org/10.1007/978-3-319-59192-6_6

Download citation

Publish with us

Policies and ethics

Search

Navigation