Anti-aging Effect of Sulfuretin in UVA-irradiated Normal Human Epidermal Keratinocytes

Joong Hyun Shim 한국피부과학연구원 2020 아시안뷰티화장품학술지 Vol.18 No.3

목적: 본 연구는 sulfuretin이 자외선에 의해 광노화가 유도된 인간각질형성세포의 항노화 효능을 확인하기 위하여 수행되었다. 방 법: 자외선으로 노화를 유도한 인각각질형성세포에서 sulfuretin의 보습효과를 확인하기 위하여 세포생존율, 보습에 관련된 유전자 발현양상, 히알루론산 단백질의 발현 정도를 확인하였다. 결과: Sufuretin의 항노화 효능을 확인하기 위하여 AQP3, HAS2, FLG, KRT1, KRT10의 유전자 발현을 확인한 결과, 자외선 조사에 의해 감소한 AQP3와 HAS2 유전자의 발현이 sulfuretin에 의해 증가 하였다. 인각각질형성세포의 과각질화를 유도하는 KRT1과 KRT10과 과분화의 표지인자인 FLG의 발현이 sufuretin에 의해 감소 하였다. 또한 히알루론산 단백질의 생성이 sulfuretin에 의해 증가함을 확인하였다. 결론: 본 연구를 통해 sulfuretin의 항노화 효능 을 확인하였고, 향후 sulfuretin이 화장품 및 의약품과 건강식품의 개발에 활용할 수 있는 소재로서의 가능성을 확인하기 위해 심도 있는 추가연구가 필요할 것으로 사료된다. Purpose: This study was carried out to investigate the epidermal moisturizing effects of sulfuretin on normal human epidermal keratinocytes (NHEKs). Methods: Epidermal moisturizing effects of sulfuretin on NHEKs were assessed by quantitative real-time RT-PCR to monitor the expression of genes related to skin hydration, hyaluronic acid (HA)-ELISA assays to detect HA production, and cell viability assays. Results: Sulfuretin increased the mRNA levels of the AQP3 /HAS2 /KRT1 /KRT10 genes and HA production in NHEKs. Conclusion: This study led to the identification of the epidermal moisturizing effects of sulfuretin. The results indicate that sulfuretin can be a potent cosmetic ingredient for skin moisturizing and antiaging products. However, further research is warranted regarding the use of sulfuretin to develop not only cosmetics but also medicines and food.

Sulfuretin, a natural Src family kinases inhibitor for suppressing solar UV-induced skin aging

Han, Ahram,Lee, Jinhyuk,Lee, Myung-hee,Lee, Sung-Young,Shin, Eun Ju,Song, Young-Ran,Lee, Kwang Min,Lee, Ki Won,Lim, Tae-Gyu Elsevier 2019 Journal of Functional Foods Vol.52 No.-

<P><B>Abstract</B></P> <P>This study suggests sulfuretin as an ant-skin aging agent. Sulfuretin significantly reduces solar UV (sUV)-increased matrix metalloproteinase-1 (MMP-1) expression and c-Jun phosphorylation in human dermal fibroblasts as well as skin tissue. An examination of the underlying mechanisms showed that sUV-activated MAPK signaling pathways are blocked by sulfuretin. Interestingly, sulfuretin directly inhibits the kinase activity of selected Src family. Because the amino acid sequence of Hck kinase which used kinase array is 230–497, it was assumed that sulfuretin interacts with this conserved domain of Src family kinase. It was also found that sulfuretin directly binds to sulfuretin with the lowest binding energy of −8.9 kcal/mol and free energy of −10.07 kcal/mol. Additionally, Hck protein was precipitated with sulfuretin-conjugated Sepharose 4B beads in HDFs cell lysate. Overall, present findings indicated that sulfuretin plays the role of anti-skin aging agent by acting as a general Src family kinase inhibitor in human skin.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The anti-wrinkle formation activity of sulfuretin was suggested. </LI> <LI> Sulfuretin acts as general Src family kinase inhibitor. </LI> <LI> The expected interaction was assumed using computer modeling. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Cytoprotective Effects of Sulfuretin from Rhus verniciflua through Regulating of Heme Oxygenase-1 in Human Dental Pulp Cells

이동성,오현철,김경수,Samell Keo,정길생,김윤철 한국생약학회 2013 Natural Product Sciences Vol.19 No.1

Rhus verniciflua Stokes (Anacadiaceae) is a plant that is native to East Asian countries, such as Korea, China, and Japan, and it has been found to exert various biological activities including antioxidative, anti-aggregatory, anti-inflammatory, anti-mutagenic, and apoptotic effects. Sulfuretin is one of the major flavonoid component isolated from the heartwood of R. verniciflua. Reactive oxygen species (ROS), produced via dental adhesive bleaching agents and pulpal disease, can cause oxidative stress. In the present study, we isolated sulfuretin from R. verniciflua and demonstrated that sulfuretin possesses cytoprotective effects against hydrogen peroxide (H2O2)-induced dental cell death. H2O2 is a representative ROS and causes cell death through necrosis in human dental pulp (HDP) cells. H2O2-induced cytotoxicity and production of ROS were blocked in the presence of sulfuretin, and these effects were dose dependent. Sulfuretin also increased heme oxygenase-1 (HO-1) protein expression. In addition, to determine whether sulfuretin-induced HO-1 expression mediated this cytoprotective effect, HDP cells were cotreated with sulfuretin in the absence or presence of SnPP, an inhibitor of HO activity. Sulfuretin-dependent HO-1 expression was required for suppression of H2O2-induced HDP cell death and ROS generation. These results indicate that sulfuretin-dependent HO-1 expression was required for the inhibition of H2O2-induced cell death and ROS generation. In addition, sulfuretin may be used to prevent functional dental cell death and thus may be useful as a pulpal disease agent.

Sulfuretin protects against cytokine-induced ${\beta}$-cell damage and prevents streptozotocin-induced diabetes

Song, Mi-Young,Jeong, Gil-Saeng,Kwon, Kang-Beom,Ka, Sun-O,Jang, Hyun-Young,Park, Jin-Woo,Kim, Youn-Chul,Park, Byung-Hyun Korean Society for Biochemistry and Molecular Bion 2010 Experimental and molecular medicine Vol.42 No.9

NF-${\kappa}B$ activation has been implicated as a key signaling mechanism for pancreatic ${\beta}$-cell damage. Sulfuretin is one of the main flavonoids produced by Rhus verniciflua, which is reported to inhibit the inflammatory response by suppressing the NF-${\kappa}B$ pathway. Therefore, we isolated sulfuretin from Rhus verniciflua and evaluated if sulfuretin could inhibit cytokine- or streptozotocin-induced ${\beta}$-cell damage. Rat insulinoma RINm5F cells and isolated rat islets were treated with IL-$1{\beta}$ and IFN-${\gamma}$ to induce cytotoxicity. Incubation of cells and islets with sulfuretin resulted in a significant reduction of cytokine-induced NF-${\kappa}B$ activation and its downstream events, iNOS expression, and nitric oxide production. The cytotoxic effects of cytokines were completely abolished when cells or islets were pretreated with sulfuretin. The protective effect of sulfuretin was further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Treatment of mice with streptozotocin resulted resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining of islets. However, the diabetogenic effects of streptozotocin were completely prevented when mice were pretreated with sulfuretin. The anti-diabetogenic effects of sulfuretin were also mediated by suppression of NF-${\kappa}B$ activation. Collectively, these results indicate that sulfuretin may have therapeutic value in preventing ${\beta}$-cell damage.

Sulfuretin protects against cytokine-induced β-cell damage and prevents streptozotocin-induced diabetes

Mi-Young Song,Gil-Saeng Jeong,권강범,Sun-O Ka,Hyun-Young Jang,박진우,Youn-Chul Kim,Byung-Hyun Park 생화학분자생물학회 2010 Experimental and molecular medicine Vol.42 No.9

NF-κB activation has been implicated as a key signaling mechanism for pancreatic β-cell damage. Sulfuretin is one of the main flavonoids produced by Rhus verniciflua,which is reported to inhibit the inflammatory response by suppressing the NF-κB pathway. Therefore, we isolated sulfuretin from Rhus verniciflua and evaluated if sulfuretin could inhibit cytokine- or streptozotocin-induced β-cell damage. Rat insulinoma RINm5F cells and isolated rat islets were treated with IL-1β and IFN-γ to induce cytotoxicity. Incubation of cells and islets with sulfuretin resulted in a significant reduction of cytokine-induced NF-κB activation and its downstream events, iNOS expression, and nitric oxide production. The cytotoxic effects of cytokines were completely abolished when cells or islets were pretreated with sulfuretin. The protective effect of sulfuretin was further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining of islets. However, the diabetogenic effects of streptozotocin were completely prevented when mice were pretreated with sulfuretin. The anti-diabetogenic effects of sulfuretin were also mediated by suppression of NF-κB activation. Collectively, these results indicate that sulfuretin may have therapeutic value in preventing β-cell damage.

The Cytoprotective Effect of Sulfuretin against <i>tert</i> -Butyl Hydroperoxide-Induced Hepatotoxicity through Nrf2/ARE and JNK/ERK MAPK-Mediated Heme Oxygenase-1 Expression

Lee, Dong-Sung,Kim, Kyoung-Su,Ko, Wonmin,Li, Bin,Jeong, Gil-Saeng,Jang, Jun-Hyeog,Oh, Hyuncheol,Kim, Youn-Chul Molecular Diversity Preservation International (MD 2014 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.15 No.5

<P>Sulfuretin is one of the major flavonoid components in <I>Rhus verniciflua</I> Stokes (Anacardiaceae) isolates. In this study, we investigated the protective effects of sulfuretin against <I>tert</I>-butyl hydroperoxide (<I>t</I>-BHP)-induced oxidative injury. The results indicated that the addition of sulfuretin before <I>t</I>-BHP treatment significantly inhibited cytotoxicity and reactive oxygen species (ROS) production in human liver-derived HepG2 cells. Sulfuretin up-regulated the activity of the antioxidant enzyme heme oxygenase (HO)-1 via nuclear factor E2-related factor 2 (Nrf2) translocation into the nucleus and increased the promoter activity of the antioxidant response element (ARE). Moreover, sulfuretin exposure enhanced the phosphorylation of c-Jun <I>N</I>-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), which are members of the mitogen-activated protein kinase (MAPK) family. Furthermore, cell treatment with a JNK inhibitor (SP600125) and ERK inhibitor (PD98059) reduced sulfuretin-induced HO-1 expression and decreased its protective effects. Taken together, these results suggest that the protective effect of sulfuretin against <I>t</I>-BHP-induced oxidative damage in human liver-derived HepG2 cells is attributable to its ability to scavenge ROS and up-regulate the activity of HO-1 through the Nrf2/ARE and JNK/ERK signaling pathways. Therefore, sulfuretin could be advantageous as a bioactive source for the prevention of oxidative injury.</P>

Sulfuretin Prevents Obesity and Metabolic Diseases in Diet Induced Obese Mice

김수지,송노준,장서혁,반가희,최유리,이동권,윤의정,최진희,이전,유재혁,신동한,박기문,강희,이석찬,구진모,조윤신,박계원 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.1

The global obesity epidemic and associated metabolic diseases require alternative biological targets for new therapeutic strategies. In this study, we show that a phytochemical sulfuretin suppressed adipocyte differentiation of preadipocytes and administration of sulfuretin to high fat diet-fed obese mice prevented obesity and increased insulin sensitivity. These effects were associated with a suppressed expression of inflammatory markers, induced expression of adiponectin, and increased levels of phosphorylated ERK and AKT. To elucidate the molecular mechanism of sulfuretin in adipocytes, we performed microarray analysis and identified activating transcription factor 3 (Atf3) as a sulfuretin-responsive gene. Sulfuretin elevated Atf3 mRNA and protein levels in white adipose tissue and adipocytes. Consistently, deficiency of Atf3 promoted lipid accumulation and the expression of adipocyte markers. Sulfuretin’s but not resveratrol’s anti-adipogenic effects were diminished in Atf3 deficient cells, indicating that Atf3 is an essential factor in the effects of sulfuretin. These results highlight the usefulness of sulfuretin as a new anti-obesity intervention for the prevention of obesity and its associated metabolic diseases.

Sulfuretin Inhibits Ultraviolet B-induced MMP Expression in Human Dermal Fibroblasts

소홍섭,김승훈,이영래 한의병리학회 2011 동의생리병리학회지 Vol.25 No.3

Sulfuretin is one of the main flavonoids produced by Rhusverniciflua. Sulfuretin has been shown to exhibit many pharmacological activities including anti-oxidant, anti-obesity, anti-inflammatory and anti-mutagenic activities. However, the anti-skin photoaging effects of sulfuretin has not yet been reported. In the present study, we investigated the inhibitory effect of sulfuretin on the expression levels of MMP-1 and -3 in the human dermal fibroblast cells. Western blot analysis and real-time PCR revealed sulfuretin inhibited UVB-induced MMP-1 and -3 expressions in a dose-dependent manner. UVB-induced MAPK/NF-κB/p50 activation and MMP expression were completely blocked by pretreatment of sulfuretin. Taken together, sulfuretin could prevent UVB-induced MMP expressions through inhibition of MAPK/NF-κB/p50 activation.

Sulfuretin Inhibits Ultraviolet B-induced MMP Expression in Human Dermal Fibroblasts

So, Hong-Seob,Kim, Seung-Hoon,Lee, Young-Rae The Physiological Society of Korean Medicine and T 2011 동의생리병리학회지 Vol.25 No.3

Sulfuretin is one of the main flavonoids produced by Rhusverniciflua. Sulfuretin has been shown to exhibit many pharmacological activities including anti-oxidant, anti-obesity, anti-inflammatory and anti-mutagenic activities. However, the anti-skin photoaging effects of sulfuretin has not yet been reported. In the present study, we investigated the inhibitory effect of sulfuretin on the expression levels of MMP-1 and -3 in the human dermal fibroblast cells. Western blot analysis and real-time PCR revealed sulfuretin inhibited UVB-induced MMP-1 and -3 expressions in a dose-dependent manner. UVB-induced MAPK/NF-${\kappa}B$/p50 activation and MMP expression were completely blocked by pretreatment of sulfuretin. Taken together, sulfuretin could prevent UVB-induced MMP expressions through inhibition of MAPK/NF-${\kappa}B$/p50 activation.

Sulfuretin from heartwood of <i>Rhus verniciflua</i> triggers apoptosis through activation of Fas, Caspase‐8, and the mitochondrial death pathway in HL‐60 human leukemia cells

Lee, Kyung‐,Won,Chung, Kyung‐,Sook,Seo, Ji‐,Hyung,Yim, Sung‐,Vin,Park, Hee‐,Jun,Choi, Jung‐,Hye,Lee, Kyung‐,Tae Wiley Subscription Services, Inc., A Wiley Company 2012 Journal of cellular biochemistry Vol.113 No.9

<P><B>Abstract</B></P><P>Sulfuretin, a flavonoid isolated from heartwood of <I>Rhus verniciflua</I>, has been reported to have anti‐cancer activities but the underlying molecular mechanism was not clear. In this study, sulfuretin induced apoptosis by activating caspases‐8, ‐9, and ‐3 as well as cleavage of poly(ADP‐ribose) polymerase. Furthermore, treatment with sulfuretin caused mitochondrial dysfunctions, including the loss of mitochondrial membrane potential (ΔΨ<SUB>m</SUB>), the release of cytochrome <I>c</I> to the cytosol, and the translocations of Bax and tBid. Sulfuretin also activated the extrinsic apoptosis pathway, that is, it increased the expressions of Fas and FasL, the activation of caspase‐8, and the cleavage of Bid. Furthermore, blocking the FasL–Fas interaction with NOK‐1 monoclonal antibody prevented the sulfuretin‐induced apoptosis. The therapeutical effect of sulfuretin in leukemia is due to its potent apoptotic activity through the extrinsic pathway driven by a Fas‐mediated caspase‐8‐dependent pathway. J. Cell. Biochem. 113: 2835–2844, 2012. © 2012 Wiley Periodicals, Inc.</P>