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  1. Mohamed J, Wei WL, Husin NN, Alwahaibi NY, Budin SB
    Pak J Biol Sci, 2011 Dec 01;14(23):1055-60.
    PMID: 22590839
    Selenium in the form of sodium selenite (SSE) is an essential micronutrient which known to possess antioxidant and anticancer properties. This study emphasizes the role of selenium on oxidative stress in experimental rats with N-diethylnitrosamine (DEN) initiated and 2-acetylaminofluorene (2-AAF) promoted multistage hepatocellular carcinogenesis (HCC). Rats were divided randomly into six groups: negative control, positive control (DEN+2-AAF), preventive group (pre-SEE 4 weeks+DEN), preventive control (respective control for preventive group), therapeutic group (DEN+post-SSE 12 weeks) and therapeutic control (respective control for therapeutic group). SSE (4 mg L(-1)) was given to animals before initiation and during promotion phase of HCC. The levels of total protein (TP), conjugated diens (CD), malondialdehyde (MDA), fluorescent pigment (FP), antioxidant activity (AOA) and DNA damage were measured. Supplementation of SSE before the initiation phase of carcinogenicity significantly increased TP and AOA level (p < 0.05) while it decreased the levels of CD, MDA, DNA damage and FP (p < 0.05). Supplementation of SSE during the promotion phase of carcinogenicity significantly decreased the DNA damage and FP level (p < 0.05) and there were negative correlation between the level of AOA and with the level of FP and CD. Thus, supplementation of SSE reduced the adverse changes which occur in liver cancer. However, the chemoprevention effect of SSE was more pronounced when it was supplemented before initiation phase of cancer when compared to promotion phase.
    Matched MeSH terms: Liver Neoplasms, Experimental/chemically induced; Liver Neoplasms, Experimental/drug therapy*; Liver Neoplasms, Experimental/metabolism
  2. Alwahaibi N, Mohamed J, Alhamadani A
    J Trace Elem Med Biol, 2010 Apr;24(2):119-23.
    PMID: 20413070 DOI: 10.1016/j.jtemb.2009.09.003
    Selenium is an essential micronutrient mineral found mainly in soils and has been shown to prevent certain cancers in humans and animals. However, the dose and effects of selenium on liver cancer are controversial. The aim of this study was to investigate the effects of sodium selenite (4 mg/kg in drinking water) on chemically induced hepatocarcinogenesis in rats. Hepatocarcinogenesis was induced by a single intraperitoneal injection of diethyl nitrosamine (DEN) (200 mg/kg body weight) and 2 weeks later, the carcinogenic effect was promoted by 2-acetylaminofluorene (2-AAF) (0.02%). 44 Sprague-Dawley rats were divided into 6 groups: negative control, positive control (DEN+2-AAF), pre-selenium group (sodium selenite for 4 weeks, then DEN+2-AAF), pre-selenium control group (sodium selenite for 4 weeks, no DEN or 2-AAF), post-selenium group (sodium selenite for 8 weeks after 4 weeks of DEN injection) and post-selenium control group (sodium selenite for 8 weeks, no DEN or 2-AAF). Hematoxylin and eosin plus Gordon and Sweet's methods were used to stain liver tissues. The results showed that the number and sizes of hepatic nodules in pre- and post-selenium treatment groups significantly decreased (P<0.05) compared with the positive control. Microscopic analysis of pre- and post-selenium groups showed that the majority of nodules were hyperplastic with preserved liver architecture, whereas the positive control was full of neoplastic nodules with a completely disrupted liver architecture. Hence, pre- and post-selenium treatments can reduce the extent of liver cancer on chemically induced hepatocarcinogenesis in rats.
    Matched MeSH terms: Liver Neoplasms, Experimental/chemically induced; Liver Neoplasms, Experimental/prevention & control*
  3. Ngah WZ, Jarien Z, San MM, Marzuki A, Top GM, Shamaan NA, et al.
    Am J Clin Nutr, 1991 04;53(4 Suppl):1076S-1081S.
    PMID: 1672785 DOI: 10.1093/ajcn/53.4.1076S
    The effects of tocotrienols on hepatocarcinogenesis in rats fed with 2-acetylaminofluorene (AAF) were followed morphologically and histologically for a period of 20 wk. No differences between treated and control rats in the morphology and histology of their livers was observed. Cell damage was extensive in the livers of AAF-treated rats but less extensive in the AAF-tocotrienols-treated rats when compared with normal and tocotrienols-treated rats. 2-Acetylaminofluorene significantly increases the activities of both plasma and liver microsomal gamma-glutamyltranspeptidase (GGT) and liver microsomal UDP-glucuronyltransferase (UDP-GT). Tocotrienols administered together with AAF significantly decrease the activities of plasma GGT after 12 and 20 wk (P less than 0.01, P less than 0.002, respectively) and liver microsomal UDP-GT after 20 wk (P less than 0.02) when compared with the controls and with rats treated only with tocotrienols. Liver microsomal GGT also showed a similar pattern to liver microsomal UDP-GT but the decrease was not significant. These results suggest that tocotrienols administered to AAF-treated rats reduce the severity of hepatocarcinogenesis.
    Matched MeSH terms: Liver Neoplasms, Experimental/prevention & control*; Liver Neoplasms, Experimental/ultrastructure
  4. Shamaan NA, Kadir KA, Rahmat A, Ngah WZ
    Nutrition, 1998 12 3;14(11-12):846-52.
    PMID: 9834927
    The effects of vitamin C and aloe vera gel extract supplementation on induced hepatocarcinogenesis in male Sprague-Dawley rats (120-150 g) by diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) was investigated. The severity of the carcinogenesis process was determined by measuring gamma-glutamyl transpeptidase (GGT) and the placental form of glutathione S-transferase (GSTP) histochemically in situ and in plasma and liver fractions. In addition, plasma alkaline phosphatase (ALP) and liver microsomal uridine diphosphate glucuronyl transferase (UDPGT) activity were also determined. Administration of DEN/AAF caused an increase in the surface area and number of enzyme-positive foci (both GGT and GSTP) compared with control. Supplementation of vitamin C or aloe vera gel extract to the cancer-induced rats suppressed this increase significantly (P < 0.05; P < 0.001). Increases in liver UDPGT, GGT, and GSTP activities were also observed with cancer induction that were again suppressed with either vitamin C or aloe vera gel supplementation. Plasma GGT in the DEN/AAF rats were determined monthly for the duration of the experiment and found to be reduced as early as 1 mo with aloe vera gel supplementation and 2 mo with vitamin C supplementation. In conclusion, vitamin C and aloe vera gel extract supplementation were found to be able to reduce the severity of chemical hepatocarcinogenesis.
    Matched MeSH terms: Liver Neoplasms, Experimental/metabolism; Liver Neoplasms, Experimental/pathology; Liver Neoplasms, Experimental/prevention & control*
  5. Hambali Z, Ngah WZ, Wahid SA, Kadir KA
    Pathology, 1995 Jan;27(1):30-5.
    PMID: 7603748
    The effects of ovariectomy and hormone replacement in control and carcinogen treated female rats were investigated by measuring whole blood and liver glutathione (WGSH, HGSH), glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GRx) and histological evaluation. Hepatocarcinogenesis was induced by diethylnitrosamine and 2-acetylaminofluorene. In control rats not receiving carcinogen, ovariectomy significantly increased the GST and GRx activities. Replacement with either estrogen or progesterone reduced the GST activities to below intact female values whereas replacement of both hormones together brought the GST activities to that of intact females. GRx activities were brought to intact female values by replacement with estrogen or progesterone, either singly or in combination. Neither ovariectomy nor sex hormone/s replacement influenced the levels of WGSH, HGSH and GPx activities. Carcinogen administration to intact rats increased all the parameters measured. Ovariectomized rats treated with carcinogen showed lower GPx and GRx activities at 2 mths. However, replacement with either progesterone or combined estrogen and progesterone increased GPx and GRx activities to original values. On the other hand GST and GPx activities in ovariectomized rats which had carcinogen treatment were lower than intact rats after 5 mths. Replacement with hormones either singly or both brought GST and GPx activities up to intact rat levels receiving carcinogen. The levels of WGSH, HGSH and GRx activities (5 mths) in carcinogen treated rats were not influenced by ovariectomy and/or hormone/s replacement. The results from this study suggested that ovariectomy reduced the severity of hepatocarcinogenesis which was restored by sex hormone/s replacement.
    Matched MeSH terms: Liver Neoplasms, Experimental/chemically induced*; Liver Neoplasms, Experimental/metabolism; Liver Neoplasms, Experimental/pathology
  6. Habib SH, Makpol S, Abdul Hamid NA, Das S, Ngah WZ, Yusof YA
    Clinics (Sao Paulo), 2008 Dec;63(6):807-13.
    PMID: 19061005
    OBJECTIVE: To evaluate the effect of ginger extract on the expression of NFkappaB and TNF-alpha in liver cancer-induced rats.

    METHODS: Male Wistar rats were randomly divided into 5 groups based on diet: i) control (given normal rat chow), ii) olive oil, iii) ginger extract (100mg/kg body weight), iv) choline-deficient diet + 0.1% ethionine to induce liver cancer and v) choline-deficient diet + ginger extract (100mg/kg body weight). Tissue samples obtained at eight weeks were fixed with formalin and embedded in paraffin wax, followed by immunohistochemistry staining for NFkappaB and TNF-alpha.

    RESULTS: The expression of NFkappaB was detected in the choline-deficient diet group, with 88.3 +/- 1.83% of samples showing positive staining, while in the choline-deficient diet supplemented with ginger group, the expression of NFkappaB was significantly reduced, to 32.35 +/- 1.34% (p<0.05). In the choline-deficient diet group, 83.3 +/- 4.52% of samples showed positive staining of TNF-alpha, which was significantly reduced to 7.94 +/- 1.32% (p<0.05) when treated with ginger. There was a significant correlation demonstrated between NFkappaB and TNF-alpha in the choline-deficient diet group but not in the choline-deficient diet treated with ginger extract group.

    CONCLUSION: In conclusion, ginger extract significantly reduced the elevated expression of NFkappaB and TNF-alpha in rats with liver cancer. Ginger may act as an anti-cancer and anti-inflammatory agent by inactivating NFkappaB through the suppression of the pro-inflammatory TNF-alpha.

    Matched MeSH terms: Liver Neoplasms, Experimental/chemically induced; Liver Neoplasms, Experimental/drug therapy*; Liver Neoplasms, Experimental/metabolism
  7. Hanachi P, Loh LN, Fauziah O, Rafiuz ZH, Tee ST, Lye CW, et al.
    Med J Malaysia, 2004 May;59 Suppl B:208-9.
    PMID: 15468891
    Neem, Azadirachta indica, is a plant from the family Meliaceae, known as "Pokok Semambu" in Malay community. It has been extensively used in India as traditional Ayurvedic and folklore minedicine for the treatment of various diseases. This study aimed to determine the distribution of selenium in the liver of rats during hepatocarcinogenesis when neem aqueous extract and dietary selenium was supplemented.
    Matched MeSH terms: Liver Neoplasms, Experimental/pathology*
  8. Alwahaibi NY, Budin SB, Mohamed J, Alhamdani A
    J Gastroenterol Hepatol, 2010 Apr;25(4):786-91.
    PMID: 20492335 DOI: 10.1111/j.1440-1746.2009.06160.x
    Selenium's molecular mechanism for cancer chemoprevention remains unknown. We aimed to study the gene expression of nuclear factor-kappaB (NF-kappaB), tumor growth factor-alpha (TGF-alpha) and cyclin D1 and the effects of sodium selenite using preventive and therapeutic approaches in chemically-induced hepatocarcinogenesis in rats.
    Matched MeSH terms: Liver Neoplasms, Experimental/chemically induced; Liver Neoplasms, Experimental/genetics; Liver Neoplasms, Experimental/metabolism; Liver Neoplasms, Experimental/prevention & control*
  9. Makpol S, Shamaan NA, Jarien Z, Top AG, Khalid BA, Wan Ngah WZ
    Gen. Pharmacol., 1997 Apr;28(4):589-92.
    PMID: 9147029
    1. alpha-Tocopherol (alpha-T) and gamma-tocotrienol (gamma-T) were supplemented continuously for 8 weeks in the diets of normal rats and rats chemically induced with cancer using diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF) and partial hepatectomy. Hepatocarcinogenesis was followed by determining the plasma gamma-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP) activities as well as placental glutathione S-transferase (PGST) and GGT activities histochemically, at 4-week intervals. 2. Male Rattus norvegicus were supplemented alpha-T and gamma-T at two different doses of 30 and 300 mg/kg diet. The supplementation was started at three different times: simultaneously with DEN administration; 4 weeks; and 8 weeks after DEN administration. 3. Elevation of plasma GGT activities and formation of PGST and GGT positive foci were attenuated significantly (P < 0.05) when alpha-T and gamma-T were supplemented simultaneously with cancer induction. Supplementation begun 4 and 8 weeks after cancer induction did not affect plasma enzyme activities and formation of enzyme-positive foci. 4. alpha-T was more effective than gamma-T, and a lower dose of 30 mg/kg was found to be more effective in reducing the severity of hepatocarcinogenesis.
    Matched MeSH terms: Liver Neoplasms, Experimental/enzymology; Liver Neoplasms, Experimental/prevention & control*
  10. Amin I, Koh BK, Asmah R
    J Med Food, 2004;7(1):7-12.
    PMID: 15117546
    This study investigated the effect of cacao liquor extract (CLE) on tumor marker enzymes--alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), glutathione-S-transferase (GST), and glutathione reductase (GR) activities--in plasma and/or liver of hepatocarcinogenic rats, which were induced with diethylnitrosamine and 2-acetylaminofluorene. Twenty-nine male Sprague-Dawley rats (weighing 150-330 g) were divided into four groups (n = 6-8): normal control group (N), normal group + CLE (NE), cancer group (C), and cancer group + CLE (CE). Analysis of variance showed significant differences (P
    Matched MeSH terms: Liver Neoplasms, Experimental/chemically induced; Liver Neoplasms, Experimental/drug therapy*; Liver Neoplasms, Experimental/enzymology
  11. Shamaan NA, Wan Ngah WZ, Ibrahim R, Jarien Z, Top AG, Abdul Kadir K
    Biochem Pharmacol, 1993 Apr 06;45(7):1517-9.
    PMID: 8471073
    The effect of tocotrienol on the activities of glutathione S-transferases (GSTs), glutathione reductase (GR) and glutathione peroxidase (GPx) in rats given 2-acetylaminofluorene (AAF) was investigated over a 20 week period. Liver and kidney GST and liver GR activities were significantly increased after AAF administration. Kidney GPx activities were significantly affected; activity assayed with cumene hydroperoxide (cu-OOH) was increased but activity assayed with H2O2 was reduced. Supplementation of the diet with tocotrienol in the AAF-treated rats reduced the increase in enzyme activities. Tocotrienol on its own had no effect on the enzyme activities.
    Matched MeSH terms: Liver Neoplasms, Experimental/prevention & control
  12. Sani HA, Rahmat A, Ismail M, Rosli R, Endrini S
    Asia Pac J Clin Nutr, 2004;13(4):396-400.
    PMID: 15563447
    The objective of this study was to determine the anti cancer effects of red spinach (Amaranthus gangeticus Linn) in vitro and in vivo. For in vitro study, microtitration cytotoxic assay was done using 3-(4,5-dimethylthiazol-2-il)-2,5-diphenil tetrazolium bromide (MTT) kit assay. Results showed that aqueous extract of A gangeticus inhibited the proliferation of liver cancer cell line (HepG2) and breast cancer cell line (MCF-7). The IC(50) values were 93.8 mu g/ml and 98.8 mu g/ml for HepG2 and MCF-7, respectively. The inhibitory effect was also observed in colon cancer cell line (Caco-2), but a lower percentage compared to HepG2 and MCF-7. For normal cell line (Chang Liver), there was no inhibitory effect. In the in vivo study, hepatocarcinogenesis was monitored in rats according to Solt and Farber (1976) without partial hepatectomy. Assay of tumour marker enzymes such as glutathione S-transferase (GST), gamma-glutamyl transpeptidase (GGT), uridyl diphosphoglucuronyl transferase (UDPGT) and alkaline phosphatase (ALP) were carried out to determine the severity of hepatocarcinogenesis. The result found that supplementation of 5%, 7.5% and 10% of A. gangeticus aqueous extract to normal rats did not show any significant difference towards normal control (P <0.05). The exposure of the rats to chemical carcinogens diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) showed a significant increase in specific enzyme activity of GGT, GST, UDPGT and ALP compared to normal control (P <0.05). However, it was found that the supplementation of A. gangeticus aqueous extract in 5%, 7.5% and 10% to cancer-induced rats could inhibit the activity of all tumour marker enzymes especially at 10% (P <0.05). Supplementation of anti cancer drug glycyrrhizin at suggested dose (0.005%) did not show any suppressive effect towards cancer control (P <0.05). In conclusion, A. gangeticus showed anticancer potential in in vitro and in vivo studies.
    Matched MeSH terms: Liver Neoplasms, Experimental/enzymology; Liver Neoplasms, Experimental/prevention & control*
  13. Har CH, Keong CK
    Asia Pac J Clin Nutr, 2005;14(4):374-80.
    PMID: 16326644
    The effects of tocotrienols on murine liver cell viability and their apoptotic events were studied over a dose range of 0-32 microg mL(-1). Normal murine liver cells (BNL CL.2) and murine liver cancer cells (BNL 1ME A.7R.1) were treated with tocotrienols (T(3)), alpha tocopherol (alpha-T) and the chemo drug, Doxorubicin (Doxo, as a positive control). Cell viability assay showed that T(3) significantly (P < or = 0.05) lowered the percentage of BNL 1ME A.7R.1 cell viability in a dose-responsive manner (8-16 microg mL(-1)), whereas T did not show any significant (P>0.05) inhibition in cell viability with increasing treatment doses of 0-16 microg mL(-1). The IC(50) for tocotrienols were 9.8, 8.9, 8.1, 9.7, 8.1 and 9.3 microg mL(-1) at 12, 24, 36, 48, 60 and 72 hours respectively. Early apoptosis was detected 6 hours following T(3) treatment of BNL 1ME A.7R.1 liver cancer cells, using Annexin V-FITC fluorescence microscopy assay for apoptosis, but none were observed for the non-treated liver cancer cells at the average IC(50) of 8.98 microg mL(-1) tocotrienols for liver cancer cells. Several apoptotic bodies were detected in BNL 1ME A.7R.1 liver cancer cells at 6 hours post-treatment with tocotrienols (8.98 microg mL(-1)) using Acridine Orange/Propidium Iodide fluorescence assay. However, only a couple of apoptotic bodies were seen in the non-treated liver cancer cells and the BNL CL.2 normal liver cells. Some mitotic bodies were also observed in the T(3)-treated BNL 1ME A.7R.1 liver cancer cells but were not seen in the untreated BNL 1ME A.7R.1 cells and the BNL CL.2 liver cells. Following T(3)-treatment (8.98 microg mL(-1)) of the BNL 1ME A.7R.1 liver cancer cells, 24.62%, 25.53% and 44.90% of the cells showed elevated active caspase 3 activity at 9, 12 and 24 hours treatment period, respectively. DNA laddering studies indicated DNA fragmentation occurred in the T(3)-treated liver cancer cells, BNL 1ME A.7R.1 but not in non-treated liver cancer cells and the T(3)-treated and non-treated normal liver cells. These results suggest that tocotrienols were able to reduce the cell viability in the murine liver cancer cells at a dose of 8-32 microg mL(-1) and that this decrease in percentage cell viability may be due to apoptosis.
    Matched MeSH terms: Liver Neoplasms, Experimental/pathology*
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