Melanogenesis In B16 Melanoma Cells Research Articles

Anti-melanogenic effects of glucosylceramides and elasticamide derived from rice oil by-products in melanoma cells, melanocytes, and human skin.

Glucosylceramides (GlcCer), which are present in many edible plants, suppress melanin production in mouse melanocytes. Rice GlcCer consist of multiple molecules that comprise different types of sphingoid bases as well as diverse lengths and stereotypes of free fatty acids. Adjacent to the GlcCer fraction, there are free ceramides (Cer) as minor constituents. However, the anti-melanogenic activities of individual GlcCer and Cer remain unknown. Therefore, we herein isolated 13 GlcCer and elasticamide, a Cer [AP] from the gummy by-products of rice bran oil, and examined their anti-melanogenic activities. In theophylline-induced melanogenesis in B16 melanoma cells, GlcCer [d18:2(4E,8Z)/18:0], GlcCer [d18:2(4E,8Z)/20:0], and elasticamide significantly suppressed melanin production with IC50 values of 6.6, 5.2, and 3.9μM, respectively. Elasticamide, but not GlcCer [d18:2 (4E,8Z)/20:0], suppressed melanogenesis in human 3D-cultured melanocytes and the expression of tyrosinase-related protein 1 in normal human melanocytes. Based on these results, we conducted a clinical trial on the effects of rice ceramide extract (Oryza ceramide®), containing 1.2mg/day of GlcCer and 56 μg/day of elasticamide, on UV-B-induced skin pigmentation. The ingestion of Oryza ceramide® for 8 weeks significantly suppressed the accumulation of melanin 7 days after UV irradiation (1288 and 1546 mJ/cm2 ·S). Rice-derived GlcCer and elasticamide, which exhibited anti-melanogenic activities, were suggested to contribute to the suppressive effects of Oryza ceramide® on UV-induced skin pigmentation. Although the mechanisms underlying the anti-melanogenic activities of GlcCer remain unclear, elasticamide was identified as a promising Cer that exhibits anti-melanogenic activity. PRACTICAL APPLICATIONS: The anti-melanogenic activities of rice-derived GlcCer and elasticamide currently remain unclear. We herein demonstrated the inhibitory effects of individual GlcCer and elasticamide on melanogenesis in melanoma cells, melanocytes, and human skin.

Elucidation of Melanogenesis-Associated Signaling Pathways Regulated by Argan Press Cake in B16 Melanoma Cells.

The beneficial effect on health of argan oil is recognized worldwide. We have previously reported that the cake that remains after argan oil extraction (argan press-cake or APC) inhibits melanogenesis in B16 melanoma cells in a time-dependent manner without cytotoxicity. In this study, the global gene expression profile of B16 melanoma cells treated with APC extract was determined in order to gain an understanding of the possible mechanisms of action of APC. The results suggest that APC extract inhibits melanin biosynthesis by down-regulating microphthalmia-associated transcription factor (Mitf) and its downstream signaling pathway through JNK signaling activation, and the inhibition of Wnt/β-catenin and cAMP/PKA signaling pathways. APC extract also prevented the transport of melanosomes by down-regulating Rab27a expression. These results suggest that APC may be an important natural skin whitening product and pharmacological agent used for clinical treatment of pigmentary disorders.

Inhibitory Effect and Mechanism of Scutellarein on Melanogenesis

Fairer skin is preferred in many Asian countries and there is a high demand for skin whitening and lightening products. However, in recent years, problems related to the safety of using whitening agents have emerged. This study demonstrates that plant-derived scutellarein effectively inhibits melanogenesis in B16 melanoma cells. However, baicalein, which is similar to scutellarein in its chemical structure, does not show any inhibitory effect on melanogenesis. Cellular tyrosinase activity is decreased by scutellarein in a dose-dependent manner. No cytotoxicity is observed at the effective concentration range. Additionally, both the protein and mRNA levels of tyrosinase are significantly decreased by scutellarein. Further, the risk of leukoderma development also is determined by evaluating the production of free hydroxyl radicals (˙OH); scutellarein treatment does not induce ˙OH production. Scutellarein shows no risk of causing leukoderma. Our results suggest that scutellarein or plant extracts containing high concentrations of scutellarein have the potential to inhibit melanin production and serve as cosmetic skin-lightening agents.

Melanogenesis Promoting Effect, Antioxidant Activity, and UPLC-ESI-HRMS Characterization of Phenolic Compounds of Argan Leaves Extract.

The use of natural products for the regulation of skin pigmentation is gaining popularity. In the present study, we evaluated the effect of argan leaves extract (ALE) on melanogenesis in B16 melanoma cells, determined its antioxidant activity, then quantified and identified its phenolic components. B16 cells were treated with various concentrations of ALE, then the cell viability and proliferation were assessed using MTT assay while the melanin content was determined using spectrophotometric methods. The expression level of tyrosinase (TYR), tyrosinase related protein-1 (TRP-1) and dopachrome tautomerase (DCT) was evaluated by Western blotting. The antioxidant activity of ALE was investigated using four different assays while UPLC-ESI-HRMS analysis was used to characterize the ALE phenolic profile. Fourteen phenolic compounds were identified, of which six are reported for the first time to be present in ALE. ALE treatment increases the melanin content of B16 cells in a dose-dependent manner without cytotoxicity. This was revealed by the observed ALE-increased expression level of TYR, DCT, and TRP-1. These bioactivities may be mainly attributed to its high flavonoids content. Argan leaves have the potential for use as a treatment for hypopigmentation disorders and as a bioactive component of cosmetic products that aim to increase pigmentation.

Oxyresveratrol inhibits cellular tyrosinase-related oxidative stress-induced melanogenesis in B16 melanoma cells

Ionic Liquid-based Microwave-Assisted Extraction (Il-MAE) of Oxyresveratrol from Morus alba RootsMazaya Fadhila, Abdul Mun’im, Mahdi Jufri

ROS-scavenging and Anti-tyrosinase Properties of Crocetin on B16F10 Murine Melanoma Cells.

Crocus sativus (Iridaceae) has been traditionally used in the Iranian folk medicine and as a culinary additive. Major components of the plant that are responsible for biological properties are saffranal, crocin, picrocrocin and crocetin. Although the level of crocetin is not high, some of the important activities of saffron such as antioxidant activity have been attributed to crocetin. In the present study, we investigated the effects of crocetin on melanogenesis in B16 melanoma cells. The effect of crocetin on intracellular and mushroom tyrosinase activity and the content of melanin was evaluated spectrophotometrically. Tyrosinase and Microphthalmia-Associated Transcription Factor (MITF) protein levels were compared between Crocetin-treated and control cells after western blot analysis. The antioxidative activity of crocetin was also investigated. Crocetin could inhibit mushroom tyrosinase activity and lower the amount of melanin in B16 melanoma cells. Protein levels of tyrosinase and MITF were also decreased by crocetin. Crocetin also showed antioxidant activity and depleted cellular Reactive Oxygen Species (ROS) content but had no cytotoxicity in alamarBlue® assay. Taken together, decreased tyrosinase activity, melanin content, tyrosinase and MITF proteins levels, and ROS production showed the inhibition of melanogenesis in B16F10 cells by crocetin. Hence, crocetin could be suggested as a potential dermatological whitening agent in skin care products.

Inhibitory effect of Buah Merah oil on melanogenesis via degradation of tyrosinase

Buah Merah ( Pandanus conoideus ) is exclusively distributed in Papua island and its neighboring areas. The extract oil from fruits (Buah Merah oil) contains rich in lipids, carotenoids and vitamin E. We assessed the effects of Buah Merah oil on melanogenesis in B16 melanoma cells. In the presence of alpha-melanocyte stimulating hormone (α-MSH), B16 melanoma cells are stimulated to enhance melanin synthesis. Buah Merah oil inhibited α-MSH-induced melanin synthesis with no cytotoxicity. This decrease in melanogenesis was correlated with reduced enzyme activity and decreased protein expression levels of tyrosinase. Tyrosinase is a type 1 membrane glycoprotein that is the critical rate-limiting enzyme involved in melanin synthesis. Furthermore, the Buah Merah oil-induced decrease in melanin content was accompanied by a decrease in the amount and activity of tyrosinase whereas the mRNA level of tyrosinase was unchanged. Moreover, treatment with proteasome inhibitor MG132 blocked the down-regulation of melanogenesis by Buah Merah oil. Immunoprecipitation analysis also revealed that treatment with Buah Merah oil modulated the ubiquitination of tyrosinase, that is Buah Merah oil increased the amount of ubiquitinated tyrosinase. Taken together, the present results indicate that the depigmenting effect of Buah Merah oil might be due to inhibition of tyrosinase expression through the ubiquitin proteasome-mediated degradation of tyrosinase.

Novel Furocoumarin Derivatives Stimulate Melanogenesis in B16 Melanoma Cells by Up-Regulation of MITF and TYR Family via Akt/GSK3β/β-Catenin Signaling Pathways.

The extracts of Ficuscarica L. and Psoralen corylifolia L. are traditional Uygur medicines for the treatment of vitiligo, and its active ingredients furocoumarins, were are found to be the most effective agents against this skin disorder nowadays. Therefore, a series of novel easter derivatives (8a–8p) of furocoumarin were designed and synthesized based on our previous research to improve this activity in the present study. The synthesized derivatives were biologically evaluated for melanin synthesis in murine B16 cells and the SAR (structure-activity relationship) was summarized. Eight derivatives were more potent than positive control (8-MOP, 8-methoxypsoralan), especially compounds 8n (200%) and 8o (197%), which were nearly 1.5-fold potency when compared with 8-MOP (136%). Furthermore, the signaling pathway by which 8n activates the melanin biosynthesis was defined. Our results showed that it not only elevated the melanin content, but also stimulated the activity of tyrosinasein a concentration-dependent manner. Increasing of phosphorylation of Akt (also named PKB, protein kinase B) and non-activated GSK3β (glycogen synthase kinase 3 beta), which inhibited the degradation of β-catenin were observed through Western blot analysis. The accumulation of β-catenin probably led to the activation of transcription of MITF (microphthalmia-associated transcription factor) and TYR (tyrosinase) family, as well as the subsequent induction of melanin synthesis.

Biological Activities of Phenolics from the Fruits of Phyllanthus emblica L. (Euphorbiaceae)

Seven phenolic compounds, 1 - 7, including a new organic acid gallate, mucic acid 1-ethyl 6-methyl ester 2-O-gallate (7), were isolated from the MeOH extract of the fruits of Phyllanthus emblica L. (Euphorbiaceae). The structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluated for their antioxidant abilities by 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), and ferric reducing antioxidant power (FRAP) assays. The inhibitory activities against melanogenesis in B16 melanoma cells induced by α-MSH, as well as cytotoxic activities against four human cancer cell lines were also evaluated. All phenolic compounds, 1 - 7, exhibited potent antioxidant abilities (DPPH: IC50 5.6 - 12.9 μm; ABTS: 0.87 - 8.43 μm Trolox/μm; FRAP: 1.01 - 5.79 μm Fe2+ /μm, respectively). Besides, 5 - 7, also exhibited moderate inhibitory activities against melanogenesis (80.7 - 86.8% melanin content), even with no or low toxicity to the cells (93.5 - 101.6% cell viability) at a high concentration of 100 μm. Compounds 1 - 3 exhibited cytotoxic activity against one or more cell lines (IC50 13.9 - 68.4%), and compound 1 with high tumor selectivity for A549 (SI 3.2).

Antimelanogenic Effect of Urolithin A and Urolithin B, the Colonic Metabolites of Ellagic Acid, in B16 Melanoma Cells.

Antimelanogenic agents from natural sources have been widely investigated. Urolithin A (UA) and B (UB), the main gut microflora metabolites of dietary ellagic acid derivatives, have various bioactivities such as anti-inflammatory and antiaging effects. In this study, the metabolites were found to possess depigmentation efficacy by suppressing tyrosinase activity. Both UA and UB could attenuate melanogenesis in B16 melanoma cells to 55.1 ± 3.8 and 76.4 ± 17.4% of control at noncytotoxic dosage, 10 μM, respectively. UA showed comparable efficacy to positive control, 5 μM of kojic acid treatment (51.2 ± 7.8). RT-PCR results revealed that UA and UB inhibited melanin formation by affecting the catalytic activity of tyrosinase rather than its mRNA expression. Kinetics for UA and UB on tyrosinase activity revealed that their inhibition behavior toward cellular tyrosinase involved competitive inhibition. UA and UB may be potent tyrosinase inhibitors and they possess significant antimelanogenesis ability as novel skin-whitening ingredients.

Triterpenoid saponins from Polaskia chichipe Backbg. and their inhibitory or promotional effects on the melanogenesis of B16 melanoma cells.

Five new oleanane-type saponins 1-5 together with a known saponin 6 and a steroidal glycoside 7 were isolated from Polaskia chichipe Backbg., and their structures were determined from their 1D and 2D NMR and HRFABMS spectral data. The six isolated saponins 1-6 were tested for their effects on the melanogenesis of B16 melanoma 4A5 cells. Compound 1 exerted an inhibitory effect at 100μM whereas compound 3 promoted melanogenesis at the same concentration, even though these two compounds contain the same aglycon structure. The dose-dependent activities of compounds 1 and 3 on melanin synthesis were investigated.

Inhibition of AGE-induced Melanogenesis in B16 Melanoma Cells by Iridoid-containing Plants

Inhibition of AGE-induced Melanogenesis in B16 Melanoma Cells by Iridoid-containing Plants

Melanogenesis-Inhibitory Activities of Isomeric C-seco Limonoids and Deesterified Limonoids.

Treatment of eight C-seco limonoids including six of salannin-type, 1 - 6, and two of nimbin-type, 7 and 8, with a combination of BF3 · Et2 O and iodide ion yielded the isomeric C-seco derivatives, i.e., six isosalannins, 1a - 6a, and two isonimbins, 7a and 8a, respectively. Ohchinin (1) was further subjected to LiAlH4 reduction which yielded a deesterified trihydroxy limonoid, nimbidinol (9). In addition, ten limonoids including seven of azadirone-type, 10 - 16, and three of gedunin-type, 17 - 19, all of which possess no ester functionality in the molecule, were obtained from the neutral fraction of Azadirachta indica seed extract after alkaline hydrolysis. Among the above, twelve compounds, i.e., 1a - 4a, 6a, 9, 13 - 16, 18, and 19, were new compounds, and their structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of all these limonoids for their inhibitory activities against melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), five structurally modified limonoids, 3-deacetyl-28-oxosalannin (6a), 9, 17-epi-17-hydroxynimbocinol (14), 17-epi-17-hydroxy-15-methoxynimbocinol (15), and 7-deacetyl-17-epinimolicinol (18), in addition to a natural limonoid, 1, exhibited potent inhibitory activities with 26 - 66% reduction of melanin content at 100 μm concentration with almost no or low toxicity to the B16 melanoma cells (70 - 99% cell viability at 100 μm).

Evaluation of antioxidant and anti-melanogenic activities of different extracts from aerial parts of Nepeta binaludensis Jamzad in murine melanoma B16F10 cells.

Nepeta binaludensis Jamzad (Lamiaceae) has been used in folk medicine of Iran to cure various diseases. The plant is an endemic species to the country that has recently been identified in Razavi Khorasan province. To evaluate the antioxidant and anti-melanogenesis of N. binaludensis, in this study the inhibitory activity of different extracts of N. binaludensis in murine melanoma B16F10 cells is investigated. The effects of petroleum ether, dichloromethane, ethyl acetate, and methanol extracts isolated from the plant on melanogenesis in B16 melanoma cells were investigated. To assess the inhibitory effects of this plant on melanogenesis, various assays were used including cytotoxicity, inhibition of mushroom tyrosinase and cellular tyrosinase, determination of melanin content, the effect of extracts on reactive oxygen species and western blot analysis of proteins involved in melanogenesis process. The content of melanin and the activity of tyrosinase were significantly reduced with different extracts of N. binaludensis in cells. Reactive oxygen species was also significantly decreased following the treatment of cell with the mentioned extracts, while a resazurin assay showed no cytotoxicity. Furthermore, we have found that the plant decreased the amount of tyrosinase and microphthalmia-associated transcription factor proteins, which verify the role of suppression of microphthalmia-associated transcription factor protein in melanogenesis inhibition. Taken together the data indicate that N. binaludensis has inhibitory activity on melanin synthesis with no cytotoxic effects in B16 melanoma cells. Therefore, it merits future investigations to apply as whitening agent in hyperpigmentation.

Sakuranetin Induces Melanogenesis in B16BL6 Melanoma Cells through Inhibition of ERK and PI3K/AKT Signaling Pathways.

Sakuranetin (Sak) is considered one of the most important flavanone phytoalexins in regard to antimicrobial activity, and accumulation, in the rice plant. The current study determined that Sak strongly stimulates melanogenesis in B16BL6 melanoma cells in a dose-dependent manner. This flavonoid upregulates the expression of microphthalmia transcription factor (MITF) and reaches its maximum after 24 h. In addition, Sak was found to increase in vitro tyrosinase (Tyr) activity, along with time-dependent upregulation of Tyr, tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2). Sakuranetin also decreased the proliferation rate in these cells without directly affecting their viability, as revealed by MTT and trypan blue assays. Further, Sak was shown to inhibit phosphorylation and activation of ERK1/2 from 12 h, without significantly affecting p38 and JNK phosphorylation. Sakuranetin was also found to inhibit the phosphorylation of AKT at threonine 308 and serine 473 and leads to activation of GSK3β via decreased phosphorylation at serine 9. Taken together, these results demonstrate that Sak stimulates melanogenesis in B16 melanoma cells via inhibition of ERK1/2 and PI3K/AKT signaling pathways, which lead to upregulation of Tyr, TRP1, and TRP2. Copyright © 2016 John Wiley & Sons, Ltd.

Antimelanogenic effects of the novel melanogenic inhibitors daidzein and equol, derived from soymilk fermented with Lactobacillus plantarum strain TWK10, in B16F0 mouse melanoma cells

Melanin functions to protect the skin; however, excessive production of melanin can cause hyperpigmentation. The antimelanogenic effects of daidzein and its microbial metabolite, equol, and the mechanisms through which they inhibit melanogenesis in B16 melanoma cells were investigated. At concentrations of less than 50 and 40 µM, respectively, daidzein and equol had no cytotoxic effects on B16 melanoma cells stimulated with α-melanocyte-stimulating hormone (α-MSH). Daidzein and equol reduced melanin content in these cells by downregulating the transcription of genes encoding melanocortin 1 receptor. Additionally, these compounds interfered with the phosphorylation of p38 mitogen-activated protein kinase and induced the phosphorylation of extracellular signal-regulated kinase 1/2 and glycogen synthase kinase 3β. Moreover, daidzein and equol decreased the expression of tyrosinase, TRP-1, and TRP-2, thereby blocking melanin production in α-MSH-stimulated B16 melanoma cells. In conclusion, daidzein and equol were noncytotoxic in B16 melanoma cells and exerted antimelanogenic effects. The functions of these bioactive compounds in fermented soymilk were confirmed, and they may be useful for developing functional foods and cosmetics, extending the range of applications of crops containing them.

Dual effects of acetylsalicylic acid on ERK signaling and Mitf transcription lead to inhibition of melanogenesis.

Acetylsalicylic acid (ASA) is widely used as an analgesic/antipyretic drug. It exhibits a wide range of biological effects, including preventative effects against heart attack and stroke, and the induction of apoptosis in various cancer cells. We previously found that ASA inhibits melanogenesis in B16 melanoma cells. However, the mechanisms of how ASA down-regulates melanin synthesis remain unclear. Here, we investigated the effect of ASA on melanogenic pathways, such as extracellular signal-regulated kinase (ERK) and microphthalmia-associated transcription factor (Mitf) transcription. ASA significantly inhibited melanin synthesis in a dose-dependent manner without oxidative stress and cell death. Semi-quantitative reverse transcription-polymerase chain reaction analysis showed that the inhibitory effect of ASA might be due to the inhibition of Mitf gene transcription. Interestingly, ASA also induced ERK phosphorylation. Additionally, treatment with PD98059, a specific ERK phosphorylation inhibitor, abolished the anti-melanogenic effect of ASA. These results suggest that the depigmenting effect of ASA results from down-regulation of Mitf, which is induced by both the induction of ERK phosphorylation and the inhibition of Mitf transcription.

Isosakuranetin, a 4'-O-methylated flavonoid, stimulates melanogenesis in B16BL6 murine melanoma cells.

The beneficial effects of 4'-O-methylated flavonoids on induction of melanogenesis are well established. Here, we report the effect of isosakuranetin (Iso) on melanogenesis in B16BL6 melanoma cells and an analysis of the signaling pathways involved in this activity. B16BL6 melanoma cells were treated with several concentrations of Iso and melanin content was measured. Activation and expression of factors involved in melanogenesis were assessed via western blotting. Iso (15 and 30μmol/L) strongly stimulated melanogenesis in a dose-dependent manner. Iso increased tyrosinase activity and up-regulated tyrosinase (Tyr), tyrosinase related protein 1 (TRP1), and tyrosinase related protein 2 (TRP2) in a time-dependent manner. Iso decreased B16 cell proliferation at a concentration above 45μmol/L, and had no effect on cell viability as revealed by MTT and trypan blue assays. Iso up-regulated expression of microphthalmia transcription factor (MITF), with a maximum effect after 12h. H89, a specific inhibitor of PKA, showed that MITF up-regulation is mediated through PKA/CREB activation. Furthermore, Iso decreased phosphorylation of MITF at Ser73 after 24h and 48h of exposure, activating MITF and leading to up-regulation of Tyr, TRP1, and TRP2. Iso inhibited phosphorylation and activation of ERK1/2 after 12h, while no significant effects on p38 and JNK phosphorylation were observed. Iso inhibited AKT phosphorylation and led to activation of GSK3β. Iso stimulates melanogenesis in B16 melanoma cells via up-regulation of MITF. Furthermore, Iso-induced inhibition of ERK1/2 and PI3K/AKT signaling pathways activate MITF and subsequent expression of Tyr, TRP1, and TRP2.

P21-Activated Kinase 4 Critically Regulates Melanogenesis via Activation of the CREB/MITF and β-Catenin/MITF Pathways

p21-activated kinase 4 (PAK4) regulates a wide range of cellular events, including cytoskeletal remodeling, cell growth, and survival. Our previous study identified PAK4 as a key regulator of cAMP-response element-binding protein (CREB) that acts upstream of microphthalmia-associated transcription factor (MITF), a master transcription factor in melanogenesis. We therefore investigated the role of PAK4 in melanogenesis. Melanocytes express both PAK2 and PAK4 isoforms, but only RNA interference knockdown of PAK4 significantly influenced α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis in B16 melanoma cells. Consistent with this result, PAK4 inhibition by PF3758309, a potent ATP-competitive inhibitor of PAKs, suppressed not only α-MSH-induced melanogenesis in B16 melanoma and human epithelial melanocyte cells but also UVB-induced melanogenesis in the skin of melanin-possessing hairless mice (HRM-2) in a dose-dependent manner. Inhibition of PAK4 over several days markedly decreased the levels of CREB, MITF, and tyrosinase in both HRM-2 mice and B16 melanoma cells. Moreover, PAK4 knockdown and inhibition suppressed α-MSH-stimulated β-catenin phosphorylation at serine 675 (S675) but enhanced phosphorylation at S33/37, an indicator for ubiquitination-dependent proteolysis. Together, our results provide evidence that PAK4 promotes α-MSH/UVB-induced melanogenesis via the CREB and Wnt/β-catenin signaling pathways and suggest that PAK4 may be a potential therapeutic target in pigmentation disorders.

Triterpene glycosides and other polar constituents of shea (Vitellaria paradoxa) kernels and their bioactivities

The MeOH extract of defatted shea (Vitellaria paradoxa; Sapotaceae) kernels was investigated for its constituents, and fifteen oleanane-type triterpene acids and glycosides, two steroid glucosides, two pentane-2,4-diol glucosides, seven phenolic compounds, and three sugars, were isolated. The structures of five triterpene glycosides were elucidated on the basis of spectroscopic and chemical methods. Upon evaluation of the bioactivity of the isolated compounds, it was found that some or most of the compounds have potent or moderate inhibitory activities against the following: melanogenesis in B16 melanoma cells induced by α-melanocyte-stimulating hormone (α-MSH); generation of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, against Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-teradecanoylphorbol 13-acetate (TPA) in Raji cells; t TPA-induced inflammation in mice, and proliferation of one or more of HL-60, A549, AZ521, and SK-BR-3 human cancer cell lines, respectively. Western blot analysis established that paradoxoside E inhibits melanogenesis by regulation of expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-1 (TRP-1) and TRP-2. In addition, tieghemelin A was demonstrated to exhibit cytotoxic activity against A549 cells (IC50 13.5μM) mainly due to induction of apoptosis by flow cytometry. The extract of defatted shea kernels and its constituents may be, therefore, valuable as potential antioxidant, anti-inflammatory, skin-whitening, chemopreventive, and anticancer agents.