Preparation and mechanistic aspect of natural xanthone functionalized gold nanoparticle.

Herein, a facile scale up and shape variable synthesis of gold nanoparticle (AuNP) and reaction mechanism by natural xanthone derivative (mangiferin) has been reported. Mangiferin (C19H18O11; 1,3,6,7-tetrahydroxyxanthone-C2-ß-d-glucoside), a xanthone derivative is isolated from Mangifera indica L. leaves which efficiently reduces Au3+ ions to Au0 and stabilizes the formed AuNP. The structural, optical and plasmonic properties of synthesized AuNP have been investigated through different instrumental techniques like UV-Vis and FTIR spectroscopy, powder XRD, FESEM and TEM analysis. It is observed that variation of the concentration of Au3+ ions and mangiferin has a great effect on controlling size and shape of nanoparticles. The role of reaction temperature is also notable. An interesting observation is that with same concentration ratio of HAuCl4/mangiferin (0.025 mM/0.002%) at the room temperature kidney shaped AuNP is produced, whereas it is spherical at boiling temperature. Moreover, mangiferin allows high scale synthesis of AuNPs (0.025 mM to 10 mM) without changing the particles size and shape. The mechanistic investigation through UV-Vis, FTIR and GCMS analyses reveal the cleavage of glucose unit and oxidation of phenolic OH groups during AuNP formation. Non-toxicity of mangiferin conjugated AuNP on normal human breast cell line (MCF-10A) suggesting its future application as a drug delivery system and other related medicinal purposes.

A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1.

Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 µM) than in DU145 cells (IC50=1.10 µM) and PC3 cells (IC50=5.60 µM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.

A novel histone deacetylase (HDAC) inhibitor MHY219 induces apoptosis via up-regulation of androgen receptor expression in human prostate cancer cells.

Histone deacetylase (HDAC) inhibitors are a new class of anticancer agents that act by inhibiting cancer cell proliferation and inducing apoptosis in various cancer cell lines. To investigate the anticancer effect of a novel histone deacetylase (HDAC) inhibitor MHY219, its efficacy was compared to that of suberoylanilide hydroxamic acid (SAHA) in human prostate cancer cells. The anticancer effects of MHY219 on cell viability, HDAC enzyme activity, cell cycle regulation, apoptosis and other biological assays were performed. MHY219 was shown to enhance the cytotoxicity on DU145 cells (IC50, 0.36 µM) when compared with LNCaP (IC50, 0.97 µM) and PC3 cells (IC50, 5.12 µM). MHY219 showed a potent inhibition of total HDAC activity when compared with SAHA. MHY219 increased histone H3 hyperacetylation and reduced the expression of class I HDACs (1, 2 and 3) in prostate cancer cells. MHY219 effectively increased the sub-G1 fraction of cells through p21 and p27 dependent pathways in DU145 cells. MHY219 significantly induced a G2/M phase arrest in DU145 and PC3 cells and arrested the cell cycle at G0/G1 phase in LNCaP cells. Furthermore, MHY219 effectively increased apoptosis in DU145 and LNCaP cells, but not PC3 cells, according to Annexin V/PI staining and Western blot analysis. These results indicate that MHY219 is a potent HDAC inhibitor that targets regulating multiple aspects of cancer cell death and might have preclinical value in human prostate cancer chemotherapy, warranting further investigation.

Comparisons of polybrominated diphenyl ethers levels in paired South Korean cord blood, maternal blood, and breast milk samples.

Polybrominated diphenyl ethers (PBDEs), commonly used flame retardants, have been reported as potential endocrine disruptor and neurodevelopmental toxicants, thus giving rise to the public health concern. The goal of this study was to investigate the relationship between umbilical cord blood, maternal blood, and breast milk concentrations of PBDEs in South Korean. We assessed PBDE levels in paired samples of umbilical cord blood, maternal blood, and breast milk. The levels of seven PBDE congeners were measured in 21 paired samples collected from the Cheil Woman's Hospital (Seoul, Korea) in 2008. We also measured thyroid hormones levels in maternal and cord blood to assess the association between PBDEs exposure and thyroid hormone levels. However, there was no correlation between serum thyroxin (T4) and total PBDEs concentrations. The total PBDEs concentrations in the umbilical cord blood, maternal blood, and breast milk were 10.7±5.1 ng g(-1) lipid, 7.7±4.2 ng g(-1) lipid, and 3.0±1.8 ng g(-1) lipid, respectively. The ranges of total PBDE concentrations observed were 2.28-30.94 ng g(-1) lipid in umbilical cord blood, 1.8-17.66 ng g(-1) lipid in maternal blood, and 1.08-8.66 ng g(-1) lipid in breast milk. BDE-47 (45-73% of total PBDEs) was observed to be present dominantly in all samples, followed by BDE-153. A strong correlation was found for major BDE-congeners between breast milk and cord blood or maternal blood and cord blood samples. The measurement of PBDEs concentrations in maternal blood or breast milk may help to determine the concentration of PBDEs in infant.

A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells.

Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC(50)=1.39 µM) than in DU145 (IC(50)=2.94 µM) and PC3 cells (IC(50)=3.72 µM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC(50)=1.55 µM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.

Functional role of phospholipase D (PLD) in di(2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague-Dawley rats.

Phospholipase D (PLD) is an enzyme that catalyzes the hydrolysis of phosphatidyl choline (PC) to generate phosphatidic acid (PA) and choline. PLD is believed to play an important role in cell proliferation, survival signaling, cell transformation, and tumor progression. However, it remains to be determined whether enhanced expression of PLD in liver is sufficient to induce hepatotoxicity. The aim of this study was to investigate the possible role of PLD in di(2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in Sprague-Dawley rats. The phthalate, DEHP (500 mg/kg/d), was administered orally, daily to prepubertal rats (4 wk of age, weighing approximately 70-90 g) for 1, 7, or 28 d. In this study, protein expression levels of PLD1/2, peroxisome proliferator-activated receptor (PPAR), and cytochrome P-450 (CYP) were determined by Western blot analysis using specific antibodies. Liver weight was significantly increased in the DEHP treatment groups. Immunohistochemical analysis demonstrated that DEHP produced strong staining of proliferating cell nuclear antigen (PCNA) at 28 d of exposure, suggestive of hepatocyte proliferation. A significant rise in PLD1/2 expression was observed in liver of DEHP-exposed rats after 7 d. Further, PPARα, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and CYP2B1 protein expression levels were markedly elevated in DEHP-treated groups. Our results suggest that DEHP significantly enhanced the expression of PLD, which may be correlated with PPARα-induced hepatotoxicity through a complex interaction with nuclear receptors including CAR and PXR.

Comparison of the short term toxicity of phthalate diesters and monoesters in sprague-dawley male rats.

This study was carried out to investigate the short term toxicity of nine phthalate diesters including di-2 (ethylhexyl) phthalate (DEHP) , di (n-butyl) phthalate (DBP) , di-n-octyl phthalate (DnOP) , diethyl phthalate (DEP) , butylbenzyl phthalate (BBP) , dimethyl phthalate (DMP) , di-isodecyl phthalate (DIDP) , diundecyl phthalate (DUP) , and di-isononyl phthalate (DINP) and five phthalate monoesters including mono- (2-ethylhexyl) phthalate (MEHP) , monobutyl phthalate (MBuP) , monobenzyl phthalate (MBeP) , monoethyl phthalate (MEP) , monomethyl phthalate (MMP) and phthalic acid (PA) in Sprague-Dawley male rats. Animals were administered 250 mg/kg/day (monoesters and PA) or 500 mg/kg/day (diesters) of phthalate for two weeks. All animals were examined for body and organ weights, blood hematology, serum biochemistry, and urine analysis. The body weight gain was significantly lower in rats treated with BBP, DBP, DINP, MEHP, MBuP, and PA than that of control. Liver weights were significantly increased in the DEHP,DBP, DnOP, DIDP, and MEHP groups as compared to the control group. Testes weights were significantly decreased only in the DEHP-, DnOP-, and DIDP-treated groups as compared to the control. Significant differences in hematological changes were not observed in any treatment groups. Significant increases in blood glucose levels were observed in the DEHP, MEHP, and MBeP groups. Aspartate aminotransferase (AST) levels were significantly increased in the DBP, DUP, DINP, MBuP, and MBeP groups, whereas alanine aminotransferase (ALT) levels were significantly increased only in the DEHP and MEHP groups. Serum ALP levels were significantly higher in phthalate diester (500 mg/kg/day) -treated rats as compared to control. However, the total cholesterol level was significantly reduced in the DEHP- and DIDP-treated groups, whereas serum triglyceride (TG) levels were higher in the DINP-, MEHP-, and MBuP-treated groups. These results suggest that short term toxicity of phthalate monoesters produces adverse effects as similar to phthalate diesters in Sprague-Dawley rats.

Exposure assessment of polybrominated diphenyl ethers (PBDE) in umbilical cord blood of Korean infants.

This study examined the levels of polybrominated diphenyl ethers (PBDE) in the umbilical cord blood of infants, and investigated the relationship between PBDE concentration and thyroid hormone levels. The concentration of PBDE were measured in the cord blood samples of 108 infants collected in Cheil Woman's Hospital, Seoul, Korea, in 2007. Of 108 pregnant woman reported, the average age was 31.9 +/- 3.54 yr (range 20-42 yr). The mean body weight of the infants was 3.15 +/- 0.57 kg (1.89-4.43 kg), and no birth defects were documented. The concentrations of the total PBDEs (7 congeners) found in the umbilical cord blood averaged 8.377 +/- 6.381 ng/g lipid, ranging from not determined (ND) to 29.407 ng/g lipid. Of the seven congeners detected, BDE-47 (4.571 +/- 2.903 ng/g lipid) accounted for the majority (38% of total PBDE) of total PBDE, followed in descending order by BDE-153 (3.080 +/- 2.231 ng/g lipid) and BDE-183 (2.933 +/- 2.386). There was no apparent correlation between the serum PBDE levels and thyroid hormone concentrations. Similarly, there was no apparent relationship between the infant thyroxine (T4) levels and four prevalent PBDE congener concentrations. Data suggest that the concentration of PBDE in umbilical cord blood of Korean infants is similar to or lower than concentrations reported from North America. In addition, PBDE readily crossed the blood placenta barrier. Therefore, further study on the relationship between the maternal and fetal blood concentrations of PBDE is recommended for a more comprehensive exposure assessment of PBDE in Koreans.