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Hair loss remains a significant problem that is difficult to treat; therefore, there is a need to identify safe natural materials that can help patients with hair loss. We evaluated the hair anagen activation effects of limonin, which is abundant in immature citrus fruits. Limonin increased the proliferation of rat dermal papilla cells (rDPC) by changing the levels of cyclin D1 and p27, and increasing the number of BrdU-positive cells. Limonin increased autophagy by decreasing phosphorylated mammalian target of rapamycin levels and increasing the phospho-Raptor, ATG7 and LC3B. Limonin also activated the Wnt/β-catenin pathway by increasing phospho-β-catenin levels. XAV939, a Wnt/β-catenin inhibitor, inhibited these limonin-induced changes, including induced autophagy, BrdU-positive cells, and cell proliferation. Limonin increased the phosphorylated AKT levels in both two-dimensional cultured rDPC and three-dimensional spheroids. Treatment with the PI3K inhibitor wortmannin inhibited limonin-induced proliferation, and disrupted other limonin-mediated changes, including decreased p27, increased BrdU-positive cells, induced autophagy, and increased ATG7 and LC3B levels. Wortmannin also inhibited limonin-induced cyclin D1 and LC3 expression in spheroids. Collectively, these results indicate that limonin can enhance anagen signaling by activating autophagy via targeting the Wnt/β-catenin and/or PI3K/AKT pathways in rDPC, highlighting a candidate nutrient for hair loss treatment.

The hair follicle goes through repetitive cycles including anagen, catagen, and telogen. The interaction of dermal papilla cells (DPCs) and keratinocytes regulates the hair cycle and hair growth. Humanin was discovered in the surviving brain cells of patients with Alzheimer&rsquo, s disease. HNG, a humanin analogue, activates cell growth, proliferation, and cell cycle progression, and it protects cells from apoptosis. This study was performed to investigate the promoting effect and action mechanisms of HNG on hair growth. HNG significantly increased DPC proliferation. HNG significantly increased hair shaft elongation in vibrissa hair follicle organ culture. In vivo experiment showed that HNG prolonged anagen duration and inhibited hair follicle cell apoptosis, indicating that HNG inhibited the transition from the anagen to catagen phase mice. Furthermore, HNG activated extracellular signal-regulated kinase (Erk)1/2, Akt, and signal transducer and activator of transcription (Stat3) within minutes and up-regulated vascular endothelial growth factor (VEGF) levels on DPCs. This means that HNG could induce the anagen phase longer by up-regulating VEGF, which is a Stat3 target gene and one of the anagen maintenance factors. HNG stimulated the anagen phase longer with VEGF up-regulation, and it prevented apoptosis by activating Erk1/2, Akt, and Stat3 signaling.

Anticancer effects of L-ascorbic acid (Vitamin C, L-AA) have been reported in various types of cancers. L-AA intake reduces breast cancer recurrence and mortality, however, the role of L-AA in the treatment of breast cancer remains poorly understood. In this study, we investigated the effect and mechanism action of L-AA on breast cancer growth. L-AA inhibited the growth of breast cancer cells by inducing apoptotic cell death at the evaluated treatment concentrations without affecting normal cells. Moreover, L-AA induces autophagosome formation via regulation of mammalian target of rapamycin (mTOR), Beclin1, and autophagy-related genes (ATGs) and increased autophagic flux. Notably, we observed that L-AA increased p62/SQSTM1 (sequestosome 1) protein levels. Accumulation of p62 protein in cancer cells in response to stress has been reported, but its role in cancer regulation remains controversial. Here, we demonstrated that L-AA-induced p62 accumulation is related to L-AA-induced breast cancer growth inhibition. Furthermore, L-AA induced endoplasmic reticulum (ER) stress via the IRE&ndash, JNK&ndash, CHOP (inositol-requiring endonuclease&ndash, c-Jun N-terminal kinase&ndash, C/EBP homologous protein) signaling pathways, which increased the nuclear levels of p62/SQSTM1. These findings provide evidence that L-AA-induced ER stress could be crucial for p62 accumulation-dependent cell death, and L-AA can be useful in breast cancer treatment.

Hair growth is regulated by the interaction between dermal papilla cells (DPC) and other cells inside the hair follicle. Here, we show the effect and action mechanism of mackerel-derived fermented fish oil (FFO) extract and its component docosahexaenoic acid (DHA) in the control of hair growth. The hair growth effect of FFO extract was evaluated by the culture method of vibrissa follicles and in vivo dotmatrix planimetry method. FFO extract increased the length of hair-fibers and enabled stimulated initiation into the anagen phase of the hair cycle. As expected, FFO extract significantly increased DPC proliferation. FFO extract induced the progression of the cell cycle and the activation of extracellular signal-regulated kinase (ERK), p38 and Akt. FFO extract induced nuclear translocation of &beta, catenin, a stimulator of anagen phase, through an increase of phospho-glycogen synthase kinase3&beta, (GSK3&beta, ) level. Since various prostaglandins are known to promote hair growth in humans and mice, we examined the effect of DHA, a main omega-3 fatty acid of FFO, on DPC proliferation. DHA not only increased DPC proliferation but also upregulated levels of cell cycle-associated proteins such as cyclin D1 and cdc2 p34. These results show that FFO extract and DHA promote hair growth through the anagen-activating pathways in DPC.

The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1) from Lobophytum sp. has been already reported in HT-29 human colorectal cancer cells. In this study, we examined the effect of LS-1 on the apoptosis induction of SNU-C5/5-FU, fluorouracil-resistant human colon cancer cells. Furthermore, we investigated whether the apoptosis-induction effect of LS-1 could arise from the activation of the TGF-beta pathway. In SNU-C5/5-FU treated with LS-1 of 7.1 mu M (IC50), we could observe the various apoptotic characteristics, such as the increase of apoptotic bodies, the increase of the sub-G1 hypodiploid cell population, the decrease of the Bcl-2 level, the increase of procaspase-9 cleavage, the increase of procaspase-3 cleavage and the increase of poly(ADP-ribose) polymerase cleavage. Interestingly, the apoptosis-induction effect of LS-1 was also accompanied by the increase of Smad-3 phosphorylation and the downregulation of c-Myc in SNU-C5/5-FU. LS-1 also increased the nuclear localization of phospho-Smad-3 and Smad-4. We examined whether LS-1 could downregulate the expression of carcinoembryonic antigen (CEA), a direct inhibitor of TGF-beta signaling. LS-1 decreased the CEA level, as well as the direct interaction between CEA and TGF-beta R1 in the apoptosis-induction condition of SNU-C5/5-FU. To examine whether LS-1 can induce apoptosis via the activation of TGF-beta signaling, the SNU-C5/5-FU cells were treated with LS-1 in the presence or absence of SB525334, a TGF-beta RI kinase inhibitor. SB525334 inhibited the effect of LS-1 on the apoptosis induction. These findings provide evidence demonstrating that the apoptosis-induction effect of LS-1 results from the activation of the TGF-beta pathway via the downregulation of CEA in SNU-C5/5-FU.

Fucoidan, a sulfated polysaccharide, has a variety of biological activities, such as anti-cancer, anti-angiogenic and anti-inflammatory. However, the mechanisms of action of fucoidan as an anti-cancer agent have not been fully elucidated. The present study examined the anti-cancer effect of fucoidan obtained from Undaria pinnatifida in PC-3 cells, human prostate cancer cells. Fucoidan induced the apoptosis of PC-3 cells by activating both intrinsic and extrinsic pathways. The induction of apoptosis was accompanied by the activation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK1/2 MAPK) and the inactivation of p38 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, fucoidan also induced the up-regulation of p21(Cip1/Waf) and down-regulation of E2F-1 cell-cycle-related proteins. Furthermore, in the Wnt/beta-catenin pathway, fucoidan activated GSK-3 beta that resulted in the decrease of beta-catenin level, followed by the decrease of c-myc and cyclin D1 expressions, target genes of beta-catenin in PC-3 cells. These results suggested that fucoidan treatment could induce intrinsic and extrinsic apoptosis pathways via the activation of ERK1/2 MAPK, the inactivation of p38 MAPK and PI3K/Akt signaling pathway, and the down-regulation of Wnt/beta-catenin signaling pathway in PC-3 prostate cancer cells. These data support that fucoidan might have potential for the treatment of prostate cancer.

This study was conducted to evaluate the promoting effect of Ishige sinicola, an alga native to Jeju Island, Korea, on hair growth. When vibrissa follicles were cultured in the presence of I. sinicola extract for 21 days, I. sinicola extract increased hair-fiber length. After topical application of I. sinicola extract onto the back of C57BL/6 mice, anagen progression of the hair shaft was induced. The I. sinicola extract significantly inhibited the activity of 5 alpha-reductase. Treatment of immortalized vibrissa dermal papilla cells (DPCs) with I. sinicola extract resulted in increase of cell proliferation, which was accompanied by the increase of phospho-GSK3 beta level, beta-catenin, Cyclin E and CDK2, whereas p27(kip1) was down-regulated. In particular, octaphlorethol A, an isolated component from the I. sinicola extract, inhibited the activity of 5 alpha-reductase and increased the proliferation of DPCs. These results suggest that I. sinicola extract and octaphlorethol A, a principal of I. sinicola, have the potential to treat alopecia via the proliferation of DPCs followed by the activation of beta-catenin pathway, and the 5 alpha-reductase inhibition.

This study was conducted to evaluate the effect of Ecklonia cava, a marine alga native to Jeju Island in Korea, on the promotion of hair growth. When vibrissa follicles were cultured in the presence of E. cava enzymatic extract (which contains more than 35% of dieckol) for 21 days, E. cava enzymatic extract increased hair-fiber length. In addition, after topical application of the 0.5% E. cava enzymatic extract onto the back of C57BL/6 mice, anagen progression of the hair-shaft was induced. The treatment with E. cava enzymatic extract resulted in the proliferation of immortalized vibrissa dermal papilla cells (DPC). Especially, dieckol, among the isolated compounds from the E. cava enzymatic extract, showed activity that increased the proliferation of DPC. When NIH3T3 fibroblasts were treated with the E. cava enzymatic extract and the isolated compounds from the E. cava enzymatic extract, the E. cava enzymatic extract increased the proliferation of NIH3T3 fibroblasts, but the isolated compounds such as eckol, dieckol, phloroglucinol and triphlorethol-A did not affect the proliferation of NIH3T3 fibroblasts. On the other hand, the E. cava enzymatic extract and dieckol significantly inhibited 5α-reductase activity. These results suggest that dieckol from E. cava can stimulate hair growth by the proliferation of DPC and/or the inhibition of 5α-reductase activity.

In this study, we investigated the effect and mechanism of Undariopsis peterseniana, an edible brown alga, on hair growth. The treatment of vibrissa follicles with U. peterseniana extract ex vivo for 21 days significantly increased the hair-fiber lengths. The U. peterseniana extract also significantly accelerated anagen initiation in vivo. Moreover, we found that U. peterseniana extract was able to open the K-ATP channel, which may contribute to increased hair growth. The U. peterseniana extract decreased 5 alpha-reductase activity and markedly increased the proliferation of dermal papilla cells, a central regulator of the hair cycle. The U. peterseniana extract increased the levels of cell cycle proteins, such as Cyclin D1, phospho(ser780)-pRB, Cyclin E, phospho-CDK2, and CDK2. The U. peterseniana extract also increased the phosphorylation of ERK and the levels of Wnt/beta-catenin signaling proteins such as glycogen synthase kinase-3 beta (GSK-3 beta) and beta-catenin. These results suggested that the U. peterseniana extract had the potential to influence hair growth by dermal papilla cells proliferation through the activation of the Wnt/beta-catenin and ERK pathways. We isolated a principal of the U. peterseniana extract, which was subsequently identified as apo-9'-fucoxanthinone, a trichogenic compound. The results suggested that U. peterseniana extract may have a pivotal role in the treatment of alopecia.