Jin-Woo Park

Publications of Jin-Woo Park

• Sulfuretin, a major flavonoid isolated from Rhus verniciflua, ameliorates experimental arthritis in mice.

  Authors: Young-Rae Lee, Jin-Ki Hwang, Hyoung-Won Koh, Kyu Yun Jang, Ju Hong Lee, Jin-Woo Park, Byung-Hyun Park

  Life sciences. 04/2012;

  AIM: Sulfuretin, a major flavonoid isolated from Rhus verniciflua, is known to have anti-inflammatory effects. However, the mechanisms underlying the anti-inflammatory effect of sulfuretin onAIM: Sulfuretin, a major flavonoid isolated from Rhus verniciflua, is known to have anti-inflammatory effects. However, the mechanisms underlying the anti-inflammatory effect of sulfuretin on rheumatoid arthritis have not been elucidated. In this study we investigated whether sulfuretin treatment modulates the severity of arthritis in an experimental model. MAIN METHODS: We evaluated the effects of sulfuretin on tumor necrosis factor-α (TNF-α)-treated human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and on collagen-induced arthritis (CIA) mice in vivo. KEY FINDINGS: In vitro experiments demonstrated that sulfuretin suppressed the chemokine production, matrix metalloproteinase secretion, and cell proliferation induced by tumor necrosis factor α in rheumatoid FLS. In addition, sulfuretin inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor and receptor activator of NF-κB ligand in bone marrow macrophages. In mice with CIA, early intervention with sulfuretin prevented joint destruction, as evidenced by a lower cumulative disease incidence and an absence of diverse disease features based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels. In mice with established arthritis, sulfuretin treatment significantly reduced synovial inflammation and joint destruction. The in vitro and in vivo protective effects of sulfuretin were mediated by inhibition of the NF-κB signaling pathway. SIGNIFICANCE: These results suggest that using sulfuretin to block the NF-κB pathway in rheumatoid joints reduces both inflammatory responses and joint destruction. Therefore, sulfuretin may have therapeutic value in preventing or delaying the progression of rheumatoid arthritis.

• Overexpression of the small GTPase Arl4D suppresses adipogenesis.

  Authors: Jiahua Yu, Sun-O Ka, Kang-Beom Kwon, Sang-Myeong Lee, Jin-Woo Park, Byung-Hyun Park

  International journal of molecular medicine. 07/2011; 28(5):793-8.

  Arl4D is a developmentally-regulated member of the ADP-ribosylation factor/ARF-like protein (ARF/Arl) family of Ras-related GTPases. Although Arl4 protein is reported to be expressed in adiposeArl4D is a developmentally-regulated member of the ADP-ribosylation factor/ARF-like protein (ARF/Arl) family of Ras-related GTPases. Although Arl4 protein is reported to be expressed in adipose tissue, the function of Arl4D is unknown. To investigate the potential role of Arl4D in adipogenesis, we examined Arl4D expression during adipocyte differentiation and the effects of Arl4D overexpression on adipogenesis. Arl4D protein increased early in adipogenesis, with the highest expression at 4 h after adipogenesis initiation, followed by a decrease thereafter. Overexpression of Arl4D in 3T3-L1 cells potently inhibited their ability to differentiate and accumulate lipid, and reduced the expression of adipogenic genes. Furthermore, treatment with valproic acid, an Arl4D inducer, suppressed adipogenesis. These results suggest that rapid reduction of Arl4D is required for adipogenesis to proceed.

• Inhibition of TNF-α-mediated inflammatory responses by a benzodioxolylacetylamino-linked benzothiazole analog in human fibroblast-like synoviocytes.

  Authors: Young-Rae Lee, Guo Hua Jin, Sang-Myeong Lee, Jin-Woo Park, Jae-Ha Ryu, Raok Jeon, Byung-Hyun Park

  Biochemical and biophysical research communications. 05/2011; 408(4):625-9.

  The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-κB. This study wasThe pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-κB. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-κB activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537 inhibited the nuclear translocation and the DNA binding of NF-κB subunits, which correlated with the inhibitory effects on IKK phosphorylation and IκBα degradation in TNF-α-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-α-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-κB ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-κB pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis.

• Dihydroavenanthramide D inhibits human breast cancer cell invasion through suppression of MMP-9 expression.

  Authors: Young-Rae Lee, Eun-Mi Noh, Hyun Ju Oh, Hyun Hur, Jeong-Mi Kim, Ji-Hey Han, Jin-Ki Hwang, Byung-Hyun Park, Jin-Woo Park, Hyun Jo Youn, Sung Hoo Jung, Byeong-Soo Kim, Ji-Youn Jung, Sung-Ho Lee, Chang-Sik Park, Jong-Suk Kim

  Biochemical and biophysical research communications. 01/2011; 405(4):552-7.

  Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Previous study demonstrates that DHAvD strongly inhibits activationDihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Previous study demonstrates that DHAvD strongly inhibits activation of nuclear factor-kappa B (NF-κB), which is a major component in cancer cell invasion. The present study investigated whether DHAvD can modulate MMP-9 expression and cell invasion in MCF-7 human breast cancer cells. MMP-9 expression and cell invasion in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) was increased, whereas these inductions were muted by DHAvD. DHAvD also suppressed activation of mitogen-activated protein kinase (MAPK), and MAPK-mediated nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activations in TPA-treated MCF-7 cells. The results indicate that DHAvD-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the MAPK/NF-κB and MAPK/AP-1 pathways in MCF-7 cells. DHAvD may have potential value in breast cancer metastasis.

• A prenylated flavan from Broussonetia kazinoki prevents cytokine-induced β-cell death through suppression of nuclear factor-κB activity.

  Authors: Ui-Jin Bae, Da Yeon Lee, Mi-Young Song, Sang-Myeong Lee, Jin-Woo Park, Jae-Ha Ryu, Byung-Hyun Park

  Biological & pharmaceutical bulletin. 01/2011; 34(7):1026-31.

  The generation of nitric oxide (NO) via inducible NO synthase (iNOS) and reactive oxygen species plays a key role in cytokine-mediated pancreatic β-cell damage. Oxidative stress due to reactiveThe generation of nitric oxide (NO) via inducible NO synthase (iNOS) and reactive oxygen species plays a key role in cytokine-mediated pancreatic β-cell damage. Oxidative stress due to reactive oxygen species activates the nuclear factor-κB (NF-κB) transcription factor, which regulates iNOS expression. In this regard, suppression of the NF-κB pathway is a novel strategy for protecting β-cells from damage. This study was performed to explore the effects of kazinol U, a prenylated flavan from Broussonetia kazinoki, on the NF-κB activation pathway in interleukin-1β (IL-1β)- and interferon-γ (IFN-γ)-treated β-cells. The cytotoxic effects of cytokines were completely abolished when RINm5F cells or islets were pretreated with kazinol U. Kazinol U inhibited the nuclear translocation and DNA binding of NF-κB subunits, which correlated with the inhibitory effects on IκB kinase (IKK) phosphorylation and IκBα degradation. In addition, kazinol U suppressed NO and hydrogen peroxide production and apoptotic cell death by cytokines in RINm5F cells. The protective effects of kazinol U were further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Taken together, these results suggest that using kazinol U to block the NF-κB pathway in pancreatic β-cells reduces cell damage. Therefore, kazinol U may have therapeutic value in delaying pancreatic β-cell destruction in type 1 diabetes.

• Aggravation of post-ischemic liver injury by overexpression of A20, an NF-κB suppressor.

  Authors: Jiahua Yu, Hwa-Suk Lee, Sang-Myeong Lee, Hee-Chul Yu, Woo Sung Moon, Myoung Ja Chung, Jin-Woo Park, Byung-Hyun Park

  Journal of hepatology. 12/2010; 55(2):328-36.

  BACKGROUD & AIMS: A20 is an intracellular ubiquitin-editing enzyme that plays an important role in the negative feedback regulation of NF-κB activation in response to a diverse range of stimuli.BACKGROUD & AIMS: A20 is an intracellular ubiquitin-editing enzyme that plays an important role in the negative feedback regulation of NF-κB activation in response to a diverse range of stimuli. Liver ischemia/reperfusion injury is associated with rapid activation of NF-κB signaling, but the role of NF-κB in hepatic ischemia/reperfusion injury remains controversial. The NF-κB signaling pathway mediates both protective and deleterious effects in the liver. Here, we examined whether A20 inhibited or aggravated hepatic ischemia/reperfusion injury. We used IκBα super-repressor as a positive control and overexpressed A20 and IκBα super-repressor in the liver of C57BL/6 mice. Mice underwent 45min of partial hepatic ischemia and were then reperfused. Protein level of A20 was increased after reperfusion. Mice subjected to ischemia/reperfusion injury showed increased NF-κB activation, as evidenced by phosphorylation of IκBα and nuclear translocation of NF-κB. Prior transfection with Ad-A20 or Ad-IκBα super-repressor attenuated NF-κB activation and aggravated liver injury. Serum aminotransferases and proinflammatory cytokines, hepatocellular necrosis, and hepatic neutrophil infiltration were markedly increased compared to those of uninfected or control virus infected mice. In addition, A20 abolished the beneficial effect of ischemic preconditioning. Our results suggest that inhibition of NF-κB activation by A20 aggravated partial hepatic ischemia/reperfusion injury. Understanding how the NF-κB pathway plays a role in directing a clinical outcome may lead to better prospects of more rational approaches to reduce post-ischemic liver injury.

• Sulfuretin protects against cytokine-induced beta-cell damage and prevents streptozotocin-induced diabetes.

  Authors: Mi-Young Song, Gil-Saeng Jeong, Kang-Beom Kwon, Sun-O Ka, Hyun-Young Jang, Jin-Woo Park, Youn-Chul Kim, Byung-Hyun Park

  Experimental & molecular medicine. 09/2010; 42(9):628-38.

  NF-kappaB 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 toNF-kappaB 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-kappaB 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-gamma 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 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-kappaB activation. Collectively, these results indicate that sulfuretin may have therapeutic value in preventing beta-cell damage.

• Sulfuretin attenuates allergic airway inflammation in mice.

  Authors: Mi-Young Song, Gil-Saeng Jeong, Haw-Suk Lee, Keun-Sang Kwon, Sang-Myeong Lee, Jin-Woo Park, Youn-Chul Kim, Byung-Hyun Park

  Biochemical and biophysical research communications. 09/2010; 400(1):83-8.

  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. Because NF-κB activation plays aSulfuretin is one of the main flavonoids produced by Rhus verniciflua, which is reported to inhibit the inflammatory response by suppressing the NF-κB pathway. Because NF-κB activation plays a pivotal role in the pathogenesis of allergic airway inflammation, we here examined the effect of sulfuretin on an ovalbumin-induced airway inflammation model in mice. We isolated sulfuretin from R. verniciflua. Sulfuretin was delivered intraperitoneally after the last ovalbumin challenge. Airway hyper-responsiveness, cytokines, mucin, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. A single administration of sulfuretin reduced airway inflammatory cell recruitment and peribronchiolar inflammation and suppressed the production of various cytokines in bronchoalveolar fluid. In addition, sulfuretin suppressed mucin production and prevented the development of airway hyper-responsiveness. The protective effect of sulfuretin was mediated by the inhibition of the NF-κB signaling pathway. Our results suggest that sulfuretin may have therapeutic potential for the treatment of allergic airway inflammation.

• A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis.

  Authors: Young-Sool Hah, Young-Rae Lee, Jin-Su Jun, Hye-Song Lim, Hyun-Ok Kim, Yong-Geun Jeong, Gang Min Hur, Sang Yong Lee, Myoung Ja Chung, Jin-Woo Park, Sang-Il Lee, Byung-Hyun Park

  Arthritis and rheumatism. 08/2010; 62(8):2313-21.

  Nuclear factor-kappaB (NF-kappaB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universalNuclear factor-kappaB (NF-kappaB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-kappaB, might have antiarthritic effects. An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally. In vitro experiments demonstrated that AdA20 suppressed NF-kappaB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus-injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-kappaB signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-kappaB. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study. These results suggest that using A20 to block the NF-kappaB pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA.

• Nardostachys jatamansi extract protects against cytokine-induced beta-cell damage and streptozotocin-induced diabetes.

  Authors: Mi-Young Song, Ui-Jin Bae, Bong-Hee Lee, Kang-Beom Kwon, Eun-A Seo, Sung-Joo Park, Min-Sun Kim, Ho-Joon Song, Keun-Sang Kwon, Jin-Woo Park, Do-Gon Ryu, Byung-Hyun Park

  World journal of gastroenterology : WJG. 07/2010; 16(26):3249-57.

  To investigate the anti-diabetogenic mechanism of Nardostachys jatamansi extract (NJE). Mice were injected with streptozotocin via a tail vein to induce diabetes. Rat insulinoma RINm5F cells andTo investigate the anti-diabetogenic mechanism of Nardostachys jatamansi extract (NJE). Mice were injected with streptozotocin via a tail vein to induce diabetes. Rat insulinoma RINm5F cells and isolated rat islets were treated with interleukin-1beta and interferon-gamma to induce cytotoxicity. Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was confirmed by immunohistochemical staining of the islets. The diabetogenic effects of streptozotocin were completely abolished when mice were pretreated with NJE. Inhibition of streptozotocin-induced hyperglycemia by NJE was mediated by suppression of nuclear factor (NF)-kappaB activation. In addition, NJE protected against cytokine-mediated cytotoxicity. Incubation of RINm5F cells and islets with NJE resulted in a significant reduction in cytokine-induced NF-kappaB activation and downstream events, inducible nitric oxide synthase expression and nitric oxide production. The protective effect of NJE was further demonstrated by the normal insulin secretion of cytokine-treated islets in response to glucose. NJE provided resistance to pancreatic beta-cell damage from cytokine or streptozotocin treatment. The beta-cell protective effect of NJE is mediated by suppressing NF-kappaB activation.

• Saponified evening primrose oil reduces melanogenesis in B16 melanoma cells and reduces UV-induced skin pigmentation in humans.

  Authors: Jeung-Hyun Koo, Ikjae Lee, Seok-Kweon Yun, Han-Uk Kim, Byung-Hyun Park, Jin-Woo Park

  Lipids. 03/2010; 45(5):401-7.

  This study was conducted to determine whether saponified evening primrose oil (sap-EPO) has the potential for use as a whitening agent and to investigate its underlying mechanisms of action. In B16This study was conducted to determine whether saponified evening primrose oil (sap-EPO) has the potential for use as a whitening agent and to investigate its underlying mechanisms of action. In B16 melanoma cells, sap-EPO dose-dependently inhibited isobutylmethylxanthine-induced melanogenesis with no cytotoxicity. This decrease in melanin production was correlated with reduced enzyme activity and decreased mRNA and protein levels of tyrosinase. The mRNA levels of tyrosinase-related proteins 1 and 2 decreased in response to treatment with sap-EPO, indicating that it regulated tyrosinase at the transcriptional level. Expression of microphthalmia-associated transcription factor was also decreased by sap-EPO as evidenced by decreased mRNA and protein levels. Additionally, topical application of sap-EPO resulted in efficient whitening of UVB-induced hyperpigmentation of human skin. Taken together, these results suggest that sap-EPO has the potential for use as a cosmetic whitening agent.

• Dihydroavenanthramide D protects pancreatic beta-cells from cytokine and streptozotocin toxicity.

  Authors: Na Lv, Mi-Young Song, Young-Rae Lee, Ha Na Choi, Kang-Beom Kwon, Jin-Woo Park, Byung-Hyun Park

  Biochemical and biophysical research communications. 10/2009; 387(1):97-102.

  Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Although its anti-inflammatory, antiatherosclerotic, and antioxidantDihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Although its anti-inflammatory, antiatherosclerotic, and antioxidant effects have been reported, the effect of DHAvD on type 1 diabetes is unknown. Therefore, in this study, the effect of DHAvD on cytokine- or streptozotocin-induced beta-cell damage was investigated. Treatment of RINm5F insulinoma cells or isolated islets with IL-1beta and IFN-gamma induced beta-cell damage through a NF-kappaB-dependent signaling pathway. DHAvD-pretreated RINm5F cells or islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced the inducible form of NO synthase expression, and decreased beta-cell destruction and the normal insulin secretion capacity. Furthermore, pretreatment with DHAvD blocked the development of type 1 diabetes in streptozotocin-treated mice. Prior injection with DHAvD maintained a normal range of plasma glucose and insulin, and retained immunoreactivity for insulin in the pancreas. These results suggest that DHAvD may be used to preserve functional beta-cell mass.

• A20 Attenuates Allergic Airway Inflammation in Mice.

  Authors: Nam-In Kang, Ha-Yong Yoon, Young-Rae Lee, Minho Won, Myoung Ja Chung, Jin-Woo Park, Gang Min Hur, Hern-Ku Lee, Byung-Hyun Park

  Journal of immunology (Baltimore, Md. : 1950). 07/2009;

  TNF receptor 1 can activate signaling pathways leading to the activation of NF-kappaB. A20, an NF-kappaB-inducible protein, negatively regulates these signaling pathways and acts as anTNF receptor 1 can activate signaling pathways leading to the activation of NF-kappaB. A20, an NF-kappaB-inducible protein, negatively regulates these signaling pathways and acts as an anti-inflammatory mediator. Therefore, A20 is viewed as a potential therapeutic target for inflammatory disease. In this study, we examined the effect of A20 on an OVA-induced allergic airway inflammation model in mice. We used an adenovirus containing A20 cDNA (Ad-A20) that was delivered intratracheally before OVA challenge. Single administration of Ad-A20 reduced airway inflammatory cell recruitment and peribronchiolar inflammation and suppressed the production of various cytokines in bronchoalveolar fluid. In addition, Ad-A20 suppressed mucus production and prevented the development of airway hyperresponsiveness. The protective effect of Ad-A20 was mediated by the inhibition of the NF-kappaB signaling pathway. Taken together, our results suggest that the development of an immunoregulatory strategy based on A20 may have therapeutic potential for the treatment of allergic asthma.

• Silibinin attenuates adipogenesis in 3T3-L1 preadipocytes through a potential upregulation of the insig pathway.

  Authors: Sun-O Ka, Kyung-Ah Kim, Kang-Beom Kwon, Jin-Woo Park, Byung-Hyun Park

  International journal of molecular medicine. 06/2009; 23(5):633-7.

  In the past few decades, the use of silibinin, a plant flavonoid extracted from the milk thistle, as a hepatoprotective and chemopreventive agent has gained much attention. In this study, weIn the past few decades, the use of silibinin, a plant flavonoid extracted from the milk thistle, as a hepatoprotective and chemopreventive agent has gained much attention. In this study, we investigated the effects of silibinin on adipogenesis. Treatment with silibinin suppressed terminal differentiation of 3T3-L1 cells into adipocytes as evidenced by Oil red O staining and TG assay results. Real-time RT-PCR analysis revealed that silibinin decreased the expression of adipogenesis-related genes such as CAAT/enhancer binding protein-alpha, fatty acid synthase, sterol response element binding protein 1c, adipocyte-specific lipid binding protein, peroxisome proliferator-activated receptor gamma and lipoprotein lipase, and increased the expression of preadipocyte factor-1, a preadipocyte marker gene. The anti-adipogenic effect of silibinin was associated with the up-regulation of insig-1 and insig-2. Collectively, these results suggest that silibinin inhibits adipocyte differentiation through a potential up-regulation of insig-1 and insig-2 at an early phase in adipocyte differentiation.

• JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-kappaB activation and the JAK/STAT pathway.

  Authors: Na Lv, Eun-Kyung Kim, Mi-Young Song, Ha Na Choi, Woo Sung Moon, Sung-Joo Park, Jin-Woo Park, Kang-Beom Kwon, Byung-Hyun Park

  Experimental cell research. 06/2009;

  JANEX-1/WHI-P131, a selective Janus kinase 3 (JAK3) inhibitor, has been shown to delay the onset of diabetes in the NOD mouse model. However, the molecular mechanism by which JANEX-1 protectsJANEX-1/WHI-P131, a selective Janus kinase 3 (JAK3) inhibitor, has been shown to delay the onset of diabetes in the NOD mouse model. However, the molecular mechanism by which JANEX-1 protects pancreatic beta-cells is unknown. In the current study, we investigated the role of JANEX-1 on interleukin (IL)-1beta and interferon (IFN)-gamma-induced beta-cell damage using isolated islets. JANEX-1-pretreated islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced inducible form of NO synthase (iNOS) expression, and decreased islet destruction. The molecular mechanism by which JANEX-1 inhibits iNOS expression was mediated through suppression of the nuclear factor kappaB (NF-kappaB) and JAK/signal transducer and activator of transcription (STAT) pathways. Islets treated with the cytokines downregulated the protein levels of suppressor of cytokine signaling (SOCS)-1 and SOCS-3, but pretreatment with JANEX-1 attenuated these decreases. Additionally, islets from JAK3(-/-) mice were more resistant to cytokine toxicity than islets from control mice. These results demonstrate that JANEX-1 protects beta-cells from cytokine toxicity through suppression of the NF-kappaB and JAK/STAT pathways and upregulation of SOCS proteins, suggesting that JANEX-1 may be used to preserve functional beta-cell mass.

• Fructus Xanthii extract protects against cytokine-induced damage in pancreatic beta-cells through suppression of NF-kappaB activation.

  Authors: Mi-Young Song, Eun-Kyung Kim, Heon-Jae Lee, Jin-Woo Park, Do-Gon Ryu, Kang-Beom Kwon, Byung-Hyun Park

  International journal of molecular medicine. 05/2009; 23(4):547-53.

  Cytokines released by infiltrating inflammatory cells around the pancreatic islets are involved in the pathogenesis of type 1 diabetes. Interleukin (IL)-1beta and interferon (IFN)-gamma are theCytokines released by infiltrating inflammatory cells around the pancreatic islets are involved in the pathogenesis of type 1 diabetes. Interleukin (IL)-1beta and interferon (IFN)-gamma are the primary cytokines responsible for stimulation of inducible nitric oxide synthase (iNOS) expression and nitric oxide overproduction, which leads to beta-cell damage. In addition, nuclear factor-kappaB (NF-kappaB) plays a crucial role in the activation of this pathway. Therefore, suppression of the cytokine-NF-kappaB pathway is considered an effective therapeutic strategy for preventing inflammatory reactions in pancreatic beta-cells. In this study, the effects of Fructus Xanthii extract (FXE) on IL-1beta and IFN-gamma-induced beta-cell damage were examined. Treatment of RINm5F cells with IL-1beta and IFN-gamma reduced cell viability, however, FXE completely protected cells from IL-1beta and IFN-gamma-mediated reduction in viability in a concentration-dependent manner. In addition, incubation with FXE resulted in a significant suppression of IL-1beta and IFN-gamma-induced nitric oxide (NO) production, which correlated with the reduced levels of the inducible form of iNOS mRNA and protein observed. The IL-1beta and IFN-gamma-stimulated RIN cells showed increases in NF-kappaB binding activity and p50 subunit levels in the nucleus, as well as increased IkappaBalpha degradation in cytosol when compared to unstimulated cells, which indicates that the mechanism by which FXE inhibited the iNOS gene involves inhibition of NF-kappaB activation. Furthermore, a protective effect of FXE was demonstrated by reduction in NO generation and iNOS expression, as well as the normal insulin secreting responses to glucose observed in IL-1beta and IFN-gamma-treated islets.

• Sulforaphane protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway.

  Authors: Mi-Young Song, Eun-Kyung Kim, Woo Sung Moon, Jin-Woo Park, Hyung-Jin Kim, Hong-Seob So, Raekil Park, Kang-Beom Kwon, Byung-Hyun Park

  Toxicology and applied pharmacology. 12/2008;

  Sulforaphane (SFN) is an indirect antioxidant that protects animal tissues from chemical or biological insults by stimulating the expression of several NF-E2-related factor-2 (Nrf2)-regulated phase 2Sulforaphane (SFN) is an indirect antioxidant that protects animal tissues from chemical or biological insults by stimulating the expression of several NF-E2-related factor-2 (Nrf2)-regulated phase 2 enzymes. Treatment of RINm5F insulinoma cells with SFN increases Nrf2 nuclear translocation and expression of phase 2 enzymes. In this study, we investigated whether the activation of Nrf2 by SFN treatment or ectopic overexpression of Nrf2 inhibited cytokine-induced beta-cell damage. Treatment of RIN cells with IL-1beta and IFN-gamma induced beta-cell damage through a NF-kappaB-dependent signaling pathway. Activation of Nrf2 by treatment with SFN and induction of Nrf2 overexpression by transfection with Nrf2 prevented cytokine toxicity. The mechanism by which Nrf2 activation inhibited NF-kappaB-dependent cell death signals appeared to involve the reduction of oxidative stress, as demonstrated by the inhibition of cytokine-induced H(2)O(2) production. The protective effect of SFN was further demonstrated by the restoration of normal insulin secreting responses to glucose in cytokine-treated rat pancreatic islets. Furthermore, pretreatment with SFN blocked the development of type 1 diabetes in STZ-treated mice.

• Overexpression of SIRT1 protects pancreatic {beta}-cells against cytokine toxicity through suppressing NF-{kappa}B signaling pathway.

  Authors: Ji-Hyun Lee, Mi-Young Song, Eun-Kyung Song, Eun-Kyung Kim, Woo Sung Moon, Myung-Kwan Han, Jin-Woo Park, Kang-Beom Kwon, Byung-Hyun Park

  Diabetes. 12/2008;

  Objective: SIRT1, a class III histone/protein deacetylase, is known to interfere NF-kappaB signaling pathway and thereby has an anti-inflammatory function. Due to the central role of NF-kappaB inObjective: SIRT1, a class III histone/protein deacetylase, is known to interfere NF-kappaB signaling pathway and thereby has an anti-inflammatory function. Due to the central role of NF-kappaB in cytokine-mediated pancreatic beta-cell damage, we postulated that SIRT1 might work in pancreatic beta-cell damage model. Research Design and Methods: RINm5F (RIN) cells or isolated rat islets were treated with IL-1beta and IFN-gamma. SIRT1 was activated by resveratrol, a pharmacological activator, or ectopic overexpression. The underlying mechanisms of SIRT1 against cytokine toxicity were further explored. Results: Treatment of RIN cells with cytokines induced cell damage, and this damage was well correlated with the expression of inducible form of NO synthase (iNOS) and nitric oxide production. However, SIRT1 overexpression completely prevented cytokine-mediated cytotoxicity, as well as nitric oxide production and iNOS expression. The molecular mechanism by which SIRT1 inhibits iNOS gene expression appeared to involve the inhibition of NF-kappaB signaling pathway through deacetylation of p65. In addition, SIRT1 activation by either resveratrol or adenoviral-directed overexpression of SIRT1 could prevent cytokine toxicity and maintain normal insulin secreting responses to glucose in isolated rat islets. Conclusions: This study will provide valuable information not only into the mechanisms underlying beta-cell destruction but also into the regulation of SIRT1 as a possible target to attenuate cytokine-induced beta-cell damage.

• Inhibition of IL-1beta-mediated inflammatory responses by the IkappaBalpha super-repressor in human fibroblast-like synoviocytes.

  Authors: Young-Rae Lee, Suc-Hyun Kweon, Kang-Beom Kwon, Jin-Woo Park, Taek-Rim Yoon, Byung-Hyun Park

  Biochemical and biophysical research communications. 12/2008;

  The IL-1beta-NF-kappaB axis is a key pathway in the pathogenesis of rheumatoid arthritis (RA) and is central in the production of proinflammatory mediators in the inflamed synovium. Therefore, weThe IL-1beta-NF-kappaB axis is a key pathway in the pathogenesis of rheumatoid arthritis (RA) and is central in the production of proinflammatory mediators in the inflamed synovium. Therefore, we examined whether fibroblast-like synoviocytes (FLS) could be spared from IL-1beta-induced toxicity by an overexpressing IkappaB super-repressor. Infection of FLS with Ad-IkappaBalpha (S32A, S36A), an adenovirus-containing mutant IkappaBalpha, inhibited IL-1beta-induced nuclear translocation and DNA binding of NF-kappaB. In addition, Ad-IkappaBalpha (S32A, S36A) prevented IL-1beta-induced inflammatory responses; namely, the production of chemokines, such as ENA-78 and RANTES, and activation of MMP-1 and MMP-3. Finally, increased cellular proliferation of FLS after IL-1beta treatment was significantly reduced by Ad-IkappaBalpha (S32A, S36A). However, Ad-IkappaBbeta (S19A, S23A), the IkappaBbeta mutant, was not effective in preventing IL-1beta toxicity. These results suggest that inhibition of IkappaBalpha degradation is a potential target for the prevention of joint destruction in patients with RA.

• Beneficial effect of Flos magnoliae extract on multiple low dose streptozotocin-induced type 1 diabetes development and cytokine-induced beta-cell damage.

  Authors: Eun-Kyung Kim, Mi-Young Song, In-Seob Kim, Woo Sung Moon, Do-Gon Ryu, Hong-Seob So, Raekil Park, Jin-Woo Park, Kang-Beom Kwon, Byung-Hyun Park

  International journal of molecular medicine. 11/2008; 22(4):481-8.

  In the present study, Flos magnoliae extract (FME) was evaluated to determine if it could protect pancreatic beta-cells against multiple low dose streptozotocin (MLDS) and interleukin-1beta andIn the present study, Flos magnoliae extract (FME) was evaluated to determine if it could protect pancreatic beta-cells against multiple low dose streptozotocin (MLDS) and interleukin-1beta and interferon-gamma. Injection of mice with MLDS resulted in hyperglycemia and hypoinsulinemia, which was confirmed by immunohistochemical staining. However, the induction of diabetes by MLDS was completely prevented when mice were pretreated with FME. FME also effectively protected beta-cells against cytokine toxicity, which was demonstrated by an increase in the viability of rat insulinoma RINm5F cells and by preserved insulin secreting responses to glucose in isolated rat islets. Moreover, cytokine-induced nitric oxide production and iNOS mRNA and protein expression were significantly reduced in RINm5F cells and islets that were preincubated with FME. The molecular mechanism by which FME inhibits iNOS gene expression in in vitro and in vivo appears to involve inhibition of NF-kappaB activation. Taken together, these results reveal the possible therapeutic value of FME for the prevention of type 1 diabetes progression.