Background The overproduction of reactive oxygen species (ROS) by oxidative damage of the cellular ingredients has a substantial role in the development of many diseases, such as cancer. Fisetin (3, 3′, 4′, 7 –tetrahydroxyflavone) is a less familiar but widely distributed plant-based flavonoid in foods. Recently, several biological activities of fisetin have been identified including neuroprotective, anti-inflammatory and anticarcinogenic effects. The antioxidant activity of fisetin as a flavonoid has been shown in several studies, but limited comprehensive data is available on the mechanistic aspects of its antioxidant activity. Scope and approach This paper reviewed the reports regarding intracellular antioxidant effects of fisetin in different settings, with a comparative view to the other structurally related flavonoids. Additionally, we have summarized the suggested mechanisms of action for fisetin considering its possible interactions with signaling pathways. Some directions for future studies, reinforcing the antioxidant capacity of the human body against oxidative stress and related disorders are identified. Key findings and conclusions Fisetin, when transmitted through cellular membranes, can interact with diverse redox-related signaling pathways. These pathways are mainly NF-κB, Nrf2, MAPK, and PI3K/Akt, so fisetin exerts its effective antioxidant activity through multiple mechanisms such as reinforcing enzymatic and non-enzymatic intracellular antioxidants, chelating transition metal ions and acting as a substrate for oxidoreductase activity. Therefore, the antioxidant effects of fisetin include more than just free radical scavenging. In the future, other cellular pathways that are also possibly involved should be explored and conducting well-designed clinical trials using low-doses of fisetin should be considered.

Antioxidant properties of the flavonoid fisetin: An updated review of in vivo and in vitro studies

Fisetin is found in many fruits and plants such as grapes and onions, and exerts anti-inflammatory, anti-proliferative, and anticancer activity. However, whether fisetin regulates melanogenesis has been rarely studied. Therefore, we evaluated the effects of fisetin on melanogenesis in B16F10 melanoma cell and zebrafish larvae. The current study revealed that fisetin slightly suppressed in vitro mushroom tyrosinase activity; however, molecular docking data showed that fisetin did not directly bind to mushroom tyrosinase. Unexpectedly, fisetin significantly increased intracellular and extracellular melanin production in B16F10 melanoma cells regardless of the presence or absence of α-melanocyte stimulating hormone (α-MSH). We also found that the expression of melanogenesis-related genes such as tyrosinase and microphthalmia-associated transcription factor (MITF), were highly increased 48 h after fisetin treatment. Pigmentation of zebrafish larvae by fisetin treatment also increased at the concentrations up to 200 µM and then slightly decreased at 400 µM, with no alteration in the heart rates. Molecular docking data also revealed that fisetin binds to glycogen synthase kinase-3β (GSK-3β). Therefore, we evaluated whether fisetin negatively regulated GSK-3β, which subsequently activates β-catenin, resulting in melanogenesis. As expected, fisetin increased the expression of β-catenin, which was subsequently translocated into the nucleus. In the functional assay, FH535, a Wnt/β-catenin inhibitor, significantly inhibited fisetin-mediated melanogenesis in zebrafish larvae. Our data suggested that fisetin inhibits GSK-3β, which activates β-catenin, resulting in melanogenesis through the revitalization of MITF and tyrosinase.

https://www.mdpi.com/1422-0067/21/1/312/pdf

GSK-3β-Targeting Fisetin Promotes Melanogenesis in B16F10 Melanoma Cells and Zebrafish Larvae through β-Catenin Activation

Unraveling the molecular mechanisms and the potential chemopreventive/therapeutic properties of natural compounds in melanoma

The present study was undertaken to investigate the mechanism behind the anti-obesity effect of the 50% ethanol extract of Chrysanthemum indicum L. flowers (CIEE) in a mouse model of high-fat diet (HFD)-induced obesity. Male C57BL/6J mice (six mice in each group) were administered CIEE (8, 40 and 200 mg/kg) for 6 weeks while being fed with a HFD. Garcinia cambogia (GC) was used as the positive control and was administered in the same manner as CIEE. Results demonstrated that oral administration of CIEE significantly reduced body weight, epididymal white adipose tissue (EWAT), liver weight and serum levels of total cholesterol and triglyceride (P<0.05). In addition, CIEE reduced serum leptin and increased adiponectin levels. CIEE significantly downregulated peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein-α and fatty acid synthase expression levels in EWAT, and upregulated the protein expression of PPARα in liver tissue of HFD-fed obese mice (P<0.05). These results suggested that Chrysanthemum indicum L. flowers may be a potentially effective therapeutic agent for obesity and its associated complications.

/pdf/chrysanthemum-indicum-l-ethanol-extract-reduces-high-fat-5bz3wl3064.pdf

Chrysanthemum indicum L. ethanol extract reduces high-fat diet-induced obesity in mice.

Skin is the largest organ in the body comprised of three different layers including the epidermis, dermis, and hypodermis. The dermis is mainly composed of dermal fibroblasts and extracellular matrix (ECM), such as collagen and elastin, which are strongly related to skin elasticity and firmness. Skin is continuously exposed to different kinds of environmental stimuli. For example, ultraviolet (UV) radiation, air pollutants, or smoking aggravates skin aging. These external stimuli accelerate the aging process by reactive oxygen species (ROS)-mediated signaling pathways and even cause aging-related diseases. Skin aging is characterized by elasticity loss, wrinkle formation, a reduced dermal-epidermal junction, and delayed wound healing. Thus, many studies have shown that natural polyphenol compounds can delay the aging process by regulating age-related signaling pathways in aged dermal fibroblasts. This review first highlights the relationship between aging and its related molecular mechanisms. Then, we discuss the function and underlying mechanism of various polyphenols for improving skin aging. This study may provide essential insights for developing functional cosmetics and future clinical applications.

/pdf/the-molecular-mechanism-of-polyphenols-with-anti-aging-1ditl7wy.pdf

The Molecular Mechanism of Polyphenols with Anti-Aging Activity in Aged Human Dermal Fibroblasts

Skin is composed of multiple layers, including the epidermis, dermis, and hypodermis. Although several biological activities of fisetin have been reported, beneficial effects and the functions of fisetin in skin remain unclear. B16F10 melanoma cells, human skin fibroblasts, and 3T3-L1 cells were used to examine the beneficial effects of fisetin in skin health. α-MSH- and IBMX-induced melanosis in B16F10 melanoma cells was inhibited by fisetin treatment, which also enhanced mRNA expression levels of skin fibril-related genes via the CCN2/TGF-β signaling pathway. Decreased intracellular lipid accumulation via down-regulation of transcriptional factors through activation of the CCN2/TGF-β signaling pathway was observed. A novel function of fisetin in skin health via down-regulation of melanosis and adipogenesis, and up-regulation of skin fibril-related genes was observed. Evidence for development of nutri-cosmetics for skin health is presented.

/pdf/beneficial-role-and-function-of-fisetin-in-skin-health-via-ano1t1f7ix.pdf

Beneficial role and function of fisetin in skin health via regulation of the CCN2/TGF-β signaling pathway

Purpose: Although several physiological properties of fisetin have been reported, the potential of fisetin as a nutri-cosmetics material has been not considered. Therefore, anti-oxidant and anti-adipogenic effects in 3T3-L1 cells of fisetin were evaluated and its potential as a nutri-cosmetic ingredient was discussed. Methods: To test anti- oxidant activity of fisetin, ABTS radical scavenging assay was used and the cytotoxicity of fisetin in 3T3-L1 preadipocytes was evaluated by EZ-cytox assay. The inhibitory effect of fisetin against 3T3-L1 adipogenesis was evaluated in various stage of adipogenesis such as pre-adipogenic (Day -2~0), early (Day 0~2), intermediate (Day 2~4), and terminal stage (Day 4~6) by oil red o (ORO) staining. The mRNA expression levels of transcriptional factors were performed by RT- PCR analysis. Results: We observed that the scavenging activity of fisetin against ABTS radicals was stronger than that of ascorbic acid, a well-known soluble anti-oxidant. Fisetin treatment resulted in the decreased triglyceride content of 3T3-L1 cells in a dose-dependent manner. Lipid accumulation of 3T3-L1 adipocytes was significantly inhibited by fisetin treatment by 54.61%, 61.74%, 56.82%, and 26.67%, respectively when compared to adipocytes control. The anti-adipogenic effect of fisetin was strongly limited in the pre-adipogenic, early, and intermediate stages of 3T3-L1 adipogenesis. In addition, the fisetin treatment down-regulated mRNA expression levels of C/EBPβ, leptin, and adiponectin in mature 3T3-L1 adipocytes. Conclusion: These results suggested that fisetin has the potential as a nutri-cosmetic material which possess anti-oxidant and anti-adipogenic activities.

/pdf/potential-of-fisetin-as-a-nutri-cosmetics-material-through-4k03rlpd3a.pdf

Potential of Fisetin as a Nutri-cosmetics Material through Evaluating Anti-oxidant and Anti- adipogenic Activities

Background We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo. Methods DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells. Results Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells. Conclusion These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

/pdf/da-1241-a-novel-gpr119-agonist-improves-hyperglycaemia-by-3r6k7pgj.pdf

DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice

Purpose: Chrysanthemum indicum Linne (CI) has been used as a traditional medicine. Although several biological effects of CI have been reported, the precise role and function of CI as nutri-cosmetic and cosmetic materials remain unclear. Therefore, we prepared water extract of Chrysanthemum indicum Linne (CIW). And nutri-cosmetic potential was discussed through evaluation of anti-oxidant, anti- adipogenic in 3T3-L1 cells and regulatory function of skin fibril- related genes in human skin fibroblast (HSF). Methods: The anti- oxidant activity of CIW was evaluated through metal chelating activity and reduction potential. The cytotoxicity of CIW in 3T3-L1 and HSF was evaluated by MTT assay. The anti-adipogenic effect of CIW was examined by Oil Red O (ORO) staining and microscopy observation in 3T3-L1 cells. The mRNA expression levels of skin fibril-related genes in HSF were analyzed by reverse transcription-polymer chain reaction (RT-PCR). Results: The anti-oxidant activity of CIW was increased in a dose dependent manner. The CIW treatment up to 100 µg/mL for 24 h did not affect to the viability of 3T3-L1 cells and HSF. Thus, up to 100 µg/mL of CIW was chosen in cell-based assay. The treatment of 10, 50, and 100 µg/mL CIW significantly inhibited 3T3- L1 adipogenesis by 5.17%, 72.80%, and 104.09%. In addition, up- regulated mRNA expression levels of skin fibril-related genes such as fibronectin and type Ⅰ collagen α2 (COL1A2) were observed in CIW- treated HSF. Conclusion: These results suggest that CIW has the potential as nutri-cosmetic and cosmetic ingredient which possess anti-oxidant and anti-adipogenic effects.

/pdf/evaluation-of-water-extract-prepared-from-chrysanthemum-9nthcm53uk.pdf

Evaluation of Water Extract Prepared from Chrysanthemum indicum Linne as Nutri-cosmetic and Cosmetic Material In Vitro Model

목적: 생강과에 속하는 다년생 초본식물 울금(Curcuma longa L.)에 대한 항산화 및 항암 등의 연구가 비교적 다수 수행되었으나, 피부건강과 관련한 연구는 상대적으로 미미한 실정이다. 따라서, 본 연구에서는 국내 진도산 울금 물 추출물(water extracts of Curcuma longa L., CLE)의 B16F10 세포에서 멜라닌 생성 저해 활성 및 human skin fibroblasts (HSFs)에서 피부 섬유구조관련 유전자의 발현조절에 미치는 영향을 분석하여 울금 추출물의 미용기능식품 및 화장품 소재로서의 가능성을 평가하고자 하였다. 방법: B16F10, HSFs에서 CLE의 세포독성은 thiazolyl blue tetrazolium bromide (MTT) assay로 평가하였다. B16F10 세포에서CLE의 멜라닌 생성 저해 활성은 세포의 배지에 용출된 멜라닌의 정량과 이미지 분석을 실시하였다. CLE가 HSFs 세포의 피부 섬유구조 관련 유전자의 발현에 미치는 영향은 reverse transcription-polymerase chain reaction (RT-PCR) 분석법을 통해 평가하였다. 결과: MTT assay를 통해 CLE의 농도는 B16F10 및 HSFs 세포에서 400 μg/mL 이하로 결정하였다. B16F10 세포에서 50, 100, 200, 400 μg/mL의 CLE 처리는 유의적으로 멜라닌 형성을 억제하였다. 또한 HSFs에서 10, 100, 200, 400 μg/mL의 농도로CLE를 처리한 결과 procollagen1α1, procollagen1α2, elastin의 mRNA 발현수준을 현저히 증가시켰다. 결론: 본 연구결과는 CLE를이용하여 미백 및 피부섬유관련 유전자의 상향조절로 인한 피부탄력 증진에 효과가 있음을 확인하였으며 이후 미용기능식품 및 화장품 소재로서 충분히 활용될 수 있음을 시사한다.

/pdf/evaluation-of-curcuma-longa-l-water-extracts-as-beauty-food-2ywtmhksxc.pdf

Ryeong-Hyeon Kim

Papers

Beneficial role and function of fisetin in skin health via regulation of the CCN2/TGF-β signaling pathway

Potential of Fisetin as a Nutri-cosmetics Material through Evaluating Anti-oxidant and Anti- adipogenic Activities

DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice

Evaluation of Water Extract Prepared from Chrysanthemum indicum Linne as Nutri-cosmetic and Cosmetic Material In Vitro Model

Evaluation of Curcuma longa L. Water Extracts as Beauty Food Materials in B16F10 and Human Skin Fibroblasts