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Yu-Ju Chu, Hwai-I Yang, Hui-Chen Wu, Mei-Hsuan Lee, Jessica Liu, Li-Yu Wang, Sheng-Nan Lu, Chin-Lan Jen, San-Lin You, Regina M Santella, Chien-Jen Chen
BACKGROUND: Hepatocarcinogenicity of aflatoxin B1 (AFB1 ) has rarely been studied in populations with hepatitis C virus (HCV) infection and those without hepatitis B virus (HBV) and HCV infection (non-B-non-C). This case-control study nested in a community-based cohort aimed to investigate the HCC risk associated with AFB1 in HCV-infected and non-B-non-C participants. METHODS: Baseline serum AFB1 -albumin adduct levels were measured in 100 HCC cases and 1767 controls seronegative for anti-HCV and HBsAg (non-B-non-C), and another 103 HCC cases and 176 controls who were anti-HCV-seropositive and HBsAg-seronegative...
March 10, 2018: European Journal of Cancer
François Chassagne, Mohamed Haddad, Aurélien Amiel, Chiobouaphong Pharkeovilay, Chanthanom Manithip, Geneviève Bourdy, Eric Deharo, Guillaume Marti
Liver cancer is a major health burden in Southeast Asia, and most patients turn towards the use of medicinal plants to alleviate their symptoms. The aim of this work was to apply to Southeast Asian plants traditionally used to treat liver disorders, a successive ranking strategy based on a comprehensive review of the literature and metabolomic data in order to relate ethnopharmacological relevance to chemical entities of interest. We analyzed 45 publications resulting in a list of 378 plant species, and our point system based on the frequency of citation in the literature allowed the selection of 10 top ranked species for further collection and extraction...
February 22, 2018: Fitoterapia
B Alex Merrick, Justin S Chang, Dhiral P Phadke, Meredith A Bostrom, Ruchir R Shah, Xinguo Wang, Oksana Gordon, Garron M Wright
The transcriptome can reveal insights into precancer biology. We recently conducted RNA-Seq analysis on liver RNA from male rats exposed to the carcinogen, aflatoxin B1 (AFB1), for 90 days prior to liver tumor onset. Among >1,000 differentially expressed transcripts, several novel, unannotated Cufflinks-assembled transcripts, or HAfTs (Hepatic Aflatoxin Transcripts) were found. We hypothesized PCR-cloning and RACE (rapid amplification of cDNA ends) could further HAfT identification. Sanger data was obtained for 6 transcripts by PCR and 16 transcripts by 5'- and 3'-RACE...
2018: PloS One
Yukun Feng, Saide Wang, Hui Wang, Ying Peng, Jiang Zheng
Methyleugenol (ME), a natural ingredient of several herbs and spices used in the human diet, is hepatocarcinogenic in rodents. Following metabolic activation to reactive carbocation intermediate, ME can bind covalently to DNA, which is directly associated with its carcinogenicity. In this work, a non-invasive approach to determine ME exposure was established by monitoring urinary ME-dA adduct. The developed method entails liquid-liquid extraction enrichment of the urinary ME-dA, incorporation of deuterated ME-dA as internal standard, and analysis by liquid chromatography coupled tandem mass spectrometry...
January 12, 2018: Journal of Agricultural and Food Chemistry
K S Koch, T Moran, W T Shier, H L Leffert
N-acetyl-2-aminofluorene (AAF) is a procarcinogen used widely in physiological investigations of chemical hepatocarcinogenesis. Its metabolic pathways have been described extensively, yet little is known about its biochemical processing, growth cycle expression and pharmacological properties inside living hepatocytes - the principal cellular targets of this hepatocarcinogen. In this report, primary monolayer adult rat hepatocyte cultures and high specific-activity [ring G-3H]-N-acetyl-2-aminofluorene were used to extend previous observations of metabolic activation of AAF by highly differentiated, proliferation-competent hepatocytes in long-term cultures...
January 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Panpan Zhu, Zhicai Zuo, Zhixiang Zheng, Fengyuan Wang, Xi Peng, Jing Fang, Hengmin Cui, Caixia Gao, Hetao Song, Yi Zhou, Xici Liu
Aflatoxin B1 (AFB1) is a natural product of the Aspergillus genus of molds, which grow on several foodstuffs stored in hot moist conditions, and is among the most potent hepatocarcinogens and immunosuppression presently known. The latter was related to the up-regulated apoptosis of immune organs. However, the effect of expression of death receptor and endoplasmic reticulum molecules in AFB1-induced apoptosis of chicken splenocytes was largely unknown. The objective of this study was to investigate this unknown field...
November 21, 2017: Oncotarget
Sara Levorato, Luca Dominici, Cristina Fatigoni, Claudia Zadra, Rita Pagiotti, Massimo Moretti, Milena Villarini
Estragole, a common component of herbs and spices, is a wellknown genotoxic hepatocarcinogen in rodents, whereas its potential toxic effect in humans is still debated. In the European contest, one of the major sources of human exposure to this phytochemical is Foeniculum vulgare Mill. (fennel). Therefore, the aim of this study was to evaluate the in vitro toxicity of estragole in the context of two complex phytochemical mixtures derived from fennel: fennel seed powder (FSPw) and fennel seed essential oil (FSEO)...
December 9, 2017: Food and Chemical Toxicology
Yu Okuda, Masahiko Kushida, Hiroko Kikumoto, Yoshimasa Nakamura, Hashihiro Higuchi, Satoshi Kawamura, Samuel M Cohen, Brian G Lake, Tomoya Yamada
High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 µM) and a major metabolite Z-CMCA (5-1,000 µM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations...
2017: Journal of Toxicological Sciences
Seoyoung Kim, Gil-Im Mun, Eun Choi, Minjeong Kim, Ji Seong Jeong, Keon Wook Kang, Sunha Jee, Kyung-Min Lim, Yun-Sil Lee
An association between bisphenol A (BPA) exposure and hepatic tumors was suggested, but the employment of high-dose levels raises questions about its relevance to human health. Here, we demonstrate that submicromolar concentrations of BPA induce the proliferation and DNA damage in human hepatocyte cell lines. In HepG2 and NKNT-3, undifferentiated and differentiated hepatocyte cell lines, respectively, submicromolar BPA concentrations promoted the cell proliferation, as indicated by enhanced DNA synthesis and elevated expression of cell-cycle proteins...
January 2018: Food and Chemical Toxicology
Azza Abdelmageed Matloub, Alaa Hamed Salama, Hadeer Ahmed Aglan, Mona Mahmoud AbouSamra, Sahar Salah Mohamed ElSouda, Hanaa Hamdy Ahmed
Bile salts containing vesicles (bilosomes) represent a portentous vesicular carrier that showed prosperous results in delivering active moieties in the gastrointestinal tract (GIT). In this study, bilosomes were exploited to deliver sulphated polysaccharide-protein complexes of Enteromorpha intestinalis (EHEM) and enhance its activity against hepatocellular carcinoma as well as resist harsh GIT conditions. Bilosomes were prepared using the sodium salt of three different bile acids (cholic, deoxycholic, taurodeoxycholic) and two different non-ionic surfactants (Span 40 and 65)...
November 8, 2017: Drug Development and Industrial Pharmacy
Yuji Ishii, Ken Kuroda, Kohei Matsushita, Yuh Yokoo, Shinji Takasu, Aki Kijima, Takehiko Nohmi, Kumiko Ogawa, Takashi Umemura
Protein phosphatase 2A (PP2A) is a serine-threonine phosphatase that regulates cell signaling pathways. Its inactivation is correlated with tumor malignancy, possibly due to the effects on cell differentiation and malignant cell transformation. Therefore, it has been noted that PP2A could be a promising target for cancer therapy. In our previous study of the hepatocarcinogen estragole (ES), cell proliferation may be required to convert ES-specific DNA adducts to mutations. To explore the trigger for cell proliferation, gpt delta rats were administered ES by gavage at doses of 3, 30 and 300mg/kg/day for 4weeks...
October 17, 2017: Toxicology and Applied Pharmacology
Xiaobo He, Qingsu Xia, Kellie Woodling, Ge Lin, Peter P Fu
There are 660 pyrrolizidine alkaloids (PAs) and PA N-oxides present in the plants, with approximately half being possible carcinogens. We previously reported that a set of four PA-derived DNA adducts is formed in the liver of rats administered a series of hepatocarcinogenic PAs and a PA N-oxide. Based on our findings, we hypothesized that this set of DNA adducts is a common biological biomarker of PA-induced liver tumor formation. In this study, we determined that rat liver microsomal metabolism of five hepatocarcinogenic PAs (lasiocarpine, retrorsine, riddelliine, monocrotaline, and heliotrine) and their corresponding PA N-oxides produced the same set of DNA adducts...
October 2017: Journal of Food and Drug Analysis
Kanokwan Sriwattanapong, Stephen L Slocum, Supawadee Chawanthayatham, Bogdan I Fedeles, Patricia A Egner, John D Groopman, Jutamaad Satayavivad, Robert G Croy, John M Essigmann
Pregnancy is a complex physiological state, in which the metabolism of endogenous as well as exogenous agents is ostensibly altered. One exogenous agent of concern is the hepatocarcinogen aflatoxin B1 (AFB1), a foodborne fungal toxin, that requires phase I metabolic oxidation for conversion to its toxic and carcinogenic form, the AFB1-8,9-exo-epoxide. The epoxide interacts with cellular targets causing toxicity and cell death; these targets include the covalent modification of DNA leading to mutations that can initiate malignant transformation...
November 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Iryna Kindrat, Kostiantyn Dreval, Svitlana Shpyleva, Volodymyr Tryndyak, Aline de Conti, Thilak K Mudalige, Tao Chen, Anna M Erstenyuk, Frederick A Beland, Igor P Pogribny
The liver, a central detoxification organ and main regulator of systemic iron homeostasis, is prone to damage by xenobiotics. In the present study, we investigated the effect of the hepatotoxicant and hepatocarcinogen methapyrilene hydrochloride on iron metabolism in rat liver in a repeat-dose in vivo toxicity study and in human HepaRG cells in vitro. Treatment of male Fischer 344 (F344) rats with methapyrilene at doses 40 and 80mg/kg body weight (bw)/day by gavage for 6 weeks resulted in changes in the expression of classic hepatotoxicity-related marker genes and iron homeostasis-related genes, especially a prominent, dose-dependent down-regulation of the transferrin (Tf) gene and an up-regulation of the ferritin, light chain (Ftl) gene...
November 5, 2017: Toxicology Letters
Alessandro Federico, Marcello Dallio, Giuseppe G Caprio, Vittorio M Ormando, Carmela Loguercio
Nowadays liver diseases represent one of major healthy problems in the world in terms of morbidity and mortality. The high prevalence of liver pathologies represents the key point to understand the necessity to identify the pathogenetic mechanisms that support these disorders in order to nurse them. Alterations of intestinal microbiota seem to play an important role in induction and promotion of liver damage progression, in addition to direct injury resulting from different causal agents. Gut microbiota is considered both as a promoting factor and as a potential therapeutic target of a large number of liver pathologies due to the connection between intestine and liver: the gut-liver axis...
December 2017: Minerva Gastroenterologica e Dietologica
Sayaka Mizukami, Yousuke Watanabe, Kota Nakajima, Yasuko Hasegawa-Baba, Meilan Jin, Toshinori Yoshida, Makoto Shibutani
We previously observed downregulation of mitochondrial oxidative phosphorylation-related protein, TMEM70, which is suggestive of disrupted cellular senescence, in GST-P-expressing (+) proliferative lesions from early hepatocarcinogenesis stages in rats. The present study investigated the immunohistochemical relationship between TMEM70 downregulation and cellular metabolic changes in carcinogenic processes, as well as the onset of the liver cell respiratory changes after repeated hepatocarcinogen treatment in rats...
September 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Sayaka Mizukami, Yousuke Watanabe, Yukie Saegusa, Kota Nakajima, Yuko Ito, Yasunori Masubuchi, Toshinori Yoshida, Makoto Shibutani
We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive ((+)) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P(+) foci, compared with GST-P(+) foci expressing UBE2E2...
November 1, 2017: Toxicology and Applied Pharmacology
Hao Dong, Li Tian, Meng Gao, Hong Xu, Chenghong Zhang, Li Lv, Jianbin Zhang, Changyuan Wang, Yan Tian, Xiaochi Ma
Liver cancer is one of the major diseases affecting human health. Modified drug delivery systems through the asialoglycoprotein receptor, which is highly expressed on the surface of hepatocytes, have become a research focus for the treatment of liver cancer. Resibufogenin (RBG) is a popular traditional Chinese medicine and natural anti-cancer drug that was isolated from Chansu, but its cardiotoxicity and hydrophobicity have limited its clinical applications. Galactosyl-succinyl-poloxamer 188 and galactosyl-succinyl-poloxamer 188-polylactide-co-glycolide (Gal-SP188-PLGA) were synthesized using galactose, P188, and PLGA to achieve active liver-targeting properties...
November 2017: Drug Delivery
Pranesh Kumar, Ashok K Singh, Vinit Raj, Amit Rai, Siddhartha Maity, Atul Rawat, Umesh Kumar, Dinesh Kumar, Anand Prakash, Anupam Guleria, Sudipta Saha
AIM: 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) was synthesized and evaluated for in-vivo antiproliferative action in diethylnitrosamine-induced hepatocarcinogenic rats. MATERIALS & METHODS: The antiproliferative effect of M1 was assessed by various biochemical parameters, histopathology of liver and HPLC analysis. Proton nuclear magnetic resonance-based serum metabolic study was implemented on rat sera to explore the effects of M1 on hepatocellular carcinoma-induced metabolic alterations...
August 2017: Future Science OA
Vikas Kumar, Prakash Chandra Bhatt, Mahfoozur Rahman, Fahad A Al-Abbasi, Firoz Anwar, Amita Verma
It is well documented that anomalous production of inflammatory proteins linked with most of the toxic expression and genesis of diverse chronic disease including cancer. Diethylnitrosamine (DEN) a well-known hepatotoxin and hepatocarcinogen, can induce oxidative stress and inflammatory reaction in it. Umbelliferone, secondary metabolites, is present in different plants and widely consumed by humans as medicine and food supplements. The aim of the current study was to scrutinize the chemoprotective potential of umbelliferon-α-d-glucopyranosyl-(2(I)→1(II))-α-d-glucopyranoside (UFD) against DEN-induced hepatocellular carcinoma (HCC) in experimental rats...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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