Sang-Won Hong

Melatonin ameliorates cerulein‐induced pancreatitis by the modulation of nuclear erythroid 2‐related factor 2 and nuclear factor‐kappaB in rats

Abstract:  Melatonin exhibits a wide variety of biological effects, including antioxidant and anti‐inflammatory functions. Its antioxidant role impedes the etiopathogenesis of pancreatitis, but little is known about the signaling pathway of melatonin in the induction of antioxidant enzymes in acute pancreatitis (AP). The aim of this study was to determine whether melatonin could prevent cerulein‐induced AP through nuclear factor erythroid 2‐related factor 2 (Nrf2) and curtail inflammation by inhibition of NF‐κB. AP was induced by two intraperitoneal (i.p.) injections of cerulein at 2 h intervals (50 μg/kg) in Sprague‐Dawley rats. Melatonin (10 or 50 mg/kg/daily, i.p.) was administered 24 h before each injection of cerulein. The rats were killed 12 h after the last injection. Acinar cell degeneration, pancreatic edema, and inflammatory infiltration were significantly different in cerulein‐ and melatonin‐treated rats. Melatonin significantly reduced amylase, lipase, MPO, and MDA levels, and increased antioxidant enzyme activities including SOD and GPx, which were decreased in AP (P < 0.05). Melatonin increased the expression of NQO1, HO‐1, and SOD2 when compared with the cerulein‐induced AP group (P < 0.05). In addition, melatonin increased Nrf2 expression, and reduced expressions of tumor necrosis factor‐alpha, IL‐1β, IL‐6, IL‐8, and iNOS. The elevated nuclear binding of NF‐κB in the cerulein‐induced pancreatitis group was inhibited by melatonin. These results show that melatonin increases antioxidant enzymes and Nrf2 expression, and limits inflammatory mediators in cerulein‐induced AP. It is proposed that melatonin may play an important role in oxidative stress via the Nrf2 pathway in parallel with reduction of inflammation by NF‐κB inhibition.

Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model

Abstract:  Melatonin has potent hepatoprotective effects as an antioxidant. However, the signaling pathway of melatonin in the induction of antioxidant enzymes against acute liver injury is not fully understood. The study aimed to determine whether melatonin could prevent dimethylnitrosamine (DMN)‐induced liver injury through nuclear erythroid 2‐related factor 2 (Nrf2) and inflammation. Liver injury was induced in rats by a single injection of DMN (30 mg/kg, i.p.). Melatonin treatment (50 mg/kg/daily, i.p.) was initiated 24 hr after DMN injection for 14 days, after which the rats were killed and samples were collected. Serum and antioxidant enzyme activities improved in melatonin‐treated rats, compared with DMN‐induced liver injury group (P < 0.01). Melatonin reduced the infiltration of inflammatory cells and necrosis in the liver, and increased the expression of NADPH: quinone oxidoreductase‐1, heme oxygenase‐1, and superoxide dismutase‐2, which were decreased by DMN. Melatonin increased expression of novel transcription factor, Nrf2, and decreased expression of inflammatory mediators including tumor necrosis factor‐alpha, interleukin (IL)‐1β, IL‐6, and inducible nitric oxide synthase. The increased nuclear binding of nuclear factor‐kappa B (NF‐κB) in the DMN‐induced liver injury group was inhibited by melatonin. Our results show that melatonin increases antioxidant enzymes and Nrf2 expression in parallel with the decrease of inflammatory mediators in DMN‐induced liver injury, suggesting that melatonin may play a role of antioxidant defense via the Nrf2 pathway, by reducing inflammation by NF‐κB inhibition.

Porous silicon as an agent for cancer thermotherapy based on near-infrared light irradiation†

In recent years, new thermotherapies based on nanoshells and more recently single-wall carbon nanotubes (SWCNTs) in combination with near-infrared (NIR) light irradiation have received significant attention as efficient techniques to destroy cancer cells selectively. Very recently we have reported that porous silicon (PSi) can also be utilized as a therapeutic agent that generates heat sufficient to kill cancer cells without toxicity upon exposure to NIR light. In this paper, we report the heat generation abilities of a PSi suspension, a PSi/NaCl suspension and a PSi/phosphate-buffered saline (PBS) suspension during continuous irradiation with NIR light and the in vitrocell test results obtained by using thermotherapy based on PSi and NIR light irradiation. The PSi/NaCl suspension showed heat generation ability superior to those of the PSi suspension and PSi/PBS suspension. The temperature of the PSi/NaCl suspension was elevated to 55 and 76 °C after 3 and 20 min NIR irradiation at 300 mW cm−2, respectively, while that of the control was elevated to 31 and 39 °C after 3 and 20 min, respectively. In vitrocell test results suggest that thermotherapy based on PSi in combination with NIR light irradiation is an efficient technique to destroy cancer cells selectively without damaging the surrounding healthy cells and that heterochromatic NIR radiation can also be utilized successfully for this purpose.

The protective effect of resveratrol on dimethylnitrosamine-induced liver fibrosis in rats.

Oxidative stress in liver injury is a major pathogenetic factor in progress of liver fibrosis. Resveratrol, a representative antioxidant derived from grapes, has been reported to show widespread pharmacological properties. In this study, we investigated the protective effects of resveratrol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Rats were treated with resveratrol daily by oral gavage for seven days after a single intraperitoneal injection of DMN (40 mg/kg). Resveratrol remarkably recovered body and liver weight loss due to DMNinduced liver fibrosis. Liver histology showed that resveratrol alleviated the infiltration of inflammatory cells and fibrosis of liver tissue. Resveratrol decreased the level of malondialdehyde and increased the levels of glutathione peroxidase and superoxide dismutase. Also, resveratrol significantly inhibited the mRNA expression of inflammatory mediators including inducible nitric oxide, tumor necrosis factor-alpha and interleukin-1beta. In addition, resveratrol showed not only reduced mRNA expression of fibrosis-related genes such as transforming growth factor beta 1, collagen type I, and alpha-smooth muscle actin, but also a significant decrease of hydroxyproline in rats with DMN-induced liver fibrosis. Our results suggest that resveratrol could be used to treat liver injury and fibrosis and be useful in preventing the development of liver fibrosis and cirrhosis.

Antioxidative and skin-whitening effect of an aqueous extract of Salicornia herbacea.

Salicornia herbacea (SH) is a halophyte that grows in the salt marshes along the coastline of South Korea, and is known to have antioxidative activity. In this study, the antioxidative and skin-whitening effects of SH aqueous extract were investigated in human dermal fibroblasts (HDFs) and B16 melanoma cells. The water extract of SH had potent antioxidative capacity and protected HDFs from tert-butyl hydroperoxide (tbOOH)-induced oxidative stress in a dose-dependent manner. In a cell cycle analysis, pretreatment with SH reversed the apoptotic cell death induced by tbOOH in HDFs. Additionally, the incubation of SH in mushroom tyrosinase inhibited the oxidation of l-dopa to o-dopaquinone, which implies that SH is a potent tyrosinase inhibitor. An SH treatment to B16 melanoma cells decreased the synthesis of melanin and inhibited tyrosinase activity. These results collectively indicate that SH had antioxidative and whitening effects on skin and would be a good candidate for skin rejuvenating agent.

Suppression by fucoidan of liver fibrogenesis via the TGF-β/Smad pathway in protecting against oxidative stress.

Fucoidan, a sulfated polysaccharide extracted from various types of brown seaweed, possesses a wide range of pharmacological properties. We investigated the protective effect of fucoidan on dimethylnitrosamine-induced liver fibrogenesis in rats and its mechanism. Liver fibrosis was induced by injecting DMN (10 mg/kg, 3 times per week, I.P.) for 4 weeks, and fucoidan was simultaneously administered (100 mg/kg, 3 times per week, P.O.). The anti-oxidative and anti-inflammatory effects of fucoidan were observed by relative mediators. Fucoidan improved liver fibrosis by inhibiting the expression of transforming growth factor beta 1 (TGF-β1)/Smad3 and the tissue inhibitor of metalloproteinase 1 (TIMP-1), and increasing the expression of metalloproteinase-9 (MMP-9). Fucoidan also significantly decreased the accumulation of the extracellular matrix (ECM) and collagen. These results suggest that fucoidan had an anti-fibrotic effect, which was exerted by inhibiting the TGF-β/Smad pathway, as well as anti-oxidative and anti-inflammatory effects.

SB365 inhibits angiogenesis and induces apoptosis of hepatocellular carcinoma through modulation of PI3K/Akt/mTOR signaling pathway

Identification of small molecules that safely inhibit cancer progression is critical for cancer therapeutics. Saponins exhibit cytostatic and cytotoxic activity against various cancer cells, but the mechanism is not well understood. Here, we investigated whether saponin D (designated SB365), an active component isolated from Pulsatilla koreana, could inhibit the progression of hepatocellular carcinoma (HCC) and considered its mechanism. SB365 strongly suppressed the growth of HCC cells in a dose‐dependent manner and induced apoptosis by increasing the proportion of sub G1 apoptotic cells from 8% to 21% through induction of expression of Bax and cleaved caspase‐3. In addition, SB365 exhibited potent anti‐angiogenic activity and decreased the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor, a key molecule for angiogenesis. Furthermore, SB365 suppressed the tube formation and migration of HUVEC, as well as in vivo neovascularization in a mouse Matrigel plug assay. In vivo study showed that SB365 significantly inhibited tumor growth in an HCC xenograft model, inducing apoptosis by increasing the expression of the cleaved caspase‐3 and DNA fragmentation. The expressions of vascular endothelial growth factor and CD34 in the tumor tissue were decreased by SB365 treatment. In examining its mechanism, SB365 was found to effectively suppress the phosphorylation of PI3K downstream factors, such as Akt, mTOR and p70S6K both in vitro and in vivo. Our study demonstrates that SB365 not only induces apoptosis but also inhibits cell growth and angiogenesis through modulation of the PI3K/Akt/mTOR pathway in human HCC. We suggest that SB365 may be a new chemotherapeutic candidate against HCC.

Morin protects acute liver damage by carbon tetrachloride (CCl4) in rat

The purpose of this study was to investigate possible beneficial effects of morin on CCl4-induced acute hepatotoxicity in rats. Rats received a single dose of CCl4 (150 μL/100 g 1:1 in corn oil). Morin treatment (20 mg/kg) was given at 48, 24, and 2 h before CCl4 administration. CCl4 challenge elevated serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) levels, but these effects were prevented by the pretreatment of rats with morin. To identify the mechanism of protective activity of morin in CCl4-induced hepatotoxicity in rats, we investigated expressions of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and inducible nitric oxide (iNOS). The expressions of TNF-α, IL-1β, IL-6, and iNOS were increased by CCl4 treatment and increased expressions of those were decreased by morin. These findings suggest that morin prevents acute liver damage by inhibiting the production of TNF-α, IL-1β, IL-6, and iNOS.

HS-116, a novel phosphatidylinositol 3-kinase inhibitor induces apoptosis and suppresses angiogenesis of hepatocellular carcinoma through inhibition of the PI3K/AKT/mTOR pathway

The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival of human cancers. As PI3K is active in many cancer patients, resulting in cancer development and progression, we developed an azaindole derivative, HS-116 as a novel PI3K inhibitor. This study aimed to clarify the anticancer effect of HS-116 in human hepatocellular carcinoma (HCC). To identify the effect of HS-116 on HCC cells, a PI3K assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blotting were conducted. IC(50) of HS-116 for PI3Kα was 31nM, and it effectively suppressed the phosphorylation of PI3K downstream factors such as AKT, mTOR, p70S6K, and 4EBP1. Also, HS-116 induced apoptosis by increasing the proportion of sub-G1 apoptotic cells from 1.8% to 35% and increasing the expressions of Bax, cleaved-caspase-3, and cleaved-PARP as well as decreasing the expression of Bcl-2. In addition, chromatin condensation and apoptotic bodies were detected in HS-116-treated HCC cells. Furthermore, HS-116 decreased protein expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), and inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs). In vivo, the ability of mice to vascularize subcutaneously implanted Matrigel plugs was diminished when the mice were treated with HS-116. These results show that HS-116 inhibits the PI3K/AKT/mTOR pathway via apoptosis and anti-angiogenesis in HCC cells. We suggest that HS-116 may be an effective novel therapeutic candidate against HCC.

SB365, Pulsatilla saponin D suppresses the proliferation of human colon cancer cells and induces apoptosis by modulating the AKT/mTOR signalling pathway

Pulsatilla koreana has been used as a traditional medicine for the treatment of several diseases. The purpose of this study was to determine if SB365, Pulsatilla saponin D isolated from the root of P. koreana inhibits the progression of colon cancer. We found that SB365 strongly suppressed the growth and proliferation of colon cancer cells and induced their apoptosis. Also, SB365 showed anti-angiogenic activity by decreasing the expression of HIF-1α and VEGF. These results were confirmed by an in vivo study showing that SB365 significantly inhibited tumor growth by the induction of apoptosis and inhibition of angiogenesis with stronger anticancer activity than 5-FU. When further examined for its anticancer mechanism, SB365 effectively suppressed the AKT/mTOR pathway both in vitro and in vivo. Taken together, our study demonstrated that SB365 inhibits the AKT/mTOR pathway, leading to the suppression of tumor growth and angiogenesis together with induction of apoptosis. Therefore, SB365 is a good candidate as a natural product for use in the treatment of colon cancer.