Soung Hoon Lee

Ras Stabilization Through Aberrant Activation of Wnt/β-Catenin Signaling Promotes Intestinal Tumorigenesis

Crosstalk between the Wnt/β-catenin and the MAPK pathways contributes to colon cancer. Blocking Ras Degradation in Colon Cancer Both the Wnt/β-catenin pathway and the Ras-activated mitogen-activated protein kinase (MAPK) pathway can contribute to cancer. Jeong et al. report an interaction between these two pathways through the β-catenin destruction complex and the E3 ubiquitin ligase adaptor β-TrCP. Ras was phosphorylated by glycogen synthase kinase 3β, a component of the β-catenin destruction complex, and this enabled the phosphorylation-dependent recruitment of β-TrCP, which increased ubiquitin- and proteasome-mediated degradation of Ras, thereby providing a brake on Ras-mediated activation of the MAPK pathway. Conditions that compromised the function of the destruction complex, such as the presence of Wnt or genetic mutations or deficiency in components of the destruction complex, stabilized Ras and increased MAPK pathway activity. The importance of this regulatory crosstalk was verified in colon cancer samples from patients and mouse models of colon cancer, suggesting that targeting both the hyperactive Wnt pathway and the Ras pathway may be an effective combination therapy. Although the guanosine triphosphate/guanosine diphosphate loading switch is a major regulatory mechanism that controls the activity of the guanosine triphosphatase Ras, we report a distinct mechanism for regulating Ras activity through phosphorylation-mediated degradation and describe the role of this second regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/β-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras after its phosphorylation by glycogen synthase kinase 3β (GSK3β) and the subsequent recruitment of β-TrCP–E3 ligase. We found a positive association between tumorigenesis and Ras stabilization resulting from the aberrant activation of Wnt/β-catenin signaling in adenomas from two mouse models of colon cancer, human colonic tumors from various stages, and colon polyps of patients with familial adenomatous polyposis. Our results indicated that GSK3β plays an essential role in Ras degradation and that inhibition of this degradation pathway by aberrant Wnt/β-catenin signaling may contribute to Ras-induced transformation in colorectal tumorigenesis.

Valproic Acid Induces Cutaneous Wound Healing In Vivo and Enhances Keratinocyte Motility

Background Cutaneous wound healing is a complex process involving several signaling pathways such as the Wnt and extracellular signal-regulated kinase (ERK) signaling pathways. Valproic acid (VPA) is a commonly used antiepileptic drug that acts on these signaling pathways; however, the effect of VPA on cutaneous wound healing is unknown. Methods and Findings We created full-thickness wounds on the backs of C3H mice and then applied VPA. After 7 d, we observed marked healing and reduced wound size in VPA-treated mice. In the neo-epidermis of the wounds, β-catenin and markers for keratinocyte terminal differentiation were increased after VPA treatment. In addition, α-smooth muscle actin (α-SMA), collagen I and collagen III in the wounds were significantly increased. VPA induced proliferation and suppressed apoptosis of cells in the wounds, as determined by Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining analyses, respectively. In vitro, VPA enhanced the motility of HaCaT keratinocytes by activating Wnt/β-catenin, ERK and phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathways. Conclusions VPA enhances cutaneous wound healing in a murine model and induces migration of HaCaT keratinocytes.

Hair growth-promoting effect of Aconiti Ciliare Tuber extract mediated by the activation of Wnt/β-catenin signaling

AIMSnThe activation of Wnt/β-catenin signaling pathway plays an important role in hair follicle morphogenesis by stimulating bulge stem cells. This study was to obtain the activator of Wnt/β-catenin signaling pathway from natural products and to determine whether this activator can induce anagen hair growth in mice.nnnMAIN METHODSnTo identify materials that activate Wnt/β-catenin signaling pathway, 800 natural product extracts were screened using pTOPFlash assay and neural progenitor cell (NPC) differentiation assay. A selected extract was further tested for its effects on alkaline phosphatase (ALP) activity in human immortalized dermal papilla cell (iDPC) and the proliferation in iDPC and immortalized rat vibrissa DPC (RvDP). Finally, hair growth-promoting effects were evaluated in the dorsal skin of C57BL/6 mice.nnnKEY FINDINGSnAconiti Ciliare Tuber (ACT) extract was one of the most active materials in both pTOPFlash and NPC differentiation assays. It promoted the differentiation of NPC cells even under proliferation-stimulating conditions (basic fibroblast growth factor: bFGF). It also increased ALP activity and proliferation of iDPC in dose-dependent manners, and it stimulated the induction of the anagen hair growth in C57BL/6 mice. These results suggest that ACT extract activates the Wnt/β-catenin signaling pathway by enhancing β-catenin transcription and has the potential to promote the induction of hair growth via activation of the stem cell activity of the dermal papilla cells.nnnSIGNIFICANCEnThis is the first report indicating benefits of ACT extract in hair loss prevention by triggering the activation of Wnt/β-catenin signaling pathway and induction of the anagen hair growth in mice.

N‐Nicotinoyl dopamine, a novel niacinamide derivative, retains high antioxidant activity and inhibits skin pigmentation

Abstract:u2002 We synthesized a novel derivative of a well‐known skin‐lightening compound niacinamide, N‐nicotinoyl dopamine (NND). NND did not show inhibitory effects of tyrosinase and melanin synthesis in B16F10 mouse melanoma cells. However, NND retains high antioxidant activity without affecting viability of cells. In a reconstructed skin model, topical applications of 0.05% and 0.1% NND induced skin lightening and decreased melanin production without affecting the viability and morphology of melanocytes and overall tissue histology. Moreover, no evidence for skin irritation or sensitization was observed when 0.1% NND emulsion was applied onto the skin of 52 volunteers. The effect of NND on skin lightening was further revealed by pigmented spot analyses of human clinical trial. Overall, NND treatment may be a useful trial for skin lightening and treating pigmentary disorders.

The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing

In human melanoma biopsies and a murine cutaneous wound model, Lee et al. identify the Dishevelled-binding protein CXXC5 as a negative modulator of skin wound healing. CXXC5-deficient mice present accelerated wound healing as well as keratin and collagen synthesis. CXXC5, interacting with Dvl, operates as a negative feedback regulator of Wnt/β-catenin signaling and may represent a potential target for wound treatment.

Cilostazol augments the inhibition of platelet aggregation in clopidogrel low-responders

Morales, M. D. Nauffal, J. A. Nieto, M. J. Núñez, J. L. Ogea, M. Oribe, J. M. Pedrajas, R. Rabuñal, A. Riera-Mestre, V. Roldán, P. Román, V. Rosa, S. Rubio, A. Ruiz-Gamietea, N. Ruı́z-Giménez, J. C. Sahuquillo, A. Samperiz, J. F. Sánchez Muñoz-Torrero, S. Soler, M. J. Soto, G. Tiberio, J. A. Todolı́, C. Tolosa, J. Trujillo, F. Uresandi, V. Valdés, R. Valle, J. Vela, J. Villalta (Spain); H. Boccalon, D. Farge-Bancel, I. Mahe, K. Rivron-Guillot (France); B. Brenner (Israel); A. Barillari, G. Barillari, M. Ciammaichella, P. DiMicco, R. Duce, R. Poggio, P.Prandoni, S. Pasca, R. Quintavalla, A. Schenone, E. Tiraferri, A. Visonà (Italy); M. Bosevski (Republic of Macedonia).

Granulomatous variant of chronic pigmented purpuric dermatosis associated with hyperlipidaemia

deposition of IgG immunoglobulins around the blood vessels of the papillary dermis and dermoepidermal junction. Treatment with hydroxychlorochine sulphate was immediately initiated with improvement of the dermatological lesions and reduction in the levels of urinary porphyrins. According to our results, patients with TM demonstrate an increased prevalence of PCT, in relation to the general population. Indeed, there is an association between the trait of beta-thalassaemia and PCT. A possible explanation of our finding is that in our patient population, coexistence of various concomitant precipitating factors such as iron overload, oestrogen replacement therapy and HCV infection, seems to facilitate cumulatively the manifestation of PCT. However, emerging data have demonstrated that only a small percentage of individuals genetically predisposed to PCT or exposed to precipitating factors are amenable to manifesting the disease. It is postulated that a more complex triggering mechanism facilitates the appearance of PCT and that the combination of more predisposing factors is crucial in the pathogenesis of PCT. Nonetheless, patients with TM and even slightly elevated urinary porphyrins should remain under medical observation, as they seem susceptible to future development of PCT. Therefore, larger cohorts are required to clarify the association between these two clinical entities as well as the exact pathogenetical mechanism that connects them.

Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound-Induced Hair Neogenesis

The Wnt/β-catenin pathway has been implicated in hair follicle development and hair regeneration in adults. We discovered that CXXC-type zinc finger protein 5 (CXXC5) is a negative regulator of the Wnt/β-catenin pathway involved in hair regrowth and wound-induced hair follicle neogenesis via an interaction with Dishevelled. CXXC5 was upregulated in miniaturized hair follicles and arrector pili muscles in human balding scalps. The inhibitory effects of CXXC5 on alkaline phosphatase activity and cell proliferation were demonstrated using human hair follicle dermal papilla cells. Moreover, CXXC5-/- mice displayed accelerated hair regrowth, and treatment with valproic acid, a glycogen synthase kinase 3β inhibitor that activates the Wnt/β-catenin pathway, further induced hair regrowth in the CXXC5-/- mice. Disrupting the CXXC5-Dishevelled interaction with a competitor peptide activated the Wnt/β-catenin pathway and accelerated hair regrowth and wound-induced hair follicle neogenesis. Overall, these findings suggest that the CXXC5-Dishevelled interaction is a potential target for the treatment of hair loss.

Polygonum aviculare L. and its active compounds, quercitrin hydrate, caffeic acid, and rutin, activate the Wnt/β‐catenin pathway and induce cutaneous wound healing

Polygonum aviculare L. is a member of the Polygonaceae family of plants, which has been known for its antioxidant and anti‐obesity effects. However, the wound healing function of P.u2009aviculare extract has not been assessed. In this study, we identified a novel property of P.u2009aviculare extract as a Wnt/β‐catenin pathway activator based on a screen of 350 plant extracts using HEK293‐TOP cells retaining the Wnt/β‐catenin signaling reporter gene. P.u2009aviculare extract accelerated the migration of HaCaT keratinocytes without showing significant cytotoxicity. Moreover, P.u2009aviculare extract efficiently re‐epithelized wounds generated on mice. Additionally, ingredients of P.u2009aviculare extract, such as quercitrin hydrate, caffeic acid, and rutin, also accelerated the motility of HaCaT keratinocytes with the activation of Wnt/β‐catenin signaling. Therefore, based on our findings, P.u2009aviculare extract and its active ingredients could be potential therapeutic agents for wound healing. Copyright

N-nicotinoyl tyramine, a novel niacinamide derivative, inhibits melanogenesis by suppressing MITF gene expression

We synthesized and investigated the inhibitory effects of a novel niacinamide derivative, N-nicotinoyltyramine (NNT) on melanogenesis. NNT inhibited melanin production in B16F10 murine melanoma cells stimulated with α-melanocyte stimulating hormone (α-MSH), in human melanocyte and in three-dimensional cultured human skin model. NNT did not affect the catalytic activity of tyrosinase, but acted as an inhibitor of microphthalmia-associated transcription factor (MITF) and tyrosinase expressions in B16F10 cells. These findings suggest that the hypopigmentary effect of NNT results from the down-regulation of MITF and subsequently of tyrosinase, although NNT did not directly inhibit tyrosinase activity. In addition, safety of NNT was verified through performing neural stem cell morphology assay and Human repeated insult patch test as whitening agent. Our findings indicate that NNT may be a potential and non-skin irritant whitening agent for use in cosmetics and in the medical treatment of pigmentary disorders.